Top 100 Drugs

Question 1

5-alpha reductase inhibitors

Answer 1

• Mechanism of action = Inhibition of 5-alpha reductase → ↓ conversion of testosterone to DHT → ↓ intraprostatic DHT levels → ↓ prostatic growth and ↑ prostatic apoptosis and involution → improvement of LUTS
• Main indications = enlarged prostate gland (benign prostatic hyperplasia leading to lower urinary tract symptoms) and male pattern hair loss (Androgenetic alopecia in men)
• Contraindications = caution around pregnant women (absorbed through skin)
• Route of admin = mouth
• Adverse effects = sexual dysfunction (e.g., erectile dysfunction, decreased libido, ejaculatory dysfunction), gynecomastia, breast cancer, suicidal thoughts
• Examples = Finasteride, Dutasteride

Question 2

Monoclonal antibodies

Answer 2

• Mechanism of action = Monodonal antibodies (mAbs) are generated by immunising animals with target proteins. B cells are selected and immortalised to create clones that produce homogenous antibodies against specific regions (epitopes) on the target protein. As animal antibodies are immunogenic in humans, their structure is altered by genetic engineering to make them more similar (humanised) or identical to human antibodies. Binding of mAbs to their target epitope inhibits or activates biological processes that leads to therapeutic effect. In inflammatory disease, mAbs suppress excessive immune responses by targeting components of the immune system. In cancer, mAbs may target tumour cells directly, enhance anti-tumour immune responses, alter the tumour microenvironment (e.g. inhibiting angiogenesis) or deliver targeted chemotherapy or radioisotopes. In infection, mAbs neutralise pathogens. In other conditions, mAbs target key proteins in disease pathology. For example, denosumab inhibits RANKL, an essential osteoclast protein, thereby decreasing bone resorption in the treatment of osteoporosis.
• Indications =
  1) Immune-mediated disorders, e.g. rheumatoid arthritis, psoriasis, psoriatic arthritis, inflammatory bowel disease.
  2) Allergic disorders, e.g. asthma, eczema, rhinitis with polyps.
  3) Precision treatment of cancers, including haematological (e.g. leukaemias, lymphomas) and solid tumours (e.g. breast and lung cancer).
  5) Prevention of adverse outcomes in high-risk COVID-19 disease or respiratory syncytial virus infections.
  6) Treatment of some long-term conditions with a target amenable to immune manipulation, e.g. osteoporosis, hypercholesterolaemia, migraine, sickle cell disease, haemophilia A.
• Contraindications = Cautions for individual mAbs vary, so refer to the BNF and seek local specialist guidance. Active and latent infection, including with tuberculosis and hepatitis B or C, should be treated before starting long-term treatment with a mAb that can cause immune suppression.
• Route of admin = mAbs have large size, poor membrane permeability, and are digested by gastric proteases. They are therefore administered parenterally by IV, SC or IM injection.
• Adverse reactions = immediate and delayed hypersensitivity reactions, e.g. local injection reaction, fever, urticaria. Adverse effects of individual mAbs depend on their biological actions. mAbs that target the immune system can cause immune imbalance, e.g. immunosuppression, increasing the risk of severe infection or cancer, or overstimulation, leading to development of a new autoimmune condition. Generally, however, due to their precisely targeted effect, monoclonal antibodies are often better tolerated than conventional cytotoxic and immune suppressing treatments.
• Examples = infliximab, adalimumab, denosumab, rituximab, omalizumab

Question 3

Allopurinol

Answer 3

• Mechanism of action = Allopurinol is a purine analogue that inhibits xanthine oxidase. Xanthine oxidase metabolises xanthine (produced from purines) to uric acid. Inhibition of xanthine oxidase lowers plasma uric acid concentrations and reduces precipitation of uric acid in the joints or kidneys.
• Main indications =
  1) To prevent recurrent attacks of gout, particularly in people with two or more attacks per year or with signs of joint damage or renal impairment.
  2) To prevent uric acid and calcium oxalate renal stones.
  3) To prevent hyperuricaemia and tumour lysis syndrome due to chemotherapy.
• Contraindications = Allopurinol should not be started during an *acute attack of gout, but can be continued if already established, to avoid sudden fluctuations in serum uric acid levels. *Recurrent skin rash or signs of more *severe hypersensitivity to allopurinol are contraindications to therapy. Allopurinol is metabolised in the liver and excreted by the kidney. The dose should therefore be reduced in severe *renal impairment or *hepatic impairment. The active metabolite (mercaptopurine) of the pro-drug A azathioprie is metabolised by xanthine oxidase. Concurrent administration with allopurinol increases the risk of azathioprine toxicity. Co-prescription of allopurinol with *ACE inhibitors or thiazides increases the risk of hypersensitivity reactions, and with amoxicillin increases the risk of skin rash.
• Route of admin = mouth
• Adverse effects = Allopurinol is generally well tolerated. However, starting allopurinol can trigger or worsen an acute attack of gout, possibly through effects on preformed crystals. The risk of triggering an attack may be reduced by co-prescription of an NSAID or colchicine in the initiation phase. The most common side effect is a skin rash, which may be mild or may indicate a more serious hypersensitivity reaction such as Stevens-Johnson syndrome or toxic epidermal necrolysis. Allopurinol hypersensitivity syndrome is a rare, life-threatening reaction to allopurinol that can include fever, eosinophila. lymphadenopathy, and involvement of other organs, such as the liver and skin. If allopurinol is not tolerated or is contraindicated, febuxostat (a non-purine xanthine oxidase inhibitor) is an alternative second-line therapy. However, a prior history of hypersensitivity to allopurinol is associated with potential hypersensitivity to febuxostat.
• Examples = allopurinol

Question 4

Acetylcholinesterase inhibitors

Answer 4

• Mechanism of action = Acetylcholine is an important CNS neurotransmiter, which is essential to many brain functions including learning and memory. A decrease in activity of the brain’s cholinergic system is seen in Alzheimer’s disease and in the form of dementia associated with Parkinson’s disease. These drugs inhibit the cholinesterase enzymes that break down acetylcholine in the CNS. It is thought that by increasing the availability of acetylcholine for neurotransmission, they improve cognitive function and reduce the rate of cognitive decline. However, recovery of function in people with these conditions on starting treatment is modest and not universal.
• Main indications =
  1) Mild to moderate dementia in Alzheimer’s disease
  2) Mild to moderate dementia in Parkinson’s disease (Rivastigmine)
• Contraindications = Acetylcholinesterase inhibitors should be used with caution in people with & asthma and *COPD and those at risk of developing *peptic ulcers. They should be avoided in people with *heart block or *sick sinus syndrome. Rivastigmine may worsen tremor in those with *Parkinson’s disease.
• Route of admin = mouth
• Adverse effects = GI upset is the most common adverse effect, arising from increased cholinergic activity in the peripheral nervous system. This may resolve over time. People with asthma or COPD may experience an exacerbation of bronchospasm. Less common, but serious, peripheral effects include peptic ulcers and bleeding, bradycardia, and heart block. Central cholinergic effects may induce hallucinations and altered/aggressive behaviour. These resolve with reduction of dose or discontinuation of therapy. There is a small risk of extrapyramidal symptoms and neuroleptic malignant syndrome.
• Examples = Rivastigmine, Donepezil

Question 5

Antiplatelet drugs, aspirin

Answer 5

• Mechanism of action = Thrombotic events occur when platelet-rich thrombus forms in atheromatous arteries and occludes the circulation. Aspirin irreversibly inhibits cyclooxygenase (COX) to reduce production of the pro-aggregatory factor thromboxane from arachidonic acid, reducing platelet aggregation and the risk of arterial occlusion. The antiplatelet effect of aspirin occurs at low doses and lasts for the lifetime of a platelet (7-10 days), as platelets do not have nuclei to allow synthesis of new COX. As a result, the effect of aspirin only wears off as new platelets are made.
• Main indications =
  1) For treatment of ACS and acute ischaemic stroke, where rapid inhibition of platelet aggregation can prevent or limit arterial thrombosis and reduce subsequent mortaity.
  2) For secondary prevention of major adverse cardiovascular events in ischaemic heart disease, cerebrovascular disease, or peripheral vascular disease.
  3) At higher doses, aspirin can be used in mild-to-moderate pain and ever, although paracetamol and other NSAIDs are usually preferred.
• Contraindications = Aspirin should not be given to *children aged under 16 years due to the risk of Reye’s syndrome, a rare but life-threatening illness that principally affects the liver and brain. It should not be taken by people with *aspirin hypersensitivity, i.e. who have had bronchospasm or other allergic symptoms triggered by exposure to aspirin or another NSAID. However, aspirin is not routinely contraindicated in asthma.
  Aspirin should be avoided in the third trimester of pregnancy when prostaglandin inhibition may lead to premature closure of the ductus arteriosus. Aspirin should be used with caution in *peptic ulceration (consider gastroprotection) and *gout, where it may trigger an attack. Caution is required in some cases, e.g. ACS, when administered with other antiplatelet agents ,e.g. clopidogrel, and *anticoagulants, e.g. heparin, warfarin.
• Route of admin = mouth (after food to minimise gastric irritation)
• Adverse effects =
  The most common adverse effect of aspirin is Gl upset. More serious effects include peptic ulceration and hemorrhage, and hypersensitivity reactions including bronchospasm. In regular high-dose therapy, aspirin can cause tinnitus. Aspirin overdose is life-threatening. Features include hyperventilation, hearing changes, metabolic acidosis, and confusion, followed by convulsions, cardiovascular collapse, and respiratory arrest.
• Examples = Aspirin

Question 6

α-blockers

Answer 6

• Mechanism of action =
  Although often described using the broad term ‘a-blocker, most drugs in this class (including doxazosin, tamsulosin, and alfuzosin) are highly selective for a1-adrenoceptors. These are found mainly in smooth muscle, including in blood vessels and the urinary tract (the bladder neck and prostate in particular). Stimulation induces contraction; blockade induces relaxation. Inhibiting the a1-adrenoceptor therefore causes vasodilation and a fall in blood pressure (BP) and reduces resistance to urine outflow from the bladder.
• Main indications =
  1) As a first-line medical option to improve lower urinary tract symptoms (LUTS) in benign prostatic enlargement, when lifestyle changes are insufficient or voiding symptoms are moderate to severe.
  5a-reductase inhibitors may be added in selected cases. Surgical treatment is also an option, particularly if there is evidence of urinary tract damage (e.g. hydronephrosis).
  2) As an add-on treatment in resistant hypertension, when other medicines (e.g. calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, thiazide diuretics) are insufficient.
• Contraindications = Avoid a-blockers in people with existing & postural hypotension.
• Route of admin = oral (best taken at night)
• Adverse effects = Predictably from their effects on vascular tone, a1-blockers can cause postural hypotension, dizziness, and syncope. This is particular prominent after the first dose.
• Examples = Tamsulosin, Doxazosin, Alfuzosin

Question 7

Antiemetics, serotonin 5-HT3-receptor antagonists

Answer 7

• Mechanism of action = Nausea and vomiting are triggered by gut irritation, drugs, motion, vestibular disorders, and higher stimuli (sights, smells, emotions). The pathways converge on a ‘vomiting centre’ in the medulla, which receives inputs from the chemoreceptor trigger zone (CTZ), the vagus nerve, the vestibular system and higher centres. Serotonin (5-hydroxytryptamine (5-HT)) plays an important role in two of these pathways. First, there is a high density of 5-HT, receptors in the CTZ, which are responsible for sensing emetogenic substances in the blood (e.g. drugs). Second, 5-HT is the key neurotransmitter released by the gut in response to emetogenic stimuli. Acting on 5-HT3 receptors, it stimulates the vagus nerve, which in turn activates the vomiting centre via the solitary tract nucleus. Of note, 5-HT is not involved in communication between the vestibular system and the vomiting centre. Thus 5-HT3 antagonists are effective against nausea and vomiting as a result of CTZ stimulation (e.g. drugs) and visceral stimuli (gut infection, radiotherapy), but not in motion sickness.
• Main indications =
  1) Prophylaxis and treatment of nausea and vomiting, particularly in the context of general anaesthesia and chemotherapy.
• Contraindications = 5-HT3 antagonists should be used with caution in people with *prolonged QT interval. If there is a risk factor for this, review an electrocardiogram (ECG) before prescribing. Ondansetron is not recommended in the first trimester of *pregnancy, as it has been linked in epidemiological studies to an increased risk of cleft lip and palate.
• Route of admin = mouth, rectum, intramuscular injection, intravenous infusion
• Adverse effects =
  Constipation, headache, and flushing are common. Serious indorse effects are rare. There is a small risk that 5-HT3 antagonsts may prolong the QT interval, although this is usually evident only at high doses (e.g. >16 mg ondansetron).
• Examples = Ondansetron, granisetron

Question 8

Antiviral drugs, aciclovir

Answer 8

• Mechanism of action = The herpesvirus family includes herpes simplex 1 and 2 and varicella-zoster. These viruses contain double-stranded DNA, which requires a herpes-specific DNA polymerase for the virus to replicate. Aciclovir enters herpes-infected cells and inhibits the herpes-specific DNA polymerase, stopping further viral DNA synthesis and therefore replication.
• Main indications =
  1) Treatment of acute episodes of herpesvirus infections, including herpes simplex (e.g. cold sores, genital ulcers, encephalitis) and varicella-zoster (e.g. chickenpox, shingles).
  2) Suppression of recurrent herpes simplex attacks where these are occurring at a frequency of 6 or more per year.
• Contraindications = Aciclovir has no major contraindications. It does cross the placenta and is expressed in breast milk, so caution is advised in *pregnant women and women who are *breastfeeding. However, infections such as viral encephalitis, varicella pneumonia, and genital herpes carry significant risks to the mother and foetus, so the benefits of treatment in such circumstances are likely to outweigh its risks. Aciclovir is excreted by the kidneys; the dose and/or frequency of administration should therefore be reduced in *severe renal impairment to prevent accumulation of the drug and subsequent toxicity.
• Route of admin = oral, IV infusion
• Adverse effects = Common adverse effects include headache, dizziness, GI upset, and skin rash. IV aciclovir can cause inflammation or phlebitis at the injection site. Aciclovir is relatively water insoluble. During high-dose IV therapy, delivery of a high concentration of aciclovir into the renal tubules can cause precipitation, leading to crystal-induced acute renal failure. The risk of this can be minimised by ensuring good hydration and slowing the rate of infusion.
• Examples = Aciclovir

Question 9

Beta blockers

Answer 9

• Mechanism of action = Via β1-adrenoreceptors, which are located mainly in the heart, β-blockers reduce force of cardiac contraction and speed of conduction. In IHD, this reduces cardiac work and oxygen demand and increases myocardial perfusion. In chronic heart failure, it improves prognosis probably by ‘protecting’ the heart from chronic sympathetic stimulation. In AF, it reduces ventricular rate by prolonging the refractory period of the atrioventricular (AV) node, and therefore the proportion of fibrillation waves that are conducted. By the same effect, β-blockers may terminate SVT if this is due to a self-perpetuating (‘re-entry’) circuit. The blood pressure-lowering effect of β-blockers is complex, likely involving reduced β1-mediated renin secretion from the kidney. Their action in migraine is thought to be via modulation of neuronal excitability in the brain, perhaps through reduced firing in noradrenergic neurons. In thyrotoxicosis, they offset the effect of β-adrenoreceptor upregulation, which causes symptoms such as tremor and palpitations. An additional effect (particularly with propranolol) is inhibition of monodeiodinase, reducing conversion of thyroxine (T4) to triiodothyronine (T3), but the clinical importance of this is doubtful.
• Main indications =
  1) Ischaemic heart disease (IHD): to improve symptoms and prognosis in angina and acute coronary syndrome (ACS).
  2) Chronic heart failure: to improve prognosis.
  3) Atrial fibrillation (AF): to reduce the ventricular rate and, in paroxysmal AF, to maintain sinus rhythm.
  4) Supraventricular tachycardia (SVT): to restore sinus rhythm.
  5) Resistant hypertension: as a fourth-line treatment option.
  6) Prophylaxis of migraine: other options are amitriptyline, valproate, and drugs targeting calcitonin gene-related peptide (e.g. galcanezumab).
  7) Thyrotoxicosis: for symptoms caused by sympathetic stimulation.
• Contraindications = In *asthma, β-blockers can cause life-threatening bronchospasm and should be avoided. This effect is mediated via β2-adrenoreceptors located in smooth muscle of the airways. β-blockers are usually safe in COPD, but it is prudent to choose a relatively β1-selective option (e.g. bisoprolol, metoprolol). In *heart failure, β-blockers should be started at a low dose and increased slowly, as they may initially impair cardiac function. They are contraindicated in *heart block and severe *hypotension and generally require dosage reduction in significant *hepatic failure.
• Route of admin = Oral, Intravenous injection
• Adverse effects = Fatigue, cold extremities, headache, and GI upset are common. β-blockers can also cause sleep disturbance, nightmares, and impotence.
• Examples = bisoprolol, atenolol, propranolol, metoprolol, carvedilol

Question 10

Angiotensin-converting enzyme (ACE) inhibitor

Answer 10

• Mechanism of action = ACE inhibitors inhibit the action of angiotensin-converting enzyme (ACE), reducing conversion of angiotensin I to angiotensin II. Angiotensin II is a vasoconstrictor and stimulates aldosterone secretion. Blocking its action reduces peripheral vascular resistance (afterload), which lowers blood pressure (BP). It particularly dilates the efferent glomerular arteriole, which reduces intraglomerular pressure and slows the progression of CKD. Reducing aldosterone concentration promotes sodium and water excretion. This can help to reduce venous return (preload), which has a beneficial effect in heart failure.
• Main indications =
  1) Hypertension: for first- or second-line treatment of hypertension, to reduce the risk of stroke, myocardial infarction, and death from cardiovascular disease.
  2) Chronic heart failure: for first-line treatment of all grades of heart failure, to improve symptoms and prognosis.
  3) Secondary prevention of major adverse cardiovascular events in people with ischaemic heart disease, cerebrovascular disease, or peripheral vascular disease.
  4) Diabetic nephropathy and chronic kidney disease (CKD) with proteinuria: to reduce proteinuria and progression of nephropathy.
• Contraindications = ACE inhibitors should be avoided in ✖ renal artery stenosis and ✖ acute kidney injury; in women who are, or could become, ▲ pregnant; or who are ▲breastfeeding. ACE inhibitors are valuable in the treatment of ▲ CKD, but lower doses should be used, and renal function monitored closely (see MONITORING).
• Route of admin = oral (best to take the first dose before bed to reduce symptomatic hypotension)
• Adverse effects = Common side effects include hypotension (particularly after the first dose), and hyperkalaemia (because a lower aldosterone level promotes potassium retention). They can cause or worsen renal failure. Renal artery stenosis presents a particular risk, as constriction of the efferent glomerular arteriole is required to maintain glomerular filtration. If detected early, these adverse effects are usually reversible on stopping the drug. Dry cough is also common and caused by increased levels of bradykinin (which is inactivated by ACE). An angiotensin receptor blocker is an alternative if this occurs. Rare but important side effects of ACE inhibitors include angioedema and other anaphylactoid reactions.
• Examples = ramipril, lisinopril, perindopril

Question 11

β2-agonists

Answer 11

• Mechanism of action = β2-receptors are found in smooth muscle of the bronchi, gut, uterus, and blood vessels. Stimulation of these G protein-coupled receptors activates a signalling cascade that leads to smooth muscle relaxation and bronchodilation. This improves airflow, reducing breathlessness. Like insulin, β2-agonists also stimulate Na+/K+-adenosine triphosphatase (ATPase) pumps on cell membranes, shifting K+ from the extracellular to intracellular compartment. This can cause the adverse effect of hypokalaemia, but may also have therapeutic benefit as an adjunct to other treatments for hyperkalaemia, particularly if IV access is difficult. β2-agonists are classified as short-acting (SABAs, e.g. salbutamol, terbutaline) or long-acting (LABAs, e.g. salmeterol, formoterol) according to their duration of effect. SABAs, which have a fast onset of action (within 5minutes), are used to relieve acute breathlessness. LABAs are used as maintenance (preventer) therapy. Taken regularly for COPD, LABAs also reduce exacerbations.
• Main indications =
  1) Asthma: short-acting β2-agonists (SABAs) are used to relieve bronchospasm during acute asthma attacks, and for intermittent breathlessness or wheeze in chronic asthma. Long-acting β2-agonists (LABAs) are added to inhaled corticosteroids (ICS) in chronic asthma if symptoms are uncontrolled by an ICS alone.
  2) COPD: SABAs are used to relieve breathlessness and exercise limitation. If a SABA is insufficient, a LABA is recommended as first-line regular therapy. Depending on whether the person does, or does not, have features of asthma or steroid responsiveness, the LABA is combined with either a long-acting antimuscarinic (LAMA) or an inhaled corticosteroid, respectively.
• Contraindications = When used for Uncomplicated premature labour under specialist supervision with intravenous use, Abruptio placenta (in adults); antepartum haemorrhage (in adults); cord compression (in adults); eclampsia (in adults); history of cardiac disease (in adults); intra-uterine fetal death (in adults); intra-uterine infection (in adults); placenta praevia (in adults); pulmonary hypertension (in adults); severe pre-eclampsia (in adults); significant risk factors for myocardial ischaemia (in adults); threatened miscarriage (in adults)
• Route of admin = The inhaler type should be selected according to the needs and capabilities of the individual. Aerosol (metered dose) inhalers (MDIs) require coordination, while dry powder inhalers (DPIs) require forceful inspiration. Training on inhaler technique is essential and should be checked at every visit.
• Adverse effects = Activation of β2-receptors in diverse tissues accounts for the common ‘fight or flight’ adverse effects of tachycardia, palpitations, anxiety, tremor, and headache. β2-agonists can cause hypokalaemia and elevate serum lactate, particularly at high doses. They promote glycogenolysis, so may cause hyperglycaemia. LABAs can cause muscle cramps.
• Examples = salbutamol, formoterol, salmeterol, indacaterol

Question 12

Aldosterone antagonists

Answer 12

• Mechanism of action = Aldosterone is a mineralocorticoid that is produced in the adrenal cortex. It acts on mineralocorticoid receptors in the distal tubules of the kidney to increase the activity of luminal epithelial sodium (Na+) channels (ENaC). This increases the reabsorption of sodium and water, elevating blood pressure, with a corresponding increase in potassium excretion. Aldosterone antagonists inhibit the effect of aldosterone by competitive inhibition at mineralocorticoid receptors. This increases sodium and water excretion and potassium retention. Their effect is greatest when circulating aldosterone is increased, e.g. in primary hyperaldosteronism or cirrhosis.
• Main indications =
  1) Ascites and oedema due to liver cirrhosis: spironolactone is the first-line diuretic in this indication.
  2) Chronic heart failure: of at least moderate severity or arising within 1month of a myocardial infarction, usually as an addition to a β-blocker and an angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker.
  3) Primary hyperaldosteronism: while awaiting surgery, or if surgery is not an option.
• Contraindications = Aldosterone antagonists are contraindicated in ✖ severe renal impairment, ✖ hyperkalaemia, and ✖ adrenal insufficiency. Aldosterone antagonists can cross the placenta during pregnancy and appear in breast milk so should be avoided where possible in ▲ pregnant or lactating women.
• Route of admin = Oral (Spironolactone should generally be taken with food).
• Adverse effects = An important adverse effect of aldosterone antagonists is hyperkalaemia, which can lead to muscle weakness, arrhythmias, and even cardiac arrest. Spironolactone causes gynaecomastia (enlargement of male breast tissue), which can have a significant impact on adherence in men (see COMMUNICATION). Eplerenone is less likely to cause endocrine side effects. Aldosterone antagonists can cause liver impairment and jaundice and spironolactone is a cause of Stevens–Johnson syndrome (a T-cell-mediated hypersensitivity reaction) that causes a bullous skin eruption.
• Examples = spironolactone, eplerenone

Question 13

Digoxin

Answer 13

• Mechanism of action = Digoxin is negatively chronotropic (it reduces the heart rate) and positively inotropic (it increases the force of contraction). In AF and flutter, its therapeutic effect arises mainly via an indirect pathway involving increased vagal (parasympathetic) tone. This reduces conduction at the atrioventricular (AV) node, preventing some impulses from being transmitted to the ventricles, thereby reducing the ventricular rate. In heart failure, it has a direct effect on myocytes through inhibition of Na+/K+-ATPase pumps, causing Na+ to accumulate in the cell. As cellular extrusion of Ca2+ requires low intracellular Na+ concentrations, elevation of intracellular Na+ causes Ca2+ to accumulate in the cell, increasing contractile force.
• Main indications =
  1) In atrial fibrillation (AF) and atrial flutter, digoxin is used to reduce the ventricular rate. However, a β-blocker or non-dihydropyridine calcium channel blocker is usually more effective.
  2) In severe heart failure, digoxin may be added if treatment with an ACE inhibitor, β-blocker and either an aldosterone antagonist or angiotensin receptor blocker is insufficient, or at an earlier stage if there is co-existing AF.
• Contraindications = Digoxin may worsen conduction abnormalities, so is contraindicated in ✖ second-degree heart block and ✖ intermittent complete heart block. It should not be used in those with or at risk of ✖ ventricular arrhythmias. The dose should be reduced in ▲ renal failure, as digoxin is eliminated by the kidneys. Certain electrolyte abnormalities increase the risk of digoxin toxicity, including ▲ hypokalaemia, ▲ hypomagnesaemia, and ▲ hypercalcaemia. Potassium disturbance is probably the most important of these, as digoxin competes with potassium to bind the Na+/K+-ATPase pump. When serum potassium levels are low, competition is reduced and the effects of digoxin are enhanced.
• Route of admin = Oral digoxin can be taken with or without food. Intravenous doses must be given slowly.
• Adverse effects = bradycardia, GI upset, rash, dizziness, and visual disturbance (blurred or yellow vision). Digoxin is proarrhythmic and has a low therapeutic index: that is, the safety margin between the therapeutic and toxic doses is narrow. A wide range of arrhythmias can occur in digoxin toxicity and these may be life threatening.
• Examples = digoxin

Question 14

Diuretics, loop

Answer 14

• Mechanism of action = As their name suggests, loop diuretics act principally on the ascending limb of the loop of Henle, where they inhibit the Na+/K+/2Cl− co-transporter. This protein is responsible for transporting sodium, potassium, and chloride ions from the tubular lumen into the epithelial cell. Water then follows by osmosis. Inhibiting this process has a potent diuretic effect. In addition, loop diuretics have a direct effect on blood vessels, causing dilation of capacitance veins. In acute heart failure, this reduces preload and improves contractile function of the ‘overstretched’ heart muscle. Indeed, this is probably the main benefit of loop diuretics in acute heart failure, as illustrated by the fact that a clinical response usually occurs before diuresis is evident.
• Main indications =
  1) For relief of breathlessness in acute pulmonary oedema in conjunction with oxygen and nitrates.
  2) For symptomatic treatment of fluid overload in chronic heart failure.
  3) For symptomatic treatment of fluid overload in other oedematous states, e.g. due to renal disease or liver failure, where they may be given in combination with other diuretics.
• Contraindications = Loop diuretics are contraindicated in severe ✖ hypovolemia and ✖ dehydration. They should be used with caution in ▲ hypokalaemia, ▲ hyponatraemia and in people at risk of ▲ hepatic encephalopathy (where hypokalaemia can cause or worsen coma). In chronic use, loop diuretics inhibit uric acid excretion, which can worsen ▲ gout.
• Route of admin = Oral, IV
• Adverse effects = Water losses due to diuresis can lead to dehydration and hypotension. Inhibiting the Na+/K+/2Cl− co-transporter increases urinary losses of sodium, potassium, and chloride ions. Indirectly, this also increases excretion of magnesium, calcium, and hydrogen ions. You can therefore associate loop diuretics with almost any low electrolyte state (i.e. hyponatraemia, hypokalaemia, hypochloraemia, hypocalcaemia, hypomagnesaemia, and metabolic alkalosis). Hypernatremia may also occur, due to loss of water in excess of sodium. A similar Na+/K+/2Cl− co-transporter is responsible for regulating endolymph composition in the inner ear. At high doses, loop diuretics can affect this too, leading to hearing loss and tinnitus.
• Examples = furosemide, bumetanide

Question 15

Statins

Answer 15

• Mechanism of action = Statins slow the atherosclerotic process and may even reverse it. They act by competitive inhibition of 3-hydroxy-3-methyl-glutaryl coenzyme A (HMG CoA) reductase, the enzyme that catalyses the rate-limiting step in cholesterol synthesis. This reduces cholesterol production by the liver and stimulates a compensatory increase in low-density lipoprotein (LDL) cholesterol uptake from the blood by hepatocytes. Together, these effects reduce LDL cholesterol levels and also, indirectly, reduce triglycerides and slightly increase high-density lipoprotein (HDL) cholesterol levels. In addition to their lipid-lowering effects, statins may modulate the inflammatory response and improve endothelial function. These effects may be due to reduced production of isoprenoid intermediates in the cholesterol synthesis pathway, which are substrates in the production of various cell-signalling proteins.
• Main indications =
  1) Primary prevention of major adverse cardiovascular events (e.g. myocardial infarction, stroke) in people over 40years of age with a 10-year cardiovascular risk >10%, as assessed using a validated tool.
  2) Secondary prevention of major adverse cardiovascular events in people with ischaemic heart disease (including after acute coronary syndrome), stroke, and peripheral vascular disease.
  3) Dyslipidaemia (e.g. primary hypercholesterolaemia, mixed dyslipidaemia, familial hypercholesterolaemia).
• Contraindications = Statins should be used with caution in ▲ hepatic impairment. With the exception of rosuvastatin, statins are dependent on the kidneys for elimination of their metabolites, so the dose should be reduced in ▲ renal impairment. Statins are contraindicated for women who are ▲ pregnant (cholesterol is essential for normal fetal development) and should be avoided in ▲ breastfeeding.
• Route of admin = Oral; Simvastatin, which has a short half-life, is best taken in the evening, because cholesterol synthesis is greatest in the early-morning hours. This is not necessary for other statins that have a longer half-life.
• Adverse effects = Statins are generally safe and well tolerated. The most common adverse effects are headache, GI upset, and muscle aches. Rare but more serious adverse effects are myopathy and rhabdomyolysis. Statins can cause a rise in liver enzymes (e.g. alanine transaminase). Minor biochemical changes are clinically unimportant (see MONITORING), but drug-induced hepatitis is a rare but serious adverse effect.
• Examples = atorvastatin, simvastatin, rosuvastatin, pravastatin

Question 16

Calcium channel blockers

Answer 16

• Mechanism of action = Calcium channel blockers decrease calcium ion (Ca2+) entry into vascular and cardiac cells, reducing intracellular calcium concentration. This causes relaxation and vasodilation in arterial smooth muscle, lowering arterial pressure. In the heart, calcium channel blockers reduce myocardial contractility. They suppress cardiac conduction, particularly across the atrioventricular (AV) node, slowing ventricular rate. Reduced ventricular rate, contractility, and afterload reduce myocardial oxygen demand, preventing angina. Calcium channel blockers can broadly be divided into two classes. Dihydropyridines, including amlodipine and nifedipine, are relatively selective for the vasculature, whereas non-dihydropyridines are more selective for the heart. Of the non-dihydropyridines, verapamil is the most cardioselective, whereas diltiazem also has some effects on blood vessels.
• Main indications =
  1) Amlodipine and, to a lesser extent, nifedipine are used for the first- or second-line treatment of hypertension, to reduce the risk of stroke, myocardial infarction, and death from cardiovascular disease.

