Mode of Action

Question 1

5α-reductase inhibitors

Answer 1

Inhibits intracellular 5α-reductase; which converts testosterone to active metabolite dihydrotestosterone, stimulating prostatic growth; inhibition reduces size of prostate gland and improves urinary flow.
Can take months for this evident effect; therefor α-blocker is usually preferred for initial therapy, and 5α-reductase inhibitor added if response is poor or prostate is particularly bulky.

Question 2

α-blockers

Answer 2

Most drugs in this class (incl doxazosin, tamsulosin and alfuzosin) are highly selective for the α1-adrenoceptor.

Are found mainly in smooth muscle of vessels and urinary tract (esp bladder neck and prostate).
Stimulation induces contraction; blockade induces relaxation

α1-blockers –> vasodilatation and a fall in BP, and reduced resistance to bladder outflow.

Question 3

Acetylcholinesterase inhibitors

Answer 3

Ach is a CNS NT, essential to many brain functions incl learning and memory.
Decrease in activity of brain’s cholinergic system seen in Alzheimer’s and in dementia associated with PD.

Drugs inhibit cholinesterase enzymes that break down acetylcholine in CNS; increasing availability of acetylcholine for neurotransmission, reduce rate of cognitive decline. However, recovery of function is modest and not universal.

Question 4

Acetylcysteine (N-acetylcysteine)

Answer 4

In therapeutic doses, paracetamol is metabolised mainly by conjugation with glucuronic acid and sulfate.
A small amount is converted to NAPQI, which is hepatotoxic.
Normally, this is quickly detoxified by conjugation with glutathione.
However, in poisoning, body’s supply of glutathione is overwhelmed and NAPQI is free to cause liver damage.
Acetylcysteine replenishes body’s supply of glutathione; also has antioxidant effects, which may contribute to its effect in preventing contrast nephropathy

If brought into contact with mucus, it breaks disulphide bonds, degrading 3D mucus matrix, reducing its viscosity. For patients who have tenacious respiratory secretions (e.g. in bronchiectasis), this may aid sputum clearance.

Question 5

Activated charcoal

Answer 5

Van der Waals forces are responsible for mechanism of action
Molecules are adsorbed onto surface ofcharcoal as they travel through gut, reducing their absorption into the circulation.
Only useful in cases where the poison ingested is likely to be adsorbed onto it; determined by its ionic status and solubility in water.
Weakly ionic, hydrophobic substances (e.g. benzos, MTX) are generally well adsorbed by activated charcoal.
Strongly ionic and hydrophilic substances (strong acids/bases, alcohols, lithium and iron) are not adsorbed.

Question 6

Adenosine

Answer 6

In the heart, activation of GPC-receptors –> decr frequency of spontaneous depolarisations (automaticity) + incr resistance to depolarisation (refractoriness).
This transiently slows sinus rate and conduction velocity and increases AV node refractoriness.
Many SVTs arise from re-entry circuits involving AV node. Increasing refractoriness in AV node breaks the re-entry circuit, allowing normal DPs from SA node to resume control of HR (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 ventricles, it allows closer inspection of the atrial rhythm on ECG.
Duration of effect of adenosine is very short; half-life in plasma is < 10 seconds.

Question 7

Adrenaline

Answer 7

Potent agonist of the α1-, α2-, β1- and β2-adrenoceptors, –> sympatheticeffects.
- vasoconstriction of vessels supplying skin, mucosa and abdominal viscera (α1);
- incr HR force of contraction and myocardial excitability (β1)
- vasodilatation of vessels supplying heart and muscles (β2).
In cardiac arrest, the redistribution of blood flow in favour of heart is desirable

Additional effects of adrenaline, mediated by β2-receptors, are bronchodilatation and suppression of inflammatory mediator release from mast cells.
Explains its use in anaphylaxis, where widespread release of inflammatory mediators from mast cells produces generalised vasodilatation, profound hypotension and often bronchoconstriction.

Question 8

ALdosterone antagonists

Answer 8

A mineralocorticoid produced in adrenal cortex; acts on mineralocorticoid receptors in distal tubules of kidney to increase activity of luminal epithelial sodium (Na+) channels (ENaC).
Increasing reabsorption of sodium + water, elevating BP, with a corresponding increase in potassium excretion.

Inhibition increases sodium and water excretion and potassium retention.
Their effect is greatest when circulating aldosterone is increased, e.g. in primary hyperaldosteronism or cirrhosis.

Question 9

Alginates and antacids

Answer 9

Most often taken as compound preparations containing an alginate with one or more antacids e.g.sodium bicarbonate, calcium carbonate, magnesium or aluminium salts.
Antacids buffer stomach acids.
Alginates increase the viscosity of stomach contents, reducesing reflux
After reacting with stomach acid they form a floating ‘raft’, which separates gastric contents from the GOJ to prevent mucosal damage. .

Question 10

Allopurinol

Answer 10

Xanthine oxidase inhibitor.
Xanthine oxidase metabolises xanthine (produced from purines) to uric acid.
Inhibition lowers plasma uric acid concentrations and reduces precipitation of uric acid in joints or kidneys.

Question 11

Aminoglycosides (gentamicin, amikacin, neomycin)

Answer 11

Bind irreversibly to bacterial ribosomes (30S); inhibit protein synthesis.
Are bactericidal (they kill bacteria)
Enter bacterial cells via an oxygen-dependent transport system. Streptococci and anaerobic bacteria do not have this transport system, so have innate aminoglycoside resistance.
As penicillins weaken bacterial cell walls, they may enhance aminoglycoside activity by increasing bacterial uptake.

Question 12

Aminosalicylates

Answer 12

In UC: mesalazine and sulfasalazine both exert therapeutic effects by releasing 5-aminosalicylic acid (5-ASA); has antiinflammatory and immunosuppressive effects acting topically on gut rather than systemically. For this reason, 5-ASA preparations are designed to delay delivery of the active ingredient to the colon.

