Pharmacology Flashcards
(376 cards)
0
Q
Volume of Distribution
A
- volume of distribution is the measure of the apparent space in the body available to contain the drug - it relates the amount of drug in the body to the concentration of the drug in blood/plasma - Vd = amount of drug in body/concentration - proportional to half life (Drugs with high Vd are tightly bound by tissues compared with blood, therefore much higher conc in extravasc tissue than in vasc compartment. Drugs with small Vd are tightly bound to plasma proteins and not tissues.)
1
Q
Factors that affect Vd
A
- drug properties - lipid soluability, pKa, pH, protein binding, blood flow - patient properties: age, gender, disease, body composition
2
Q
What is the importance of Vd in overdose situation?
A
Drugs with large Vd (TCAs) cannot be dialysed, whereas drugs with small Vd (ASA, lithium) can.
3
Q
Drugs with a high Vd (>70L/70kg)
A
Diazepam, B-blockers, TCAs, digoxin, morphine, colonising, fluoxetine, chloroquine, cyclosporin
4
Q
Drugs with low Vd (< 50L/70kg)
A
Warfarin, lithium, phenytoin, aspirin, frusemide, valproic acid, tolbutamide, cephalexin
5
Q
What is a ‘second messenger’?
A
A second messenger is an intracellular substance which has its concentration altered by a process initiated by an extra cellular ligand. The second messenger then acts to initiate or facilitate an intracellular process. 1. Extra cellular process 2. Transmembrane signalling system 3. Intracellular process
6
Q
If a drug is distributed in the TBW, what is it’s Vd?
A
TBW: 0.6L/kg or 42L/70kg
7
Q
What formula describes drug clearance?
A
Ratio of rate of elimination of a drug to its concentration in blood/plasma Drug clearance (CL) = rate of elimination/concentration
8
Q
What is Flow Dependent Elimination?
A
For drugs that are readily cleared by their organ of elimination (high extraction ratio), the rate of elimination is dependent on rate of drug delivery to the organ, which is determined by blood flow and plasma protein binding. Systemic CL = CLrenal + CLliver + CLother
9
Q
Name drugs that have flow dependent elimination
A
Hepatic: lignocaine, propranolol, verapamil, morphine, pethidine
10
Q
Sites of drug biotransformation
A
Liver GIT Lung Skin Kidneys
11
Q
Describe phase 1 biotransformation reaction
A
Conversion of a parent drug to a more polar/water soluble form by the adding or unmasking of a functional group. Most commonly by oxidation, also reduction and hydrolysis. Hepatic CYP (P450) enzymes are responsible for the majority of phase 1 reactions.
12
Q
What is meant by enzyme induction in liver biotransformation?
A
Repeated administration of a substrate brings about either enhanced enzyme synthesis or reduced enzyme degradation causing increased metabolism of the substrate.
13
Q
Describe the difference between a competitive and an irreversible antagonist
A
Competitive - in fixed concentration of agonist, increasing conc of antagonist will lead to progressively inhibited response, but an increasing agonist conc can overcome to still evoke maximal response (agonist conc/effect curve shift to right) - high competitive antagonist conc can prevent response completely if agonist conc fixed - eg naloxone, flumazenil, propranolol, isoprenaline, naltrexone, nalmefene Irreversible - binds so tightly/covalently as to make receptor unavailable to agonist - number of remaining receptors may then be too low to allow maximal response to occur regardless of agonist conc (unless spare receptors) - length of effect of irreversible antagonist will reflect turnover of receptors involved rather than rate of elimination of antagonist - phenoxyenxamine, MAOI
14
Q
What is Total Body Clearance of a drug?
A
- describes the ability of the body to eliminate a drug - refers to the theoretical volume of plasma emptied of drug per unit time (usually L/h) - total body clearance reflects the sum of all clearance process including renal/hepatic/other
15
Q
Name 2 drugs that have a high hepatic clearance and explain why this is important.
A
- lignocaine, morphine, propranolol, pethidine - drugs with high hepatic elimination may only be suitable for parental administration or have significant dosing variations depending on route of administration
16
Q
What factors determine drug half-life?