2) All calcium channel blockers can be used to control angina in people with ischaemic heart disease; β-blockers are the main alternative.

3) Diltiazem and verapamil are used to control heart rate in people with supraventricular arrhythmias, including supraventricular tachycardia, atrial flutter, and atrial fibrillation.

• Contraindications = Verapamil and diltiazem should be used with caution in ▲ impaired left ventricular function, as they can precipitate or worsen heart failure. They should generally be avoided in ▲ AV nodal conduction delay, as they may provoke complete heart block. Amlodipine and nifedipine should be avoided in ✖ unstable angina as vasodilation causes a reflex increase in contractility and tachycardia, which increases myocardial oxygen demand. In ✖ severe aortic stenosis, amlodipine and nifedipine should be avoided as they can cause collapse.
• Route of admin = Oral
• Adverse effects = Common adverse effects of amlodipine and nifedipine include ankle swelling, flushing, headache, and palpitations, which are caused by vasodilation and compensatory tachycardia. Verapamil commonly causes constipation and less often, but more seriously, bradycardia, heart block, and cardiac failure. As diltiazem has mixed vascular and cardiac actions, it can cause any of these adverse effects.
• Examples = amlodipine, felodipine, nifedipine, diltiazem, verapamil

Question 17

Nitrofurantoin

Answer 17

• Mechanism of action = Nitrofurantoin is metabolised (reduced) in bacterial cells by nitrofuran reductase. Its active metabolite damages bacterial DNA and causes cell death (bactericidal). Bacteria with lower nitrofuran reductase activity are resistant to nitrofurantoin. Some organisms that are less common causes of UTI (such as Klebsiella and Proteus species) have intrinsic resistance to nitrofurantoin. It is relatively rare for E. coli to acquire nitrofurantoin resistance. Nitrofurantoin requires concentration in the urine by renal excretion for therapeutic effect against UTIs; for the same reason, it is not useful for infections elsewhere in the body. Nitrofurantoin is active against most organisms that cause uncomplicated UTIs, including Escherichia coli (Gram-negative) and Staphylococcus saprophyticus (Gram-positive).
• Main indications =
  1) Nitrofurantoin is a first-line option for acute, uncomplicated lower urinary tract infection (UTI) (an alternative is trimethoprim).
  2) Prophylaxis of recurrent UTIs.
• Contraindications = Nitrofurantoin should not be prescribed for ✖ pregnant women towards term, for ✖ babies in the first 3months of life or for people with ✖ G6PD deficiency because of the risk of haemolysis. It is contraindicated in ✖ renal impairment, as impaired excretion increases toxicity and reduces efficacy due to lower urinary drug concentrations. Caution is required when using nitrofurantoin for ▲ long-term prevention of UTIs, as chronic use increases the risk of pulmonary, hepatic and neurological adverse effects, particularly in older people.
• Route of admin = Oral nitrofurantoin is available as tablets, immediate- or modified-release capsules and in suspension. It should be taken with food or milk to minimise GI effects. There is no parenteral formulation.
• Adverse effects = As with many antibiotics, nitrofurantoin can cause GI upset and immediate and delayed hypersensitivity reactions (see Penicillins, broad-spectrum). Nitrofurantoin, specifically, can turn urine dark yellow or brown. Less commonly, it may cause chronic pulmonary reactions (including inflammation (pneumonitis) and fibrosis), hepatitis, and peripheral neuropathy, which all are more likely with prolonged administration. In neonates, haemolytic anaemia may occur because immature red blood cells are unable to mop up nitrofurantoin-stimulated superoxides, which damage red blood cells.
• Examples = nitrofurantoin

Question 18

Angiotensin receptor blockers (ARBs)

Answer 18

• Mechanism of action = ARBs have similar effects to angiotensin-converting enzyme (ACE) inhibitors, but instead of inhibiting the conversion of angiotensin I to angiotensin II, ARBs block the action of angiotensin II on the angiotensin type 1 (AT1) receptor. Angiotensin II is a vasoconstrictor and stimulates aldosterone secretion. Blocking its action reduces peripheral vascular resistance (afterload), which lowers blood pressure. It particularly dilates the efferent glomerular arteriole, which reduces intraglomerular pressure and slows the progression of CKD. Reducing aldosterone concentration promotes sodium and water excretion. This can help to reduce venous return (preload), which has a beneficial effect in heart failure.
• Main indications =
  1) Hypertension: for first- or second-line treatment of hypertension, to reduce the risk of stroke, myocardial infarction, and death from cardiovascular disease.
  2) Chronic heart failure: for first-line treatment of all stages of heart failure, to improve symptoms and prognosis.
  3) Secondary prevention of major adverse cardiovascular events in people with ischaemic heart disease, cerebrovascular disease or peripheral vascular disease.
  4) Diabetic nephropathy and chronic kidney disease (CKD) with proteinuria: to reduce proteinuria and progression of nephropathy.
• Contraindications = ARBs should be avoided in ✖ renal artery stenosis and ✖ acute kidney injury; in women who are, or could become, ▲ pregnant; or who are ▲ breastfeeding. ARBs are valuable in the treatment of ▲ CKD, but lower doses should be used, and renal function monitored closely.
• Route of admin = Oral; ARBs can be taken with or without food. It is best to take the first dose before bed to reduce symptomatic hypotension.
• Adverse effects = ARBs can cause hypotension (particularly after the first dose), hyperkalaemia, and renal failure. The mechanism is the same as for ACE inhibitors. Renal artery stenosis presents a particular risk, as constriction of the efferent glomerular arteriole is required to maintain glomerular filtration. ARBs are less likely than ACE inhibitors to cause cough and angioedema, as they do not inhibit ACE, so do not affect bradykinin metabolism. They may therefore preferred in Black people of African or Caribbean origin, who are at higher risk of angioedema.
• Examples = losartan, candesartan, irbesartan

Question 19

Antimuscarinics, genitourinary uses

Answer 19

• Mechanism of action = Antimuscarinic drugs bind to muscarinic receptors, where they act as a competitive inhibitor of acetylcholine. Contraction of the smooth muscle of the bladder is under parasympathetic control. Blocking muscarinic receptors therefore promotes bladder relaxation, increasing bladder capacity. In overactive bladder, this may reduce urinary frequency, urgency, and urge incontinence. Antimuscarinics work in overactive bladder through antagonism at the M3 receptor, which is the main muscarinic receptor subtype in the bladder. Solifenacin is more selective for the M3 receptor, which may reduce side effects caused by actions on other muscarinic receptor subtypes (see Antimuscarinics, cardiovascular and GI uses).
• Main indications =
  1) To reduce urinary frequency, urgency and urge incontinence in overactive bladder, as a first-line pharmacological treatment if bladder training is ineffective.
• Contraindications = Antimuscarinics are contraindicated in ✖ urinary tract infection. Urinalysis is therefore an important part of assessment before prescribing treatment for overactive bladder. Cognitive effects can be particularly problematic in ▲ older people and those with ▲ dementia. Antimuscarinics should be used with caution in people susceptible to ▲ angle-closure glaucoma, in whom they can precipitate a dangerous rise in intraocular pressure. They should be used with caution in people at risk of ▲ arrhythmias (e.g. those with significant cardiac disease) and, for obvious reasons, those at risk of ▲ urinary retention.
• Route of admin = Oral; Immediate-release antimuscarinics should be taken at roughly equal intervals, with or without food. MR forms should be taken at a similar time each day and swallowed whole, not chewed.
• Adverse effects = Predictably from their antimuscarinic action, dry mouth is a very common side effect of these drugs. Other classic antimuscarinic side effects such as tachycardia, constipation, and blurred vision are also common. Urinary retention may occur if there is bladder outflow obstruction. Cognitive effects (e.g. drowsiness, confusion) are most problematic with oxybutynin, because it is lipid soluble (so readily crosses the blood–brain barrier) and also acts on the M1 receptor (which is widely distributed in the brain).
• Examples = solifenacin, oxybutynin, tolterodine

Question 20

Antidepressants, selective serotonin reuptake inhibitors

Answer 20

• Mechanism of action = Selective serotonin reuptake inhibitors (SSRIs) preferentially inhibit neuronal reuptake of 5-hydroxytryptamine (serotonin) (5-HT) from the synaptic cleft, thereby increasing its availability for neurotransmission. This appears to be the mechanism by which SSRIs improve mood and physical symptoms in depression and relieve symptoms of panic and obsessive disorders. SSRIs differ from tricyclic antidepressants in that they do not inhibit noradrenaline uptake and cause less blockade of other receptors. The efficacy of the two drug classes in the treatment of depression is similar. However, SSRIs are generally preferred as they have fewer adverse effects and are less dangerous in overdose.
• Main indications =
  1) As first-line treatment for moderate-to-severe depression, and in mild depression if psychological treatments alone are insufficient.
  2) Panic disorder.
  3) Obsessive compulsive disorder.
• Contraindications = Caution is required in ▲ epilepsy and ▲ peptic ulcer disease. In ▲ young people, SSRIs have poor efficacy and are associated with an increased risk of self-harm and suicidal thoughts, so should be prescribed by specialists only. As SSRIs are metabolised by the liver, dose reduction may be required in people with ▲ hepatic impairment.
• Route of admin = tablets and as oral drops, which can be mixed with water or other drinks.
• Adverse effects = Common adverse effects include GI upset, changes in appetite and weight (loss or gain), and hypersensitivity reactions, including skin rash. Hyponatraemia is an important adverse effect, particularly in older people, and may present with confusion and reduced consciousness. Suicidal thoughts and behaviour may be associated with SSRIs. They may lower the seizure threshold, though the evidence for this is conflicting. Some (e.g. citalopram) can prolong the QT interval, predisposing to arrhythmias. SSRIs also increase the risk of bleeding. At high doses, in overdose or in combination with other serotonergic drugs (e.g. other antidepressants, tramadol), SSRIs can cause serotonin syndrome. This triad of autonomic hyperactivity, altered mental state, and neuromuscular excitation usually responds to treatment withdrawal and supportive therapy. Sudden withdrawal of SSRIs can cause GI upset, neurological and flu-like symptoms, and sleep disturbance.
• Examples = sertraline, citalopram, fluoxetine, escitalopram

Question 21

Opioids

Answer 21

• Mechanism of action = Opioids include naturally occurring opiates (e.g. morphine) and their synthetic analogues (e.g. oxycodone). The therapeutic effects of opioids are mediated by agonism of opioid µ (mu) receptors in the central nervous system (CNS). Activation of these G protein-coupled receptors has several effects that, overall, reduce neuronal excitability and pain transmission. In the medulla, they blunt the response to hypoxia and hypercapnoea, reducing respiratory drive and breathlessness. By relieving pain, breathlessness, and associated anxiety, opioids reduce sympathetic nervous system (fight or flight) activity. In acute coronary syndrome and pulmonary oedema, this reduces cardiac work and oxygen demand. In practical use, opioids are classified by strength. This refers to the intensity of effect that can be elicited with typical therapeutic doses. For example, morphine and oxycodone are strong opioids, while codeine and dihydrocodeine are weak. The latter examples are prodrugs—they are metabolised in the liver to more active metabolites (including morphine and dihydromorphine, respectively). Tramadol is a synthetic analogue of codeine. It is perhaps best classified as having moderate strength. In addition to agonism of the µ receptor, it inhibits neuronal noradrenaline and serotonin uptake. This contributes to analgesia by potentiating descending inhibitory pain pathways.
• Main indications =
  1) Acute pain, e.g. in trauma, surgery or acute coronary syndrome.
  2) Chronic pain, as part of a multimodal approach, if non-pharmacological treatments, paracetamol, NSAIDs, and adjuvant analgesics (e.g. pregabalin) are insufficient.
  3) Breathlessness in palliative care.
  4) Acute pulmonary oedema, alongside oxygen, furosemide, and nitrates.
• Contraindications = Most opioids rely on the liver and the kidneys for elimination, so doses should be reduced in ▲ hepatic failure and ▲ renal impairment and in ▲ older people. Do not give opioids in ▲ respiratory failure except under senior guidance (e.g. in palliative care).
• Route of admin = IV, oral
• Adverse effects = Opioids may cause respiratory depression, euphoria, detachment, and in higher doses, neurological depression. They can activate the chemoreceptor trigger zone, causing nausea and vomiting. Pupillary constriction occurs due to stimulation of the Edinger–Westphal nucleus. Activation of µ receptors increases intestinal smooth muscle tone and reduces motility, leading to constipation. Opioids may cause histamine release, leading to itching, urticaria, vasodilation, and sweating. Prolonged use can lead to dependence and hyperalgesia.
• Examples = morphine, oxycodone (strong) codeine, dihydrocodeine, tramadol (weak/moderate)

Question 22

Serotonin 5-HT1-receptor agonists (triptans)

Answer 22

• Mechanism of action = Serotonin 5-HT1-receptor agonists relieve the symptoms of acute migraine, including headache and nausea. Although the mechanisms underlying migraine are not completely understood, the primary disturbance is thought to be a slowly propagating wave of cortical depolarisation (cortical spreading depression). This is associated with local vasoconstriction and, depending on the area of the brain affected, may cause early focal neurological symptoms (aura). Subsequently, activation of trigeminal nerve afferents that innervate cerebral blood vessels and the meninges (the trigeminovascular pathway) causes release of vasoactive peptides such as calcitonin gene-related peptide (CGRP). This, in turn, simulates neurogenic inflammation and dilation of cranial blood vessels, causing headache and other symptoms of acute migraine. Triptans are thought to act by inhibiting neurotransmission in the peripheral trigeminal nerve and in the trigeminocervical complex (via 5-HT1B and 5-HT1D receptors) and constricting cranial blood vessels (via 5-HT1B receptors).
• Main indications =
  1) In acute migraine with or without aura, serotonin 5-HT1-receptor agonists, often referred to as ‘triptans’, are used to reduce the duration and severity of symptoms. Paracetamol and NSAIDs are alternative options and may be combined with triptans.
• Contraindications = Due to their vasoconstrictor properties these drugs should not be used in ✖ ischaemic heart disease, ✖ cerebrovascular disease, ✖ peripheral vascular disease, and ✖ uncontrolled hypertension. Triptans should also not be used in ✖ hemiplegic migraine or ✖ migraine with brainstem aura (e.g. with vertigo or diplopia).
• Route of admin = tablets, nasal spray
• Adverse effects = Common adverse effects of triptans include chest and throat discomfort, which can be intense but resolves quickly. Rarely, triptans can cause angina and myocardial infarction due to coronary vasospasm. Other common adverse effects include nausea and vomiting, tiredness, dizziness, and transient high blood pressure. In general, adverse effects are more common with SC administration of sumatriptan than with other drugs by other routes.
• Examples = sumatriptan, zolmitriptan

Question 23

Oestrogens and progestogens

Answer 23

• Mechanism of action = Luteinising hormone (LH) and follicle-stimulating hormone (FSH) control ovulation and ovarian production of oestrogen and progesterone. In turn, oestrogen and progesterone exert predominantly negative feedback on LH and FSH release. In hormonal contraception, oestrogens (e.g. ethinylestradiol) and/or progestogens (e.g. desogestrel) are given to suppress LH/FSH release and hence ovulation. Oestrogens and progestogens also have effects outside the ovary. Some, such as in the cervix and endometrium, may contribute to their contraceptive effect (most relevant in progestogen-only contraception). Others offer additional benefits, e.g. reduced menstrual pain and bleeding, and improvements in acne. At the menopause, a fall in oestrogen and progesterone levels may generate symptoms such as vaginal dryness and vasomotor instability (‘hot flushes’). Oestrogen replacement (usually combined with a progestogen) alleviates these.
• Main indications =
  1) Hormonal contraception in those requiring highly effective, reversible contraception, particularly if its other effects (e.g. improved acne control) are also desirable.
  2) Hormone replacement therapy (HRT) to delay early menopause and treat distressing menopausal symptoms (any age). Systemic formulations (tablets or patches) are used for systemic symptoms (e.g. hot flushes), and vaginal gels for vaginal symptoms (e.g. dryness).
• Contraindications = Oestrogens and progestogens are contraindicated in women with ✖ breast cancer. CHC should be avoided in those with a ✖ personal or ▲ family history of VTE; ✖ thrombogenic mutation; or risk factors for ▲ cardiovascular disease (including age >35years; migraine with aura; heavy smoking history). Women who have a uterus should not receive oestrogen-only HRT, due to the risk of endometrial benign prostatic enlargement.
• Route of admin = Oral
• Adverse effects = Hormonal contraception may cause irregular bleeding and mood changes. It does not appear to cause weight gain. The oestrogens in combined hormonal contraception (CHC) double the risk of venous thromboembolism (VTE), but the absolute risk is low. They increase the risk of cardiovascular disease and stroke, most relevant in women with other vascular risk factors. They may be associated with increased risk of breast and cervical cancer. In both cases the effect is small, and for breast cancer, it gradually resolves after stopping the pill. Progestogen-only pills do not increase the risk of VTE or cardiovascular disease. The adverse effects of HRT are similar to those of CHC but, as baseline rates of disease are higher, the relative risks have more significant effects.
• Examples = ethinylestradiol, estradiol (oestrogens) levonorgestrel, desogestrel (progestogens)

Question 24

Direct oral anticoagulants

Answer 24

• Mechanism of action = The coagulation cascade is a series of reactions triggered by vascular injury that generates a fibrin clot. The DOACs act on the final common pathway of the coagulation cascade, comprising factor X, thrombin, and fibrin. ApiXaban, edoXaban, and rivaroXaban directly inhibit activated factor X (Xa), preventing conversion of prothrombin to thrombin. Dabigatran directly inhibits thrombin, preventing the conversion of fibrinogen to fibrin. All DOACs therefore inhibit fibrin formation, preventing clot formation or extension in the veins and heart. They are less effective in the arterial circulation where dols a largely platelet driven, and are better prevented by antiplatelet agents.
• Main indications =
  1) VTE = treatment and prevention of recurrence (secondsry prevention) of VTE. Heparin and warfarin are alternatives. DOACs are also indicated as primary prevention if VTE in elective surgeries.
  2) Atrial Fibrillation = DOACs are indicated to prevent stroke and systemic emboism in non-valvular AF associated with at least one risk factor (including previous stroke, symptomatic heart failure, diabetes mellitus, or hypertension). Warfarin is an alternative.
• Contraindications = DOACs should be avoided in people with *active, clinically significant bleeding and in those with *risk factors for major bleeding, such as peptic ulceration, cancer, and recent surgery or trauma, particularly of the brain, spine or eye. As DOACs are excreted by multiple routes, including cytochrome P450 (CYP) enzyme metabolsm and elimination in faeces and urine, dose reduction or an alternative agent may be required in *hepatic or *renal disease. DOACs are containdicated in *pregnancy and *breastfeeding, where the ridk of harm to the baby is unknown, but has been seen in animal studies. Risk of bleeding with DOACs is increased by concurrent therapy with other antithrombotic agents (e.g. *heparin, *antiplatelets, and *NSAIDs). Other interactions can arise with drugs that affect DOAC metabolism or excretion. E.g anticoagulant effect is increased by macrolides, protease inhibitors and fluconazole, but decreased by rifampicin and phenytoin.
• Route of admin = oral (rivaroxaban must be taken with food) which is advantageous over heparin (injection) in the outpatient setting.
• Adverse effects = Bleeding is an important adverse effect, most commonly epistaxis, Gl, and genitourinary haemorrhage. The risk of intracranial haemorrhage and major bleeding is less with DOACs than with warfarin. However, the risk of Gl bleeding is greater, possibly due to intraluminal drug accumulation causing local anticoagulant effects. Other adverse effects include anaemia, Gl upset, dizziness, and elevated liver enzymes.
• Examples = Apixaban, Rivaroxaban, Edoxaban, Dabigatran

Question 25

Nitrates

Answer 25

- Mechanism of action = Nitrates are rapidly converted to nitric oxide (NO) following absorption. NO increases cyclic guanosine monophosphate (cGMP) synthesis and reduces intracellular Ca2+ in vascular smooth muscle cells, causing them to relax. This results in venous and, to a lesser extent, arterial vasodilation. Relaxation of the venous capacitance vessels reduces cardiac preload and left ventricular filling. These effects reduce cardiac work and myocardial oxygen demand, relieving angina and cardiac failure. Nitrates can relieve coronary vasospasm and dilate collateral vessels, improving coronary perfusion. They also relax the systemic arteries, reducing peripheral resistance and afterload. However, most of the antianginal effects are mediated by reduction of preload. - Main indications = 1) Short-acting nitrates (glyceryl trinitrate) are used in acute angina and chest pain associated with acute coronary syndrome (ACS). 2) Long-acting nitrates (e.g. isosorbide mononitrate) are used for prophylaxis of angina where a β-blocker and/or a calcium channel blocker are insufficient or not tolerated. 3) IV nitrate infusions are used in the treatment of ACS (if there is ongoing ischaemia), pulmonary oedema (usually in combination with furosemide and oxygen), and hypertensive emergencies (although other agents, such as labetalol or sodium nitroprusside, are preferred). - Contraindications = Nitrates are contraindicated in ✖ severe aortic stenosis, where arterial constriction is necessary to maintain blood pressure in the face of relatively fixed cardiac output. Abrupt vasodilation due to nitrate administration may therefore cause cardiovascular collapse. Nitrates should be avoided in ✖ hypotension. - Route of admin = Intravenous, sublingual spray - Adverse effects = Due to their vasodilator effects, nitrates commonly cause flushing, headaches, light-headedness, and hypotension. Regular use of nitrates can lead to tolerance, with reduced symptom relief despite continued use. This can be minimised by careful timing of doses to avoid significant nitrate exposure overnight, when it tends not to be needed. - Examples = glyceryl trinitrate, isosorbide mononitrate

Question 26

Diuretics, thiazide and thiazide-like

Answer 26

- Mechanism of action = Thiazide diuretics (e.g. bendroflumethiazide) and thiazide-like diuretics (e.g. indapamide, chlortalidone) differ chemically but have similar effects and clinical uses. We refer to them here collectively as ‘thiazides’. Thiazides inhibit the Na+/Cl− co-transporter in the distal convoluted tubule of the nephron. This prevents reabsorption of sodium and its osmotically associated water. The resulting diuresis causes an initial fall in extracellular fluid volume. Over time, compensatory changes (e.g. activation of the renin–angiotensin system) tend to reverse this, at least in part. The longer-term antihypertensive effect may be mediated by vasodilation, the mechanism of which is incompletely understood. - Main indications = 1) As an alternative first-line treatment for hypertension where a calcium channel blocker would otherwise be used, but is either unsuitable (e.g. due to oedema) or there are features of heart failure. 2) Add-on treatment for hypertension if blood pressure (BP) is not adequately controlled by a calcium channel blocker plus an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB). - Contraindications = Thiazides should be avoided in ✖ hypokalaemia and ▲ hyponatraemia. As they reduce uric acid excretion, they may precipitate acute attacks of ▲ gout. - Route of admin = oral; generally best to take the tablet in the morning, so that the diuretic effect is maximal during the day rather than at night and does not therefore interfere with sleep. - Adverse effects = Preventing sodium ion reabsorption from the nephron can cause hyponatraemia, although this is not usually problematic. The increased delivery of sodium to the distal tubule, where it can be exchanged for potassium, increases urinary potassium losses and may therefore cause hypokalaemia. This, in turn, may cause cardiac arrhythmias. Thiazides may increase plasma concentrations of glucose (which may unmask type 2 diabetes), low-density lipoprotein (LDL)-cholesterol, and triglycerides. However, their net effect on cardiovascular risk is protective. They may cause impotence in men. - Examples = bendroflumethiazide, indapamide, chlortalidone

Question 27

Aminosalicylates

Answer 27

- Mechanism of action = In ulcerative colitis, mesalazine and sulfasalazine both exert their therapeutic effects by releasing 5-aminosalicylic acid (5-ASA). The precise mechanism of action of 5-ASA is unknown, but it has both antiinflammatory and immunosuppressive effects and appears to act topically on the gut rather than systemically. For this reason, 5-ASA preparations are designed to delay delivery of the active ingredient to the colon. The oral form of mesalazine comprises a tablet with a coating that resists gastric breakdown, instead releasing 5-ASA further down the gut. Sulfasalazine consists of a molecule of 5-ASA linked to sulfapyridine. In the colon, bacterial enzymes break this link and release the two molecules. Sulfapyridine does not contribute to its therapeutic effect in ulcerative colitis, but it does cause side effects, and for this reason it has largely been replaced by mesalazine for this indication. By contrast, sulfapyridine is probably the active component of sulfasalazine in rheumatoid arthritis, though its mechanism is unclear. Mesalazine has no role in rheumatoid arthritis. - Main indications = 1) Mesalazine is a first-line option for mild-moderate ulcerative colitis (UC); sulfasalazine is an alternative but has largely been replaced by mesalazine for this indication. Corticosteroids are also used. 2) Sulfasalazine is one of several options for rheumatoid arthritis, in which it is used as a disease-modifying antirheumatic drug (DMARD), usually as part of combination therapy. - Contraindications = Mesalazine and sulfasalazine are salicylates, like aspirin. They are contraindicated in people with ✖ aspirin hypersensitivity. - Route of admin = rectum (enema, suppositories), oral - Adverse effects = Mesalazine generally causes fewer side effects than sulfasalazine. Most commonly, these are GI upset (e.g. nausea, dyspepsia) and headache. Both drugs can cause rare but serious blood abnormalities (e.g. leukopenia, thrombocytopenia) and renal impairment. In men, sulfasalazine may induce a reversible decrease in the number of sperm (oligospermia). It can also cause a serious hypersensitivity reaction, comprising fever, rash, and liver abnormalities. - Examples = mesalazine, sulfasalazine

Question 28

Corticosteroids, systemic

Answer 28

- Mechanism of action = Corticosteroids bind to cytosolic glucocorticoid receptors, which translocate to the nucleus and bind to glucocorticoid-response elements, which regulate gene expression. Corticosteroids are used to modify the immune response. They upregulate antiinflammatory genes and downregulate pro-inflammatory genes (e.g. cytokines, tumour necrosis factor α). Direct actions on inflammatory cells include suppression of circulating monocytes and eosinophils. Their metabolic effects include increased gluconeogenesis from circulating amino and fatty acids, released by catabolism (breakdown) of muscle and fat. Corticosteroids also have mineralocorticoid activity, stimulating Na+ and water retention and K+ excretion by the kidneys. This effect is greatest with hydrocortisone and negligible with dexamethasone. - Main indications = 1) Allergic or inflammatory disorders, e.g. anaphylaxis; exacerbations of asthma or chronic obstructive pulmonary disease (COPD). 2) Suppression of autoimmune disease, e.g. inflammatory bowel disease, inflammatory arthritis. 3) To reduce tissue damage due to excessive inflammation in response to infection, e.g. in severe bacterial meningitis, COVID-19, and croup. 4) In the treatment of some cancers as part of chemotherapy or to reduce tumour-associated swelling. 5) Hormone replacement in adrenal insufficiency or hypopituitarism. - Contraindications = Corticosteroids should be prescribed with caution in people with ▲ infection and in ▲ children (in whom they can suppress growth). - Route of admin = oral, parenteral (IV or IM), inhalation, topical; Once-daily corticosteroid treatment should be taken in the morning, to mimic the natural circadian rhythm and reduce insomnia. - Adverse effects = Immunosuppression increases the risk and severity of infection. Metabolic effects include diabetes mellitus and osteoporosis. Increased catabolism causes proximal muscle weakness and skin thinning with easy bruising and gastritis. Mood and behavioural changes include insomnia, confusion, psychosis, and suicidal ideas. Hypertension, hypokalaemia, and oedema can result from mineralocorticoid actions. Corticosteroid treatment suppresses pituitary adrenocorticotropic hormone (ACTH) secretion, switching off the stimulus for adrenal cortisol production. In prolonged treatment, this can cause adrenal atrophy, reducing endogenous cortisol secretion. If the exogenous steroid is then withdrawn suddenly, an adrenal crisis with cardiovascular collapse may occur. Slow withdrawal is required to allow recovery of adrenal function. Chronic glucocorticoid deficiency (e.g. during treatment withdrawal) can cause fatigue, weight loss and arthralgia. - Examples = dexamethasone, prednisolone, hydrocortisone

Question 29

Bisphosphonates

Answer 29

- Mechanism of action = Bisphosphonates reduce bone turnover by inhibiting the action of osteoclasts, the cells responsible for bone resorption. Bisphosphonates have a similar structure to naturally occurring pyrophosphate, and therefore are readily incorporated into bone. As bone is resorbed, bisphosphonates accumulate in osteoclasts, where they inhibit activity and promote apoptosis. The net effect is reduction in bone loss and improvement in bone mass. - Main indications = 1) Alendronic acid and risedronate sodium are first-line drug treatment options to reduce risk of osteoporotic fragility fractures. 2) Pamidronate and zoledronic acid are used in the treatment of severe hypercalcaemia of malignancy, after appropriate IV rehydration. 3) In myeloma and breast cancer with bone metastases, pamidronate and zoledronic acid reduce the risk of pathological fractures, cord compression, and the need for radiotherapy or surgery. 4) Bisphosphonates are used first-line in the treatment of metabolically active Paget’s disease, with the aim of reducing bone turnover and pain. - Contraindications = Bisphosphonates are renally excreted and should be avoided in ✖ severe renal impairment. They are contraindicated in ✖ hypocalcaemia, so calcium and vitamin D levels should be checked before starting treatment and, if necessary, corrected. Oral administration is contraindicated in active ✖ upper GI disorders. Because of the risk of jaw osteonecrosis, care should be exercised in prescribing bisphosphonates for ▲ smokers and people with major ▲ dental disease. - Route of admin = oral - Adverse effects = Common side effects include oesophagitis (when taken orally) and hypophosphataemia. A rare but serious adverse effect of bisphosphonates is osteonecrosis of the jaw, which is more likely with high-dose IV therapy. Good dental care is important to minimise the risk of this. Another rare but important adverse effect is atypical femoral fracture, particularly in long-term treatment. - Examples = alendronic acid, risedronate, disodium pamidronate, zoledronic acid