Sulfasalazine consists of a molecule of 5-ASA linked to sulfapyridine. In colon, bacterial enzymes break this link and release the two molecules.
Sulfapyridine does not contribute to its therapeutic effect in UC s, but it does cause side effects; largely replaced by mesalazine
By contrast, sulfapyridine is probably the active component of sulfasalazine in RA; Mesalazine has no role in rheumatoid arthritis.

Question 13

Amiodarone

Answer 13

Many effects on myocardial cells,
Including blockade of sodium, calcium and potassium channels, and antagonism of α- and β-adrenergic receptors.
These reduce spontaneous DP, slow conduction velocity and increase resistance to depolarisation (refractoriness), including in the AVN.
By interfering with AV node conduction, amiodarone reduces ventricular rate in AF and atrial flutter.

Through its other effects, it may also incr 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

Question 14

ACEi

ramipril, lisinopril, perindopril

Answer 14

Block action of ACE; prevent conversion of angiotensin I to angiotensin II.
Angiotensin II is a vasoconstrictor + stimulates aldosterone secretion. Blocking it reduces peripheral vascular resistance (afterload), lowering BP.
Particularly dilates efferent glomerular arteriole, which decr intraglomerular pressure and slows progression of CKD.

Reducing aldosterone level promotes sodium and water excretion. This can help to help decr venous return (preload); has a beneficial effect in heart failure.

Question 15

Angiotensin receptor blockers

losartan, candesartan, irbesartan

Answer 15

Similar effects to ACEi, but instead of inhibiting conversion of a-I to a-II, ARBs block action of a-II on the angiotensin type 1 (AT1) receptor.
Angiotensin II is a vasoconstrictor and stimulates aldosterone secretion.

Blocking it reduces peripheral vascular resistance (afterload), lowering BP.
Particularly dilates efferent glomerular arteriole, which decr intraglomerular pressure and slows progression of CKD.

Reducing aldosterone level promotes sodium and water excretion. This can help to help decr venous return (preload); has a beneficial effect in heart failure.

Question 16

SSRI

Answer 16

preferentially inhibit neuronal reuptake of 5-HT from synaptic cleft, increasing its availability
Differ from TCA in that they do not inhibit NA uptake and cause less blockade of other receptors

Question 17

Tricyclics

Answer 17

Inhibit neuronal reuptake of 5-HT and NA from synaptic cleft, increasing availability for neurotransmission.

Improve mood and physical symptoms in moderate-to-severe (but not mild) depression and probably accounts for their effect in modifying neuropathic pain.

TCAs also block muscarinic, (H1), (α1 and α2) and (D2) receptors; accounting for extensive adverse-effects

Question 18

Venlafaxine, Mirtazepine

Answer 18

Venlafaxine is a 5-HT and NA reuptake inhibitor (SNRI)

Mirtazapine is an antagonist of inhibitory pre-synaptic α2-adrenoceptors.

Both increase availability of monoamines for neurotransmission, improving mood and physical symptoms in moderate-to-severe (but not mild) depression.

Venlafaxine is a weaker antagonist of muscarinic and histamine (H1) receptors than TCAs;
Mirtazapine is a potent antagonist of H1 but not muscarinic receptors.
They therefore have fewer antimuscarinic side effects than TCAs, although mirtazapine commonly causes sedation.

Question 19

Antiemetic D2 antagonists

metoclopramide, domperidone

Answer 19

N&V are triggered by gut irritation, drugs, motion and vestibular disorders, higher stimuli (sights, smells, emotions).
These pathways converge on a ‘vomiting centre’ in medulla, receiving inputs from chemoreceptor trigger zone, solitary tract nucleus (innervated by vagus), the vestibular system and higher neurological centres.

Dopamine, via D2 receptors, is relevant in two respects: First, D2 receptor is the main receptor in the CTZ, which is the area responsible for sensing emetogenic substances in blood. D2-receptor antagonists are therefore effective in nausea and vomiting caused by CTZ stimulation (e.g. by emetogenic drugs).

Second, dopamine is an important NT in gut, where it promotes relaxation of stomach and lower oesophageal sphincter and inhibits gastroduodenal coordination.
D2-receptor antagonists therefore have a prokinetic effect, promoting gastric emptying; contributes to their antiemetic action in conditions associated with reduced gut motility (e.g. opioids or diabetic gastroparesis).

Question 20

Antiemetics, histamine H1-receptor antagonists

cyclizine, cinnarizine, promethazine

Answer 20

N&V are triggered by gut irritation, drugs, motion and vestibular disorders, higher stimuli (sights, smells, emotions).
These pathways converge on a ‘vomiting centre’ in medulla, receiving inputs from chemoreceptor trigger zone, solitary tract nucleus (innervated by vagus), the vestibular system and higher neurological centres.

Histamine (H1) and ACh (muscarinic) receptors predominate in vomiting centre and in its communication with 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, post-operative, radiotherapy), particularly when associated with motion or vertigo.

Question 21

Antiemetics, serotonin 5-HT3-receptor antagonists

Ondansetron

Answer 21

Nausea and vomiting are triggered by gut irritation, drugs, motion and vestibular disorders, as well as higher stimuli (sights, smells, emotions). The various pathways converge on a ‘vomiting centre’ in the medulla, which receives inputs from the chemoreceptor trigger zone (CTZ), the solitary tract nucleus (which is innervated by the vagus nerve), the vestibular system and higher neurological centres. 5-HT plays an important role in two of these pathways. First, there is a high density of 5-HT3 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.

Question 22

Antifungal drugs

Answer 22

Fungal cell membranes contain ergosterol. As ergosterol is not seen 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 immunosuppressed patients. Mechanisms include alteration of membrane synthesis to exclude ergosterol, changes in target enzymes or increased drug efflux.