Question 30

Antidepressants, tetracyclic and serotonin-noradrenaline reuptake inhibitors

Answer 30

- Mechanism of action = Venlafaxine and duloxetine are a serotonin–noradrenaline reuptake inhibitors (SNRIs), interfering with uptake of these neurotransmitters from the synaptic cleft. Mirtazapine is a tetracyclic antidepressant. It antagonises inhibitory pre-synaptic α2-adrenoceptors. All three drugs increase availability of monoamines for neurotransmission, which appears to be the mechanism whereby they improve mood and physical symptoms in moderate-to-severe (but not mild) depression. Duloxetine is also used in neuropathic pain, where it may act by increasing synaptic noradrenaline concentration in descending spinal inhibitory pathways. Venlafaxine and duloxetine are weaker antagonists of muscarinic and histamine (H1) receptors than tricyclic antidepressants, whereas mirtazapine is a potent antagonist of histamine (H1) but not muscarinic receptors. They therefore have fewer antimuscarinic side effects than tricyclic antidepressants, although mirtazapine commonly causes sedation. - Main indications = 1) As an option for major depression, if first-line selective serotonin reuptake inhibitor (SSRI) treatment is ineffective or not tolerated. 2) Generalised anxiety disorder (venlafaxine, duloxetine). 3) Diabetic neuropathy (duloxetine) - Contraindications = As with many centrally acting medications, ▲ older people are more at risk of adverse effects. Dose reduction should be considered in ▲ hepatic or ▲ renal impairment, and duloxetine avoided in severe renal impairment. Venlafaxine should be avoided, or otherwise used with caution, in people at risk of ▲ arrhythmias (e.g. due to ischaemic heart disease). - Route of admin = oral; should be taken at night to mitigate (or benefit from) its sedative effects. - Adverse effects = Common adverse effects of both drugs include GI upset (e.g. nausea, change in weight, and diarrhoea or constipation), dry mouth, and neurological effects (e.g. headache, abnormal dreams, insomnia, confusion, and convulsions). Less common but serious adverse effects include hyponatraemia and serotonin syndrome (see Antidepressants, selective serotonin reuptake inhibitors). Suicidal thoughts and behaviour may increase. Venlafaxine prolongs the QT interval and can increase the risk of ventricular arrhythmias. Sudden drug withdrawal can cause GI upset, neurological and flu-like symptoms, and sleep disturbance. Venlafaxine is associated with a greater risk of withdrawal effects than other antidepressants. Mirtazepine may cause bone marrow suppression. - Examples = venlafaxine, mirtazapine, duloxetine

Question 31

Antidepressants, tricyclics and related drugs

Answer 31

- Mechanism of action = Tricyclic antidepressants inhibit neuronal reuptake of 5-hydroxytryptamine (serotonin) (5-HT) and noradrenaline from the synaptic cleft, increasing their availability for neurotransmission. This is likely the mechanism by which they improve mood and physical symptoms in depression. Increasing synaptic noradrenaline concentration in descending spinal inhibitory pathways probably accounts for their effect in modifying neuropathic pain and reducing abdominal pain associated with irritable bowel syndrome (where reduction in gut transit time may also reduce diarrhoea) and migraine. Tricyclic antidepressants block an array of receptors, including muscarinic, histamine (H1), α-adrenergic (α1 and α2), and dopamine (D2) receptors. This accounts for the extensive adverse effect profile. - Main indications = 1) As second-line treatment for moderate-to-severe depression where first-line selective serotonin reuptake inhibitors (SSRIs) are ineffective. 2) Neuropathic pain, particularly if this is interfering with sleep. 3) Irritable bowel syndrome, if abdominal pain persists despite an antispasmodic (e.g. an antimuscarinic or mebeverine). 4) Amitriptyline is an option to prevent frequent migraine attacks. - Contraindications = Caution is required in ▲ older people and those with ▲ epilepsy or ▲ cardiovascular disease. Due to their antimuscarinic effects, these drugs may worsen ▲ constipation, ▲ glaucoma, and urinary symptoms due to ▲ prostatic enlargement. - Route of admin = Tablets, oral solution - Adverse effects = Blockade of antimuscarinic receptors causes dry mouth, constipation, urinary retention, blurred vision and can cause and exacerbate cognitive impairment, particularly in older people. Blockade of histamine (H1)- and adrenergic (α1)-receptors causes sedation and hypotension. Through multiple mechanisms, cardiac adverse effects include arrhythmias and electrocardiogram (ECG) changes (including prolongation of the QT and QRS durations). In the brain, serious effects include seizures, hallucinations, and mania. Blockade of dopamine (D2) receptors can cause breast changes and sexual dysfunction, and rarely extrapyramidal symptoms (tremor and dyskinesia). Tricyclic antidepressants are dangerous in overdose, causing life-threatening hypotension, arrhythmias, seizures, coma, and respiratory failure. Sudden withdrawal can cause GI upset, neurological and flu-like symptoms, and sleep disturbance. - Examples = amitriptyline, trazodone, nortriptyline, lofepramine

Question 32

Acetylcysteine and carbocisteine

Answer 32

- Mechanism of action = In therapeutic doses, paracetamol is metabolised mainly by conjugation with glucuronic acid and sulfate. A small amount is converted to N-acetyl-p-benzoquinone imine (NAPQI), which is hepatotoxic. Normally, this is quickly detoxified by conjugation with glutathione. However, in paracetamol poisoning, the body’s supply of glutathione is overwhelmed, and NAPQI is left free to cause liver damage. Acetylcysteine works mainly by replenishing the body’s supply of glutathione. If carbocisteine or acetylcysteine are brought into contact with mucus, they break disulfide bonds, degrading the three-dimensional mucus matrix and reducing its viscosity. This may aid sputum clearance if respiratory secretions are tenacious. - Main indications = 1) IV acetylcysteine is the antidote for paracetamol poisoning. 2) Oral carbocisteine and acetylcysteine are used as mucolytics to reduce the viscosity of respiratory secretions associated with chronic cough and sputum. Nebulised acetylcysteine is an alternative for people in hospital. - Contraindications = History of an anaphylactoid reaction to IV acetylcysteine does not contraindicate its use in future if it is required. It is important that such reactions are not erroneously labelled as ‘allergic’, which may lead to effective treatment for paracetamol poisoning being inappropriately denied. However, it is essential to obtain specialist advice if there is any doubt. Oral carbocisteine and acetylcysteine should be used with caution in people with ▲ peptic ulcer disease. - Route of admin = IV infusion, oral solution, capsules - Adverse effects = When administered IV in paracetamol poisoning, acetylcysteine can cause an anaphylactoid reaction. This is similar to an anaphylactic reaction (presenting with nausea, tachycardia, rash, and wheeze) but involves histamine release independent of immunoglobulin E (IgE) antibodies. Therefore once the reaction has settled (by stopping the acetylcysteine and giving an antihistamine ± a bronchodilator, e.g. salbutamol), it is usually safe to restart acetylcysteine, but at a lower rate of infusion. Oral carbocisteine and acetylcysteine uncommonly cause GI upset. Carbocisteine can disrupt the gastric mucosal barrier and has been reported to cause GI bleeding. When administered in nebulised form as a mucolytic, acetylcysteine may cause bronchospasm. Therefore a bronchodilator should usually be given immediately beforehand. - Examples = carbocisteine, acetylcysteine

Question 33

Metformin

Answer 33

- Mechanism of action = Metformin (a biguanide) lowers blood glucose primarily by reducing hepatic glucose output (glycogenolysis and gluconeogenesis) and, to a lesser extent, increasing glucose uptake and utilisation by skeletal muscle. It does not stimulate insulin secretion and therefore does not cause hypoglycaemia. The cellular mechanisms are complex, involving activation of adenosine monophosphate-activated protein kinase (AMP kinase). This is a cellular metabolic sensor, activation of which has diverse effects on cell functions. Its effects on glucose metabolism can be accompanied by other metabolic changes, notably modest weight loss, which can be a desirable side effect (see CLINICAL TIP). - Main indications = 1) Type 2 diabetes, as the first-choice medication for control of blood glucose, used alone or in combination with other oral hypoglycaemic drugs (e.g. sulphonylureas, dipeptidylpeptidase-4 (DPP-4) inhibitors, sodium–glucose co-transporter 2 inhibitors) or insulin. - Contraindications = Metformin is excreted unchanged by the kidney. It must therefore be used cautiously in ▲ renal impairment, with dosage reduction required if the estimated glomerular filtration rate (eGFR) is <45 mL/min per 1.73 m2 and the drug stopped if eGFR falls below 30 mL/min per 1.73 m2. Metformin should be withheld in ✖ acute kidney injury or states of ✖ severe tissue hypoxia, e.g. sepsis, cardiac or respiratory failure or myocardial infarction. Caution is required in ▲ hepatic impairment as clearance of excess lactate may be impaired. Metformin should be withheld during ▲ acute alcohol intoxication, and be used with caution in ▲ chronic alcohol abuse, where there is a risk of hypoglycaemia. - Route of admin = Oral - Adverse effects = Metformin commonly causes GI upset, including nausea, vomiting, taste disturbance, anorexia, and diarrhoea. Lactic acidosis has been associated very rarely with metformin use, although the evidence for this is largely derived from case reports. There is no strong evidence of an increased risk in general, but metformin may be a contributory factor in people who develop an intercurrent illness that causes metformin accumulation (e.g. renal impairment), increased lactate production (e.g. sepsis, hypoxia) or reduced lactate metabolism (e.g. liver failure). - Examples = Metformin

Question 34

Anaesthetics, local

Answer 34

- Mechanism of action = Local anaesthetics reversibly inhibit voltage-gated sodium channels on plasma membranes. In neurons, this prevents initiation and propagation of action potentials, inducing local anaesthesia in the area supplied by the blocked nerve fibres. The pharmacokinetics of local anaesthetics determines their speed of onset and duration of effect, and this in turn guides drug choice. For example, lidocaine is readily absorbed through epithelia and has a rapid onset, making it a good choice for topical anaesthesia or medicated plasters. Bupivacaine has high affinity for binding sites, providing a longer duration of action and making it a good choice for regional anaesthesia for surgery. Sodium channel blockade in cardiac conductive tissue slows conduction and reduces automatic firing. This explains lidocaine’s antiarrhythmic effect and the adverse cardiac effects of local anaesthetics in overdose. - Main indications = 1) Surface anaesthesia to facilitate urinary catheterisation (lidocaine gel), venepuncture (lidocaine with prilocaine cream) or to treat pain arising from a small, well-defined area of skin (lidocaine plasters). 2) Subcutaneously to provide local anaesthesia for procedures such as suturing, vascular access or lumbar puncture (predominantly lidocaine). 3) To provide regional anaesthesia/analgesia, for example spinal or epidural analgesia (bupivacaine, lidocaine, prilocaine). 4) Lidocaine is a second-line option for ventricular tachycardia. - Contraindications = Used appropriately, local anaesthetics are generally safe. They are metabolised by the liver, so lower doses should be considered in significant ▲ liver disease. Lidocaine has a high hepatic extraction ratio (about 70% of drug entering the liver is removed in one pass), meaning that its clearance is particularly influenced by hepatic blood flow. Lower doses should therefore also be considered in ▲ cardiac failure. - Route of admin = gel, subcutaneous injection, epidural infusion - Adverse effects = The most common side effect is an initial stinging sensation during administration. Systemic adverse effects are uncommon provided care is taken to avoid excessive dosing or intravenous administration. Where this does occur, it may lead to neurological (drowsiness, restlessness, tremor, and fits) and cardiovascular (hypotension and arrhythmias) effects. Adverse effects in spinal/epidural anaesthesia include complications of the insertion procedure (e.g. bleeding, infection). In addition, inadvertent infiltration or tracking of the drug higher than the intended anaesthetic level, or at high doses, may lead to hypotension and bradycardia (due to blockade of sympathetic fibres) and weakness or paralysis (blockade of motor fibres). Skin reactions can occur with use of medicated plasters. - Examples = lidocaine, bupivacaine, levobupivacaine

Question 35

Antihistamines (H1-receptor antagonists)

Answer 35

- Mechanism of action = The term ‘antihistamine’ is generally applied to antagonists of the H1 receptor. H2-receptor antagonists have different uses and are discussed separately. Histamine is released from storage granules in mast cells in response to antigen binding to IgE on the cell surface. Mainly via H1 receptors, histamine induces the features of immediate-type (type 1) hypersensitivity: increased capillary permeability causing oedema formation (wheal), vasodilation causing erythema (flare) and itch as a result of sensory nerve stimulation. When histamine is released in the nasopharynx, as in hay fever, it causes nasal irritation, sneezing, rhinorrhoea, congestion, conjunctivitis, and itch. In the skin, it causes urticaria. Widespread histamine release, as in anaphylaxis, produces generalised vasodilation and vascular leakage, with consequent hypotension. Antihistamines work in these conditions by antagonism at the H1 receptor, blocking the effects of excess histamine. In anaphylaxis, their effect is too slow to be life-saving. They are not recommended in initial emergency treatment (in which adrenaline and intravenous fluid resuscitation are the critical components), but they may be used subsequently to treat the skin symptoms. - Main indications = 1) As a first-line treatment for allergies, particularly seasonal allergic rhinitis (hay fever). 2) To aid relief of itchiness (pruritus) and hives (urticaria) due, for example, to insect bites, infections (e.g. chickenpox) and drug allergies. 3) As symptomatic treatment for skin symptoms in anaphylaxis, but only after administration of adrenaline and other life-saving measures. - Other drugs in this class may be used for nausea and vomiting (see Antiemetics, histamine H1-receptor antagonists). - Contraindications = Commonly used antihistamines, including those mentioned above, are safe in most people. Sedating antihistamines (e.g. chlorphenamine) should be avoided in ▲ severe liver disease, as they may precipitate hepatic encephalopathy. - Route of admin = oral - Adverse effects = The ‘first-generation’ antihistamines (e.g. chlorphenamine) cause sedation. This is because histamine, via H1 receptors, has a role in the brain in maintaining wakefulness. Newer ‘second-generation’ antihistamines (including loratadine, cetirizine, and fexofenadine) do not cross the blood–brain barrier, so tend not to have this effect. They have few adverse effects. - Examples = cetirizine, fexofenadine, loratadine, chlorphenamine

Question 36

Heparins and fondaparinux

Answer 36

- Mechanism of action = In simple terms, venous and atrial clot formation is driven largely by the coagulation cascade, while arterial thrombosis is more a phenomenon of platelet activation. The coagulation cascade is an amplification reaction between clotting factors that generates a fibrin clot. Antithrombin inactivates clotting factors, particularly factors Ila (thrombin) and Xa, providing a natural break to the clotting process. Heparins and fondaparinux enhance the anticoagulant effect of antithrombin. The size of heparin molecules determines their molecular specificity: unfractionated heparin (UFH) (large and small molecules) promotes inactivation of both factors Ila and Xa, whereas LMWH (smaller molecules) is more specific for factor Xa. Fondaparinux is a synthetic pentasaccharide that mimics the sequence of the binding site of heparin to antithrombin and is very specific for factor Xa. - Main indications = 1) Heparin, usually LMWH, is used for prevention of DVT and PE (VTE) in hospital inpatients. It is also an option for treatment of VTE until oral anticoagulation (e.g. with warfarin) is established. Fondaparinux and DOACs, e.g. Rivaroxaban, are alternatives. 2) Alongside antiplatelet drugs, heparin (usually LMWH) or fondaparinux is given in ACS to reduce clot progression. - Contraindications = Anticoagulants should be used with caution if there are risk factors for bleeding, including *clotting disorders and *severe uncontrolled hypertension. They should be withheld immediately before and after *invasive procedures, particularly lumbar puncture and spinal anaesthesia. In *renal impairment, LMWH and fondaparinux accumulate, so a lower dose or UFH should be used instead. - Route of admin = subcutaneous injections into the abdominal wall - Adverse effects = The main adverse effect is haemorrhage. This risk may be lower with fondaparinux than with LMWH or UFH. Bruising may occur, particularty at the injection site. Hyperkalaemia occurs occasionally, due to an effect on adrenal aldosterone secretion. Rarely, heparins can cause a dangerous immune reaction characterised by low platelet count and thrombosis (heparin-induced thrombocytopenia (HIT)). This is less likely with LMWH than UFH, and far less likely with fondaparinux. - Examples = enoxaparin, dalteparin, fondaparinux, unfractionated heparin

Question 37

Carbamazepine

Answer 37

- Mechanism of action = The mechanism of action of carbamazepine is incompletely understood. It inhibits neuronal sodium channels, stabilising resting membrane potentials and inhibiting repetitive neuronal firing. This may inhibit spread of seizure activity in epilepsy and control neuralgic pain by blocking synaptic transmission in the trigeminal nucleus. - Main indications = 1) Seizure prophylaxis in epilepsy. Specifically, carbamazepine is a second-line option for prophylaxis of focal seizures (with or without secondary generalisation). It is not recommended in absence or myoclonic seizures. 2) Trigeminal neuralgia, as a first-line option to control pain and reduce frequency and severity of attacks. - Contraindications = Carbamazepine exposure in utero is associated with neural tube defects, cardiac and urinary tract abnormalities and cleft palate. Women with epilepsy planning ▲ pregnancy should discuss treatment with a specialist and start taking high-dose folic acid supplements before conception. The risk of Stevens–Johnson syndrome is strongly associated with ▲ carriage of the HLA-B*1502 allele. This is most prevalent in people of Han Chinese and Thai origin, who should be tested for this allele before starting treatment. Caution is also required in ▲ hepatic, ▲ renal or ▲ cardiac disease, due to an increased risk of toxicity. - Route of admin = Oral - Adverse effects = The most common dose-related adverse effects are GI upset (e.g. nausea and vomiting) and neurological effects (particularly dizziness and ataxia). Other adverse effects include oedema and hyponatraemia due to an antidiuretic hormone-like effect, and skin rashes. More severe hypersensitivity reactions affect around 1 in 5000 people taking carbamazepine, and rarely there is cross-sensitivity with other antiepileptic drugs. Clinical features include severe skin reactions (e.g. Stevens–Johnson syndrome, toxic epidermal necrolysis), fever, and lymphadenopathy with systemic (e.g. haematological, hepatic, renal) involvement. These severe reactions are life-threatening. - Examples = carbamazepine

Question 38

Corticosteroids, topical

Answer 38

- Mechanism of action = Corticosteroids have anti-inflammatory and immunosuppressive effects (see Corticosteroids, systemic). In skin disease they suppress inflammation during flares and reduce recurrence during maintenance therapy, but they are not curative. Other actions, including metabolic effects and adrenal suppression, contribute to their adverse effects. Topical corticosteroids are classified depending on their type, concentration, and formulation as mildly potent (e.g. hydrocortisone 0.1%–2.5%), moderately potent (e.g. betamethasone valerate 0.025%) potent (e.g. betamethasone valerate 0.1%) or very potent (e.g. clobetasol propionate 0.05%). Potency determines efficacy and safety, with more potent corticosteroids being used to treat more severe disease, and also more likely to cause adverse events. - Main indications = 1) Inflammatory skin conditions, e.g. eczema, psoriasis, to treat disease flares or control chronic disease where emollients alone are ineffective. - Contraindications = do not use topical corticosteroids where ▲ untreated bacterial, viral or fungal infection is present as this can cause it to worsen or spread. Avoid prescribing potent corticosteroids for use on the ▲ face, genitals, and axillae where the skin is thin or flexural. - Route of admin = Emollients (creams, ointments etc). - Adverse effects = Where corticosteroids are applied topically, adverse effects are mostly limited to the site of application. These include skin thinning, striae, telangiectasia, contact dermatitis, and worsening and spreading of untreated infection. When used on the face, they can cause perioral dermatitis and cause or exacerbate acne. As topical corticosteroids do not cure the underlying skin condition, withdrawal reactions can occur on treatment cessation, particularly after prolonged treatment with moderate- to high-potency corticosteroids. These commonly manifest as a flare of skin inflammation occurring days to weeks after treatment cessation, which may be more extensive and uncomfortable than the original condition. Systemic adverse effects are rare, but include adrenal suppression, Cushing’s syndrome and, in children, growth retardation. They are more likely when systemic absorption is increased, for example in prolonged treatment, larger areas of application, poor skin condition (inflammation or thinner skin at extremes of age), higher potency of corticosteroid, and use of occlusive dressings. - Examples = hydrocortisone, betamethasone, clobetasone

Question 39

Warfarin

Answer 39

- Mechanism of action = Production of clotting factors II, VII, IX, and X (termed the ‘vitamin K-dependent clotting factors’) requires vitamin K in its reduced form to act as a cofactor. Oxidised vitamin K generated from this reaction is then recycled into its reduced form by the enzyme vitamin K epoxide reductase, which is inhibited by warfarin. This reduces production of vitamin K-dependent clotting factors (and proteins C and S) which, over several days, produces an anticoagulant effect. - Main indications = 1) To treat and prevent recurrence of venous thromboembolism (VTE, the collective term for deep vein thrombosis and pulmonary embolism). However, direct oral anticoagulants (DOACs) are usually preferred. 2) To prevent arterial embolism from atrial fibrillation (AF). DOACs are usually preferred in non-valvular AF, but warfarin is the first-line option for AF associated with mechanical heart valves, bioprosthetic valves (within 3–6 months of insertion) and rheumatic mitral stenosis. 3) To prevent arterial embolism from mechanical heart valves, whether or not this is associated with atrial fibrillation. - Contraindications = The benefits of preventing clots must be carefully balanced against the risks of bleeding. Warfarin is obviously contraindicated if there is ✖ active bleeding or an immediate risk of this, including after trauma and peri-operatively. ▲ Liver disease impairs both warfarin metabolism and clotting factor synthesis. Warfarin should be avoided in the first trimester of ✖ pregnancy due to teratogenicity (cardiac and cranial abnormalities) and near term due to the risk of peripartum haemorrhage. Heparins are preferred in this context. - Route of admin = Oral (taken each day at ~18:00) - Adverse effects = Bleeding is the main adverse effect. In therapeutic use or minor over-warfarinisation, there is increased risk of bleeding from minor trauma (e.g. intracerebral haemorrhage after minor head injury) and existing abnormalities such as peptic ulcers. Severe over-warfarinisation can trigger apparently spontaneous bleeding, such as epistaxis or retroperitoneal haemorrhage. The effect of warfarin can be reversed with phytomenadione (vitamin K1) or dried prothrombin complex. - Examples = Warfarin

Question 40

Thyroid hormones

Answer 40

- Mechanism of action = The thyroid gland produces thyroxine (T4), which is converted to the more active triiodothyronine (T3) in target tissues. Thyroid hormones regulate metabolism and growth. Deficiency of these hormones causes hypothyroidism, with clinical features including lethargy, weight gain, constipation and slowing of mental processes. Hypothyroidism is treated by long-term replacement of thyroid hormones, usually with levothyroxine (synthetic T4). Liothyronine (synthetic T3) has a shorter half-life and quicker onset (a few hours) and offset (24–48 hours) than levothyroxine. It is therefore reserved for emergency treatment of severe or acute hypothyroidism. - Main indications = 1) Primary hypothyroidism. 2) Hypothyroidism secondary to hypopituitarism. - Contraindications = Thyroid hormones increase heart rate and metabolism. They can therefore precipitate cardiac ischaemia in people with ▲ coronary artery disease, in whom replacement should be started cautiously at a low dose and with careful monitoring. In ▲ hypopituitarism, corticosteroid therapy must be initiated before thyroid hormone replacement to avoid precipitating acute adrenal insufficiency (Addisonian crisis). - Route of admin = Oral - Adverse effects = The adverse effects of levothyroxine are usually due to excessive doses, so are predictably similar to symptoms of hyperthyroidism. These include GI upset, cardiac (e.g. palpitations, arrhythmias, angina), and neurological (e.g. tremor, restlessness, insomnia) manifestations. Weight loss is also an expected and often desirable effect of treatment. - Examples = levothyroxine, liothyronine

Question 41

Sulfonylureas

Answer 41

- Mechanism of action = Sulfonylureas lower blood glucose by stimulating pancreatic insulin secretion. They block ATP-dependent K+ channels in pancreatic β-cell membranes, causing depolarisation of the cell membrane and opening of voltage-gated Ca2+ channels. This increases intracellular Ca2+ concentrations, stimulating insulin secretion. Sulfonylureas are effective only in people with residual pancreatic function. As insulin is an anabolic hormone, stimulation of insulin secretion by sulfonylureas causes weight gain. Weight gain increases insulin resistance and can worsen diabetes mellitus in the long term. - Main indications = 1) In type 2 diabetes, sulphonylureas are options for combination therapy with metformin (and/or other antihyperglycaemic agents) if blood glucose is not adequately controlled, or as monotherapy if metformin is contraindicated or not tolerated. - Contraindications = Gliclazide is metabolised in the liver and has a plasma half-life of 10–12 hours. Unchanged drug and metabolites are excreted in the urine. A dose reduction may therefore be required in ▲ hepatic impairment and blood glucose should be monitored carefully in ▲ renal impairment. Sulfonylureas should be prescribed with caution for people at ▲ increased risk of hypoglycaemia, including those with hepatic impairment (reduced gluconeogenesis), malnutrition, adrenal or pituitary insufficiency (lack of counter-regulatory hormones), and in older people. - Route of admin = Oral (taken with meals) - Adverse effects = Dose-related side effects such as GI upset are usually mild and infrequent. Hypoglycaemia is a potentially serious adverse effect, which is more likely with high doses; if drug metabolism is reduced (see WARNINGS); or if other glucose-lowering medications are prescribed (see INTERACTIONS). Depending on the duration of action of the drug, sulfonylurea-induced hypoglycaemia may last for many hours. If severe, it should be managed in hospital. Rare hypersensitivity reactions include hepatic toxicity (e.g. cholestatic jaundice), drug hypersensitivity syndrome (rash, fever, internal organ involvement) and haematological abnormalities (e.g. agranulocytosis). - Examples = gliclazide, glimepride, glipizide

Question 42

Proton pump inhibitors

Answer 42

- Mechanism of action = Reduce gastric acid secretion. They act by irreversibly inhibiting H+/K+-ATPase in gastric parietal cells. This is the ‘proton pump’ responsible for secreting H+ and generating gastric acid. An advantage of targeting the final stage of the process is that they suppress gastric acid production almost completely. They differ in this respect to H2-receptor antagonists. In Barrett’s oesophagus, acid-suppressive therapy may prevent progression to cancer as well as treating reflux symptoms. - Main indications = 1) Prevention and treatment of peptic ulcer disease, including NSAID-associated ulcers. 2) Treatment of gastro-oesophageal reflux disease (GORD) and dyspepsia, including in the management of Barrett’s oesophagus. 3) Eradication of Helicobacter pylori infection, for which they are used in combination with antibiotic therapy. - Contraindications = PPIs may mask symptoms of gastric or oesophageal cancer and significant ulcer disease caused by H. pylori, so prescribers should enquire about ‘alarm symptoms’ before and during treatment. There is epidemiological evidence that PPIs, particularly at high dose for prolonged courses in older people, can increase the risk of fracture. People with or at risk of ▲ osteoporosis should therefore be identified and treated as appropriate. - Route of admin = Oral PPIs are best taken in the morning, with or without food. IV preparations are given by slow injection or infusion. - Adverse effects = Common side effects of PPIs include GI upset and headache. By increasing the gastric pH, PPIs may reduce one of the body’s defences against infection, and in this respect there is some evidence that they increase the risk of Clostridioides difficile colitis. Prolonged treatment with PPIs can cause hypomagnesaemia which, if severe, can lead to neuromuscular symptoms (including tetany in extreme cases) and arrhythmias. - Examples = omeprazole, lansoprazole, esomeprazole

Question 43

Paracetamol

Answer 43

- Mechanism of action = Poorly understood. In the central nervous system, it acts as a reducing co-substrate of cyclo-oxygenase 2 (COX-2). This reduces the availability of oxidised COX-2, necessary for conversion of arachidonic acid to an intermediate metabolite in the prostaglandin synthesis pathway. This interferes with transmission of pain signals between the spinal cord and higher centres, reducing pain sensitivity. It also reduces prostaglandin E2 (PGE2) concentrations in the thermoregulatory region of the hypothalamus, reducing fever. However, it has little anti-inflammatory action in peripheral tissues. This may be because its effects are inhibited by peroxides, the concentration of which is low in the central nervous system, but high in inflamed tissue. It is likely that other actions of paracetamol and its metabolites contribute to the therapeutic effect. These may include activation of descending serotonergic pathways, and inhibition of neuronal reuptake of endogenous cannabinoids. - Main indications = 1) Paracetamol is a first-line analgesic for most forms of acute and chronic pain. It may be used alone for mild pain, or combined with other analgesics (e.g. opioids, non-steroidal anti-inflammatory drugs). 2) Paracetamol is an antipyretic that can reduce fever and its associated symptoms (e.g. shivering). - Contraindications = Paracetamol dose should be reduced in people at increased risk of liver toxicity, either because of increased NAPQI production (e.g. in ▲ chronic excessive alcohol use, inducing metabolising enzymes) or reduced glutathione stores (e.g. in ▲ malnutrition, ▲ low body weight (<50 kg) and ▲ severe hepatic impairment). This is particularly important where paracetamol is given by IV infusion. - Route of admin = Oral, IV - Adverse effects = At treatment doses, paracetamol is very safe with few side effects. Lack of COX-1 inhibition means that it does not cause peptic ulceration or renal impairment or increase the risk of major adverse cardiovascular events (unlike NSAIDs). Its safety makes it a popular choice as a first-line analgesic. In overdose, paracetamol causes liver failure. It is, in part, metabolised by cytochrome P450 (CYP) enzymes to a toxic metabolite (N-acetyl-p-benzoquinone imine (NAPQI)), which is conjugated with glutathione before elimination. In overdose, this elimination pathway is saturated, and NAPQI accumulation causes hepatocellular necrosis. Hepatotoxicity can be prevented by treatment with the glutathione precursor acetylcysteine. - Examples = Paracetamol

Question 44

Benzodiazepines

Answer 44

- Mechanism of action = Water losses due to diuresis can lead to dehydration and hypotension. Inhibiting the Na+/K+/2Cl− co-transporter increases urinary losses of sodium, potassium, and chloride ions. Indirectly, this also increases excretion of magnesium, calcium, and hydrogen ions. You can therefore associate loop diuretics with almost any low electrolyte state (i.e. hyponatraemia, hypokalaemia, hypochloraemia, hypocalcaemia, hypomagnesaemia, and metabolic alkalosis). Hypernatraemia may also occur, due to loss of water in excess of sodium. A similar Na+/K+/2Cl− co-transporter is responsible for regulating endolymph composition in the inner ear. At high doses, loop diuretics can affect this too, leading to hearing loss and tinnitus. - Main indications = 1) First-line in the management of status epilepticus. 2) First-line in the management of alcohol withdrawal reactions. 3) Sedation in palliative care, for interventional procedures (if general anaesthesia is unnecessary or undesirable) or for rapid tranquilisation. 4) For short-term treatment of severe, disabling or distressing anxiety or insomnia, although non-pharmacological treatment (or treatment of the underlying cause, if applicable) is invariably preferable. - Contraindications = ▲ Older people are more susceptible to the effects of benzodiazepines and so should receive a lower dose. Benzodiazepines are best avoided in significant ▲ respiratory impairment or ▲ neuromuscular disease (e.g. myasthenia gravis). Benzodiazepines should also be avoided in ▲ liver failure as they may precipitate hepatic encephalopathy. If their use is essential (e.g. for alcohol withdrawal), lorazepam may be the best choice, as it depends less on the liver for its elimination. - Route of admin = IV, oromucosal formulation - Adverse effects = Predictably, benzodiazepines cause dose-dependent drowsiness, sedation, and coma. There is relatively little cardiorespiratory depression in benzodiazepine overdose (in contrast to opioid overdose), but loss of airway reflexes can lead to airway obstruction and death. If used repeatedly for more than a few weeks, a state of dependence can develop. Abrupt cessation then produces a withdrawal reaction similar to that seen with alcohol. - Examples = diazepam, midazolam, lorazepam, chlordiazepoxide

Question 45

Alginates and antacids

Answer 45

- Mechanism of action = These drugs are most often taken as compound preparations containing an alginate with one or more antacids, such as sodium bicarbonate, calcium carbonate, magnesium or aluminium salts. Antacids work by buffering stomach acid. Alginates act to increase the viscosity of the stomach contents, which reduces the reflux of acid into the oesophagus. After reacting with stomach acid they form a floating ‘raft’, which separates the gastric contents from the gastro-oesophageal junction to prevent mucosal damage. There is some evidence that they also inhibit pepsin production. Antacids alone (usually aluminium or magnesium compounds) can be used for the short-term relief of dyspepsia. - Main indications = 1) Gastro-oesophageal reflux disease (GORD): for symptomatic relief of heartburn. 2) Dyspepsia: for short-term relief of indigestion. - Contraindications = Compound alginates are well tolerated and are safe in pregnancy. Sodium- and potassium-containing preparations should be used with caution in people with fluid overload or hyperkalaemia (e.g. ▲ renal failure). Some preparations contain sucrose, which can worsen hyperglycaemia in people with diabetes mellitus. - Route of admin = They should be taken following meals, before bedtime and/or when symptoms occur. For infants, oral powder can be mixed with feeds or water. - Adverse effects = Compound alginates cause few side effects, which vary depending on their constituents and the dose taken. Magnesium salts can cause diarrhoea, whereas aluminium salts can cause constipation. - Examples = alginic acid compound preparations, sodium bicarbonate

Question 46

Aminoglycoside (-cin)

Answer 46

- Mechanism of action = Aminoglycosides bind irreversibly to bacterial ribosomes (30S subunit) and inhibit protein synthesis. They are bactericidal (they kill bacteria), an effect that probably involves other, incompletely understood, mechanisms. Aminoglycosides enter bacterial cells via an oxygen-dependent transport system. Streptococci and anaerobic bacteria do not have this transport system, so have innate aminoglycoside resistance. Other bacteria acquire resistance through reduced cell membrane permeability to aminoglycosides or acquisition of enzymes that modify aminoglycosides to prevent them from reaching the ribosomes. As penicillins weaken bacterial cell walls, they may enhance aminoglycoside activity by increasing penetration into bacterial cells. The main activity of aminoglycosides that is clinically relevant is against Gram-negative aerobic bacteria. They also have some activity against staphylococci and mycobacteria, but other agents are preferred. They are inactive against streptococci and anaerobes, so are often used as part of combination treatment (e.g. with a penicillin and metronidazole). - Main indications = Systemic aminoglycosides (gentamicin, amikacin) are used to treat severe infections, particularly those caused by Gram-negative aerobes (including Pseudomonas aeruginosa): 1) Sepsis, including cases where the source is unidentified. 2) Pyelonephritis and complicated urinary tract infection. 3) Intraabdominal infection. 4) Endocarditis. 5) Topical neomycin is an option for otitis externa. - Contraindications = Aminoglycosides are renally excreted. In systemic therapy, careful dose adjustment based on plasma drug concentrations is essential to prevent renal, cochlear, and vestibular damage, particularly in ▲ neonates, ▲ older people and those with ▲ renal impairment. Aminoglycosides can impair neuromuscular transmission and so should not be given to people with ▲ myasthenia gravis unless unavoidable. - Route of admin = For IV administration, aminoglycosides are infused slowly (e.g. over 30 min). This limits exposure of the ear to high peak concentrations (a potential hazard of impatience during IV injection). - Adverse effects = The most important adverse effects of systemic treatment are nephrotoxicity and ototoxicity. Aminoglycosides accumulate in renal tubular epithelial cells and cochlear and vestibular hair cells where they trigger apoptosis and cell death. Nephrotoxicity presents as reduced urine output and rising serum creatinine and is potentially reversible. Ototoxicity may cause hearing loss, tinnitus (cochlear damage) and/or vertigo (vestibular damage) and is more likely to be irreversible. - Examples = gentamicin, amikacin, neomycin

Question 47

Amiodarone

Answer 47

- Mechanism of action = Amiodarone has many effects on myocardial cells, including blockade of sodium, calcium and potassium channels, and antagonism of α- and β-adrenergic receptors. These effects reduce spontaneous depolarisation (automaticity), slow conduction velocity and increase resistance to depolarisation (refractoriness), including in the atrioventricular (AV) node. By interfering with AV node conduction, amiodarone reduces the ventricular rate in AF and atrial flutter. Through its other effects, it may also increase the chance of conversion to, and maintenance of, sinus rhythm. In SVT involving a self-perpetuating (‘re-entry’) circuit that includes the AV node, amiodarone may break the circuit and restore sinus rhythm. Amiodarone’s effects in suppressing spontaneous depolarisations make it an option for both treatment and prevention of VT and for improving the chance of successful defibrillation in refractory VF. - Main indications = Amiodarone is used in a wide range of tachyarrhythmias, including atrial fibrillation (AF), atrial flutter, supraventricular tachycardia (SVT), ventricular tachycardia (VT) and refractory ventricular fibrillation (VF). It is generally used only if other treatments (drugs or electrical cardioversion) are ineffective or contraindicated. - Contraindications = Amiodarone is a potentially dangerous drug that should be used only when the risk–benefit balance justifies it. It should generally be avoided in ▲ severe hypotension, ▲ heart block, and ▲ active thyroid disease. - Route of admin = In cardiac arrest, amiodarone is given as a bolus injection. It is often provided in a pre-filled syringe to facilitate easy administration. It should be given through the ‘best’ IV cannula available. Outside cardiac arrests, if continuous or repeated IV infusions are anticipated, these should be given via a central line. This is because peripheral IV administration can cause significant phlebitis. - Adverse effects = In acute use, compared with other antiarrhythmic drugs, amiodarone causes relatively little myocardial depression. It can cause hypotension during IV infusion, although this is probably an effect of the solvent rather than the drug itself. When taken chronically, amiodarone has many side effects, several of which are serious. These include effects on the lungs (pneumonitis), heart (bradycardia, AV block), liver (hepatitis) and skin (photosensitivity and grey discolouration). Due to its iodine content (amIODarone) and structural similarities to thyroid hormone, it may cause thyroid abnormalities, including hypo- and hyperthyroidism. Amiodarone has an extremely long half-life. After discontinuation, it may take months to be completely eliminated.

Question 48

Anaesthetics, general

Answer 48

- Mechanism of action = General anaesthetics are a family of diverse compounds, pragmatically grouped by their route of administration. Intravenous anaesthetics include propofol, thiopental, and ketamine, while inhalational anaesthetics include volatile liquids (e.g. sevoflurane) and simple gases (nitrous oxide). To access the central nervous system (CNS), anaesthetics must be lipid soluble, and this is a strong determinant of their potency. Possible molecular mechanisms of their effects include disruption of neuronal cell membranes and interactions with specific ion channels. For example, a family of two-pore potassium channels (K2P), which are widely distributed in the CNS and regulate membrane resting potential, are sensitive to volatile anaesthetics. Anaesthetics may interact with K2P channels directly or indirectly by disrupting crystallin lipids (‘lipid rafts’) that surround them. Collectively, these molecular effects enhance the inhibitory action of γ-aminobutyric acid (GABA), particularly via GABAA receptor activation, and/or antagonise excitatory N-methyl-D-aspartate (NMDA) and nicotinic cholinergic receptors. This decreases cortical and thalamic activity, leading to varying degrees of unconsciousness, analgesia, and muscle relaxation. The balance of effects varies between drugs. For example, nitrous oxide and ketamine have useful analgesic effects, whereas most other general anaesthetics do not. - Main indications = 1) To induce reversible unconsciousness, allowing interventional (e.g. surgical) procedures to be performed without awareness or interaction (general anaesthesia). 2) Some drugs in this group (e.g. propofol) may be used at sub-anaesthetic doses to reduce discomfort from procedures that do not require full general anaesthesia, or as an infusion to improve tolerability of invasive ventilation in critical illness (sedation). - Contraindications = General anaesthesia and sedation should only be undertaken by expert clinicians in appropriate facilities. Assessment of ‘fitness for anaesthesia’ is complex and beyond the scope of this book. Risk is often classified using the American Society of Anesthesiologists (ASA) Physical Status Classification system, based on the severity of systemic disease. - Route of admin = IV anaesthetics are given by bolus injection to induce anaesthesia, and infusion to maintain anaesthesia (or sub-anaesthetic sedation). Inhalational anaesthetics are administered by blending them with the gaseous mixture in the breathing circuit. For volatile anaesthetics, this requires the liquid first to be vaporised using a device that allows the concentration of anaesthetic vapour to be precisely controlled. - Adverse effects = CNS depression causes suppression of airway reflexes and respiratory drive, usually necessitating airway management (e.g. endotracheal intubation) and ventilation. Most anaesthetics cause bradycardia, vasodilation, and hypotension (ketamine is an exception, more often causing tachycardia and hypertension). Nausea and vomiting are common on emergence from anaesthesia, though this is likely multifactorial. Propofol may cause pain on injection. - Examples = propofol, thiopental, sevoflurane, nitrous oxide, ketamine

Question 49

Antidepressants, tetracyclic and serotonin–noradrenaline reuptake inhibitors

Answer 49

- Mechanism of action = Venlafaxine and duloxetine are a serotonin–noradrenaline reuptake inhibitors (SNRIs), interfering with uptake of these neurotransmitters from the synaptic cleft. Mirtazapine is a tetracyclic antidepressant. It antagonises inhibitory pre-synaptic α2-adrenoceptors. All three drugs increase availability of monoamines for neurotransmission, which appears to be the mechanism whereby they improve mood and physical symptoms in moderate-to-severe (but not mild) depression. Duloxetine is also used in neuropathic pain, where it may act by increasing synaptic noradrenaline concentration in descending spinal inhibitory pathways. Venlafaxine and duloxetine are weaker antagonists of muscarinic and histamine (H1) receptors than tricyclic antidepressants, whereas mirtazapine is a potent antagonist of histamine (H1) but not muscarinic receptors. They therefore have fewer antimuscarinic side effects than tricyclic antidepressants, although mirtazapine commonly causes sedation. - Main indications = 1) As an option for major depression, if first-line selective serotonin reuptake inhibitor (SSRI) treatment is ineffective or not tolerated. 2) Generalised anxiety disorder (venlafaxine, duloxetine). 3) Diabetic neuropathy (duloxetine) - Contraindications = As with many centrally acting medications, ▲ older people are more at risk of adverse effects. Dose reduction should be considered in ▲ hepatic or ▲ renal impairment, and duloxetine avoided in severe renal impairment. Venlafaxine should be avoided, or otherwise used with caution, in people at risk of ▲ arrhythmias (e.g. due to ischaemic heart disease). - Route of admin = Mirtazapine should be taken at night to mitigate (or benefit from) its sedative effects. - Adverse effects = Common adverse effects of both drugs include GI upset (e.g. nausea, change in weight, and diarrhoea or constipation), dry mouth, and neurological effects (e.g. headache, abnormal dreams, insomnia, confusion, and convulsions). Less common but serious adverse effects include hyponatraemia and serotonin syndrome (see Antidepressants, selective serotonin reuptake inhibitors). Suicidal thoughts and behaviour may increase. Venlafaxine prolongs the QT interval and can increase the risk of ventricular arrhythmias. Sudden drug withdrawal can cause GI upset, neurological and flu-like symptoms, and sleep disturbance. Venlafaxine is associated with a greater risk of withdrawal effects than other antidepressants. Mirtazepine may cause bone marrow suppression. - Examples = venlafaxine, mirtazapine, duloxetine

Question 50

Antiemetics, dopamine D2-receptor antagonists

Answer 50

- Mechanism of action = Nausea and vomiting are triggered by gut irritation, drugs, motion, vestibular disorders, and higher stimuli (sights, smells, emotions). The pathways converge on a ‘vomiting centre’ in the medulla, which receives inputs from the chemoreceptor trigger zone (CTZ), the vagus nerve, the vestibular system, and higher centres. Dopamine is relevant in two respects. First, the dopamine D2 receptor is the main receptor in the CTZ, which senses emetogenic substances (e.g. drugs) in blood. Antagonism of the D2-receptor is therefore useful in nausea and vomiting caused by CTZ stimulation. Second, dopamine is an important neurotransmitter in the gut, where it promotes relaxation of the stomach and lower oesophageal sphincter and inhibits gastroduodenal coordination. D2-receptor antagonists (particularly metoclopramide, which is augmented with enteric 5-HT4 agonist activity) therefore have a prokinetic effect. This contributes to their antiemetic action in states of reduced gut motility (e.g. due to opioids or diabetic gastroparesis). D2-receptor antagonists are classified as benzamides (e.g. metoclopramide, domperidone) and phenothiazines (e.g. prochlorperazine). - Main indications = Prophylaxis and treatment of nausea and vomiting in a wide range of conditions, but particularly in the context of reduced gut motility. - Contraindications = Metoclopramide should be avoided in ✖ neonates, ▲ children, and ▲ young adults. Domperidone is contraindicated in ▲ severe hepatic impairment and ✖ cardiac conduction defects. It is not licensed for ✖ children under 12 years or people ✖ weighing less than 35 kg. Prokinetics are contraindicated in ▲ intestinal obstruction and ✖ perforation. D2-antagonists are avoided in ▲ Parkinson’s disease, but domperidone may be used as it does not cross the blood–brain barrier. - Route of admin = IV injections of metoclopramide should be given slowly (over at least 3 minutes for a standard 10-mg dose). - Adverse effects = Diarrhoea is common. Metoclopramide and prochlorperazine can induce extrapyramidal effects (movement abnormalities) by the same mechanism as antipsychotics. Domperidone does not, as it does not cross the blood–brain barrier (note the CTZ is largely outside the blood–brain barrier). It causes QT interval prolongation and arrhythmias. Prochloperazine causes drowsiness (see Antipsychotics, first generation). - Examples = metoclopramide, prochlorperazine, domperidone

Question 51

Antiemetics, histamine H1-receptor antagonists

Answer 51

- Mechanism of action = Nausea and vomiting are triggered by gut irritation, drugs, motion, vestibular disorders, and higher stimuli (sights, smells, emotions). The pathways converge on a ‘vomiting centre’ in the medulla, which receives inputs from the chemoreceptor trigger zone, the vagus nerve (via the solitary tract nucleus), the vestibular system, and higher centres. Histamine H1 and muscarinic acetylcholine receptors predominate in the vomiting centre and in its communication with the vestibular system. Drugs such as cyclizine block both receptors. This makes them useful treatments for nausea and vomiting in a wide range of conditions (e.g. drug-induced, postoperative, radiotherapy), particularly when associated with motion or vertigo. - Main indications = Prophylaxis and treatment of nausea and vomiting, particularly in the context of motion sickness or vertigo. Other drugs in this class are used in the treatment of allergies (see Antihistamines (H1-receptor antagonists)). - Contraindications = Due to their sedating effect, these drugs should be avoided in people at risk of ▲ hepatic encephalopathy. They should also be avoided in people susceptible to anticholinergic side effects, such as those with ▲ prostatic enlargement (who may develop urinary retention). - Route of admin = Intravenous injections of cyclizine should be given slowly (over about 2 minutes). - Adverse effects = The most common adverse effect is drowsiness. Cyclizine is the least sedating drug in this class and is therefore usually preferred. Due to their anticholinergic effects they may cause dry throat and mouth. This is usually undesirable, but in people with copious mucosal secretions it may be beneficial. After IV injection they may cause transient tachycardia, which may be experienced as palpitations. Along with their central anticholinergic effects (excitation or depression) this may make for a rather unpleasant experience. - Examples = cyclizine, promethazine, cinnarizine

Question 52

Antifungal drugs

Answer 52

- Mechanism of action = Fungal cell membranes contain ergosterol. As ergosterol is not found in animal or human cells it is a target for antifungal drugs. Polyene antifungals (e.g. nystatin) bind to ergosterol in fungal cell membranes, creating a polar pore which allows intracellular ions to leak out of the cell. This can kill or slow growth of the fungi. Imidazole (e.g. clotrimazole) and triazole antifungals (e.g. fluconazole) inhibit ergosterol synthesis, impairing cell membrane synthesis, cell growth, and replication. Resistance to antifungals is relatively infrequent but can occur during long-term treatment in people with immune suppression. Mechanisms include alteration of membrane synthesis to exclude ergosterol, changes in target enzymes or increased drug efflux. - Main indications = 1) Treatment of local fungal infections, including of the oropharynx, vagina or skin. They may be applied topically (nystatin, clotrimazole) or taken orally (fluconazole). 2) Systemic treatment of invasive or disseminated fungal infections. Specialist treatment is required for these infections, which will not be discussed further in this book. - Contraindications = Topically administered nystatin and clotrimazole have no major contraindications. Fluconazole should be prescribed with caution in ▲ liver disease and ▲ QT interval prolongation. A dose reduction is required in ▲ moderate renal impairment. It should be avoided in ✖ pregnancy due to the risk of fetal malformation. - Route of admin = Oral nystatin should be administered after food and held in the mouth to allow good contact with the lesions. Dentures should be removed to expose affected areas to treatment. - Adverse effects = Nystatin and clotrimazole are used topically at the site of infection, so have few adverse effects apart from occasional local irritation where applied. Fluconazole is taken orally and so has systemic adverse effects. The most common are GI upset (including nausea, vomiting, diarrhoea, and abdominal pain), headache, increase in liver enzymes, and hypersensitivity causing skin rash. Rare but potentially life-threatening reactions include severe hepatic toxicity; prolonged QT interval predisposing to arrhythmias; and severe hypersensitivity, including cutaneous reactions and anaphylaxis. - Examples = nystatin, clotrimazole, fluconazole

Question 53

Antimuscarinics, bronchodilators

Answer 53

- Mechanism of action = Antimuscarinic drugs bind to muscarinic receptors, where they act as competitive inhibitors of acetylcholine. Stimulation of muscarinic receptors, of which there are various subtypes (designated M1–M5), brings about a wide range of parasympathetic ‘rest and digest’ effects. In blocking the receptors, antimuscarinics have the opposite effects: they increase heart rate and conduction (M2 receptors); reduce smooth muscle tone, including in the respiratory tract, gut, and urinary tract (M3 receptors); and reduce secretions from glands in the respiratory tract and gut (M1 and M3 receptors). In the eye, they cause relaxation of the pupillary constrictor and ciliary muscles (M3 receptors), causing pupillary dilation and preventing accommodation, respectively. Inhaled antimuscarinics relieve airway obstruction in COPD and asthma by allowing smooth muscle relaxation, causing bronchodilation, and by reducing respiratory secretions. - Main indications = 1) In chronic obstructive pulmonary disease (COPD), short-acting antimuscarinics are used to relieve acute breathlessness associated with, for example, exercise or exacerbations. Long-acting antimuscarinics (LAMAs) are used to prevent breathlessness and exacerbations either (1) in COPD with no features of asthma or steroid responsiveness, as first-line regular therapy in combination with a long-acting β2-agonist (LABA); or (2) in COPD with features of asthma or steroid responsiveness, as second-line regular therapy in combination with a LABA and inhaled corticosteroid (see Corticosteroids, inhaled). 2) In acute severe asthma, short-acting antimuscarinics may augment the bronchodilator effects of short-acting β2 agonists (e.g. salbutamol). In chronic asthma, LAMAs can be trialled if control is insufficient despite moderate-dose inhaled corticosteroid and LABA treatment. - Contraindications = Antimuscarinics should be used with caution in people susceptible to ▲ angle-closure glaucoma, in whom they can precipitate a dangerous rise in intraocular pressure, and those with or at risk of ▲ arrhythmias or ▲ urinary retention. However, in practice, most people can take these drugs by inhalation without major problems. - Route of admin = Inhaled medication comes in a range of inhaler devices, with the choice of medicine often being directed by the device that best suits the individual. Liquid for nebulisation is put into the chamber below a mask covering the mouth and nose. Gas is bubbled through the liquid, vaporising the medicine. In asthma, the driving gas is usually oxygen. In people with ▲ chronic type 2 (hypercapnic) respiratory failure, who are at risk of carbon dioxide retention, medical air is used. - Adverse effects = Dry mouth is common. Inhalation may irritate the respiratory tract, causing cough or hoarse voice. As a class, antimuscarinics can also cause tachycardia, constipation, urinary retention, and blurred vision. However, as very little active drug enters the systemic circulation in inhaled therapy, these adverse effects are much less likely than with oral/IV antimuscarinics. This is particularly so for aclidinium, which is hydrolysed rapidly after absorption, and has a low frequency of systemic adverse reactions, including dry mouth. - Examples = tiotropium, umeclidinium, glycopyrronium, ipratropium

Question 54

Antimuscarinics, cardiovascular and GI uses

Answer 54

- Mechanism of action = Antimuscarinic drugs bind to the muscarinic receptor, where they act as a competitive inhibitor of acetylcholine. Stimulation of muscarinic receptors, of which there are various subtypes (designated M1–M5), brings about a wide range of parasympathetic ‘rest and digest’ effects. In blocking the receptors, antimuscarinics have the opposite effects: they increase heart rate and conduction (M2 receptors); reduce tone and peristaltic contraction of smooth muscle in the gut and urinary tract (M3 receptors); and reduce secretions from glands in the respiratory tract and gut (M1 and M3 receptors). In the eye, they cause relaxation of the pupillary constrictor and ciliary muscles (M3 receptors), causing pupillary dilation and preventing accommodation, respectively. - Main indications = 1) Atropine and glycopyrronium are first-line options in the management of severe or symptomatic bradycardia, to increase heart rate. 2) Antimuscarinics (particularly hyoscine butylbromide) are first-line drug treatment options for irritable bowel syndrome (IBS), where they are used for their antispasmodic effect. Mebeverine (a direct-acting smooth muscle relaxant) is an alternative that may be better tolerated. 3) In palliative care, antimuscarinics (e.g. glycopyrronium, hyoscine butylbromide) are used to prevent or reduce copious respiratory secretions, which can cause distressing noisy breathing. - Contraindications = There are no contraindications to the use of antimuscarinics for life-threatening bradycardia. In other indications, caution should be exercised in people susceptible to ▲ angle-closure glaucoma, in whom they can precipitate a dangerous rise in intraocular pressure. They should generally be avoided in people at risk of ▲ arrhythmias (e.g. those with significant cardiac disease, unless of course the indication for use is bradycardia). They may precipitate urinary retention in people with ▲ benign prostatic enlargement. - Route of admin = In general, IV administration of atropine should be performed only by, or under direct supervision of, an individual experienced in its use. The concentration of atropine in pre-filled syringes may be 100, 200 or 300 micrograms/mL—be sure to check this before administration. - Adverse effects = Predictably from their antagonism of parasympathetic ‘rest and digest’ effects, antimuscarinics can cause tachycardia, dry mouth, and constipation. By reducing detrusor (bladder) muscle activity, they can cause urinary retention. Their ocular effects may cause blurred vision, especially for near objects. Muscarinic receptors (particularly M1) are widely distributed in the brain, and lipid-soluble antimuscarinics (the tertiary amines such as atropine) have central effects including drowsiness and confusion, particularly in older people. Quaternary ammonium compounds such as glycopyrronium and hyoscine butylbromide (but not hyoscine hydrobromide—see CLINICAL TIP) are less lipid soluble, and so have fewer central nervous system effects. - Examples = hyoscine butylbromide, atropine, glycopyrronium

Question 55

Antiplatelet drugs, ADP-receptor antagonists

Answer 55

- Mechanism of action = Thrombotic events occur when platelet-rich thrombus forms in atheromatous arteries and occludes the circulation. ADP-receptor antagonists prevent platelet aggregation and reduce the risk of arterial occlusion by binding irreversibly to adenosine diphosphate (ADP) receptors (P2Y12 subtype) on the surface of platelets. As this process is independent of the cyclooxgenase (COX) pathway, its actions are synergistic with those of aspirin. Clopidogrel and prasugrel are irreversible inhibitors of ADP receptors, whereas ticagrelor acts reversibly. This has important implications for decisions based on their duration of action (see CLINICAL TIP). - Main indications = 1) For treatment of acute coronary syndrome (ACS), usually in combination with aspirin, where rapid inhibition of platelet aggregation can prevent or limit arterial thrombosis and reduce subsequent mortality. 2) To prevent coronary artery stent occlusion, usually in combination with aspirin. 3) For secondary prevention of major adverse cardiovascular events in people with ischaemic heart disease, cerebrovascular disease or peripheral vascular disease, alone or in combination with aspirin. - Contraindications = Antiplatelet drugs should not be prescribed for people with ✖ active bleeding and may need to be stopped 7 days before ▲ elective surgery and other procedures (see CLINICAL TIP). They should be used with caution in ▲ renal and ▲ hepatic impairment, especially if there are any other risk factors for bleeding. - Route of admin = Clopidogrel, ticagrelor, and prasugrel can be taken with or without food. They should be taken at regular intervals. - Adverse effects = The most common adverse effect is bleeding, which can be serious, particularly if GI or intracranial. GI upset, including dyspepsia, abdominal pain, and diarrhoea, is also common. Rarely, antiplatelet agents can affect platelet numbers as well as function, causing thrombocytopenia. - Examples = clopidogrel, ticagrelor, prasugrel

Question 56

Antipsychotics, first-generation (typical)

Answer 56

- Mechanism of action = Antipsychotic drugs block post-synaptic dopamine D2 receptors. There are three main dopaminergic pathways in the brain. The mesolimbic/mesocortical pathway runs between the midbrain and the limbic system/frontal cortex. D2 blockade in this pathway is probably the main determinant of antipsychotic effect, but this is incompletely understood. The nigrostriatal pathway connects the substantia nigra with the corpus striatum of the basal ganglia. The tuberohypophyseal pathway connects the hypothalamus with the pituitary gland. Activity in these pathways explains some of the drugs’ adverse effects. D2 receptors are also found in the chemoreceptor trigger zone, where blockade accounts for their use in nausea and vomiting. All antipsychotics, but particularly chlorpromazine, have some sedative effect. This may be beneficial in acute psychomotor agitation. - Main indications = 1) Rapid tranquilisation in severe psychomotor agitation that is causing dangerous or violent behaviour, or to enable assessment. 2) Schizophrenia, particularly when the metabolic side effects of second-generation (atypical) antipsychotics are problematic. 3) Bipolar disorder, particularly in acute mania or hypomania. 4) Nausea and vomiting, particularly in the palliative care setting. - Contraindications = ▲ Older people are particularly sensitive to antipsychotics, so start with lower doses. Antipsychotics should ideally be avoided in ▲ dementia, as they may increase the risk of death and stroke. They should be avoided if possible in ▲ Parkinson’s disease due to their extrapyramidal effects. - Route of admin = For regular administration, typical antipsychotics can be taken orally (tablet and liquid) or given by slow-release IM (‘depot’) injection. For rapid tranquilisation, haloperidol is usually given by rapid-acting IM injection and occasionally IV, although it is not licensed by this route. IV haloperidol should only be administered by clinicians capable of managing its acute adverse effects, including arrhythmias such as torsade de pointes (a form of ventricular tachycardia), which are more likely when antipsychotics are given by injection or in high dose. - Adverse effects = Extrapyramidal effects—movement abnormalities that arise from D2 blockade in the nigrostriatal pathway—are the main drawback of first-generation antipsychotics. They take several forms: acute dystonic reactions are involuntary parkinsonian movements or muscle spasms; akathisia is a state of inner restlessness; and neuroleptic malignant syndrome is a rare but life-threatening side effect characterised by rigidity, confusion, autonomic dysregulation, and pyrexia. These tend to occur early in treatment. By contrast, tardive dyskinesia is a late adverse effect (tardive, late), occurring after months or years. This comprises movements that are pointless, involuntary, and repetitive (e.g. lip smacking). It is disabling and may not resolve on stopping treatment. Other adverse effects include drowsiness, hypotension, QT interval prolongation (and consequent arrhythmias), erectile dysfunction, and symptoms arising from hyperprolactinaemia due to tuberohypophyseal D2 blockade (e.g. menstrual disturbance, galactorrhoea, and breast pain). - Examples = haloperidol, chlorpromazine, flupentixol

Question 57

Antipsychotics, second-generation (atypical)

Answer 57

- Mechanism of action = Like first-generation antipsychotic drugs, second-generation antipsychotics block post-synaptic dopamine D2 receptors. Blockade in the mesolimbic/mesocortical pathway (between the midbrain and the limbic system/frontal cortex) probably accounts for at least part of the drugs’ antipsychotic effects, and activity in the nigrostriatal pathway (between the substantia nigra and the corpus striatum of the basal ganglia) and tuberohypophyseal pathway (hypothalamus to pituitary gland) probably accounts for some of their adverse effects. However, second-generation antipsychotics have greater activity at other receptors (particularly 5-HT2A antagonism), and a characteristic of ‘looser’ binding to D2 receptors (in the case of clozapine and quetiapine). This may explain why the second-generation agents are more efficacious in ‘treatment-resistant’ schizophrenia (particularly clozapine) and against negative symptoms, and why they have a lower risk of extrapyramidal symptoms. - Main indications = 1) Schizophrenia, particularly when extrapyramidal side effects have complicated the use of first-generation (typical) antipsychotics, or when negative symptoms are prominent. Clozapine is more effective than other antipsychotics in refractory schizophrenia. 2) Bipolar disorder, particularly in acute mania or hypomania. - Contraindications = Antipsychotics should be used with caution in ▲ cardiovascular disease. Clozapine must not be used in ✖ severe heart disease or people with a history of ✖ neutropenia. - Route of admin = Oral second-generation antipsychotics should generally be taken at the same time every day. In once-daily administration, if drowsiness is an issue, some people may prefer to take the dose in the evening. - Adverse effects = Second-generation antipsychotics are generally better tolerated than first-generation agents. Extrapyramidal effects (see Antipsychotics, first-generation), in particular, are less common, and drowsiness and cognitive impairment are less marked. However, metabolic disturbances, including weight gain, diabetes mellitus, and lipid changes, are common with second-generation antipsychotics. Antipsychotics can prolong the QT interval and thus cause arrhythmias. Risperidone has particular effects on dopaminergic transmission in the tuberohypophyseal pathway, which regulates secretion of prolactin. This can cause breast symptoms (in both women and men) and sexual dysfunction. Clozapine causes a severe deficiency of neutrophils (agranulocytosis) in about 1% of individuals, which can lead to severe infections. Rarely, it causes myocarditis. - Examples = quetiapine, olanzapine, risperidone, clozapine

Question 58

Antiviral drugs, other

Answer 58

- Mechanism of action = Viruses consist of nucleic acid (RNA or DNA), encapsulated in a protein coat. They attach to and invade host cells, then use cell machinery to synthesise new viral nucleic acids and proteins. These are assembled and released as whole virions. Antiviral drugs target key stages of viral replication. For treatment of influenza A and B, oseltamivir and zanamivir inhibit neuraminidases, viral surface enzymes important for entry into and release from host cells. For SARS-CoV-2, molnupiravir and remdesivir are nucleotide analogues that block viral RNA synthesis, and nirmatrelvir (with ritonavir) is a protease inhibitor that inhibits viral replication. Antiretroviral drugs used in the treatment of HIV and hepatitis B include nucleoside/nucleotide (e.g. emtricitabine, tenofovir) and non-nucleoside (e.g. efavirenz) reverse transcriptase inhibitors (NRTIs and NNRTIs, respectively). These inhibit synthesis of DNA from viral RNA. Protease inhibitors (e.g. atazanavir) inhibit the enzyme which cleaves inert polyproteins into structural and functional viral proteins. Drugs used for hepatitis C include RNA-dependent RNA polymerase inhibitors (e.g. sofosbuvir). - Main indications = 1) Acute treatment of certain viral infections, e.g. influenza or SARS-CoV-2 (the cause of COVID-19), to reduce illness duration and severity. 2) Pre-exposure prophylaxis (PrEP), to reduce the risk of human immunodeficiency virus (HIV) infection in people at high risk (e.g. those whose partner has HIV) and post-exposure prophylaxis (PEP), e.g. for influenza in unvaccinated adults, or HIV after needle-stick injury. 3) Chronic treatment to suppress (and if possible, eliminate) viral load in hepatitis B, C or HIV infection, to reduce morbidity, mortality, and onward transmission. - Contraindications = People with ▲ asthma or COPD are at increased risk of bronchospasm with inhaled zanamivir. NNRTIs and protease inhibitors are contraindicated in ✖ acute porphyria and should be used with caution in those at risk of ▲ QT prolongation. - Route of admin = Antivirals should be administered at equal dosage intervals, to avoid periods of subtherapeutic drug concentration. A short-acting bronchodilator (e.g. β2 agonist) should be available in case of bronchospasm when administering inhaled zanamivir to people with airways disease. - Adverse effects = These include GI upset, skin reactions, dizziness, and sleep problems, which are usually mild and self-limiting. Inhaled zanamivir may cause bronchospasm. Immune-mediated effects include hypersensitivity reactions, hepatitis, blood dyscrasias, and severe cutaneous reactions. Long-term treatment can cause dyslipidaemia, hyperglycaemia, hypertension, and weight gain, increasing cardiovascular risk. - Examples = oseltamivir, nirmatrelvir, tenofovir, efavirenz, atazanavir