Question 23

Antihistamines (H1-receptor antagonists)

Answer 23

The term ‘antihistamine’ is generally used to mean an antagonist 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), vasodilatation 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 vasodilatation 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, so adrenaline is the more important first-line treatment.

Question 24

Anti-motility drugs

Answer 24

Loperamide is an opioid that is pharmacologically similar to pethidine. However, unlike pethidine, is does not penetrate the central nervous system (CNS), so has no analgesic effects. It is an agonist of the opioid µ-receptors in the gut. This increases non-propulsive contractions of the gut smooth muscle but reduces propulsive (peristaltic) contractions. As a result, transit of bowel contents is slowed and anal sphincter tone is increased. Slower gut transit also allows more time for water absorption, which (in the context of watery diarrhoea) has a desirable effect in hardening the stool. Other opioids (e.g. codeine phosphate) have similar effects but, unless analgesia is also required, there is little reason to prefer them over loperamide.

Question 25

Antimuscarinics (bronchodilators)

ipratropium, tiotropium

Answer 25

Antimuscarinic drugs bind to the muscarinic receptor, where they act as a competitive inhibitor of acetylcholine. Stimulation of the muscarinic receptor brings about a wide range of parasympathetic ‘rest and digest’ effects. In blocking the receptor, antimuscarinics have the opposite effects: they increase heart rate and conduction; reduce smooth muscle tone, including in the respiratory tract and bladder; and reduce secretions from glands in the respiratory and GI tracts. In the eye, they cause relaxation of the pupillary constrictor and ciliary muscles, causing pupillary dilatation and preventing accommodation, respectively.

Question 26

Antimuscarinics, cardiovascular and gastrointestinal uses

atropine, hyoscine butylbromide

Answer 26

Antimuscarinic drugs bind to the muscarinic receptor, where they act as a competitive inhibitor of acetylcholine. Stimulation of the muscarinic receptor brings about a wide range of parasympathetic ‘rest and digest’ effects. In blocking the receptor, antimuscarinics have the opposite effects: they increase heart rate and conduction; reduce smooth muscle tone and peristaltic contraction, including in the gut and urinary tract; and reduce secretions from glands in the respiratory tract and gut. In the eye they cause relaxation of the pupillary constrictor and ciliary muscles, causing pupillary dilatation and preventing accommodation, respectively.

Question 27

Antimuscarinics, genitourinary uses

oxybutynin, tolterodine

Answer 27

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 patients with overactive bladder, this may reduce urinary frequency, urgency and urge incontinence. Antimuscarinics help in overactive bladder through antagonism of 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.

Question 28

Antipsychotics, first-generation (typical)

haloperidol, chlorpromazine, prochlorperazine

Answer 28

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 the context of acute psychomotor agitation.

Question 29

Antipsychotics, second-generation (atypical)

quetiapine, olanzapine, risperidone, clozapine

Answer 29

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 probably explains the drugs’ antipsychotic effects, 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. As compared with first-generation antipsychotics, second-generation agents seem more efficacious in ‘treatment-resistant’ schizophrenia (particularly clozapine) and against negative symptoms, and have a lower risk of extrapyramidal symptoms. This may be because of a higher affinity for other receptors (particularly 5-HT2A), and a characteristic of ‘looser’ binding to D2 receptors (in the case of clozapine and quetiapine).

Question 30

Antiplatelets - ADP-receptor anatagonists

clopidogrel, ticagrelor, prasugrel

Answer 30

Thrombotic events occur when platelet-rich thrombus forms in atheromatous arteries and occludes the circulation. These drugs 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.

Question 31

Anitplatelets - Aspirin

Answer 31

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 (which does not have a nucleus to allow synthesis of new COX) and thus only wears off as new platelets are made.

Question 32

B - blockers

Answer 32

β1-adrenoreceptors are located mainly in the heart, whereas β2-adrenoreceptors are found mostly in smooth muscle of blood vessels and airways. Via the β1-receptor, β-blockers reduce force of contraction and speed of conduction in the heart. This relieves myocardial ischaemia by reducing cardiac work and oxygen demand, and increasing myocardial perfusion. They improve prognosis in heart failure, probably by ‘protecting’ the heart from chronic sympathetic stimulation. They slow the ventricular rate in AF mainly by prolonging the refractory period of the atrioventricular (AV) node. Through the same effect they may terminate SVT if this is due to a self-perpetuating (‘re-entry’) circuit that takes in the AV node. In hypertension, β-blockers lower BP through a variety of means, one of which is by reducing renin secretion from the kidney, since this is mediated by β1-receptors.

Question 33

β2-AGonists

Answer 33

β2-receptors are found in smooth muscle of the bronchi, gut, uterus and blood vessels. Stimulation of this G protein-coupled receptor activates a signalling cascade that leads to smooth muscle relaxation. This improves airflow in constricted airways, reducing the symptoms of breathlessness. Like insulin, β2-agonists also stimulate Na+/K+-adenosine triphosphatase (ATPase) pumps on cell surface membranes, thereby causing a shift of K+ from the extracellular to intracellular compartment. This makes them a useful adjunct in the treatment of hyperkalaemia, particularly when IV access is difficult. However, their effect is less reliable than other therapies, so they should not be used in isolation. β2-agonists are classified as short-acting (salbutamol, terbutaline) or long-acting (e.g. salmeterol, formoterol) according to their duration of effect.

Question 34

Benzodiazepines

Answer 34

The target of benzodiazepines is the γ-aminobutyric acid type A (GABAA) receptor. The GABAA receptor is a chloride 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. Benzodiazepines facilitate
and enhance binding of GABA to the GABAA receptor. This has a
widespread depressant effect on synaptic transmission. The clinical
manifestations of this include reduced anxiety, sleepiness, sedation and
anticonvulsive effects. Ethanol (‘alcohol’) also acts on the GABAA
receptor, and in chronic excessive use the patient becomes tolerant
to its presence. Abrupt cessation then provokes the excitatory state
of alcohol withdrawal. This can be treated by introducing a
benzodiazepine, which can then be withdrawn in a gradual and more
controlled way

Question 35

Bisphosphonates

Answer 35

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, hence 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.

Question 36

Calcium Channel blockers

amlodipine, nifedipine, diltiazem, verapamil

Answer 36

Calcium channel blockers decrease 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 cardiac 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 the vessels

Question 37

Carbamezapine

Answer 37

The mechanism of action of carbamazepine is incompletely understood.
It appears to inhibit neuronal sodium channels, stabilising resting
membrane potentials and reducing neuronal excitability (see Phenytoin).
This may inhibit spread of seizure activity in epilepsy, control neuralgic
pain by blocking synaptic transmission in the trigeminal nucleus and
stabilise mood in bipolar disorder by reducing electrical ‘kindling’ in the
temporal lobe and limbic system.

Question 38

Cephalosporins and Carbapenems

Answer 38

Cephalosporins and carbapenems are derived from naturally occurring
antimicrobials produced by fungi and bacteria. Like penicillins, their
antimicrobial 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. Both types of antibiotic
have a broad spectrum of action. For cephalosporins, progressive
structural modification has led to successive ‘generations’ (first to fifth),
with increasing activity against Gram-negative bacteria and less oral
activity. 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).

Question 39

Clopidogrel

Answer 39

Thrombotic events occur when platelet-rich thrombus forms in
atheromatous arteries and occludes the circulation. Clopidogrel
prevents platelet aggregation and reduces 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 cyclooxygenase pathway, its actions are synergistic
with those of aspirin.

Question 40

Compound (β2-agonist–corticosteroid) inhalers

Answer 40

Compound inhalers contain an inhaled corticosteroid to suppress airway
inflammation, and a long-acting β2-agonist (LABA) to stimulate
bronchodilation. The prescription of these drugs in combination reduces
the number of different inhalers that need to be taken and increases
adherence to treatment. In asthma, compound inhalers ensure that
long-acting β2-agonists are not taken without an inhaled corticosteroid.
This is important because, without a steroid, long-acting β2-agonists are
associated with increased asthma deaths. In COPD, combined
treatment is more effective in reducing exacerbations than either drug
alone.
Seretide® contains fluticasone and salmeterol. Symbicort® contains
budesonide and formoterol.

Question 41

Corticosteroids (glucocorticoids), systemic

Answer 41

These corticosteroids exert mainly glucocorticoid effects. They bind to
cytosolic glucocorticoid receptors, which then translocate to the nucleus
and bind to glucocorticoid-response elements, which regulate gene
expression. Corticosteroids are most commonly prescribed to modify
the immune response. They upregulate anti-inflammatory genes
and downregulate pro-inflammatory genes (e.g. cytokines, tumour
necrosis factor alpha). Direct actions on inflammatory cells include
suppression of circulating monocytes and eosinophils. Their metabolic
effects include increased gluconeogenesis from increased circulating
amino and fatty acids, released by catabolism (breakdown) of muscle
and fat. These drugs also have mineralocorticoid effects, stimulating
Na+
and water retention and K+
excretion in the renal tubule.

Question 42

Corticosteroids (glucocorticoids), inhaled

Answer 42

Corticosteroids pass through the plasma membrane and interact with
receptors in the cytoplasm. The activated receptor then passes into
the nucleus to modify the transcription of a large number of genes.
Pro-inflammatory interleukins, cytokines and chemokines are
downregulated, while anti-inflammatory 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.

Question 43

Digoxin

Answer 43

Digoxin is negatively chronotropic (it reduces the heart rate) and
positively inotropic (it increases the force of contraction). In atrial
fibrillation 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.

Question 44

Loop diuretics

Answer 44

As their name suggests, loop diuretics act principally on the ascending
limb of the loop of Henle, where they inhibit the Na+
/K+
/2Cl−
cotransporter. 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 dilatation 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 the
clinical response is usually evident before a diuresis is established.

Question 45

Diuretics - Potassium sparing

Answer 45

Potassium-sparing diuretics such as amiloride are relatively weak
diuretics alone. However, in combination with another diuretic, they
can counteract potassium loss and enhance diuresis. Amiloride
acts on the distal convoluted tubules in the kidney. It inhibits the
reabsorption of sodium (and therefore water) by epithelial sodium
channels (ENaC), leading to sodium and water excretion, and retention
of potassium. This counteracts the potassium losses associated with
loop- or thiazide-diuretic therapy. Amiloride is available as a medicine in
its own right, but tends more often to be used as part of a combination
tablet with furosemide (a loop diuretic) as co-amilofruse, or with
hydrochlorothiazide (a thiazide diuretic) as co-amilozide. The ratio of the
two drugs in the combination tablets is designed to have a neutral effect
on potassium balance, although in practice this may not always be the
case

Question 46

Diuretics, thiazide and thiazide-like

bendroflumethiazide, indapamide, chlortalidone

Answer 46

Thiazide diuretics (e.g. bendroflumethiazide) and thiazide-like diuretics
(e.g. indapamide, chlortalidone) differ chemically but have similar effects
and uses; we refer to them 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 long-term antihypertensive effect is probably mediated by
vasodilatation, the mechanism of which is incompletely understood.

Question 47

Dopaminergic drugs for Parkinson’s disease

levodopa (as co-careldopa, co-beneldopa), ropinirole, pramipexol

Answer 47

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.

Question 48

Fibrinolytic drugs

Alteplase, Streptokinase

Answer 48

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 patient outcomes.