Question 59

Calcium and vitamin D

Answer 59

- Mechanism of action = Calcium is essential for normal function of muscle, nerves, bone, and clotting. Calcium homeostasis is controlled mainly by parathyroid hormone and vitamin D, which elevate serum calcium levels by increasing its intestinal absorption and renal reabsorption, and promote bone resorption. In osteoporosis there is a loss of bone mass, which increases the risk of fracture. Restoring positive calcium balance, either by dietary means or with calcium and vitamin D supplements, may reduce the rate of bone loss; whether this prevents fractures is less clear. In severe CKD, impaired phosphate excretion and reduced activation of vitamin D cause hyperphosphataemia and hypocalcaemia. This stimulates secondary hyperparathyroidism, which leads to a range of bone changes called renal osteodystrophy. Treatment may include oral calcium to bind phosphate in the gut, and alfacalcidol to provide vitamin D that does not depend on renal activation. In hyperkalaemia, calcium raises the myocardial threshold potential, reducing excitability and the risk of arrhythmias (it has no potassium-lowering effect). The rationale for giving calcium in hypocalcaemia and vitamin D in vitamin D deficiency is self-explanatory. - Main indications = 1) Calcium and vitamin D are used in osteoporosis to ensure positive calcium balance when dietary intake and/or sunlight exposure are insufficient. Other treatments, such as bisphosphonates, may be given to reduce the risk of fragility fractures. 2) Calcium and vitamin D are used in chronic kidney disease (CKD) to treat and prevent secondary hyperparathyroidism and renal osteodystrophy. 3) Calcium (usually as calcium gluconate) is used in severe hyperkalaemia to prevent life-threatening arrhythmias. Other treatments, e.g. insulin with glucose, are given to lower the potassium concentration. 4) Calcium is used in hypocalcaemia that is symptomatic (e.g. paraesthesia, tetany, seizures) or severe (<1.9 mmol/L). 5) Vitamin D is used in the prevention and treatment of vitamin D deficiency, including rickets (in children) and osteomalacia (adults). - Contraindications = Calcium and vitamin D should be avoided in ✖ hypercalcaemia. - Route of admin = Oral calcium preparations should usually be chewed then swallowed. Doses should be separated from potentially interacting medicines by about 4 hours. They may also interact with certain foods, including spinach, bananas, and whole cereals; about 2 hours’ separation is required if these have been consumed. Calcium gluconate should be administered by slow IV injection over 5–10 minutes into a large vein. Make sure the cannula is working by first flushing it with sodium chloride 0.9%, to avoid accidental subcutaneous administration (‘extravasation’). - Adverse effects = Oral calcium is usually well tolerated, but may cause dyspepsia and constipation. When administered IV for the treatment of hyperkalaemia, calcium gluconate can cause hypotension if administered too fast, and local tissue damage if accidentally given into subcutaneous tissue. - Examples = colecalciferol, alfacalcidol, calcium carbonate, calcium gluconate

Question 60

Cephalosporins and carbapenems

Answer 60

- Mechanism of action = Cephalosporins and carbapenems are derived from naturally occurring antimicrobials produced by fungi and bacteria. Like penicillins, their bactericidal effect is due to their β-lactam ring. During bacterial cell growth, cephalosporins and carbapenems inhibit enzymes responsible for cross-linking peptidoglycans in bacterial cell walls. This weakens cell walls, preventing them from maintaining an osmotic gradient, resulting in bacterial cell swelling, lysis, and death. Cephalosporins and carbapenems have a broad spectrum of activity. For cephalosporins, structural modification has led to successive ‘generations’ (first to fifth), with increasing activity against Gram-negative bacteria including Pseudomonas aeruginosa and variable activity against Gram-positive bacteria including Staphylococcus aureus. Cephalosporins and carbapenems are naturally more resistant to β-lactamases than penicillins, due to fusion of the β-lactam ring with a dihydrothiazine ring (cephalosporins) or a unique hydroxyethyl side chain (carbapenems). - Main indications = 1) Oral cephalosporins are second- and third-line options for treatment of urinary tract infections, pneumonia, and other respiratory tract infections (e.g. epiglottitis). 2) Parenteral cephalosporins and carbapenems are reserved for infections that are very severe or complicated, or caused by antibiotic-resistant organisms. - Contraindications = Cephalosporins and carbapenems should be used with caution in people ▲ at risk of C. difficile infection, particularly older people and those in hospital. The main contraindication is ✖ allergy to a β-lactam antibiotic, particularly if the history is suggestive of ✖ immediate-type hypersensitivity. Dose reduction is required in ▲ renal impairment. - Route of admin = Cephalosporins can be administered orally, as tablets, capsules or oral suspension, or by injection, which can be IV, as bolus injection or infusion or IM. Carbapenems can be administered as IV injection or infusion. Ertapenem is a carbapenem that is administered once daily. This facilitates administration of IV antibiotic therapy outside hospital, to allow prolonged treatment to be continued at home. - Adverse effects = GI upset (e.g. nausea, diarrhoea) is common. Less frequently, disturbance of normal gut flora allows overgrowth of toxin-producing Clostridioides difficile, producing antibiotic-associated colitis. This can be complicated by perforation and death. Immediate- and delayed-type hypersensitivity reactions may occur (see Penicillins, broad-spectrum). And as cephalosporins, carbapenems, and penicillins are structurally similar, there is a risk of cross-reactivity in ‘true’ allergy. This is not a concern for mild, non-allergic reactions (e.g. GI upset). Rarely, in parenteral therapy, cephalosporins and carbapenems can cause seizures. - Examples = cefuroxime, ceftriaxone, cefalexin, meropenem, ertapenem

Question 61

Chloramphenicol

Answer 61

- Mechanism of action = Chloramphenicol binds to bacterial ribosomes, inhibiting protein synthesis. It is thus bacteriostatic (stopping bacterial growth), which helps the immune system to clear microorganisms. In high concentrations and with highly susceptible organisms it can be bactericidal (killing). The most common mechanism of bacterial resistance to chloramphenicol is production of acetyltransferase enzymes that directly inactivate the drug. Other mechanisms include target modification, decreased membrane permeability, and increased expression of efflux pumps. Bacteria share antibiotic resistance genes by ‘horizontal transfer’ in plasmids. Many bacteria remain sensitive to chloramphenicol, probably due to its restricted use over recent decades. Chloramphenicol has a broad spectrum of activity against many Gram-positive, Gram-negative, aerobic, and anaerobic organisms. - Main indications = 1) Bacterial conjunctivitis using eye drops or ointment. 2) Chloramphenicol as ear drops can be used to treat otitis externa, but is considered less suitable than alternative antibiotics. Systemic (oral or IV) chloramphenicol is rarely used due to toxicity. In the UK, it is restricted to the treatment of life-threatening infection, and only where other, safer antibiotic classes cannot be used due to allergy or bacterial resistance. This may include occasional cases of epiglottitis (Haemophilus influenzae) and typhoid fever (Salmonella spp.). - Contraindications = Chloramphenicol is contraindicated in people with previous ✖ hypersensitivity reactions or a personal or family history of ✖ bone marrow disorders. Systemic chloramphenicol is contraindicated in the ✖ third trimester of pregnancy, ✖ breastfeeding, and ✖ children <2 years because of the risk of grey baby syndrome. Topical preparations should also be avoided in these groups unless essential. Chloramphenicol is metabolised by the liver, so dose adjustment and monitoring are required in ▲ hepatic impairment when used systemically. - Route of admin = Eye drops (optic) and ear drops (otic) are formulated differently. Ear drops should not be put into the eye, where they can cause injury with burning, stinging and blurred vision. - Adverse effects = The most common adverse effects of topical administration are transient stinging, burning, and itching. Systemic administration, which is unusual in high-income countries, carries a significant risk of bone marrow toxicity. Dose-related bone marrow suppression is more likely with high-dose therapy, or when the drug accumulates due to impaired metabolism. It occurs during treatment and improves on withdrawal. Aplastic anaemia is a rare, idiosyncratic reaction to systemic therapy. It has an unpredictable relationship with dose and may be delayed. Grey baby syndrome is circulatory collapse occurring in exposed neonates, who are unable to metabolise and excrete the drug. Optic and peripheral neuritis may occur with prolonged use.

Question 62

Clindamycin

Answer 62

- Mechanism of action = Clindamycin has a similar mechanism of action to macrolides and chloramphenicol, in that it binds to bacterial ribosomes and inhibits the early stages of bacterial protein synthesis. It is mainly bacteriostatic—inhibiting bacterial growth—thus facilitating clearance of microorganisms by the immune system. Bacteria resist the actions of clindamycin by modifying target proteins, reducing binding affinity. Clindamycin is active against Gram-positive aerobes (staphylococcus and streptococcus), explaining its clinical utility in skin, bone, and joint infections; and against a wide range of anaerobes, explaining its utility in intraabdominal sepsis and bacterial vaginosis. - Main indications = 1) As topical treatment to the skin for acne vulgaris and by vaginal administration for bacterial vaginosis. 2) Orally or parenterally for the treatment of moderate-to-severe infections including cellulitis, osteomyelitis, septic arthritis, and intraabdominal infection. Usually second- or third-line treatment, given in combination with other antibiotics. 3) For treatment of Plasmodium falciparum malaria, with quinine. - Contraindications = Clindamycin should not be prescribed if there is a history of ✖ clindamycin hypersensitivity. It is a useful option where penicillin is contraindicated by allergy, as there is no cross-sensitivity between these drug classes. It should be used with caution in ▲ inflammatory bowel disease. Clindamycin should be avoided in ✖ acute porphyria unless needed for a serious or life-threatening infection. - Route of admin = Topical clindamycin is available as a cream for skin or vaginal (PV) application, or as a gel for the skin only. Oral clindamycin is formulated as capsules. Parenteral clindamycin can be given IM or IV. As there have been rare reports of cardiorespiratory arrest with rapid IV administration, clindamycin must be diluted in 5% glucose or 0.9% sodium chloride and infused over 10–60 minutes. - Adverse effects = Clindamycin is generally well tolerated, but side effects, including diarrhoea, abdominal pain, skin rash, and abnormal liver enzyme levels occur in between 1-in-10 and 1-in-100 people. Antibiotic-associated colitis (see Penicillins, broad-spectrum) occurs more frequently with clindamycin than other antibiotics. You should have a high index of suspicion for Clostridioides difficile colitis if diarrhoea occurs. Consider sending a stool sample to test for C. difficile toxin and change or stop the antibiotic if appropriate. GI side effects are much rarer with topical application but may still occur. Other rare, but severe, adverse reactions to clindamycin include blood dyscrasias (e.g. neutropenia) and severe cutaneous adverse reactions, such as Stevens–Johnson syndrome (SJS) and drug reaction with eosinophilia and systemic symptoms (DRESS).

Question 63

Corticosteroids, inhaled

Answer 63

- Mechanism of action = Corticosteroids pass through the plasma membrane and interact with receptors in the cytoplasm. The activated receptor then passes into the nucleus to modify transcription of a large number of genes. Pro-inflammatory interleukins, cytokines, and chemokines are downregulated, while antiinflammatory proteins are upregulated. In the airways, this reduces mucosal inflammation, widens the airways, and reduces mucus secretion. This improves symptoms and reduces exacerbations in asthma and COPD. - Main indications = 1) Asthma: to treat airway inflammation and control symptoms where occasional use of a short-acting β2-agonist is insufficient. 2) Chronic obstructive pulmonary disease (COPD): to control symptoms and prevent exacerbations. Place in therapy depends on whether there are features suggesting the disease is likely to be responsive to steroids (e.g. atopy, higher blood eosinophils, variable airflow obstruction). In COPD with features of asthma or steroid responsiveness, an inhaled corticosteroid (ICS), with a long-acting β2-agonist (LABA), is recommended for first-line regular therapy (i.e. if a short-acting bronchodilator is insufficient). In COPD without features of asthma or steroid responsiveness, an ICS is recommended for second-line regular therapy (i.e. if regular treatment with a long-acting β2-agonist and long-acting antimuscarinic (LAMA) is insufficient). - Contraindications = High-dose inhaled corticosteroids, particularly fluticasone, should be used with caution in people with COPD who have a ▲ history of pneumonia, and in ▲ children due to the risk of growth retardation. - Route of admin = Using a spacer with MDIs can improve airway deposition and treatment efficacy and reduce oral adverse effects. - Adverse effects = The main adverse effects of inhaled corticosteroids are in the respiratory tract, including changes in taste sensation and voice, and oral candidiasis (thrush infection). In people with COPD, inhaled corticosteroids cause a dose-dependent increase in the risk of pneumonia. Systemic absorption can occur, particularly at high doses and with prolonged administration, causing adverse effects seen with systemic corticosteroids, including adrenal suppression, osteoporosis, and, in children, growth retardation. Inhalation of corticosteroids uncommonly triggers paradoxical bronchospasm, with an immediate increase in wheezing after taking treatment. This can often be prevented by taking a short-acting bronchodilator before the inhaled corticosteroid. - Examples = beclometasone, fluticasone, budesonide

Question 64

Corticosteroids, nasal

Answer 64

- Mechanism of action = Corticosteroids have antiinflammatory effects and cause vasoconstriction. In rhinitis, this reduces mucosal inflammation, oedema, and secretions and improves symptoms. The diverse actions of corticosteroids are also responsible for their adverse effects, with immunosuppressive effects increasing the risk of infection and anti-mitotic effects reducing healing after nasal surgery. Where systemic absorption occurs, metabolic effects and adrenal suppression may be evident (see ADVERSE EFFECTS and Corticosteroids, systemic). - Main indications = 1) Prevention and treatment of seasonal or perennial allergic rhinitis where symptoms are moderate to severe, or treatment with antihistamines is insufficient. 2) As first-line treatment to shrink nasal polyps. - Contraindications = Nasal corticosteroids should be used with caution if there is ▲ co-existing nasal infection, which should be treated first. People with ▲ nasal trauma or surgery should not use nasal corticosteroids until healing has occurred. Nasal corticosteroids should be avoided in ▲ pulmonary tuberculosis. - Route of admin = Before administration, they should gently blow their nose, shake the spray well, and remove the cap. They should sit upright and tilt their head forwards slightly. They should take the spray in the opposite hand to the nostril they intend to treat and insert the nozzle into the nostril, pointing away from the nasal septum back towards their ear. As they press the button to release the spray they should breathe in gently through their nose, then take the nozzle out and breathe through their mouth. This is repeated for a second spray in the same nostril if required and, after swapping hands, in the other nostril. - Adverse effects = Nasal corticosteroids commonly (1%–10%) cause local adverse effects such as nasal irritation, epistaxis, pharyngitis and change in sense of taste and smell. Headache is also common. Ocular adverse effects, which are rare, include glaucoma, cataracts, and central serous retinopathy. People who report blurred or abnormal vision may require ophthalmological review. Around 70% of the dose administered in the nose is swallowed, and some of this may be absorbed. In high-dose treatment for prolonged periods, this may rarely lead to adrenal suppression and, in children, growth retardation. Systemic adverse effects are less common with mometasone and fluticasone than with beclometasone. This is because the proportion of the dose that enters the circulation in an active form (bioavailability) is less than 1% for mometasone and fluticasone, due to extensive first-pass metabolism in the liver by cytochrome P450 (CYP) 3A4 enzymes. The bioavailability of beclomethasone is much higher (about 40%). - Examples = beclometasone, mometasone, fluticasone

Question 65

Dipeptidylpeptidase-4 inhibitors

Answer 65

- Mechanism of action = The incretins (glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP)) are released by the intestine throughout the day, but particularly in response to food. They promote insulin secretion and suppress glucagon release, lowering blood glucose. Incretins are rapidly inactivated by hydrolysis by the enzyme DPP-4. DPP-4 inhibitors (‘gliptins’) therefore lower blood glucose by preventing incretin degradation and increasing plasma concentrations of their active forms. The actions of the incretins are glucose dependent, occurring when blood glucose is elevated, so they do not stimulate insulin secretion at normal blood glucose concentrations or suppress glucagon release in response to hypoglycaemia. This means that DPP-4 inhibitors are less likely to cause hypoglycaemia than sulphonylureas, which stimulate insulin secretion irrespective of blood glucose. - Main indications = In type 2 diabetes, dipeptidylpeptidase-4 (DPP-4) inhibitors are options for combination therapy with metformin (and/or other antihyperglycaemic agents) if blood glucose is not adequately controlled, or as monotherapy if metformin is contraindicated or not tolerated. - Contraindications = DPP-4 inhibitors are contraindicated in people with a history of ✖ hypersensitivity to the drug class and should not be used in the treatment of ✖ type 1 diabetes or ✖ ketoacidosis. As there is animal evidence of reproductive toxicity and insufficient human data to ascertain safety, they should not be used during ✖ pregnancy or ✖ breastfeeding. They should be used with caution in ▲ older people (>80 years) and those with a ▲ history of pancreatitis. Many of the DPP-4 inhibitors are renally excreted, so a dose reduction may be required in ▲ moderate-to-severe renal impairment and some (e.g. saxagliptin) should be avoided in ▲ hepatic impairment. - Route of admin = DPP-4 inhibitors are formulated as tablets. They may be taken with or without food. - Adverse effects = DPP-4 inhibitors are generally well tolerated. Common side effects are GI upset, headache, nasopharyngitis, and peripheral oedema. Hypoglycaemia can occur, particularly where DPP-4 inhibitors are prescribed in combination with other drugs that cause hypoglycaemia, such as sulphonylureas or insulin. All the DPP-4 inhibitors are associated with a small risk of acute pancreatitis, affecting 0.1%–1% of people taking the drugs. This should be suspected if there is persistent abdominal pain and usually resolves on stopping the drug. - Examples = sitagliptin, linagliptin, alogliptin

Question 66

Dopaminergic drugs for Parkinson’s disease

Answer 66

- Mechanism of action = In Parkinson’s disease, there is a deficiency of dopamine in the nigrostriatal pathway that links the substantia nigra in the midbrain to the corpus striatum in the basal ganglia. Via direct and indirect circuits, this causes the basal ganglia to exert greater inhibitory effects on the thalamus which, in turn, reduces excitatory input to the motor cortex. This generates the features of Parkinson’s disease, such as bradykinesia and rigidity. Treatment seeks to increase dopaminergic stimulation to the striatum. It is not possible to give dopamine itself because it does not cross the blood–brain barrier. By contrast, levodopa (L-dopa) is a precursor of dopamine that can enter the brain via a membrane transporter. Ropinirole and pramipexol are relatively selective agonists for the D2 receptor, which predominates in the striatum. - Main indications = 1) To improve motor symptoms in Parkinson’s disease. Levodopa is preferred if motor symptoms are impacting quality of life. Dopamine agonists (e.g. ropinirole, pramipexol) are options for milder symptoms, or as add-on treatment in advanced disease. 2) Levodopa and dopamine agonists are options for secondary parkinsonism (parkinsonian symptoms due to a cause other than idiopathic Parkinson’s disease), but addressing the underlying cause (e.g. discontinuation of an offending drug) generally takes precedence. - Contraindications = Dopaminergic drugs should be used cautiously in ▲ older people and in those with existing ▲ cognitive or psychiatric disease, due to the risk of causing confusion and hallucinations. Caution is also required in ▲ cardiovascular disease, because of the risk of hypotension. - Route of admin = It is very important with levodopa that doses are taken at times that produce the best symptom control. This is especially important to note in people admitted to hospital. - Adverse effects = All dopaminergic drugs can cause nausea and hypotension. They can also cause sleepiness, confusion, and hallucinations, which are more common with dopamine agonists than levodopa. Conversely, excessive and involuntary movements (dyskinesias) are more problematic with levodopa. A particular problem with levodopa is the wearing-off effect, where symptoms worsen towards the end of the dosage interval. This tends to worsen in more advanced disease. It can be overcome to an extent by increasing the dose or frequency, but this can exacerbate dyskinesias early in the dosage interval. When these occur together, this is called the on–off effect. Modified-release formulations may improve control by providing a more continuous supply of dopamine. - Examples = levodopa (as co-careldopa, co-beneldopa), ropinirole, pramipexol

Question 67

Emollients

Answer 67

- Mechanism of action = Emollients help to replace water content in dry skin. They contain oils or paraffin-based products that help to soften the skin and can reduce water loss by protecting against evaporation from the skin surface. Many preparations can be used as a soap substitute, as soap is drying to the skin. Bath or shower emollient preparations are also available. - Main indications = As a topical treatment for all dry or scaling skin disorders. Specifically, emollients are used alone or in combination with topical corticosteroids in the treatment of eczema. They can reduce skin dryness and cracking in psoriasis, where, depending on severity, they are used alone or in combination with other therapies. - Contraindications = While these drugs are usually very safe to use, paraffin-based emollients are a significant fire hazard. The risk is proportional to the paraffin content (highest if >50%), but exists for all emollient products. Emollients also make the skin slippery, which may be a particular hazard when bathing children. - Route of admin = Apply emollients in the direction of hair growth to reduce the risk of folliculitis. - Adverse effects = Emollients have few adverse effects. The main tolerability issue is that they cause greasiness of the skin, but this is integral to their therapeutic effect. Emollient ointments can exacerbate acne vulgaris and folliculitis by blocking pores and hair follicles. - Examples = aqueous cream, liquid paraffin

Question 68

Gabapentinoids

Answer 68

- Mechanism of action = From a structural point of view, gabapentin and pregabalin (collectively ‘gabapentinoids’) are related to γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain. However, they do not bind with GABA receptors and their mechanism of action, although not completely understood, seems to be mediated through inhibition of pre-synaptic voltage-gated calcium (Ca2+) channels in the neocortex and hippocampus. This reduces Ca2+ entry into neurons, and thereby inhibits release of excitatory neurotransmitters such as glutamate. The resulting reduction of neuronal excitability in the brain probably explains the drugs’ anticonvulsant effects. These central effects, along with similar effects in peripheral nerves, may also explain the mechanism by which they reduce neuropathic pain. - Main indications = 1) Gabapentin and pregabalin are first-line options in neuropathic pain, including painful diabetic neuropathy (carbamazepine is preferred in trigeminal neuralgia). 2) Gabapentin and pregabalin are licensed for the prevention of focal seizures (with or without secondary generalisation) in epilepsy, although other options, such as lamotrigine and levetiracetam are preferred. 3) Pregabalin is an option for generalised anxiety disorder. - Contraindications = Both drugs depend on the kidneys for their elimination, so their doses should be reduced in ▲ renal impairment. Careful assessment is required to identify risk factors for ▲ substance misuse. - Route of admin = There are no special considerations with regard to the oral administration of gabapentin and pregabalin. - Adverse effects = Gabapentinoids are generally better tolerated than older antiepileptic drugs. However, side effects can still be problematic, particularly during treatment initiation. These include drowsiness, impaired concentration, dizziness, and ataxia. Weight gain is also reported with both drugs. Increasingly, they are recognised as drugs of misuse and dependency, presumably for their dissociative effects and relaxation. - Examples = pregabalin, gabapentin

Question 69

Glycopeptide antibiotics

Answer 69

- Mechanism of action = Glycopeptide antibiotics inhibit growth and cross-linking of peptidoglycan chains. This inhibits synthesis of the cell wall in Gram-positive bacteria, causing cell lysis (bactericidal). They are inactive against most Gram-negative bacteria, which have a different (lipopolysaccharide) cell wall structure. Acquired resistance to glycopeptide antibiotics is increasingly reported. One mechanism is bacterial modification of cell wall structure to prevent antibiotic binding. Glycopeptide antibiotics have a relatively narrow spectrum of activity against Gram-positive bacteria, notably Staphylococcus spp. (including MRSA), Streptococcus spp., and C. difficile. They are inactive against Gram-negative organisms. - Main indications = 1) Treatment of complicated skin and soft tissue, bone and joint infections; infective endocarditis; and other infections caused by Gram-positive organisms where infection is severe and/or penicillins cannot be used due to allergy or resistance (e.g. methicillin-resistant Staphylococcus aureus (MRSA)). 2) Vancomycin is a first-line treatment for Clostridioides difficile colitis. - Contraindications = Glycopeptide antibiotics should be used with caution in people with ▲ immune-mediated hypersensitivity (there is cross-sensitivity between vancomycin and teicoplanin) and those with ▲ hearing impairment, who are at increased risk of ototoxicity. People with ▲ reduced renal function, including ▲ neonates and ▲ older adults, are at increased risk of nephrotoxicity. Glycopeptide antibiotics are renally excreted and may accumulate in renal impairment. Dose adjustment based on plasma drug concentration monitoring is important to reduce toxicity. - Route of admin = When given by intermittent or continuous IV infusion, glycopeptide antibiotics should be diluted to ≤5 mg/mL in glucose 5% or sodium chloride 0.9%. This is particularly important for vancomycin, which should be given no faster than 10 mg/min, and over at least 60 minutes, to reduce the risk of flushing syndrome. Vancomycin should not be given IM because of the risk of muscle necrosis, though teicoplanin can be given by this route. Oral vancomycin is formulated as capsules. - Adverse effects = Pain and thrombophlebitis from vancomycin infusion are common. Rapid infusion of vancomycin (and, less often, teicoplanin) may cause vancomycin flushing syndrome (‘red man syndrome’) due to direct, non-immune release of histamine. This presents with a pruritic erythematous rash over the upper body, occasionally with hypotension. True immune-mediated allergy to glycopeptide antibiotics, including immediate and delayed hypersensitivity (see Penicillins, broad-spectrum), may also occur. Glycopeptide antibiotics cause nephrotoxicity and ototoxicity, which is more common at higher doses. Rarely, idiosyncratic reactions may occur, including blood dyscrasias (neutropenia, thrombocytopenia) and severe cutaneous adverse reactions. - Examples = vancomycin, teicoplanin

Question 70

H2-receptor antagonists

Answer 70

- Mechanism of action = Histamine H2-receptor antagonists (‘H2-blockers’) reduce gastric acid secretion. Acid is normally produced by the proton pump of the gastric parietal cell, which secretes H+ into the stomach lumen in exchange for drawing K+ into the cell. The proton pump is regulated by, among other things, histamine. Histamine is released by local paracrine cells and binds to H2-receptors on the gastric parietal cell. Via a second-messenger system, this activates the proton pump. Blocking H2-receptors therefore reduces acid secretion. However, as the proton pump can also be stimulated by other pathways, H2-blockers cannot completely suppress gastric acid production. In this respect they differ from PPIs, which tend to have a more complete acid-suppressive effect. Because of this, PPIs are the preferred first-line agents, and H2-blockers are reserved for cases in which PPIs are not tolerated or symptoms persist despite PPI therapy. - Main indications = 1) Peptic ulcer disease: as a second-line option for treatment and prevention of gastric and duodenal ulcers (including NSAID-associated ulcers), where proton pump inhibitor (PPI) therapy alone is inadequate or not tolerated. 2) Gastro-oesophageal reflux disease (GORD) and dyspepsia: as a second-line option for relief of symptoms, where proton pump inhibitor (PPI) therapy alone is inadequate or not tolerated. - Contraindications = H2-blockers are excreted by the kidneys, so their dose should be reduced in renal impairment. Like PPIs, they can disguise the symptoms of gastro-oesophageal cancer or significant ulcer disease caused by H. pylori. So it is important not just to treat symptoms, but to consider and, as appropriate, investigate their cause. - Route of admin = Oral preparations can be taken before, with or after food. - Adverse effects = H2-blockers are generally well tolerated. Side effects are usually mild and include bowel disturbance (diarrhoea or, less often, constipation), headache, and dizziness. Ranitidine products have been found to contain low levels of an impurity called N-nitrosodimethylamine, a substance that could cause cancer. There is no evidence that ranitidine increases the risk of cancer, and any theoretical risk associated with the contaminant is likely to be very low. However, at the time of writing, all ranitidine formulations have been withdrawn from the market. Whether it returns will depend on the source of the impurity and whether it can be kept below acceptable levels. - Examples = ranitidine, cimetidine, famotidine

Question 71

Hormone antagonists and agonists used in breast and prostate cancer

Answer 71

- Mechanism of action = Approximately two-thirds of breast cancers express oestrogen receptors (ER-positive), which stimulate cell proliferation. Antagonising oestrogen therefore suppresses tumour growth in ER-positive cancers. Tamoxifen is a selective oestrogen receptor modulator, which acts to prevent oestrogen binding to its receptor. Anastrozole and letrozole are aromatase inhibitors. They interfere with synthesis of oestrogens outside the ovary (e.g. in fat and muscle) by inhibiting the conversion of androgens to oestrogens by aromatase. They are superior to tamoxifen in post-menopausal women, but ineffective in women with functioning ovaries because they have relatively little effect on ovarian oestrogen synthesis. By a similar mechanism, around 90-percent of prostate cancers will respond to hormone therapies that suppress androgens. Gonadotrophin-releasing hormone (GnRH, gonadorelin) analogues (e.g. goserelin, leuprorelin) initially over-stimulate production of luteinising hormone (LH) in the anterior pituitary, but GnRH receptors are then rapidly downregulated causing LH, and consequently androgens, to decrease to ‘medical castration’ levels. Androgen receptor inhibitors like bicalutamide directly block androgen receptors to prevent testosterone driven cancer cell growth. - Main indications = 1) Tamoxifen, anastrozole, and letrozole are used in estrogen (oestrogen)-receptor positive (ER-positive) breast cancer, as an adjuvant (after surgery) treatment option to reduce the risk of recurrent disease or to slow progression in advanced disease. 2) Leuprorelin, bicalutamide, and goserelin are used in prostate cancer, as systemic antiandrogen therapy for hormone sensitive tissue subtypes that cannot be resected. - Contraindications = Tamoxifen is contraindicated in ✖ pregnancy and ✖ breastfeeding. Aromatase inhibitors should not be used in ✖ pre-menopausal women unless ovarian function is suppressed or ablated (e.g. by oophorectomy). Initial overstimulation of LH production by goserelin and leuprorelin may stimulate tumour growth. This risks causing cord compression if there are spinal metastases. - Route of admin = Tamoxifen, bicalutamide, and aromatase inhibitors are formulated as tablets to be taken with water. It does not matter if they are taken with or without food. GnRH analogues may be formulated as implants or suspension for injection, to be administered from a pre-filled syringe by SC or IM injection. - Adverse effects = The most common adverse effects of tamoxifen and aromatase inhibitors are symptoms of oestrogen depletion (e.g. vaginal dryness, hot flushes, loss of bone density). Tamoxifen increases the risk of venous thromboembolism and endometrial cancer. Rarely, tamoxifen and aromatase inhibitors can cause agranulocytosis and liver failure. Antiandrogen therapy may lead to hair loss, gynaecomastia, and mood disturbance. Bicalutamide may cause photosensitivity. - Examples = letrozole, tamoxifen, anastrozole (breast cancer) bicalutamide, goserelin (prostate cancer)