Question 49

Gabapenting & Pregablin

Answer 49

From a structural point of view, gabapentin is closely related to
γ-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the
brain. However, its mechanism of action, although not completely
understood, appears largely unrelated to GABA. It binds with voltagesensitive calcium (Ca2+
) channels, where it presumably prevents
inflow of Ca2+
and, in so doing, inhibits neurotransmitter release. This
interferes with synaptic transmission and reduces neuronal excitability.
Pregabalin is a structural analogue of gabapentin that probably has a
similar mechanism of action.

Question 50

Histamine H2-receptor antagonists

ranitidine

Answer 50

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, among other
things, by histamine. Histamine is released by local paracrine cells and
binds to H2-receptors on the gastric parietal cell. Via a secondmessenger 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 suppressive effect.

Question 51

Heparins and fondaparinux

enoxaparin, dalteparin, fondaparinux, unfractionated heparin

Answer 51

Thrombin and factor Xa are key components of the final commoncoagulation pathway that leads to formation of a fibrin clot. By inhibiting their function, heparins and fondaparinux prevent the formation and propagation of blood clots. Unfractionated heparin (UFH) activates
antithrombin that, in turn, inactivates clotting factor Xa and thrombin. Low molecular weight heparins such as dalteparin and
enoxaparin have a similar mechanism of action but preferentially
inhibit factor Xa. Low molecular weight heparins have a more predictable effect and, unlike UFH, do not usually require laboratory monitoring. Consequently, LMWHs are now preferred in most indications. Fondaparinux is a synthetic compound that is similar to heparin. It inhibits factor Xa only. It appears to have similar efficacy to
LMWH and has become the anticoagulant of choice in the treatment of ACS in many hospitals in the UK.

Question 52

Insulin

Answer 52

In diabetes mellitus, exogenous insulin functions similarly to endogenous insulin. It stimulates glucose uptake from the circulation into tissues, including skeletal muscle and fat, and increases use of glucose as an energy source. Insulin stimulates glycogen, lipid and
protein synthesis and inhibits gluconeogenesis and ketogenesis. For the
treatment of hyperkalaemia, insulin drives K+ into cells, reducing serum K+ concentrations. However, once insulin treatment is stopped,K+ leaks back out of the cells into the circulation, so this is 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): insulin aspart, e.g. Novorapid®; short acting (early onset,
short duration): soluble insulin, e.g. Actrapid®; intermediate acting
(intermediate onset and duration): isophane (NPH) insulin, e.g. Humulin
I
®; and long acting (flat profile with regular administration): insulin
glargine (Lantus®), insulin detemir (Levemir®). Biphasic insulin
preparations contain a mixture of rapid- and intermediate-acting insulins,
e.g. Novomix® 30 (insulin aspart/insulin aspart protamine).
Where IV insulin is required (hyperkalaemia, diabetic emergencies,
peri-operative glucose control), soluble insulin (Actrapid®) is usually used.

Question 53

Iron

Answer 53

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.

Question 54

Bulk-forming laxatives

(ispaghula husk, methylcellulose, sterculia

Answer 54

Bulk-forming laxatives contain a hydrophilic substance, such as a
polysaccharide or cellulose, which is not absorbed or broken down in
the gut. Like dietary fibre, this attracts water into the stool and
increases its mass. Adequate fluid intake is therefore important to the
action of bulk-forming laxatives. Increased stool bulk stimulates
peristalsis and helps to relieve constipation. It can also help in chronic
diarrhoea. This can be useful for some patients with diverticular disease,
irritable bowel syndrome, or when managing stoma output.

Question 55

Osmotic laxatives

lactulose, macrogol, phosphate enema

Answer 55

These medicines are based on osmotically active substances (sugars
or alcohols) that are not digested or absorbed, and which therefore
remain in the gut lumen. They hold water in the stool, maintaining its
volume and stimulating peristalsis. Lactulose, in particular, also
reduces ammonia absorption. It does this by increasing gut transit rate
and acidifying the stool, which inhibits the proliferation of ammoniaproducing bacteria. This is helpful in patients with liver failure, in
whom ammonia plays a major role in the pathogenesis of hepatic
encephalopathy.

Question 56

Stimulant laxatives
(senna, bisacodyl, glycerol suppositories, docusate sodium)

Answer 56

Stimulant (also known as irritant or contact) laxatives increase water
and electrolyte secretion from the colonic mucosa, thereby
increasing 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. Rectal
administration of stimulant laxatives, such as glycerol suppositories,
provokes a similar but more localised effect and can be useful to treat
faecal impaction. Docusate sodium has both stimulant and faecal
softening actions.

Question 57

Lidocaine

Answer 57

Lidocaine (formerly known as lignocaine) enters cells in its uncharged
form, then accepts a proton to become positively charged. From inside
the cell, it enters and then blocks voltage-gated sodium channels on
the surface membrane. This prevents initiation and propagation of action
potentials in nerves and muscle, inducing local anaesthesia in the area
supplied by blocked nerve fibres. In the heart, it reduces the duration of
the action potential, slows conduction velocity and increases the
refractory period. These effects may terminate VT and improve the
chances of successfully treating VF.

Question 58

Macrolides

clarithromycin, erythromycin, azithromycin

Answer 58

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 bacteria growth), which assists the
immune system in killing and removing bacteria from the body.
Erythromycin, the first macrolide, was isolated from Streptomycetes
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.
Bacterial resistance to macrolides is common, mainly due to ribosomal
mutations preventing macrolide binding.

Question 59

Metformin

Answer 59

Metformin (a biguanide) lowers blood glucose by increasing the
response (sensitivity) to insulin. It suppresses hepatic glucose
production (glycogenolysis and gluconeogenesis), increases glucose
uptake and utilisation by skeletal muscle and suppresses intestinal
glucose absorption. It achieves this by diverse intracellular mechanisms,
which are incompletely understood. It does not stimulate pancreatic
insulin secretion and therefore does not cause hypoglycaemia. It
reduces weight gain and can induce weight loss, which can prevent
worsening of insulin resistance and slow deterioration of diabetes
mellitus.

Question 60

Methotrexate

Answer 60

Methotrexate inhibits dihydrofolate reductase, which converts dietary
folic acid to tetrahydrofolate (FH4). FH4 is required for DNA and protein
synthesis, so lack of FH4 prevents cellular replication. Actively
dividing cells are particularly sensitive to the effects of methotrexate,
accounting for its efficacy in cancer. Methotrexate also has antiinflammatory and immunosuppressive effects. These are mediated in
part by inhibition of inflammatory mediators such as interleukin (IL)-6,
IL-8 and tumour necrosis factor (TNF)-α, although the underlying
mechanisms are not fully understood.

Question 61

Metronidazole

Answer 61

Metronidazole enters bacterial cells 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. As aerobic bacteria are not able to
reduce metronidazole in this manner, the spectrum of action of
metronidazole is restricted to anaerobic bacteria (and protozoa).
Bacterial resistance to metronidazole is generally low but is increasing
in prevalence. Mechanisms include reduced uptake of metronidazole
and reduced generation of nitroso free radicals.

Question 62

Naloxone

Answer 62

Naloxone binds to opioid receptors (particularly the pharmacologicallyimportant 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 its receptors and, in so doing, it reverses its effects.
In opioid toxicity, this is used to restore an adequate level of
consciousness and respiratory rate.

Question 63

Nicorandil

Answer 63

Nicorandil causes both arterial and venous vasodilatation through its
actions as a nitrate (see Nitrates) and by activating K+
-ATP
channels. Efflux of K+
through activated K+
-ATP channels leads to
hyperpolarisation of the cell membrane and subsequent inactivation of
voltage-gated Ca2+
channels. The net effect is a decrease in free
intracellular calcium. As calcium is required for smooth muscle
contraction, relaxation and vasodilatation occur. The effect of this is to
reduce cardiac preload and systemic and coronary vascular resistance.
This improves myocardial perfusion, and decreases myocardial
work and oxygen demand. Clinically, this reduces the frequency and
severity of angina attacks.

Question 64

Nitrates

Answer 64

Nitrates are converted to nitric oxide (NO). 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 vasodilatation. 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 anti-anginal
effects are mediated by reduction of preload.

Question 65

NSAIDs

Answer 65

NSAIDs inhibit synthesis of prostaglandins from arachidonic acid by
inhibiting cyclooxygenase (COX). COX exists as two main isoforms.
COX-1 is the constitutive form. It stimulates prostaglandin synthesis that
is essential to preserve integrity of the gastric mucosa; maintain renal
perfusion (by dilating afferent glomerular arterioles); and inhibit 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
between the two. Selective COX-2 inhibitors (e.g. etoricoxib) were
developed in an attempt to reduce the adverse effects of NSAIDs.

Question 66

Opiods - compound preparations

co-codamol, co-dydramol

Answer 66

The mechanism of action of paracetamol is poorly understood.
Paracetamol is a weak inhibitor of cyclooxygenase (COX), the
enzyme involved in prostaglandin metabolism. In the central nervous
system, COX inhibition appears to increase the pain threshold. Codeine
and dihydrocodeine are weak opioids. They are metabolised by
cytochrome P450 enzymes to morphine and morphine-related
metabolites. These metabolites, which are agonists of opioid
µ-receptors, probably account for most of their analgesic effect (see
Opioids, strong). Combining two analgesics with different mechanisms
of action may offer better pain control than can be achieved with either
drug alone. Putting them together in a fixed-ratio compound product
improves convenience for the patient, although at a cost of reduced
flexibility in terms of dose titration

Question 67

Strong opioids 
(Morphine, oxycodone)

Answer 67

The term opioids encompasses naturally-occurring opiates (e.g.
morphine) plus synthetic analogues (e.g. oxycodone). Morphine and
oxycodone are strong opioids. The therapeutic action of opioids arises
from activation of opioid µ (mu) receptors in the central nervous
system. 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. Thus, in myocardial
infarction and acute pulmonary oedema they may reduce cardiac work
and oxygen demand, as well as relieving symptoms. That said, although
commonly used, the efficacy and safety of morphine in acute pulmonary
oedema is not firmly established.

Question 68

Opioids, weak

Tramadol, codeine, duhydrocodeine

Answer 68

In unmodified form, codeine and dihydrocodeine are very weak opioids.
They are metabolised in the liver to produce relatively small amounts of
morphine (from codeine) or dihydromorphine (from dihydrocodeine).
These metabolites, which are stronger agonists of opioid µ (mu)
receptors (see Opioids, strong), probably account for most of the
analgesic effect. About 10% of Caucasians have a less active form of
the key metabolising enzyme (called cytochrome P450 2D6), and these
people may find codeine and dihydrocodine largely ineffective. Tramadol
is a synthetic analogue of codeine; it is perhaps best classified as a
‘moderate’ strength opioid. Like codeine, tramadol and its active
metabolite are µ-receptor agonists. Unlike other opioids, tramadol also
affects serotonergic and adrenergic pathways, where it is thought to act
as a serotonin and noradrenaline reuptake inhibitor. This probably
contributes to its analgesic effect.

Question 69

Paracetamol

Answer 69

The mechanisms of action of paracetamol are poorly understood.
Paracetamol is a weak inhibitor of cyclooxygenase (COX), the
enzyme involved in prostaglandin metabolism. In the central nervous
system, COX inhibition appears to increase the pain threshold and
reduce prostaglandin (PGE2) concentrations in the thermoregulatory
region of the hypothalamus, controlling fever. Paracetamol has specificity
for COX-2 (the isoform induced in inflammation) rather than COX-1 (the
isoform involved in protecting the gastric mucosa and regulating renal
blood flow and clotting). However, despite its COX-2 selectivity,
paracetamol is a weak anti-inflammatory, as its actions are inhibited in
inflammatory lesions by the presence of peroxides.