Question 72

Insulin

Answer 72

- Mechanism of action = Exogenous insulin functions similarly to endogenous insulin. It stimulates glucose uptake and utilisation from the circulation into tissues, including skeletal muscle and fat. Insulin stimulates glycogen, lipid, and protein synthesis and inhibits gluconeogenesis and ketogenesis. The overall effect is to lower blood glucose concentration, and this is the primary measure of its therapeutic effect. Insulin also activates Na+/K+-ATPase, driving K+ into cells, and reducing serum K+ concentrations. However, once insulin treatment is stopped, K+ leaks back out of the cells into the circulation, so this is only a short-term measure while other treatment is commenced. The wide choice of insulin preparations for treatment of diabetes mellitus can be classified as rapid acting (immediate onset, short duration)—e.g. NovoRapid® (insulin aspart); short acting (early onset, short duration)—e.g. Actrapid® (soluble insulin); intermediate acting (intermediate onset and duration)—e.g. Humulin I® (isophane or NPH insulin); and long acting (flat profile with regular administration)—e.g. Lantus® (insulin glargine), Levemir® (insulin detemir), Tresiba® (insulin degludec). Biphasic insulin preparations contain a mixture of rapid- and intermediate-acting insulins, e.g. NovoMix® 30 (30% insulin aspart, 70% insulin aspart protamine). Where IV insulin is required (hyperkalaemia, diabetic emergencies, peri-operative glucose control), soluble insulin (Actrapid®) is used. To account for the different potencies of insulin preparations, they are dosed in units, which correspond to the glucose-lowering activity of a defined mass of an internationally approved ‘standard insulin’. - Main indications = 1) For insulin replacement in type 1 diabetes, and control of blood glucose in type 2 diabetes if oral antihyperglycaemic treatment is insufficient or poorly tolerated. 2) Given intravenously, in the treatment of diabetic emergencies such as diabetic ketoacidosis and hyperosmolar hyperglycaemic state, and for peri-operative glycaemic control in selected cases. 3) To treat hyperkalaemia, while other measures (such as treatment of the underlying cause) are initiated. For this indication, it must be given with IV glucose. - Contraindications = In ▲ renal impairment, insulin clearance is reduced, so there is an increased risk of hypoglycaemia. - Route of admin = SC insulin is usually administered using ‘pens’, on which the required dose can simply be ‘dialled up’. Alternatively, smart pumps monitor glucose continuously and automatically adjust insulin delivery. - Adverse effects = The main adverse effect of insulin is hypoglycaemia, which can be severe enough to cause coma and death. When administered by repeated SC injection at the same site, insulin can cause fat overgrowth (lipohypertrophy), which may be unsightly or uncomfortable. - Examples = insulin aspart, insulin glargine, biphasic insulin, soluble insulin

Question 73

Iron

Answer 73

- Mechanism of action = The aim of iron therapy is to replenish iron stores. Iron is essential for erythropoiesis (the formation of new red blood cells). It is required for the synthesis of the haem component of haemoglobin, which gives red blood cells the ability to carry oxygen. Iron is best absorbed in its ferrous state (Fe2+) in the duodenum and jejunum. Its absorption is increased by stomach acid and dietary acids such as ascorbic acid (vitamin C). Once absorbed into the blood stream, iron is bound by transferrin. Transferrin transports it either to be used in the bone marrow for erythropoiesis or to be stored as ferritin in the liver, reticuloendothelial system, bone marrow, spleen, and skeletal muscle. - Main indications = 1) Treatment of iron-deficiency anaemia. 2) Prophylaxis of iron-deficiency anaemia in people with risk factors such as a low-iron diet, malabsorption, menorrhagia, gastrectomy, haemodialysis, and infants with low birth weight. - Contraindications = Oral iron therapy may exacerbate bowel symptoms in ▲ intestinal disease, including inflammatory bowel disease, diverticular disease, and intestinal strictures. IV iron should be used with caution in people with an ▲ atopic predisposition due to the risk of anaphylactic reaction. - Route of admin = Although oral iron salts are better absorbed on an empty stomach, they can be taken with food to reduce GI side effects. IV iron can be given as an injection over 10 minutes or as an infusion. Facilities for the management of anaphylaxis should be available. - Adverse effects = The most common adverse effect of oral iron salts is GI upset, including nausea, epigastric pain, constipation, and diarrhoea. The stool may turn black. IV iron administration can cause injection site irritation and hypersensitivity reactions, including anaphylaxis. - Examples = ferrous sulfate, ferrous fumarate

Question 74

Lamotrigine

Answer 74

- Mechanism of action = The mechanism of action of lamotrigine is incompletely understood. Like carbamazepine and phenytoin, it binds to voltage-sensitive neuronal Na+ channels, producing use-dependent inhibition of Na+ influx into the neuron. This impedes repetitive neuronal firing, which is a characteristic of seizure activity. Additionally, lamotrigine reduces release of the excitatory neurotransmitter, glutamate. These effects, and others, likely explain its antiepileptic action. The mechanism by which it reduces depressive symptoms in bipolar disorder is uncertain. - Main indications = 1) Seizure prophylaxis in epilepsy. Specifically, lamotrigine is an option for first-line monotherapy or add-on therapy in focal seizures (with or without secondary generalisation) and generalised tonic–clonic seizures. 2) Bipolar depression, but not mania or hypomania. - Contraindications = Lamotrigine should be avoided if possible in people with a prior history of ▲ hypersensitivity to other antiepileptic drugs, due to the risk of cross-reactivity. Lamotrigine is metabolised by hepatic glucuronidation, so dosage reduction may be necessary in moderate or severe ▲ hepatic impairment. In general, there is no evidence that lamotrigine exposure in pregnancy increases the overall risk of congenital malformations, so it is a reasonable choice in women of childbearing age. During pregnancy, due to changes in lamotrigine metabolism, plasma concentration measurement should be considered to guide dosage adjustment. - Route of admin = Standard lamotrigine tablets should be swallowed whole with water. Chewable/dispersible tablets can be taken whole, chewed with a little water or dispersed with water. - Adverse effects = The most common adverse effects are headache, drowsiness, irritability, blurred vision, dizziness, and GI upset. A minority develop a skin rash within a few weeks of starting lamotrigine. This is usually mild, but requires urgent review and possibly discontinuation of the drug. This is because it may be the first sign of a severe hypersensitivity reaction. Although rare, this may be life threatening, and early discontinuation of the drug is essential (see Carbamazepine).

Question 75

Laxatives, oral

Answer 75

- Mechanism of action = Laxatives may be classified by their mechanism of action as either osmotic or stimulant laxatives. Osmotic laxatives are based on osmotically active substances (sugars or alcohols) that are not digested or absorbed, and which therefore remain in the gut lumen. For example, macrogol 3350 is a non-absorbable polymer of ethylene glycol; it may be formulated alone, or with electrolytes to counteract water, sodium, and potassium shifts. Osmotic laxatives hold water in the stool, maintaining its volume and stimulating peristalsis. Lactulose has a useful additional effect of reducing ammonia absorption by increasing gut transit rate and acidifying the stool. This latter effect inhibits the proliferation of ammonia-producing bacteria. This is helpful in liver failure, where ammonia plays a major role in encephalopathy. Stimulant laxatives (also known as irritant or contact laxatives) increase water and electrolyte secretion from the colonic mucosa, thereby increasing the volume of colonic content and stimulating peristalsis. They also have a direct pro-peristaltic action, although the exact mechanism differs between agents. For example, bacterial metabolism of senna in the intestine produces metabolites that have a direct action on the enteric nervous system, stimulating peristalsis. - Main indications = 1) Constipation 2) Bowel preparation prior to surgery or endoscopy (usually osmotic laxatives only). 3) Hepatic encephalopathy (lactulose only, to reduce ammonia absorption). - Suppositories and enemas (see Laxatives, rectal) are alternatives in most indications, and may be used in conjunction with orally administered drugs. - Contraindications = Laxatives are contraindicated in ✖ intestinal obstruction as there is a risk of perforation. - Route of admin = Laxatives may be taken with or without food. Oral solutions can be taken as they are or diluted in another liquid; powdered forms are dissolved in water. Macrogols must not be administered with feeds that contain a starch-based thickener. - Adverse effects = Flatulence, abdominal cramps, diarrhoea, and nausea are common adverse effects. With prolonged use, some stimulant laxatives cause melanosis coli (reversible pigmentation of the intestinal wall). - Examples = macrogol 3350, lactulose (osmotic laxatives) senna, docusate sodium (stimulant laxatives)

Question 76

Laxatives, rectal

Answer 76

- Mechanism of action = Glycerol is an osmotic laxative. Administered as a suppository (a medicine in solid form, inserted through the anus), it creates a significant osmotic gradient that draws water and electrolytes into the faeces. This increases its volume and stimulates peristalsis that leads to bowel opening. It also has lubricant and faecal softening effects, and a mild irritant effect on the rectal mucosa. The latter augments the stimulus for peristalsis. Sodium acid phosphate with sodium phosphate (more commonly referred to as ‘phosphates enema’) and sodium citrate are also osmotic laxatives that are administered rectally as enemas (a medicine in liquid form, injected through the anus). By virtue of the volume and liquid form of enemas, their effect is generally more pronounced than suppositories. Arachis oil is a peanut derivative that directly softens and lubricates the stool. - Main indications = 1) Constipation and faecal impaction. 2) Bowel preparation prior to surgery or endoscopy. 3) Hepatic encephalopathy as an adjunct to lactulose, where this alone does not provide sufficiently frequent bowel movements. Oral laxatives are alternatives in most indications and may be used in conjunction with rectally administered drugs. - Contraindications = Phosphates enemas can cause significant fluid shifts, so should be used with caution in ▲ heart failure, ▲ ascites and when ▲ electrolyte disturbances are present. Arachis oil should not be used when there is a history of ✖ peanut or ▲ soya allergy. - Route of admin = Suppositories may be self-administered if the person is able to. They should be advised to lie on their non-dominant side and, using their dominant hand, insert the bullet-shaped suppository (pointed end first) through their anus, pushing it as far in as possible. Wetting the suppository first with cold water can aid insertion. Ideally, it should be pushed against the wall of the bowel. They should then try to retain the drug for the first 15–30 minutes, if possible (i.e. initially resisting the urge to go to the toilet), to maximise the effect. The procedure is similar for enemas, but involves squeezing a liquid from a bottle or syringe. The precise details vary by preparation. - Adverse effects = Flatulence and abdominal cramps are common adverse effects. As with other laxatives, diarrhoea is a possible complication. Enemas in particular can be uncomfortable because of the relatively large volume that must be instilled into the rectum (>100 mL). Phosphates enemas can cause pain, volume depletion (leading to hypotension), and electrolyte disturbances, including hyperphosphataemia and hyper- or hypokalaemia. - Examples = glycerol, sodium citrate, phosphates

Question 77

Leukotriene receptor antagonists

Answer 77

- Mechanism of action = In asthma, leukotrienes produced by mast cells and eosinophils (among other sources) activate the G protein-coupled leukotriene receptor CysLT1. This activates a cascade of pathways that result in inflammation and bronchoconstriction, which contribute to the pathophysiology of asthma. Leukotriene receptor agonists reduce inflammation and bronchoconstriction in asthma by blocking the CysLT1 receptor and damping down the inflammatory cascade. - Main indications = 1) Initial add-on therapy for chronic asthma, where symptoms are not adequately controlled by a short-acting β2 agonist and a low-dose inhaled corticosteroids (see CLINICAL TIP). 2) A treatment option for allergic rhinitis in those who also have asthma, where nasal symptoms have not responded to usual treatments such as antihistamines and/or intranasal corticosteroids - Contraindications = The safety of leukotriene receptor antagonists in ▲ pregnancy is uncertain because of a lack of evidence, although no harmful effects have been demonstrated. However, as poorly controlled asthma is also a risk during pregnancy, it is considered reasonable to continue leukotriene receptor antagonists where they have led to significant improvement in asthma symptoms not achieved with other therapies. - Route of admin = Montelukast is available in tablet, chewable tablet, and granule form for oral administration. Standard tablets can be taken with or without food, but the chewable tablets must be taken 1 hour before or 2 hours after food on an empty stomach. Granules may be easier for younger children to manage and can be administered directly or mixed with a spoonful of cold or room temperature soft food. - Adverse effects = Leukotriene receptor antagonists are generally well tolerated. Headache, abdominal pain, and GI upset are the most common adverse effects, but they are usually mild. They also increase the risk of upper respiratory tract infections. Neuropsychiatric reactions, including sleep disturbance, depression, and agitation occur in up to 1 in 100 of those taking montelukast. Rarely, disturbances of attention or memory and, very rarely, hallucinations and suicidal behaviour may occur. Churg–Strauss syndrome, an eosinophilic autoimmune disorder, has been seen in association with leukotriene receptor antagonists. However, there is no conclusive evidence that it is an adverse effect of the drug. - Examples = montelukast, zafirlukast

Question 78

Levetiracetam and brivaracetam

Answer 78

- Mechanism of action = The molecular target of levetiracetam is synaptic vesicle protein 2A (SV2A). SV2A is expressed throughout the brain, in both excitatory and inhibitory synapses, as a glycoprotein located within the membranes of synaptic vesicles. Synaptic vesicles are where neurotransmitters are stored in the pre-synaptic nerve terminal. During depolarisation, synaptic vesicles fuse with the pre-synaptic membrane to release neurotransmitters into the synaptic cleft. Through its effects on synaptic vesicle function, levetiracetam modulates release of neurotransmitters. This inhibits synchronised epileptiform burst firing and reduces propagation of seizure activity. Brivaracetam has a similar action, supplemented with additional activity on voltage-gated Na+ channels. - Main indications = 1) Seizure prophylaxis in epilepsy. Levetiracetam is recommended for both generalised tonic-clonic seizures and focal seizures. It can be used as first-line monotherapy, or as an add-on treatment. Lamotrigine and sodium valproate (for generalised seizures in boys/men) are alternatives. 2) Levetiracetam is increasingly the preferred option for treating established convulsive status epilepticus, following inadequate response to a benzodiazepine. Alternatives are phenytoin and sodium valproate. - Contraindications = Levetiracetam is eliminated by the kidneys, so dosage reduction may be required in ▲ renal impairment. In contrast, brivaracetam is metabolised in the liver, so caution is required in ▲ hepatic impairment. There is no evidence that levetiracetam increases the overall risk of birth defects when taken during pregnancy, although it is difficult to exclude effects on specific congenital defects. Little data is available on the safety of brivaracetam in pregnancy. - Route of admin = Tablets should ideally be swallowed whole. They should not be chewed. If necessary to facilitate administration (e.g. in children), they may be crushed and taken with food. IV doses are usually given by infusion over 15 minutes. - Adverse effects = Levetiracetam and brivaracetam have similar adverse effect profiles. In contrast to many other antiepileptic drugs, they are generally well tolerated. Most have only mild adverse effects, or none at all. Drowsiness (affecting about 10%), weakness, dizziness, and headache are the most common adverse effects. Mood disturbance and psychiatric adverse effects are less common (about 5% and 2.5%, respectively), but more likely to cause discontinuation. Suicidal ideation and serious hypersensitivity reactions have been reported rarely. - Examples = levetiracetam, brivaracetam

Question 79

Macrolides

Answer 79

- Mechanism of action = Macrolides inhibit bacterial protein synthesis. They bind to the 50S subunit of the bacterial ribosome and block translocation, a process required for elongation of the polypeptide chain. Inhibition of protein synthesis is bacteriostatic (stops bacterial growth), which assists the immune system in killing and removing bacteria from the body. Bacterial resistance to macrolides is common, mainly due to ribosomal mutations preventing macrolide binding. Erythromycin was isolated from Streptomyces erythraeus in the 1950s. It has a relatively broad spectrum of activity against Gram-positive and some Gram-negative organisms. Synthetic macrolides (e.g. clarithromycin and azithromycin) have increased activity against Gram-negative bacteria, particularly Haemophilus influenzae. - Main indications = 1) Treatment of respiratory, skin and soft tissue infections as an alternative to a penicillin if this is contraindicated (e.g. allergy). 2) In severe pneumonia, added to a penicillin to cover atypical organisms including Legionella pneumophila and Mycoplasma pneumoniae. 3) Eradication of Helicobacter pylori (e.g. causing peptic ulcer disease) in combination with a proton pump inhibitor and either amoxicillin or metronidazole. - Contraindications = Macrolides should not be prescribed if there is a history of ✖ macrolide hypersensitivity, although they are a useful option where penicillin is contraindicated by allergy, as there is no risk of cross-sensitivity. Macrolide elimination is mostly hepatic, with a small renal contribution. Caution is therefore required in ▲ severe hepatic impairment, and doses should be reduced in ▲ severe renal impairment. - Route of admin = Macrolides can be taken as tablets or oral suspension with or without food (although food may improve GI tolerability). IV macrolides are irritant, so should be diluted in a large volume, e.g. 500 mg in 250 mL sodium chloride 0.9%, before infusion into a large proximal vein and must not be given as IV bolus or IM. The duration of infusion should be at least 60 minutes to reduce the risk of arrhythmias. - Adverse effects = Adverse effects are most common and severe with erythromycin but can occur with any macrolide. Macrolides are irritant, causing nausea, vomiting, abdominal pain, and diarrhoea when taken orally, and thrombophlebitis when given IV. Other important side effects include allergy, antibiotic-associated colitis (see Penicillins, broad-spectrum), cholestatic hepatitis, prolongation of the QT interval (predisposing to arrhythmias) and ototoxicity at high doses. - Examples = clarithromycin, azithromycin, erythromycin

Question 80

Metronidazole

Answer 80

- Mechanism of action = Metronidazole enters bacteria by passive diffusion. In anaerobic bacteria, reduction of metronidazole generates a nitroso free radical. This binds to DNA, reducing synthesis and causing widespread damage, DNA degradation, and cell death (bactericidal). As aerobic bacteria are not able to reduce metronidazole in this manner, they are not susceptible to its effects. Bacterial resistance to metronidazole is generally low, but increasing. Mechanisms include reduced uptake of metronidazole and reduced generation of nitroso free radicals. Spectrum of activity = Anaerobic bacteria and protozoa. - Main indications = 1) Infections from oropharyngeal Gram-negative anaerobes, including dental infections, infected human/animal bites and aspiration pneumonia. 2) Eradication of Helicobacter pylori (e.g. causing peptic ulcer disease) in combination with a proton pump inhibitor and either amoxicillin or clarithromycin. 3) Intraabdominal infection and pelvic inflammatory disease, which may involve Gram-negative anaerobes. 4) Protozoal infections including trichomonal vaginal infection, amoebic dysentery, and giardiasis. 5) Clostridioides difficile colitis, if IV treatment is required (otherwise vancomycin or fidaxomicin is preferred). - Contraindications = Metronidazole is metabolised by hepatic cytochrome P450 (CYP) enzymes, so the dose should be reduced in ▲ severe liver disease. Metronidazole inhibits the enzyme acetaldehyde dehydrogenase, which is responsible for clearing the intermediate alcohol metabolite acetaldehyde from the body. ✖ Alcohol should be avoided while taking metronidazole as the combination causes an unpleasant reaction including flushing, headache, nausea, and Metronidazole is metabolised by hepatic cytochrome P450 (CYP) enzymes, so the dose should be reduced in ▲ severe liver disease. Metronidazole inhibits the enzyme acetaldehyde dehydrogenase, which is responsible for clearing the intermediate alcohol metabolite acetaldehyde from the body. ✖ Alcohol should be avoided while taking metronidazole as the combination causes an unpleasant reaction including flushing, headache, nausea, and vomiting. - Route of admin = Oral metronidazole may be taken as tablets or oral suspension. IV metronidazole is given as an infusion over 20 minutes. Topical metronidazole is administered PV or to the skin as a cream or gel. - Adverse effects = As with many antibiotics, metronidazole can cause GI upset (such as nausea, vomiting, metallic taste) and immediate and delayed hypersensitivity reactions (see Penicillins, broad-spectrum). When used at high doses or for a prolonged course, metronidazole can cause neurological adverse effects, including peripheral and optic neuropathy, seizures, and encephalopathy.

Question 81

Non-steroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors

Answer 81

- Mechanism of action = Non-steroidal antiinflammatory drugs (NSAIDs) inhibit prostaglandin synthesis from arachidonic acid by inhibiting cyclo-oxygenase (COX). COX exists as two main isoforms. COX-1 is the constitutive form. It stimulates prostaglandin synthesis that preserves integrity of the gastric mucosa, maintains renal perfusion (by dilating afferent glomerular arterioles), and inhibits thrombus formation at the vascular endothelium. COX-2 is the inducible form, expressed in response to inflammatory stimuli. It stimulates production of prostaglandins that cause inflammation and pain. The therapeutic benefits of NSAIDs are principally mediated by COX-2 inhibition, and adverse effects by COX-1 inhibition, although there is some overlap. Selective COX-2 inhibitors (e.g. etoricoxib) were developed in an effort to reduce the adverse GI effects of NSAIDs. - Main indications = 1) ‘As-needed’ treatment of mild-to-moderate pain (e.g. dysmenorrhoea, dental pain, trauma) and fever. Paracetamol produces similar analgesic effect, so is preferred in those at risk of adverse effects. 2) Regular treatment for pain related to inflammation, particularly of the musculoskeletal system, e.g. in rheumatoid arthritis, severe osteoarthritis, and acute gout. - Contraindications = NSAIDs are contraindicated in ✖ severe renal impairment, ✖ heart failure, ✖ liver failure and known ✖ NSAID hypersensitivity. They should be avoided in ▲ peptic ulcer disease (especially if there are additional risk factors, see CLINICAL TIP), ▲ cardiovascular disease and milder forms of ▲ renal impairment. If unavoidable, use the safest NSAID for the relevant risk, at the lowest effective dose, for the shortest possible time. - Route of admin = NSAIDs are generally taken orally, but are also available as topical gels, suppositories and injectable preparations. Oral NSAIDs should be taken with food to minimise GI upset. - Adverse effects = The main adverse effects of NSAIDs are GI toxicity, renal impairment, and major adverse cardiovascular events (MACE, e.g. myocardial infarction and stroke). The adverse effect profile differs between NSAIDs. Selective COX-2 inhibitors and low-dose ibuprofen are least likely to cause GI toxicity. Cardiovascular events are most likely with COX-2 inhibitors, high-dose ibuprofen and diclofenac, and less likely with naproxen. All NSAIDs, including selective COX-2 inhibitors, can cause renal impairment. Other adverse effects include hypersensitivity reactions, e.g. bronchospasm and angioedema, and fluid retention, which can worsen hypertension and heart failure. - Examples = ibuprofen, diclofenac, naproxen (NSAIDs) etoricoxib (COX-2 inhibitor)

Question 82

Ocular lubricants (artificial tears)

Answer 82

- Mechanism of action = In dry eye conditions, ocular lubricants have a soothing effect and help protect the eye surfaces from abrasive damage. Lubricant eye drops typically consist of an electrolyte solution with a viscosity agent, such as a cellulose polymer (e.g. hypromellose). Gels, such as carbomer 980 (the active ingredient of Viscotears®), have greater viscosity and are retained in the eye for longer. Ointments such as white soft paraffin with liquid paraffin (e.g. Lacri-Lube®) are highly viscous and may provide greater protection, but at a cost of causing blurred vision. - Main indications = For first-line symptomatic treatment of dry eye conditions, including keratoconjunctivitis sicca and Sjögren’s syndrome, alongside environmental coping strategies and avoiding precipitants. - Contraindications = As ocular lubricants are not absorbed, there are no major safety considerations from a systemic illness perspective. - Route of admin = Ocular lubricants are usually self-administered. After washing their hands, the person tips the head back (‘look at the ceiling’) and pulls down slightly on the lower eyelid. Then, with the bottle held upside-down just above the eye, they squeeze to release a drop. For drops, they should then close the eye and press gently on the corner nearest the nose for 1 minute. For gels, they should blink a few times to spread it over the eye. They should try not to let the tip of the dispenser touch the eye (or anything else) and should replace the cap directly after use to prevent infection. - Adverse effects = Ocular lubricants have few side effects other than mild stinging on application and temporary blurring of vision. The risk of blurring increases with viscosity and is therefore greatest for ointments. Unless specified as ‘preservative-free’, it can be assumed that the preparation contains some form of preservative. This may incite a local inflammatory (allergic) reaction, particularly in frequent or long-term use. - Examples = hypromellose, carbomers, liquid and white soft paraffin

Question 83

Penicillins, antipseudomonal

Answer 83

- Mechanism of action = Penicillins inhibit enzymes responsible for cross-linking peptidoglycans. This weakens bacterial cell walls, reducing their ability to maintain an osmotic gradient and resulting in cell swelling, lysis, and death. Penicillins contain a β-lactam ring, which is responsible for their bactericidal activity. Side chains attached to the β-lactam ring can be modified to make semi-synthetic penicillins. Piperacillin is similar to ampicillin, but with a longer side chain. This improves its affinity to penicillin-binding proteins, increasing the spectrum of activity. Antipseudomonal penicillins (e.g. piperacillin) have a broad spectrum of activity against a wide range of Gram-positive and Gram-negative bacteria (notably including Pseudomonas spp.) and anaerobes. They are formulated with a β-lactamase inhibitor (e.g. tazobactam), which confers antimicrobial activity against β-lactamase-producing bacteria (e.g. Staphylococcus aureus, Gram-negative anaerobes). - Main indications = Antipseudomonal penicillins are reserved for severe infections, particularly where there is a broad spectrum of potential pathogens, if antibiotic resistance is likely (e.g. hospital-acquired infection) or in people who have immune suppression (e.g. neutropenia). Specific infections treated with these drugs include: 1) Lower respiratory tract infection. 2) Urinary tract infection. 3) Intraabdominal infection. - Contraindications = Antipseudomonal penicillins should be used with caution in people at risk of ▲ C. difficile infection, particularly older people and those in hospital. The main contraindication is ✖ penicillin allergy. Note that allergy to one type of penicillin implies allergy to all types, as it is due to a reaction to the basic penicillin structure. People with hypersensitivity to penicillins may also react to cephalosporins and other β-lactam antibiotics. The dose of antipseudomonal penicillins should be reduced in ▲ moderate/ severe renal impairment. - Route of admin = Piperacillin with tazobactam is formulated as a powder to be reconstituted in 10 mL sterile water or 0.9% sodium chloride. This is diluted further in 50–150 mL of 0.9% sodium chloride or 5% glucose for IV infusion. Infusion duration varies according to local protocols. - Adverse effects = GI upset is common. Less frequently, antibiotic-associated colitis occurs. Broad-spectrum antibiotics kill normal GI flora, allowing overgrowth of toxin-producing Clostridioides difficile. The resulting colitis can be complicated by colonic perforation and/or death. Delayed or immediate hypersensitivity may occur (see Penicillins, broad-spectrum). - Examples = piperacillin with tazobactam (e.g. Tazocin®)

Question 84

Penicillins, broad-spectrum

Answer 84

- Mechanism of action = Penicillins inhibit enzymes responsible for cross-linking peptidoglycans. This weakens the bacterial cell wall, reducing its ability to maintain an osmotic gradient, causing cell swelling, lysis, and death. Penicillins contain a β-lactam ring, which is responsible for their bactericidal activity. Broad-spectrum penicillins are synthesised by addition of an amino group to the β-lactam ring side chains, broadening activity against aerobic Gram-negative bacteria. Amoxicillin has a broad spectrum of activity against Gram-positive and Gram-negative cocci and bacilli (rods). However, it is inactivated by bacterial penicillinases, and resistance is increasingly prevalent. Combination with clavulanic acid (a β-lactamase inhibitor) as co-amoxiclav restores activity against many amoxicillin-resistant strains. - Main indications = 1) Amoxicillin is used in many infections, including sinusitis, otitis media, community-acquired pneumonia, and urinary tract infection (UTI), and to eradicate Helicobacter pylori in peptic ulcer disease (with a proton pump inhibitor and clarithromycin or metronidazole). 2) Co-amoxiclav is a common choice for severe, resistant, and hospital-acquired infections, including pneumonia, UTI, intraabdominal infection, cellulitis, and bone and joint infection. Unless supported by microbiological evidence of sensitivity, amoxicillin is not generally used for these indications, as resistance is common. - Contraindications = The main contraindication is ✖ severe allergy to a β-lactam antibiotic. Broad-spectrum penicillins should be avoided in ▲ young people with a sore throat, as they can cause a rash with glandular fever that may be mislabelled as penicillin allergy. They should be used with caution in older or hospitalised people at risk of ▲ C. difficile infection, and in those with a history of ▲ penicillin-associated liver injury. Dosage should be reduced in ▲ severe renal impairment (risk of crystalluria). - Route of admin = Amoxicillin and co-amoxiclav are available as capsules, tablets, and oral suspensions. Co-amoxiclav suspension may cause dental staining. IV preparations may be given by slow injection or infusion. - Adverse effects = GI upset is common. Less often but importantly, antibiotic-associated colitis may occur. This is where broad-spectrum antibiotics kill normal gut flora, allowing overgrowth of toxin-producing Clostridioides difficile. The resulting colitis can be complicated by colonic perforation and/or death. Penicillin allergy, affecting 1%–10% of people exposed, usually presents as a skin rash 7–10 days after first, or 1–2 days after repeat exposure (delayed IgG-mediated reaction). IgE-mediated (immediate-type) hypersensitivity, including anaphylaxis, is less common but important. Acute liver injury (cholestatic jaundice or hepatitis) may develop during or shortly after co-amoxiclav treatment, and generally improves if treatment is stopped. - Examples = co-amoxiclav, amoxicillin