Question 70

Penicillins

Answer 70

Penicillins inhibit the enzymes responsible for cross-linking
peptidoglycans in bacterial cell walls. This weakens cell walls,
preventing them from maintaining an osmotic gradient. Uncontrolled
entry of water into bacteria causes cell swelling, lysis and death.
Penicillins contain a β-lactam ring, which is responsible for their
antimicrobial activity. Side chains attached to the β-lactam ring can be
modified to make semi-synthetic penicillins. The nature of the side chain
determines the antimicrobial spectrum and other properties of the drug.
Bacteria resist the actions of penicillins by making β-lactamase, an
enzyme which breaks the β-lactam ring and prevents antimicrobial
activity. Other mechanisms of resistance include limiting the intracellular
concentration of penicillin (reduced bacterial permeability or increased
extrusion) or changes in the target enzyme to prevent penicillin binding.

Question 71

Penicillins - antipseudomonal

piperacillin with tazobactam (e.g. Tazocin®

Answer 71

Penicillins inhibit the enzymes responsible for cross-linking
peptidoglycans in bacterial cell walls. This weakens cell walls,
preventing them from maintaining an osmotic gradient. Uncontrolled
entry of water into bacteria causes cell swelling, lysis and death.
Penicillins contain a β-lactam ring, which is responsible for their
antimicrobial activity. Side chains attached to the β-lactam ring can be
modified to make semi-synthetic penicillins. For piperacillin, the side
chain of broad-spectrum penicillins has been converted to a form of
urea. This longer side chain may improve affinity to penicillin binding
proteins, increasing the spectrum of antimicrobial activity to include
Pseudomonas aeruginosa. Addition of the β-lactamase inhibitor
tazobactam confers antimicrobial activity against β-lactamaseproducing bacteria (e.g. Staphylococcus aureus, Gram-negative
anaerobes).

Question 72

Penicillins - Broad Spectrum

amoxicillin, co-amoxiclav

Answer 72

Penicillins inhibit the enzymes responsible for cross-linking peptidoglycans
in bacterial cell walls. This weakens cell walls, preventing them from
maintaining an osmotic gradient. Uncontrolled entry of water into bacteria
causes cell swelling, lysis and death. Penicillins contain a β-lactam
ring, which is responsible for their antimicrobial activity. Side chains
attached to the β-lactam ring can be modified to make semi-synthetic
penicillins. For amoxicillin, addition of an amino group to the side chain
increases activity against aerobic Gram-negative bacteria, making this a
‘broad-spectrum’ antibiotic. Addition of the β-lactamase inhibitor
clavulanic acid (creating co-amoxiclav) increases the spectrum of
antimicrobial activity further to include β-lactamase-producing bacteria
(e.g. Staphylococcus aureus, Gram-negative anaerobes).

Question 73

Penicillins - Penicillinase resistant

Flucloxacillin

Answer 73

Penicillins inhibit the enzymes responsible for cross-linking
peptidoglycans in bacterial cell walls. This weakens cell walls,
preventing them from maintaining an osmotic gradient. Uncontrolled
entry of water into bacteria causes cell swelling, lysis and death.
Penicillins contain a β-lactam ring, which is responsible for their
antimicrobial activity. Side chains attached to the β-lactam ring can be
modified to make semi-synthetic penicillins. The nature of the side chain
determines the antimicrobial spectrum and other properties of the drug.
For flucloxacillin, an acyl side chain protects the β-lactam ring from
β-lactamases, which are enzymes made by bacteria to deactivate
penicillin. This makes flucloxacillin effective against β-lactamase
producing staphylococci. Meticillin-resistant Staphylococcus aureus
(MRSA) resists the actions of flucloxacillin by reducing penicillin binding
affinity.

Question 74

Phenytoin

Answer 74

The mechanism of action of phenytoin is incompletely understood.
Phenytoin reduces neuronal excitability and electrical conductance
among brain cells, which inhibits the spread of seizure activity. It
appears to do this by binding to neuronal Na+
channels in their
inactive state, prolonging inactivity and preventing Na+
influx into the
neuron. This prevents a drift in membrane potential from the resting
(−70 mV) to the threshold (−55 mV) value required to trigger an action
potential. A similar effect in cardiac Purkinje fibres may account for
both antiarrhythmic and cardiotoxic effects of phenytoin.

Question 75

Phosphodiesterase (type 5) inhibitors

Answer 75

Sildenafil is a phosphodiesterase (PDE) inhibitor. It is selective for PDE
type-5 that is found predominantly in the smooth muscle of the corpus
cavernosum of the penis and arteries of the lung.
For an erection to occur, sexual stimulation is required. This releases
nitric oxide, which stimulates cyclic guanosine monophosphate (cGMP)
production, causing arterial smooth muscle relaxation, vasodilatation and
penile engorgement. As PDE5 is responsible for the breakdown of
cGMP, inhibition of this enzyme by sildenafil increases cGMP
concentrations, improving penile blood flow and erection quality.
It is worth noting sildenafil does not cause an erection without sexual
stimulation.
In the pulmonary vasculature, sildenafil causes arterial vasodilatation
by similar mechanisms so is used to treat primary pulmonary
hypertension.