Question 85

Penicillins, narrow-spectrum

Answer 85

- Mechanism of action = Penicillins inhibit enzymes responsible for cross-linking peptidoglycans. This weakens the bacterial cell wall, reducing its ability to maintain an osmotic gradient, causing cell swelling, lysis, and death. Originally isolated from moulds, penicillins comprise a β-lactam ring, responsible for bactericidal activity, and a side chain that modifies their properties and antimicrobial spectrum. Some bacteria produce β-lactamase enzymes, which break the β-lactam ring, conferring resistance. Flucloxacillin contains an acyl side chain that protects the β-lactam ring and is effective against β-lactamase-producing staphylococci. Meticillin-resistant Staphylococcus aureus (MRSA) resists flucloxacillin by changes in its target enzyme to reduce penicillin-binding affinity. Bacteria can also acquire efflux pumps to reduce intracellular drug concentrations. Narrow-spectrum penicillins are active against Gram-positive organisms (penicillin—streptococci, bacillus, and some anaerobes (clostridia); flucloxacillin—staphylococci) and Gram-negative cocci (penicillin—meningococcus and gonococcus). Narrow-spectrum antibiotics can reduce emergence of antimicrobial resistance, but often need to be combined with other antibiotics for optimal treatment, particularly where the infecting organism has not been identified or infection is severe. - Main indications = 1) Benzylpenicillin/ phenoxymethylpenicillin (penicillin): streptococcal infections, including tonsillitis, pneumonia, and endocarditis; and meningococcal disease, including meningitis (although cephalosporins are usually preferred in hospital settings). 2) Penicillinase-resistant penicillin (flucloxacillin): staphylococcal infections including skin, soft tissue, bone and joint infections, otitis externa, and endocarditis. - Contraindications = Dose reduction is required in ▲ severe renal impairment. The main contraindication is ✖ allergy to any penicillin. Note that allergy to one type of penicillin implies allergy to all types as it is due to a reaction to the basic penicillin structure. Severe hypersensitivity to any β-lactam antibiotic generally precludes use of the others. - Route of admin = IV benzylpenicillin and flucloxacillin can be given either as a slow injection or by infusion. Phenoxymethylpenicillin and flucloxacillin are available orally as tablets or capsules and as oral solutions for infants and those with difficulty swallowing. - Adverse effects = Minor GI upset is common. Penicillin allergy affects 1%–10% of people. This is usually IgG-mediated (delayed-type) hypersensitivity, causing skin rash. IgE-mediated (immediate-type) hypersensitivity, including anaphylaxis, is less common but important. Neurological toxicity (including convulsions and coma) can occur at very high doses or in toxic accumulation due to renal failure. Flucloxacillin rarely causes liver toxicity, which can be severe. - Examples = flucloxacillin, benzylpenicillin, phenoxymethylpenicillin

Question 86

Phosphodiesterase (type 5) inhibitors

Answer 86

- Mechanism of action = A key local mediator in the initiation and maintenance of an erection is nitric oxide (NO). This is synthesised in the penis in response to parasympathetic stimulation induced by physical (sexual) stimulation and psychological arousal. NO activates soluble guanylyl cyclase, which produces the second-messenger cyclic guanosine monophosphate (cGMP). This, in turn, activates protein kinase G, which causes vasodilation in penile arteries. The resulting penile engorgement (and its secondary effects on venous outflow) produces an erection. Phosphodiesterase type 5 (PDE-5) degrades cGMP to GMP, terminating its effect. PDE-5 inhibitors therefore increase cGMP concentration in the penis, improving the likelihood of achieving an erection and prolonging its duration. PDE-5 is also expressed in pulmonary vasculature, where it causes pulmonary arterial vasodilation by a similar mechanism. PDE-5 inhibitors are therefore also used to treat primary pulmonary hypertension. - Main indications = 1) Erectile dysfunction 2) Primary pulmonary hypertension - Contraindications = PDE-5 inhibitors should not be taken by people in whom vasodilation could be dangerous, including those with ✖ recent stroke or ✖ recent acute coronary syndrome, or who have ✖ significant cardiovascular disease. PDE-5 inhibitors should be avoided or used at a lower dose in people with severe ▲ hepatic or ▲ renal impairment, due to reduced metabolism and excretion. - Route of admin = Absorption of oral sildenafil and onset of effect will be delayed if it is taken with food. This does not apply to tadalafil. - Adverse effects = Most adverse effects of PDE-5 inhibitors are predictable from their vasodilator action. Headache is most common, along with flushing, dizziness, and nasal congestion. Hypotension and arrhythmias occur uncommonly and may rarely be associated with acute coronary syndrome. Prolonged, painful erection in the absence of stimulation (priapism) is a rare adverse effect which requires urgent medical review. Visual symptoms, including colour distortion, are due to inhibition of PDE type 6 in the retina, where it is involved in phototransduction. - Examples = sildenafil, tadalafil, vardenafil

Question 87

Potassium, oral

Answer 87

- Mechanism of action = Potassium is the predominant cation (positively charged ion) in the intracellular compartment. However, its concentration is measured in serum, and if low this is termed hypokalaemia. Hypokalaemia may be due to potassium depletion (e.g. GI losses) or redistribution (e.g. high-dose β-agonist treatment). It has potentially life-threatening effects, particularly in the heart (arrhythmias) and skeletal muscles (weakness). Clinical effects are usually not apparent until the serum potassium falls below 3 mmol/L (normal range 3.5–5.0 mmol/L), unless there is concomitant therapy with digoxin. Oral potassium replacement is an option for treatment of hypokalaemia caused by potassium depletion. This is most commonly administered using a combined preparation of potassium bicarbonate and potassium chloride. If losses are due to loop or thiazide diuretic therapy, supplementation is largely ineffective. This is because although the serum potassium concentration is low, intake and output are in balance. Potassium supplementation results simply in increased potassium excretion and only minimal effect on serum concentration. This can be overcome by starting a potassium-sparing diuretic or aldosterone antagonist. Potassium supplementation lacks rationale if hypokalaemia is a result of redistribution, where treatment is best directed at correction of the underlying cause. - Main indications = Prevention and treatment of potassium depletion and hypokalaemia. Addition of a drug with potassium-sparing diuretic effects (e.g. an aldosterone antagonist or amiloride) is preferred when potassium losses are due to loop- or thiazide-diuretic therapy. IV potassium chloride is preferred in the initial treatment of hypokalaemia that is severe (<2.5 mmol/L), symptomatic or causing arrhythmias. - Contraindications = Potassium supplementation is contraindicated in ✖ hyperkalaemia and care must be taken when prescribing for people with, or at risk of, ▲ renal impairment. - Route of admin = Effervescent tablets (e.g. Sando-K®) are stirred in about half a glassful of water for administration. Some people find it easier to take with food. - Adverse effects = Oral potassium is unpalatable, which may reduce tolerability. The most important adverse effect is inadvertent hyperkalaemia, and for this reason serum potassium should be monitored during treatment. - Examples = potassium bicarbonate, potassium chloride

Question 88

Prostaglandin analogue and carbonic anhydrase inhibitor eye drops

Answer 88

- Mechanism of action = Glaucoma is characterised by progressive optic nerve damage associated with visual field loss and eventually blindness. It is usually associated with elevated intraocular pressure (ocular hypertension), and lowering intraocular pressure reduces glaucoma progression. Intraocular pressure is determined by the balance of aqueous humour production from ciliary processes, and outflow via the trabecular (‘conventional’) and uveoscleral (‘non-conventional’) pathways. Prostaglandin F2α analogues act via prostaglandin receptors to increase expression of matrix metalloproteinases, reducing resistance to aqueous humour outflow, primarily in the uveoscleral pathway. In contrast, carbonic anhydrase inhibitors reduce aqueous humour production. By inhibiting bicarbonate formation, they interfere with Na+ transport across the ciliary epithelium and, in turn, the flow of water by osmosis. - Main indications = Topical prostaglandin analogues are the first-line choice to lower intraocular pressure in open-angle glaucoma and ocular hypertension. Prostaglandin analogues are generally preferred over topical β-blockers as they cause fewer systemic side effects. Topical carbonic anhydrase inhibitors are second-line options, if topical prostaglandin analogues are not tolerated or insufficient. - Contraindications = Caution is needed when contemplating prostaglandin analogue treatment in eyes in which the lens is absent (▲ aphakia) or artificial (▲ pseudophakia); and in people with or at risk of ▲ iritis, uveitis, or macular oedema. In severe asthma, there is a theoretical risk of provoking bronchoconstriction, but in practice this does not seem to be a problem. It is certainly less of a concern than with topical β-blockers. - Route of admin = It is best to administer latanoprost eye drops in the evening. Contact lenses should be removed before instilling prostaglandin analogue or carbonic anhydrase inhibitor eye drops. They may be reinserted 15 minutes later. - Adverse effects = Topical prostaglandin analogues and carbonic anhydrase inhibitors have few systemic side effects. Locally, they commonly cause eye discomfort immediately after administration, and blurred vision. Prostaglandin analogues also cause transient conjunctival reddening (hyperaemia) and may cause a permanent change in eye colour by increasing the amount of melanin in stromal melanocytes of the iris. This affects about a third of people and is most noticeable if treatment is restricted to one eye. - Examples = latanoprost (prostaglandin analogue) brinzolamide (carbonic anhydrase inhibitor)

Question 89

Prostaglandins and analogues

Answer 89

- Mechanism of action = Prostaglandins are a family of lipid autacoids (‘local messengers’) synthesised from arachidonic acid. They are produced by all cells, but the relative importance of each one varies between tissues. Prostaglandin (PG) E2 (dinoprostone) is synthesised by the uterine mucosa (decidua) and cells lining the amniotic sac during pregnancy. It stimulates uterine contraction and acts on collagenase enzymes that thin and soften the cervix, facilitating cervical effacement. It plays a key role in the initiation of labour, and this is exploited therapeutically to induce labour. PGE1 (alprostadil, and its synthetic analogue misoprostol) is produced in vascular smooth muscle, where it stimulates cAMP production, causing muscle relaxation and vasodilation. Applied locally to the penis, alprostadil induces erection, and so is an option for the treatment of erectile dysfunction. Misoprostol may be administered systemically or vaginally to simulate uterine contraction. It is used in combination with the antiprogestogen mifepristone for medical termination of pregnancy. Iloprost is a synthetic analogue of prostacyclin (PGI2) that has vasodilatory effects by relaxing smooth muscle. This is useful in pulmonary hypertension and peripheral vascular disease. - Main indications = 1) Induction of labour (dinoprostone); oxytocin is a second-line option. 2) Erectile dysfunction (alprostadil), although it is largely superseded by sildenafil for this indication. 3) Medical termination of pregnancy (misoprostol). 4) As a vasodilator in pulmonary hypertension and peripheral vascular disease causing debilitating pain or ischaemia (iloprost). - Contraindications = Induction of labour with dinoprostone should not be attempted if there are ✖ risk factors for difficult delivery (e.g. fetal malposition, placenta praevia, previous difficult delivery) or fetal or maternal complications (e.g. fetal distress, previous caesarean section or major uterine surgery). In general, due to their vasodilating effects, prostaglandins should be used with caution in people with ▲ severe cardiac disease. Iloprost should be avoided in people with a significant ▲ bleeding risk. - Route of admin = Dinoprostone is usually administered by a midwife or doctor to ensure correct placement in the posterior fornix. Alprostadil is most conveniently administered into the urethra using cream from a pre-filled syringe, or a urethral stick that delivers a medicated pellet. Misoprostol may be taken at home, usually as a sublingual or buccal preparation. Iloprost administration, as an IV infusion or by nebuliser, is complex, and given under specialist direction only. - Adverse effects = Dinoprostone may cause uterine hyperstimulation that can be harmful to the fetus and increase the risk of uterine rupture. Alprostadil may cause prolonged painful erections (priapism) that can lead to tissue ischaemia. Iloprost may cause problematic hypotension when given systemically. Prostaglandins may cause nausea and vomiting from stimulation of gastro-intestinal smooth muscle. - Examples = dinoprostone, misoprostol, alprostadil, iloprost

Question 90

Quinine

Answer 90

- Mechanism of action = Leg cramps are caused by sudden, painful involuntary contraction of skeletal muscle. Quinine is thought to act by reducing the excitability of the motor end plate in response to acetylcholine stimulation. This reduces the frequency of muscle contraction. In malaria, quinine interferes with detoxification of haem monomers, which are produced from digestion of haemoglobin within the malarial parasite. The monomers accumulate, impairing membrane integrity and killing the parasites in the schizont stage. In contrast to other antimalarials, P. falciparum resistance to quinine is uncommon. - Main indications = 1) Quinine is an option for nocturnal leg cramps, but only if these are severe, impacting on quality of life (e.g. regularly disrupt sleep) and refractory to non-pharmacological methods such as passive stretching exercises. It is likely that many quinine prescriptions for this indication are inappropriate. 2) A first-line treatment option for Plasmodium falciparum malaria. - Contraindications = Quinine should be prescribed with caution in people with existing ▲ hearing or visual loss. It is teratogenic, so should not be used in the ▲ first trimester of pregnancy, although in the case of malaria its benefit may outweigh this risk. Quinine should be avoided in people with ▲ glucose-6-phosphate dehydrogenase (G6PD) deficiency, in whom it may precipitate haemolysis. - Route of admin = Oral quinine for leg cramps should be taken in the evening. For malaria, oral quinine doses should be taken at 8-hrly intervals. IV quinine is given by slow infusion. - Adverse effects = Although quinine is usually safe at recommended doses, it is potentially very toxic and can be fatal in overdose. It can cause tinnitus, deafness and blindness (which may be permanent), GI upset, and hypersensitivity reactions. Quinine prolongs the QT interval and may therefore predispose to arrhythmias, particularly after administration of IV loading doses. Hypoglycaemia, caused by stimulation of insulin secretion, can occur and is particularly problematic in malaria, since this condition also predisposes to hypoglycaemia. - Examples = quinine sulfate

Question 91

Quinolones

Answer 91

- Mechanism of action = Quinolones kill bacteria (bactericidal effect) by inhibiting DNA synthesis. However, resistance is problematic. Some bacteria prevent intracellular accumulation of the drug by reducing permeability and/or increasing efflux. Others develop protective mutations in target enzymes. Quinolone resistance genes are spread horizontally between bacteria by plasmids, accelerating acquisition of resistance. Quinolones have a relatively broad spectrum of activity, particularly against Gram-negative bacteria. Ciprofloxacin is unusual among oral antibiotics in having significant activity against Pseudomonas aeruginosa. Moxifloxacin and levofloxacin have enhanced activity against Gram-positive organisms (so are preferred over ciprofloxacin for treatment of lower respiratory tract infections. - Main indications = Systemically administered quinolones are best reserved for severe bacterial infections in which other treatment options are limited. With these caveats in mind, they are used in: 1) Urinary tract infection (UTI) (mostly Gram-negative organisms). 2) Severe gastroenteritis (e.g. due to Shigella, Campylobacter). 3) Lower respiratory tract infections, including infective exacerbation of COPD and pneumonia (Gram-positive and Gram-negative organisms). - Contraindications = A careful risk–benefit assessment and consideration of other options are required before prescribing quinolones. They should be used with caution in ▲ pregnancy and in ▲ children and young adults who are growing (risk of arthropathy); ▲ adults >60 years (risk of tendon damage); people with ▲ renal impairment; and people with or at risk of ▲ neurological or ▲ cardiovascular morbidity. - Route of admin = Oral quinolones are available as tablets, with ciprofloxacin also being formulated as a (more expensive) oral suspension. IV quinolones come pre-prepared in solution for infusion, usually over 60 minutes. - Adverse effects = Quinolones are generally well tolerated although they can cause GI upset and immediate- and delayed-type hypersensitivity reactions (see Penicillins, broad-spectrum). Quinolones and cephalosporins are the antibiotics most commonly associated with Clostridioides difficile colitis. Class-specific adverse reactions may be neurological (convulsions, peripheral neuropathy), musculoskeletal (tendon damage and rupture) or cardiovascular (QT interval prolongation, valvular regurgitation, and aortic aneurysm/dissection). Although rare, these may be disabling and long-lasting or irreversible. - Examples = ciprofloxacin, levofloxacin, ofloxacin, moxifloxacin

Question 92

Sodium-glucose co-transporter 2 inhibitors

Answer 92

- Mechanism of action = These drugs selectively and reversibly inhibit the sodium–glucose co-transporter 2 (SGLT2) in the proximal convoluted tubule of the nephron. SGLT2 mediates active transport of glucose and sodium from filtrate into blood, controlling sodium content of the filtrate and, under physiological conditions, recovering most of the filtered glucose. SGLT2 inhibition impairs glucose reabsorption in the nephron, increasing renal excretion of glucose (glycosuria) and treating hyperglycaemia. Additionally, by increasing renal sodium excretion (natriuresis) and water excretion (osmotic diuresis), SGLT2 inhibitors reduce extracellular water volume, blood pressure, and cardiac preload. Increased sodium delivery to the macula densa (in the wall of the distal tubule) triggers tubuloglomerular feedback mechanisms that reduce intra-glomerular pressure. Together, these actions have favourable effects on renal and cardiovascular outcomes in type 2 diabetes, heart failure, and CKD. - Main indications = 1) Type 2 diabetes, usually in combination with other antidiabetic drugs (e.g. metformin, insulin), but also as an option for monotherapy if metformin is not tolerated. 2) Symptomatic chronic heart failure with reduced ejection fraction, inadequately controlled with a β-blocker, ACE inhibitor/angiotensin receptor blocker, and an aldosterone antagonist. 3) Chronic kidney disease (CKD) with albuminuria, alongside an ACE inhibitor/angiotensin receptor blocker. - Contraindications = SGLT2 inhibitors should be withheld during ▲ intercurrent illness that causes or presents a risk of ✖ volume depletion or hypotension. - Route of admin = Canagliflozin and dapagliflozin are formulated as tablets which are swallowed with water. They can be taken with or without food, and at any time of day, though this should be the same time each day. - Adverse effects = As the effect of SGLT2 inhibitors diminishes at lower serum glucose concentrations, they rarely cause hypoglycaemia, although they may exacerbate hypoglycaemia due to other glucose-lowering drugs. Osmotic diuresis can cause thirst and, in the context of intercurrent illness, increase the risk of hypovolaemia and electrolyte disturbance. Glycosuria increases the risk of genital and urinary tract infections, and, rarely, Fournier’s gangrene (acute necrotic infection of the perineum). SGLT2 inhibitors have been associated with ketoacidosis with a near-normal glucose concentration (euglycaemic diabetic ketoacidosis). This is rare in type 2 diabetes, but common if the drugs are used in type 1 diabetes (which is not recommended). - Examples = empagliflozin, dapagliflozin, canagliflozin

Question 93

Tetracyclines and glycylcyclines

Answer 93

- Mechanism of action = Tetracyclines inhibit bacterial protein synthesis. They bind to the ribosomal 30S subunit, which is specific to bacteria. This prevents binding of transfer RNA to messenger RNA, interfering with the addition of amino acids to growing polypeptide chains. Inhibition of protein synthesis is bacteriostatic (stops bacterial growth), which assists the immune system in killing and removing bacteria. Resistance is widespread, particularly in Gram-positive organisms. A common mechanism is an efflux pump, which allows bacteria to pump out tetracyclines, preventing cytoplasmic accumulation. Tigecycline is a glycylcycline antibiotic which is structurally and mechanistically similar to tetracyclines, but less susceptible to resistance. Tetracyclines have a relatively broad spectrum of activity against Gram-positive and Gram-negative organisms. Resistance is common, although less problematic for the newer related drug, tigecycline. - Main indications = 1) Acne vulgaris, particularly where there are inflamed papules, pustules and/or cysts (Propionibacterium acnes). 2) Lower respiratory tract infections, including infective exacerbation of COPD (e.g. Haemophilus influenzae) and pneumonia. 3) Chlamydial infection, including pelvic inflammatory disease. 4) Other infections such as typhoid, malaria, and Lyme disease. 5) Tigecycline is used for severe skin, soft-tissue, and abdominal infections, but reserved for cases where other options are limited. - Contraindications = Tetracyclines bind to teeth and bones during childhood development, so should not be prescribed during ✖ pregnancy, ✖ breastfeeding or for ✖ children ≤12 years of age. They should be used with caution in ▲ renal impairment as their antianabolic effects can raise serum urea and reduced drug excretion can increase the risk of adverse effects. - Route of admin = Oral tetracycline products are formulated as capsules or tablets. These should be swallowed whole with plenty of water while sitting or standing to stop them getting stuck in the oesophagus, where they may cause ulceration. - Adverse effects = Like most antibiotics, tetracyclines commonly cause GI upset, although with a lower risk of Clostridioides difficile infection than other broad-spectrum antibiotics (see Penicillins, broad-spectrum). Hypersensitivity reactions occur in about 1%, including immediate and delayed reactions. There is no cross-reactivity with β-lactam antibiotics (e.g. penicillins). Tetracycline-specific side effects include oesophageal ulceration and dysphagia; photosensitivity (an exaggerated sunburn reaction); and discolouration and/or hypoplasia of tooth enamel in children. Rare but serious adverse effects include hepatotoxicity and intracranial hypertension, the latter causing headache and visual disturbance. - Examples = doxycycline, lymecycline (tetracyclines); tigecycline (glycylcycline)

Question 94

Tranexamic acid

Answer 94

- Mechanism of action = Tranexamic acid is an antifibrinolytic drug that can prevent, reduce, and stop bleeding. It is a lysine analogue that acts by competitively binding to plasminogen, inhibiting its activation to plasmin. Plasmin is a fibrinolytic enzyme, responsible for breaking down (lysing) clots. Inhibiting plasmin production therefore promotes haemostasis. - Main indications = 1) As a second-line treatment for menorrhagia (heavy menstrual bleeding) if a levonorgestrel intrauterine system is ineffective, declined or unsuitable, and after the underlying cause has been established (or while awaiting specialist review). An alternative option is hormonal contraception. 2) For epistaxis (nose bleeding), as an option if management with first aid, nasal cautery and nasal packing have been unsuccessful. For this indication, it may be applied topically. 3) In major trauma, where early IV administration reduces mortality. 4) For post-partum haemorrhage (PPH) as an option to reduce blood loss in women with established PPH, or those undergoing caesarean section and at high risk of PPH, in addition to oxytocin, blood products, and other measures. - Contraindications = Before starting tranexamic acid for abnormal menstrual bleeding, investigations for a cause should be started. Tranexamic acid should be avoided in people with history of ▲ seizures and ▲ thromboembolic disease, unless the benefits are thought to outweigh these risks (e.g. in major trauma). It should be avoided in overt ✖ disseminated intravascular coagulation (DIC), although it is beneficial in trauma-induced coagulopathy, where some features of DIC may be present. - Route of admin = Tablets can be taken with or without food and, when given regularly, doses should be spaced evenly throughout the day. For trauma, the loading dose is given over 10 minutes followed by a slow IV infusion over 8 hours. For epistaxis, it may be administered topically by saturating a nasal pack with the IV formulation before insertion. - Adverse effects = Tranexamic acid tablets are well tolerated. GI upset and rash are common with IV use. Rare adverse effects include deep vein thrombosis, pulmonary embolism, seizures, and visual disturbance.

Question 95

Trimethoprim

Answer 95

- Mechanism of action = Bacteria are unable to use external sources of folate, so need to make their own for essential functions such as DNA synthesis. Trimethoprim inhibits bacterial folate synthesis, slowing bacterial growth (bacteriostasis). Its clinical utility is reduced by widespread bacterial resistance. Mechanisms of resistance include reduced intracellular antibiotic accumulation and reduced sensitivity of target enzymes. Sulfamethoxazole, a sulfonamide, also inhibits bacterial folate synthesis, but at a different step in the pathway. Given together, the drugs cause more complete inhibition of folate synthesis. Trimethoprim ought to have broad activity against many Gram-positive and Gram-negative bacteria (particularly enterobacteria, e.g. Escherichia coli), but this is increasingly limited by resistance. Combination with a sulfonamide (e.g. sulfamethoxazole, as co-trimoxazole) extends the spectrum to include activity against the fungus Pneumocystis jirovecii. - Main indications = Trimethoprim is a first-line antibiotic for ➊ acute lower urinary tract infection (UTI) in men and non-pregnant women, provided the risk of trimethoprim resistance is low; and ➋ prevention of recurrent UTI if non-antibiotic measures are ineffective. Nitrofurantoin is an alternative. Trimethoprim is also an option for ➌ acne vulgaris and ➍ prostatitis. The main use of co-trimoxazole is ➎ treatment and prevention of pneumocystis pneumonia in immune suppression, e.g. HIV infection. - Contraindications = Trimethoprim is contraindicated in the ✖ first trimester of pregnancy because, as a folate antagonist, it could potentially increase the risk of fetal abnormalities. It should be used cautiously in people with ▲ folate deficiency, who are more susceptible to adverse haematological effects. As trimethoprim is mostly excreted unchanged into urine it is less suitable in ▲ renal impairment; if it is used, a dose reduction is necessary. ▲ Neonates, ▲ older people, and individuals with ▲ HIV infection are more susceptible to adverse effects. - Route of admin = Oral trimethoprim and co-trimoxazole are available as tablets and suspension. Intravenous co-trimoxazole must be diluted immediately before use (to prevent crystallisation) in 125–500 mL sodium chloride 0.9% or glucose 5%, and infused slowly over 60–90 minutes. - Adverse effects = Trimethoprim most commonly causes GI upset and skin rash (3%–7%). Severe hypersensitivity reactions, including anaphylaxis, drug fever, and erythema multiforme, are rare with trimethoprim, but more common with sulfonamides, limiting their use. As a folate antagonist, trimethoprim can impair haematopoiesis, causing megaloblastic anaemia, leukopenia, and thrombocytopenia. It can also cause hyperkalaemia and elevation of plasma creatinine concentration. - Examples = trimethoprim, co-trimoxazole

Question 96

Uterotonics

Answer 96

- Mechanism of action = Oxytocin is a naturally occurring hormone produced in the hypothalamus and secreted from the posterior pituitary. Oxytocin receptors are expressed on myometrium and endometrium, increasing significantly in density in the latter weeks of pregnancy. At this time, stimulation by oxytocin leads to a rise in intracellular calcium, causing contractions. This is beneficial in the third stage of labour, when it reduces the risk of PPH. It can also be used to stimulate or augment labour, but only after maturation of the cervix and rupture of membranes (naturally or artificially). Ergometrine is an ergot alkaloid that acts on uterine α-adrenergic and 5-HT2 receptors to stimulate contractions. It has a similar effect to oxytocin in PPH. - Main indications = 1) Prevention of post-partum haemorrhage (PPH), as part of ‘active management’ of the third stage of labour. Oxytocin and ergometrin are similarly effective, but oxytocin is better tolerated. 2) Treatment of PPH. Oxytocin and ergometrin, alone or in combination, are first-line options for treatment of PPH. Oxytocin may also be given by infusion if there is inadequate response. 3) Induction and augmentation of labour. Oxytocin (but not ergometrine) is a second-line option for induction of labour (e.g. after prostaglandin application and artificial rupture of membranes). It is also used in protracted or arrested labour (hypotonic uterine inertia). - Contraindications = Oxytocin should not be administered for induction or augmentation of labour in atypical fetal presentation (e.g. ✖ breech) or ✖ placenta praevia. It should be used with caution in those with ▲ ischaemic heart disease. Ergometrine should not be given in the ✖ first or second stage of labour, or to people with severe ✖ cardiac disease, ✖ hypertension or ✖ vascular disease. - Route of admin = For prevention of PPH, oxytocin is administered to the mother by IM injection (usually in the thigh) immediately after the baby is born and before the cord is clamped. If IV administration is required, it should be given by slow injection or infusion, because rapid bolus injection can cause hypotension, tachycardia, and QT interval prolongation. - Adverse effects = Oxytocin may cause abdominal pain through uterine contraction. When used to stimulate or augment labour, it may cause uterine hyperstimulation (more than five contractions in 10 minutes, or lasting more than 2 minutes). This should be managed promptly as it can cause fetal distress, asphyxia, and death and may lead to uterine rupture. Rarely, oxytocin causes hyponatraemia and pulmonary oedema (see CLINICAL TIP). Other adverse effects include nausea and vomiting, headaches, and arrhythmias. Ergometrine has similar adverse effects. In addition, stimulation of extra-uterine α-adrenergic receptors may cause systemic hypertension, pulmonary oedema, coronary vasospasm, and myocardial infarction. - Examples = oxytocin, ergometrine

Question 97

Vaccines and immunoglobulins

Answer 97

- Mechanism of action = Vaccines deliver an antigen to induce a protective immune response to a pathogen, without causing disease. The antigen stimulates B cells to produce antibodies (humoral immunity) and activates T cells (cell-mediated immunity). Antibody persistence and memory cells provide long-term protection against infection. To deliver the antigen, vaccines may comprise the whole pathogen (live attenuated or killed) or a subunit (recombinant protein or inactivated toxin). The latter may be linked (conjugated) with another protein to amplify the immune response. Other vaccines contain genetic material encoding the antigen, to be synthesised in vivo by host cells. This may be delivered as nucleic acid (e.g. modified messenger RNA (mRNA) in lipid nanoparticles) or in a viral vector (e.g. a live, non-replicating adenovirus). Immunoglobulins are human antibodies. Normal immunoglobulin is prepared from pooled human plasma and confers passive immunity in immunodeficiency states. It also has complex immunomodulatory effects that are useful in some immune-mediated conditions. Disease-specific immunoglobulin is prepared from plasma of donors with high antibody levels against specific diseases (e.g. hepatitis B). - Main indications = 1) Active immunisation (vaccines), according to a routine immunisation schedule or in specific risk scenarios (e.g. travel) to prevent infection. 2) Passive immunisation (immunoglobulins) to prevent infection in immunodeficiency or as post-exposure treatment of specific infections. 3) Prevention of Rh0 (D) sensitisation (anti-D immunoglobulin) in rhesus negative women following birth of a rhesus positive infant. 4) Treatment of immune-mediated conditions (immunoglobulins) such as Guillain–Barré syndrome. - Contraindications = Vaccine efficacy is impaired in ▲ severe immunosuppression, where there is also a theoretical risk of infection from live attenuated and replicating viral-vector vaccines. Live vaccines should generally be avoided in ▲ pregnancy due to a similar theoretical risk of fetal infection. Allergy is not a contraindication unless it was a ✖ confirmed anaphylactic reaction to a previous dose or component of the vaccine. - Route of admin = Most vaccines are administered by IM injection. Exceptions are cholera (given orally), Bacillus Calmette–Guérin (BCG; intradermal) and influenza vaccination in children (intranasal). Deep SC injection is preferred over IM injection in those at increased risk of bleeding. Immunoglobulins are given by IM, IV or SC injection. Vaccines and immunoglobulins can be inactivated by heat and light, so must be stored and handled in accordance with the product literature. - Adverse effects = Local reactions (pain, swelling, redness) and mild systemic symptoms (fever, malaise, headache, GI upset, myalgia) are common and short lived. Fever may trigger febrile convulsions in susceptible children. Abnormal immune responses to vaccines are rare but can be life threatening (∼1 per million vaccine doses). These include anaphylaxis and delayed immune-mediated reactions (e.g. vaccine-induced immune thrombotic thrombocytopenia associated with adenoviral-vectored COVID-19 vaccines). - Examples = vaccines, normal immunoglobulin, tetanus immunoglobulin

Question 98

Valproate (valproic acid)

Answer 98

- Mechanism of action = Valproate has multiple actions. It increases activity of glutamic acid decarboxylase (GAD), which increases production of γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain. It also appears to be a weak inhibitor of voltage-dependent sodium channels. Together these effects, and others, reduce neuronal excitability, suppressing both initial seizure discharges and their propagation. - Main indications = 1) Seizure prophylaxis in epilepsy. Valproate has a broad spectrum of antiepileptic activity, so is effective in most seizure types. In people who cannot become pregnant, it is a first-line option for generalised tonic–clonic seizures. It is also an option for focal seizures, but toxicity (particularly in women and girls) limits its use. 2) Selected cases of established convulsive status epilepticus that have not responded to adequate treatment with a benzodiazepine. 3) Bipolar disorder, for the acute treatment of manic episodes and prophylaxis against recurrence. 4) As an option to prevent frequent migraine attacks. - Contraindications = Unless there is no alternative, valproate should be avoided in ✖ girls and women who could become pregnant particularly around the time of ✖ conception and in the ✖ first trimester of pregnancy. It is the antiepileptic drug associated with the greatest risk of fetal abnormalities, including neural tube defects, craniofacial, cardiac and limb abnormalities, and developmental delay. If use is unavoidable, highly effective contraception is essential. It should be avoided in ▲ hepatic impairment and dose reduction is required in ▲ severe renal impairment. - Route of admin = Valproate is available in a bewildering array of normal or enteric-coated tablets, capsules, granules, and oral solutions. Some formulations can be crushed (tablets) or mixed with food (granules), whereas modified-release and enteric-coated formulations must be swallowed whole. Give appropriate instructions for the formulation chosen. Valproate can be given IV if oral administration is not possible. - Adverse effects = The most common dose-related adverse events are GI upset, neurological and psychiatric effects (including tremor, ataxia, and behavioural disturbances), thrombocytopenia and transient increase in liver enzymes. Hypersensitivity reactions include hair loss, with subsequent regrowth being curlier than original hair. Rare, life-threatening, idiosyncratic adverse effects include severe liver injury, pancreatitis, bone marrow failure, and antiepileptic hypersensitivity syndrome (see Carbamazepine). - Examples = sodium valproate, valproic acid

Question 99

Vitamins

Answer 99

- Mechanism of action = Vitamins are organic substances required in small amounts for normal metabolic processes. Vitamin deficiencies and their associated clinical manifestations may be treated with a pharmaceutical form of the relevant vitamin (see INDICATIONS). In pregnancy and the preconception period, folic acid reduces the risk of congenital neural tube defects. As it is required for normal cell division, it may work by facilitating cell proliferation involved in neural tube closure, but this is not completely understood. Phytomenadione reverses warfarin by providing a fresh supply of vitamin K for the synthesis of vitamin K-dependent clotting factors by the liver. - Main indications = 1) Thiamine (vitamin B1) is used in the treatment and prevention of Wernicke’s encephalopathy and Korsakoff’s psychosis, which are manifestations of severe thiamine deficiency. 2) Folic acid (the synthetic form of folate or vitamin B9) is used in megaloblastic anaemia due to folate deficiency, and in the first trimester of pregnancy to reduce the risk of neural tube defects. 3) Hydroxocobalamin and cyanocobalamin (synthetic forms of cobalamin or vitamin B12) are used in the treatment of megaloblastic anaemia and subacute combined degeneration of the cord as a result of vitamin B12 deficiency. 4) Phytomenadione (the plant form of vitamin K) is recommended for all newborn babies to prevent vitamin K deficiency bleeding and is used for reversal of warfarin anticoagulation (prothrombin complex concentrate should also be given in cases of major bleeding). - Contraindications = If there is ▲ co-existing vitamin B12 and folate deficiency, both vitamins should be replaced simultaneously. This is because replacing folate alone may be associated with (and perhaps hasten) progression of the neurological manifestations of vitamin B12 deficiency. The major concern is the risk of provoking subacute combined degeneration of the cord. Phytomenadione is less effective in reversing warfarin in severe liver disease, as clotting factors are synthesised in the liver. - Route of admin = Each carton of Pabrinex® contains 2 ampules labelled No 1 and No 2. The contents of both ampules are added to a small bag (50–100 mL) of 0.9% sodium chloride or 5% glucose, mixed, and infused over 30 minutes. Phytomenadione, when given IV, should be injected very slowly. - Adverse effects = When given IV, phytomenadione and high-dose thiamine may rarely cause anaphylaxis. Most other vitamin preparations are relatively non-toxic. - Examples = folic acid, thiamine, hydroxocobalamin, phytomenadione

Question 100

Z-drugs

Answer 100

- Mechanism of action = The ‘Z-drugs’ have a similar mechanism of action to benzodiazepines, although they are chemically distinct. Their target is the γ-aminobutyric acid type A (GABAA) receptor. The GABAA receptor is a chloride (Cl–) channel that opens in response to binding by GABA, the main inhibitory neurotransmitter in the brain. Opening the channel allows chloride to flow into the cell, making the cell more resistant to depolarisation. Like benzodiazepines, Z-drugs facilitate and enhance binding of GABA to the GABAA receptor (allosteric modulation). This has a widespread depressant effect on synaptic transmission. The clinical manifestations of this include reduced anxiety, sleepiness, and sedation. Note that Z-drugs are not useful anticonvulsants, as they cannot be given by injection. Z-drugs have a shorter duration of action than most benzodiazepines. - Main indications = 1) Short-term treatment of insomnia which is debilitating or distressing, although non-pharmacological treatment (or treatment of the underlying cause, if applicable) is invariably preferable. - Contraindications = Z-drugs should be used with caution in ▲ older people, who are often more sensitive to drugs with neurological effects. They should not be prescribed for people with ✖ obstructive sleep apnoea, ✖ respiratory muscle weakness or ✖ respiratory depression, in whom they may worsen respiratory failure during sleep. - Route of admin = oral administration only, as tablets or capsules. - Adverse effects = All Z-drugs can cause daytime sleepiness, which may affect ability to drive or perform complex tasks the day after taking the medication. Rebound insomnia may occur when the drugs are stopped. Other neurological effects include headache, confusion, nightmares, and (rarely) amnesia. As Z-drugs differ chemically from one another, their adverse effects are also different. Zopiclone can cause taste disturbance, whereas zolpidem more commonly causes GI upset. Prolonged use of Z-drugs beyond 4 weeks can lead to dependence, with withdrawal symptoms on stopping, including headaches, muscle pains, and anxiety. In overdose, Z-drugs cause drowsiness, coma, and respiratory depression. - Examples = zopiclone, zolpidem

Question 101

Additional emergency drugs = Adenosine

Answer 101

- Mechanism of action = Adenosine is an agonist of adenosine receptors on cell surfaces. In the heart, activation of these G protein-coupled receptors induces several effects, including reducing the frequency of spontaneous depolarisations (automaticity) and increasing resistance to depolarisation (refractoriness). In turn, this transiently slows the sinus rate and conduction velocity and increases the refractory period in the atrioventricular (AV) node. SVT is usually evident on the electrocardiogram (ECG) as a regular, narrow-complex tachycardia, and often it is caused by a self-perpetuating electrical (re-entry) circuit that includes the AV node. Increasing refractoriness in the AV node temporarily breaks the re-entry circuit, which allows normal depolarisations from the sinoatrial (SA) node to resume control of heart rhythm (cardioversion). Where the circuit does not involve the AV node (e.g. in atrial flutter), adenosine will not induce cardioversion. However, by blocking conduction to the ventricles, it allows closer inspection of the atrial rhythm on the ECG. This may reveal the diagnosis. The duration of effect of adenosine is very short because it is rapidly taken up by cells (e.g. red cells). Its half-life in plasma is less than 10 seconds. - Main indications = 1) As a first-line diagnostic and therapeutic agent in supraventricular tachycardia (SVT) without life-threatening features. If life-threatening features (e.g. shock) are present, electrical cardioversion is preferred. - Contraindications = Adenosine is contraindicated in ✖ hypotension, ✖ coronary ischaemia or ✖ decompensated heart failure, where its transient haemodynamic effects may be intolerable. Adenosine may induce bronchospasm in susceptible individuals, so should be avoided in ✖ asthma and ▲ COPD. People with a ▲ heart transplant are very sensitive to the effects of adenosine, because in the absence of vagal innervation, the sinus and AV nodes show an exaggerated response to neurotransmitter stimulation. Lower doses should be used, and under specialist direction only. - Route of admin = Adenosine should be administered only by doctors experienced in its use, or under their direct supervision, in a suitably equipped high-dependency environment. It is important that adenosine reaches the heart quickly to minimise cellular uptake en route. This requires a large-bore cannula (e.g. 18 G [green] or bigger), sited as proximally as possible (e.g. in the antecubital fossa). Administer the dose as a rapid injection and then immediately follow it with a flush, e.g. 20 mL of 0.9% sodium chloride. The effect will usually be evident on the cardiac monitor within 10–15 seconds, and then dissipate over about 30–60 seconds. - Adverse effects = By interfering with the functions of the SA and AV nodes, adenosine can induce bradycardia and even asystole. Inevitably, this is accompanied by a deeply unpleasant sensation. It is said to feel like a sinking feeling in the chest, often accompanied by breathlessness and a sense of ‘impending doom’. Fortunately, due to the drug’s short-lived effect, this feeling is only brief.

Question 102

Additional emergency drugs = Adrenaline (epinephrine)

Answer 102

- Mechanism of action = Adrenaline is a potent agonist of the α1-, α2-, β1- and β2-adrenoceptors, and correspondingly has a multitude of sympathetic (‘fight or flight’) effects. These include vasoconstriction of vessels supplying skin, mucosa, and abdominal viscera (mainly α1 mediated); increases in heart rate, force of contraction, and myocardial excitability (β1); and vasodilation of vessels supplying the heart and muscles (β2). These explain its use in cardiac arrest, where the redistribution of blood flow in favour of the heart is desirable, at least theoretically. However, clinical trials have shown mixed results, and there is some evidence of harm if adrenaline is administered too early in those with shockable rhythms (see PRESCRIPTION). In anaphylaxis, where widespread release of inflammatory mediators from mast cells produces generalised vasodilatation, profound hypotension and often bronchoconstriction, the vasoconstrictor effects of adrenaline may be life-saving. In addition, via β2-receptors, it causes bronchodilatation and suppresses inflammatory mediator release from mast cells. - Main indications = 1) In cardiac arrest (given IV) as part of the Advanced Life Support (ALS) treatment algorithm for shockable and non-shockable rhythms. 2) In anaphylaxis (given IM) for immediate management. 3) In croup (by nebuliser) if response to initial treatment with a corticosteroid is insufficient. 4) Adrenaline may be injected directly into tissues to induce local vasoconstriction, e.g. during endoscopy to control mucosal bleeding, or premixed with local anaesthetics to prolong their effect. - Contraindications = There are no contraindications to the use of adrenaline for life-threatening conditions. When given to induce local vasoconstriction, it should be used with caution in ▲ heart disease. Combination adrenaline–anaesthetic preparations should not be used in ✖ areas supplied by an end-artery (i.e. with poor collateral supply), such as fingers and toes, where vasoconstriction can cause tissue necrosis. - Route of admin = In cardiac arrest, adrenaline is administered from a pre-filled syringe containing a 1:10,000 (1 mg in 10 mL) solution. For adults, administer the whole 10 mL, followed by a flush (e.g. 10 mL of 0.9% sodium chloride). In anaphylaxis, give 0.5 mL of a 1:1000 (1 mg in 1 mL) adrenaline solution by IM injection. Inject this into the anterolateral aspect of the thigh halfway between the knee and the hip, from where it should be rapidly absorbed. If there is thick subcutaneous tissue (e.g. in obesity), you may need to inject deeply in order to be confident of IM administration. - Adverse effects = Adrenaline is a dangerous drug, but its risks are balanced against the severity of the condition being treated. In cardiac arrest, restoration of output is often followed by adrenaline-induced hypertension. It may cause anxiety, tremor, headache, and palpitations. It may also precipitate angina, myocardial infarction, and arrhythmias, particularly in people with existing heart disease.

Question 103

Additional emergency drugs = Fibrinolytic drugs

Answer 103

- Mechanism of action = Fibrinolytic drugs, also known as thrombolytic drugs, catalyse the conversion of plasminogen to plasmin, which acts to dissolve fibrinous clots and re-canalise occluded vessels. This allows reperfusion of affected tissue, preventing or limiting tissue infarction and cell death and improving outcomes. - Main indications = 1) In acute ischaemic stroke, alteplase increases the chance of living independently if it is given within 4.5 hours of the onset of the stroke, alone or in combination with mechanical thrombectomy (see CLINICAL TIP). 2) In ST-elevation acute coronary syndrome, fibrinolytic drugs can reduce mortality when they are given within 12 hours of the onset of symptoms in combination with antiplatelet agents and anticoagulants. However, primary percutaneous coronary intervention (where available) has largely superseded fibrinolytics in this context. 3) For massive pulmonary embolism (PE) with haemodynamic instability, fibrinolytic drugs reduce clot size and pulmonary artery pressures, but there is no clear evidence that they improve mortality. - Contraindications = There are many contraindications to thrombolysis, which are mostly factors that predispose to ✖ bleeding, including recent haemorrhage, recent trauma or surgery, bleeding disorders, severe hypertension, and peptic ulcers. In acute stroke, ✖ intracranial haemorrhage must be excluded with a computed tomography (CT) scan before treatment. ✖ Previous streptokinase treatment is a contraindication to repeat dosing (although other fibrinolytics can be used), as development of antistreptokinase antibodies can block its effect. - Route of admin = Fibrinolytic drugs should be administered in a high-dependency area such as the emergency department, hyperacute stroke unit or coronary care unit, by staff with expertise in their use. Alteplase comes as a powder, which is reconstituted with sterile water (also provided in the package), and then either given directly as an IV bolus injection or diluted further in 0.9% sodium chloride and given as an IV infusion. - Adverse effects = Common adverse effects include nausea and vomiting, bruising around the injection site, and hypotension. Adverse effects that require treatment to be stopped include serious bleeding, allergic reaction, cardiogenic shock, and cardiac arrest. Serious bleeding may require treatment with coagulation factors and antifibrinolytic drugs, e.g. tranexamic acid, but this is usually avoidable as fibrinolytic agents have a very short half-life. Reperfusion of infarcted brain or heart tissue can lead to cerebral oedema and arrhythmias, respectively. - Examples = alteplase, streptokinase

Question 104

Additional emergency drugs = Naloxone

Answer 104

- Mechanism of action = Naloxone binds to opioid receptors, particularly the pharmacologically important opioid µ-receptors, where it acts as a competitive antagonist. It has little or no effect in the absence of an exogenous opioid (e.g. morphine). However, if an opioid is present, naloxone displaces it from receptors and reverses its effects. In opioid toxicity, this is used to restore an adequate level of consciousness and respiratory rate. - Main indications = 1) Acute treatment of opioid toxicity associated with respiratory and/or neurological depression. A pre-filled syringe formulation, suitable for administration in the community, may be indicated for individuals at high risk of recurrent opioid toxicity due to drug misuse. It is intended for administration (after appropriate training) by someone close to that person as a life-saving intervention. - Contraindications = There are no specific contraindications to the use of naloxone. However, caution should be exercised in people with ▲ opioid dependence (whether from therapeutic or recreational use) because of the risk of precipitating opioid withdrawal. Lower doses should be used in ▲ palliative care to reduce the risk of complete reversal of analgesia. - Route of admin = In hospital, naloxone is usually administered by the prescriber or under their direct supervision. Incremental doses (e.g. 200–400 micrograms IV) are given every 2–3 minutes until satisfactory reversal is achieved (rousable with adequate respiration). For opioid toxicity in the context of chronic use (especially in palliative care), smaller incremental doses (e.g. 40–100 micrograms) should be used. The form of naloxone intended for use by members of the public is given by IM injection in doses of 400 micrograms (0.4 mL of the 1 mg/mL solution) every 2–3 minutes until professional help arrives. - Adverse effects = Naloxone has few intrinsic adverse effects. However, the effect of opioid reversal in an opioid-dependent individual may be a significant opioid withdrawal reaction. This presents with pain (if the opioid was being taken for its analgesic effect), restlessness, nausea and vomiting, dilated pupils, and cold, dry skin with piloerection (‘cold turkey’).

Question 105

Additional emergency drugs = Oxygen

Answer 105

- Mechanism of action = An abnormally low partial pressure of oxygen (PO2) in arterial blood (PaO2), termed hypoxaemia, may be a consequence of a wide range of disease processes. It reduces delivery of oxygen to tissues (hypoxia), increasing their reliance on anaerobic metabolism for energy generation. Supplemental oxygen therapy increases PO2 in alveolar gas (PAO2), driving more rapid diffusion of oxygen into blood. The resulting rise in PaO2 increases delivery of oxygen to the tissues (but note CLINICAL TIP), which in effect ‘buys time’ while the underlying disease is corrected. In pneumothorax, supplemental oxygen has an additional benefit of reducing the fraction of nitrogen in alveolar gas. This accelerates the diffusion of nitrogen out of the body. Since pleural air is composed mostly of nitrogen, this increases its rate of reabsorption. In CO poisoning, oxygen competes with CO to bind with haemoglobin and thereby shortens the half-life of carboxyhaemoglobin, returning haemoglobin to a form that can transport oxygen to tissues. - Main indications = 1) To increase tissue oxygen delivery in acute hypoxaemia. It is also used for long-term oxygen therapy (LTOT) in chronic hypoxaemia, but this is outside the scope of this monograph. 2) To accelerate reabsorption of pleural gas in pneumothorax. 3) To reduce carboxyhaemoglobin half-life in carbon monoxide (CO) poisoning. - Contraindications = People with chronic type 2 respiratory failure (e.g. those with severe COPD) exhibit several adaptive changes in response to persistent hypoxaemia and hypercapnia. If exposed to high inspired oxygen concentrations, this finely balanced adaptive state may be disturbed, resulting in a rise in PaCO2. This may lead to respiratory acidosis, depressed consciousness, and worsened tissue hypoxia. This necessitates a different approach to oxygen therapy (see PRESCRIPTION and ADMINISTRATION). Oxygen accelerates combustion and therefore presents a fire risk if exposed to a heat source or naked flame, including from smoking. - Route of admin = Reservoir masks have a bag (reservoir) that is continuously filled by the incoming oxygen supply. Inspired gas is drawn from the bag and so contains a high oxygen concentration (at least 60%–80%). The oxygen flow rate should be 15 L/min. Venturi devices blend oxygen with air in a fixed ratio. These devices may be colour-coded nozzles attached to masks (delivering a fixed FiO2) or wall-mounted devices (adjustable FiO2, usually with humidification). Nasal cannulae deliver a variable oxygen concentration (roughly 24%–50% at flow rates of 2–6 L/min). Simple face masks are also variable-performance devices; they have few advantages over nasal cannulae and are less comfortable. Humidified high-flow nasal oxygen is an advanced therapy in which a warmed, humidified air/oxygen mixture (with specified FiO2) is delivered at a high flow rate (typically >40 L/min). This can provide high FiO2 (up to 100%), together with a low level of positive end-expiratory pressure. It may be a better option than a reservoir mask in non-hypercapnic (type 1) respiratory failure. - Adverse effects = The most common adverse effects of oxygen are related to the delivery device (e.g. the discomfort of a face mask; nasal cannulae may be more comfortable) or its lack of water vapour (dry throat; humidification may improve this). Except in pneumothorax and CO poisoning, there is little to be gained from an abnormally high PaO2 and, indeed, there is some evidence that hyperoxaemia may be harmful. Routine oxygen administration to non-hypoxaemic patients with stroke and myocardial infarction does not improve, and may worsen, outcomes. This may be because hyperoxaemia induces vasoconstriction in systemic arteries.

Question 106

Commonly used intravenous fluid = Colloids (plasma substitutes)

Answer 106

- Mechanism of action = Colloid fluid preparations contain comparatively large, osmotically active molecules, such as albumin or modified gelatin. These do not readily cross semipermeable membranes, such as vascular endothelium, so in principle, their osmotic effect should ‘hold’ the infused volume in the intravascular compartment. Their effect in expanding circulating volume is therefore potentially greater than that of a crystalloid (a solution of small, water-soluble molecules, e.g. sodium chloride). Under experimental conditions, 70%–80% of a gelatin-based colloid remains in the plasma. However, in pathological states in which volume expansion is required (e.g. sepsis), the capillaries are ‘leaky’, and the colloid is lost into the interstitium more rapidly than predicted. On balance, evidence suggests that colloids are no better than crystalloids, and trials using starch-based colloids have demonstrated harm. Sodium-based crystalloids (e.g. compound sodium lactate, sodium chloride 0.9%) are therefore usually preferred. In people with ascites due to cirrhotic liver disease, large-volume paracentesis (generally defined as >5 L) can abruptly lower intraabdominal pressure. This reduces systemic vascular resistance, increases the capacitance of abdominal veins, and encourages fluid shifts from the intravascular to extracellular compartment. The resulting haemodynamic effects can be mitigated by plasma volume expansion, for which albumin is recommended. - Main indications = 1) To expand circulating volume in states of impaired tissue perfusion (including shock). However, compound sodium lactate and sodium chloride 0.9% are preferred. 2) In cirrhotic liver disease, albumin is used to mitigate haemodynamic effects from large-volume paracentesis (ascitic fluid drainage). - Contraindications = Caution is required in ▲ heart failure, due to the risk of worsening cardiac output (see ADVERSE EFFECTS). If fluid resuscitation is required, it is best to reduce the volume of fluid challenges, but still to infuse them rapidly so that the effect of transient volume expansion is appreciated. In ▲ renal impairment, monitor fluid balance closely to avoid volume overload. - Route of admin = Infusions may be administered simply through a giving set, in which case the flow is controlled with a roller valve. A pressure bag can be applied to infuse the fluid more quickly if required. An infusion pump can be used to control the rate and volume precisely, although the maximum infusion rate is usually too slow for an effective fluid challenge. An alternative is to use a 50-mL syringe and a three-way tap to give the desired volume by successive injection of aliquots. - Adverse effects = Infusion of colloid solutions promotes oedema. Excessive plasma volume expansion may increase left ventricular filling beyond the point of maximal contractility on the Starling curve, worsening cardiac output and potentially precipitating pulmonary oedema. Gelatins may cause hypersensitivity reactions, including anaphylaxis—another reason to prefer crystalloids, which are non-allergenic. - Examples = gelatins, albumin

Question 107

Commonly used intravenous fluid solutions = Balanced crystalloid solutions

Answer 107

- Mechanism of action = Compound sodium lactate (more commonly known by its eponymous name, Hartmann’s solution) is a balanced crystalloid solution. Its electrolyte composition approximates serum: 1 L contains Na+ 131 mmol, Cl– 111 mmol, K+ 5 mmol, Ca2+ 2 mmol, and lactate 29 mmol. The infused lactate is readily metabolised, generating bicarbonate. This makes it a suitable choice for providing sodium and water in patients unable to take enough orally. As compound sodium lactate contains sodium in a concentration similar to extracellular fluid, the infused volume is largely retained in the extracellular water compartment. As intravascular water accounts for about 20% of extracellular water, about 20% of the infused volume will remain in vessels to expand circulating volume (a transiently greater increase may occur before distribution is complete). This makes it a viable choice for use in fluid resuscitation. Its main advantage over sodium chloride 0.9% is its lower chloride content, making it less likely to cause hyperchloraemic acidosis. - Main indications = 1) To provide sodium and water for people unable to meet their water and electrolyte requirements orally (or by enteral tube). 2) To expand circulating volume in states of impaired tissue perfusion (including shock). This may be done as a ‘fluid challenge’, where a bolus of fluid (e.g. 500 mL) is infused rapidly. Sodium chloride 0.9% and colloids are alternatives. - Contraindications = Exercise caution during rapid infusion of IV fluid in patients with ▲ heart failure, due to the risk of pulmonary oedema (see Colloids). In renal impairment, monitor fluid balance closely to avoid overload. Compound sodium lactate contains potassium 5 mmol/L; this does not cause hyperkalaemia, but the serum potassium concentration should be monitored as part of overall disease management. Conventional advice is to avoid compound sodium lactate in ▲ severe liver disease because of reduced capacity to metabolise lactate. However, as lactate (the conjugate base) does not itself cause acidosis, the clinical implications of this are debatable. - Route of admin = Infusions may be administered simply through a giving set, in which case the flow is controlled with a roller valve and the rate estimated from the number of drips per minute. A pressure bag can be applied to infuse fluid more quickly if required. Preferably, however, an infusion pump should be used to control the rate precisely. The maximum rate of infusion using a pump is usually too slow for an effective fluid challenge. An alternative is to use a 50-mL syringe and a three-way tap to give the desired volume by successive injection of aliquots. - Adverse effects = Compound sodium lactate contains sodium, diffusion of which into the interstitium promotes oedema. Excessive plasma volume expansion may increase left ventricular filling beyond the point of maximal contractility on the Starling curve, worsening cardiac output and potentially precipitating pulmonary oedema. - Examples = Compound sodium lactate (Hartmann’s solution)

Question 108

Commonly used intravenous fluid solutions = Glucose (dextrose)

Answer 108

- Mechanism of action = Glucose (C6H12O6) is a monosaccharide that is the principal source of energy for cellular metabolism. Of its several isomeric configurations, D-glucose (dextrose) is most relevant in mammalian biology. Glucose 5% is given by IV infusion as a means of providing water and may be used in the reconstitution and dilution of drugs. Its glucose content ensures it is initially isotonic with serum, so that it does not induce osmotic lysis of cells in the immediate vicinity of infusion. Glucose is rapidly taken up by cells and metabolised, leaving ‘free’ (hypotonic) water that distributes across all body water compartments. Higher-concentration glucose solutions are used to treat hypoglycaemia; the mechanism for this is self-explanatory. In hyperkalaemia, soluble insulin is given to stimulate Na+/K+-ATPase and shift potassium into cells. In this context, glucose is given to prevent hypoglycaemia. - Main indications = 1) To provide water for people unable to meet their water requirements orally (or by enteral tube). 2) Severe hypoglycaemia. Glucagon is an alternative (see CLINICAL TIP). 3) As a substrate fluid in people receiving IV insulin infusions. 4) With insulin to treat hyperkalaemia. Calcium gluconate may also be given to stabilise the myocardium, and an ion-exchange agent (e.g. sodium zirconium cyclosilicate) to bind potassium in the gut. 5) Reconstitution and dilution of drugs administered by injection or infusion. Sodium chloride 0.9% and sterile water are alternatives. - Contraindications = Giving IV glucose in ▲ thiamine deficiency can cause Wernicke’s encephalopathy. If glucose is required for hypoglycaemia, thiamine (as Pabrinex®; see Vitamins) must also be given. In ▲ renal failure, close monitoring of fluid balance is essential to avoid overload. Administering hypotonic fluid in ▲ hyponatraemia (or in people more susceptible to its effects, e.g. ▲ children and those with ▲ acute brain injuries) may precipitate hyponatraemic encephalopathy. - Route of admin = IV fluids are provided in bags of various volumes, the largest of which is 1 L. Infusions may be administered simply through a giving set, in which case the flow is controlled with a roller valve, and the rate estimated from the number of drips per minute. It is preferable, though, to use an infusion pump to control the rate and volume precisely. - Adverse effects = Glucose 50% is highly irritant to veins and may cause local pain, phlebitis and thrombosis. Its use is now discouraged, unless it can be given via a central line. Glucose 20% is also irritant, but less so. Hyperglycaemia will occur if glucose administration exceeds its utilisation (more likely in people with diabetes mellitus). - Examples = glucose 5%, 10%, 20%, 50%

Question 109

Commonly used intravenous fluid solutions = sodium chloride

Answer 109

- Mechanism of action = Extracellular fluid (ECF) is made up of intravascular water (about 20%) and interstitial water (about 80%). Sodium is partitioned into ECF by Na+/K+-ATPase on cell membranes, which pumps sodium out of cells in exchange for potassium. As sodium is the main cation in ECF, it is the principal determinant of its osmolality. Osmolality is tightly regulated within a narrow range, so an increase in body sodium content (e.g. due to administration of a sodium-containing fluid) leads to an increase in ECF volume. The amount by which a fluid expands ECF depends on its sodium concentration. Sodium chloride 0.9% contains sodium 154 mmol/L, similar to ECF. Accordingly, ECF expands by approximately the same amount as the volume of sodium chloride 0.9% administered. This distributes between the intravascular and interstitial compartments, so about 20% of the volume administered remains in vessels to expand circulating volume. Sodium chloride solutions are also used to provide sodium and water if oral intake is insufficient. - Main indications = 1) To provide sodium and water for people unable to meet their water and electrolyte requirements orally (or by enteral tube). 2) To expand circulating volume in states of impaired tissue perfusion (including shock). Compound sodium lactate and colloids are alternatives. 3) Reconstitution and dilution of drugs administered by injection or infusion. Glucose solutions and sterile water are alternatives. - Contraindications = Caution is required with rapid IV infusions in ▲ heart failure, due to the risk of pulmonary oedema (see Colloids for further discussion). In renal impairment, monitor fluid balance closely to avoid overload. - Route of admin = Infusions may be administered through a giving set, in which case the flow is controlled with a roller valve, and the rate estimated from the number of drips per minute. Preferably, though, an infusion pump should be used to control the rate and volume precisely. The maximum rate of infusion using a pump is usually too slow for an effective fluid challenge. An alternative is to use a 50-mL syringe and a three-way tap to give the desired volume by successive injection of aliquots. - Adverse effects = Diffusion of sodium and water into the interstitium promotes oedema. The concentration of chloride in sodium chloride 0.9% (154 mmol/L) is significantly higher than that of ECF (about 100 mmol/L). This may cause hyperchloraemia which, in turn, promotes acidaemia. Probably the best explanation for this (among the several proposed) is that as Cl– concentration rises, so HCO3– concentration must fall (and/or H+ and K+ rise) to maintain electroneutrality. Excessive plasma volume expansion may increase left ventricular filling beyond the point of maximal contractility on the Starling curve, worsening cardiac output and potentially precipitating pulmonary oedema. - Examples = sodium chloride 0.9%, 0.45%

Question 110

Commonly used intravenous fluid solutions = Potassium, intravenous

Answer 110

- Mechanism of action = The normal requirement to prevent potassium depletion is about 1 mmol/kg/day in adults with normal renal function. In people unable to tolerate dietary intake, who are instead receiving their sodium and water requirement by IV infusion, potassium may be provided intravenously. Established potassium depletion and hypokalaemia may be caused, for example, by diarrhoea, vomiting, drugs (e.g. loop and thiazide diuretics), and secondary hyperaldosteronism. In severe cases, hypokalaemia may result in arrhythmias (which may be life-threatening) and muscle weakness. IV potassium repletion in these scenarios may be life-saving. For best effect, IV potassium is given with sodium chloride rather than glucose. This is because infusion of negatively charged Cl– ions promotes retention of K+ in the serum, whereas glucose may promote insulin release with resultant stimulation of Na+/K+-ATPase, shifting potassium into cells. Hypokalaemia is often associated with hypomagnesaemia. When it is, it may be difficult to correct unless magnesium is also replaced. Always check the magnesium level and prescribe magnesium replacement if necessary. - Main indications = 1) Prevention of potassium depletion in people unable to meet their electrolyte requirements orally (see also Potassium, oral). 2) Treatment of established potassium depletion and hypokalaemia. IV administration is necessary when this is severe (<2.5 mmol/L), symptomatic or associated with electrocardiogram (ECG) changes. - Contraindications = It is generally unnecessary and potentially dangerous to prescribe potassium in ▲ renal impairment or ▲ oliguria, as potassium losses are minimal and susceptibility to hyperkalaemia is high. - Route of admin = Potassium should be infused at a rate no higher than 10 mmol/hr, due to the risks of venous irritation and cardiac toxicity. For routine use in prevention of potassium depletion, the other considerations for the administration of potassium are the same as those for fluid replacement in general. In the treatment of established potassium depletion and hypokalaemia, when the patient may be at heightened risk of arrhythmias, IV potassium should ideally be given into a large vein and under close monitoring. In intensive care units, higher concentrations may be given via a central venous catheter. - Adverse effects = The major risk of IV potassium infusion is overcorrection leading to hyperkalaemia and a resultant risk of arrhythmias. Close monitoring is essential to avoid this. Potassium-containing solutions are irritant to veins if infused rapidly or in too high concentration. For this reason, the infusion rate in a peripheral vein should generally not exceed 10 mmol/hr. - Examples = potassium chloride 0.15% (20 mmol/L), 0.3% (40 mmol/L)