Question 76

Oral potassium

Answer 76

Hypokalaemia is usually, although not always, due to potassium
depletion. This may be because of, for example, diarrhoea, vomiting, or
secondary hyperaldosteronism. Potassium supplementation may restore
normal potassium balance in this scenario. By contrast, 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. Treatment with a potassium-sparing diuretic
(or aldosterone antagonist) is therefore preferred. In redistributive
hypokalaemia the total body potassium content is normal, but the
serum concentration is low because of redistribution into cells. Drug
therapy (e.g. with insulin, salbutamol) is most often the culprit.
Management should ideally be to address the underlying cause

Question 77

PPIs

lansoprazole, omeprazole, pantoprazole

Answer 77

Proton pump inhibitors (PPIs) 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 gastric acid production
is that they are able to suppress gastric acid production almost
completely. In this respect they differ from H2-receptor antagonists.

Question 78

Quinine

Answer 78

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, the
mechanism of action of quinine is not well understood, but its overall
effect leads to rapid killing of P. falciparum parasites in the schizont
stage in the blood.

Question 79

Quinolones(ciprofloxacin, moxifloxacin, levofloxacin )

Answer 79

Quinolones kill bacteria by inhibiting DNA synthesis. They are particularly
active against aerobic Gram-negative bacteria, which explains their utility in
treatment of urinary and gastrointestinal infections. Moxifloxacin and
levofloxacin are newer quinolones with enhanced activity against
Gram-positive organisms. They can therefore be used to treat LRTI, which
may be caused by either Gram-positive or Gram-negative organisms.
Bacteria rapidly develop resistance to quinolones. 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.

Question 80

Statins

Answer 80

Statins reduce serum cholesterol levels. They inhibit 3-hydroxy-3-
methyl-glutaryl coenzyme A (HMG CoA) reductase, an enzyme
involved in making cholesterol. They decrease cholesterol production by
the liver and increase clearance of LDL-cholesterol from the blood,
reducing LDL-cholesterol levels. They also indirectly reduce triglycerides
and slightly increase HDL-cholesterol levels. Through these effects they
slow the atherosclerotic process and may even reverse it.

Question 81

Sulphonylureas

Gliclazide

Answer 81

Sulphonylureas 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. Sulphonylureas are only
effective in patients with residual pancreatic function. As insulin is an
anabolic hormone, stimulation of insulin secretion by sulphonylureas is
associated with weight gain. Weight gain increases insulin resistance
and can worsen diabetes mellitus in the long term

Question 82

Tetracyclines

doxycycline, lymecycline

Answer 82

Tetracyclines inhibit bacterial protein synthesis. They bind to the
ribosomal 30S subunit found specifically in bacteria. This prevents
binding of transfer RNA to messenger RNA, which prevents addition of
new 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 from the body.
Tetracyclines have a relatively broad spectrum of antibacterial activity.
Tetracyclines were discovered in 1945 and have been widely used.
Consequently, some bacteria have acquired resistance to these antibiotics. A
common mechanism is through acquisition of an efflux pump, which allows
bacteria to pump out tetracyclines, preventing cytoplasmic accumulation.

Question 83

Thyroid hormones

Answer 83

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, most usually as
levothyroxine (synthetic T4). Liothyronine (synthetic T3) has a shorter
half-life and quicker onset (a few hours) and offset (24–48 hours) of
action than levothyroxine. It is therefore reserved for emergency
treatment of severe or acute hypothyroidism.

Question 84

Trimethoprim

trimethoprim, co-trimoxazole

Answer 84

Bacteria are unable to use external sources of folate, so need to make
their own for essential functions including DNA synthesis. Trimethoprim
inhibits bacterial folate synthesis, slowing bacterial growth
(bacteriostatic). It has a broad spectrum of action against Gram-positive
and Gram-negative bacteria, particularly enterobacteria, e.g. Escherichia
coli. However, its clinical utility is reduced by widespread bacterial
resistance. Mechanisms of resistance include reduced intracellular
antibiotic accumulation and reduced sensitivity of target enzymes.
Sulfonamides (e.g. sulfamethoxazole) also inhibit bacterial folate
synthesis, but at a different step in the pathway to trimethoprim.
Together trimethoprim and sulfamethoxazole cause more complete
inhibition of folate synthesis (at least in vitro), making them bactericidal.

Question 85

Valproate

Answer 85

The mechanism of action of valproate is incompletely understood. It
appears be a weak inhibitor of neuronal sodium channels, stabilising
resting membrane potentials and reducing neuronal excitability (see
Phenytoin). It also increases the brain content of γ-aminobutyric acid
(GABA), the principal inhibitory neurotransmitter, which regulates
neuronal excitability.

Question 86

Vancomycin

Answer 86

Vancomycin inhibits growth and cross-linking of peptidoglycan chains,
inhibiting synthesis of the cell wall of Gram-positive bacteria. It
therefore has specific activity against Gram-positive aerobic and
anaerobic bacteria and is inactive against most Gram-negative bacteria,
which have a different (lipopolysaccharide) cell wall structure. Bacterial
resistance to vancomycin is increasingly reported. One mechanism is
modification of cell wall structure to prevent vancomycin binding.

Question 87

Warfarin

Answer 87

Warfarin inhibits hepatic production of vitamin K-dependent coagulation
factors and cofactors. Vitamin K must be in its reduced form for
synthesis of coagulation factors. It is then oxidised during the synthetic
process. An enzyme called vitamin K epoxide reductase reactivates
oxidised vitamin K. Warfarin inhibits vitamin K epoxide reductase,
preventing reactivation of vitamin K and coagulation factor
synthesis.

Question 88

5a-reductase inhibitors

Answer 88

5α-reductase inhibitors reduce the size of the prostate gland. They do
this by inhibiting the intracellular enzyme 5α-reductase, which
converts testosterone to its more active metabolite dihydrotestosterone.
As dihydrotestosterone stimulates prostatic growth, inhibition of its
production by 5α-reductase inhibitors reduces prostatic enlargement
and improves urinary flow. However, it can take several months for this
effect to become evident clinically. For this reason, an α-blocker is
usually preferred for initial therapy, with a 5α-reductase inhibitor added if
the response is poor or if the prostate is particularly bulky.