A
- volume of distribution and clearance T1/2 = 0.7 x Vd/Cl - Vd and Cl change with disease states - cardiac, hepatic, and renal failure
17
Q
Routes of drug administration
A
- Enteral: sublingual, buccal, oral, rectal - Parenteral: SC, IM, IV, intrathecal, epidural - Inhalational - Topical
18
Q
Factors affecting the rate of drug absorption from the small intestine
A
Ionisation status of the drug - solubility of drug, formulation of drug Gut factors - gut surface area, blood flow, intestinal motility (reduced transit time and gut absorption)
19
Q
What are potential disadvantages of rectal drug administration?
A
- erratic absorption due to rectal contents - local drug irritation - uncertainty of drug retention
20
Q
What is drug ‘potency’?
A
- potency is the measure of how much drug is required for effect - potency refers to the affinity or attraction between an agonist and its receptor - a good measure of drug potency is the EC50 - the concentration that produces 50% of the maximal response
21
Q
What is drug efficacy?
A
Efficacy is the maximal effect,response that the drug (agonist) can produce (Emax) when all receptors are occupied, irrespective of the concentration required to produce that response.
22
Q
Draw a concentration-response curve showing 2 drugs with the same potency but different efficacy
A
See pic
23
Q
Draw and explain a dose-response curve for an agonist. Show how this curve is altered in the presence of an irreversible antagonist. How does this differ from a competitive antagonist?
A
See pic
24
Factors affecting placental drug transfer
- lipid solubility - molecular size - placental transporters - protein binding - placental and foetal drug metabolism
25
What is meant by foetal therapeutics? Give examples.
Drug administration to the pregnant woman with the foetus as the target. Examples - corticosteroids (for lung maturation) - phenobarbitone (induce enzymes for glucuronidation of bilirubin) - antiretrovirals (decrease HIV transmission) - antiarrhythmics
26
In children, what factors change with age and alter pharmacokinetics?
Body Size + Composition - growth of child (doses calculated in mg/kg), adult/neonate water 50/70% extracellular 20/40%, preterm neonate 85% water, influences drugs distributed in extracellular space, fat adults 15% pre term infants 1%, plasma proteins (decreased albumin in neonate, potential for increased toxicity in neonate so if drugs are highly protein bound), jaundiced neonate so (if drug highly protein bound will displace bilirubin and cause kernicterus) Drug Metabolism - most drugs metabolised in liver, only 50-70% of adult values, slow clearance and prolonged elimination half lives Drug Excretion - GFR lower in newborns than older infants, neonate 30-40% of adult values, 3 weeks 50-60%, 6-12 months hit adult values
27
Define drug elimination half life Formula How does half life help clinically?
Time required to change the amount of drug in the body by 1/2 during elimination T1/2 = 0.7 x Vd/Cl Indicates time to steady state after dose change (50% after 1, \>90% after 4)
28
What is the difference between full agonist and a partial agonist?
High concentrations of full agonists can evoke a maximal response, but partial agonists cannot evoke maximal response at any concentration.
29
Under what circumstances can a partial agonist act as an antagonist?
In the presence of a full agonist Eg buprenorphine
30
What factors determine the difference in drug metabolism between individuals?
Genetic - enzyme level differences Age - extremes have dec enzyme activity/cofactors Drug-drug interactions - enzyme induction/inhibition, substrate comp Disease states - hepatic, pulmonary, cardiac, thyroid, inflam Diet - induce/inhibit enzymes Environmental - exposure to enzyme inducers Sex - males inc metabolic rate Liver size & function
31
What is meant by enzyme induction?
Drug causes an increased rate of synthesis or decreased rate of degradation of enzyme, causing: - accelerated substrate metabolism - decreased pharmacological action of the inducer or co-administered drug
32
List the various molecular mechanisms of transmembrane signalling.
1. Lipid soluble ligand crosses membrane and binds to intracellular receptor 2. Transmembrane receptor protein with ligand binding to extracellular domain regulating intracellular enzymatic activity 3. Transmembrane receptor protein that binds & stimulates protein tyrosine kinase 4. Ligand-gated transmembrane ion channels 5. Transmembrane receptor protein, G protein, intracellular second messenger
33
Describe the function of the system involving G proteins
Transmembrane signalling system with 3 separate components. Extracellular ligand binds to the specific cell surface receptor. This receptor then activates G protein located on cytoplasmic surface membrane. Activated G protein changes activity of effector element (enzyme/ion channel) leading to a change in concentration of second messenger.
34
What is first pass metabolism?
After absorption of an orally ingested drug, portal blood delivers drug to liver where it is changed before reaching systemic circulation (metabolised in gut wall/portal blood/liver, excreted into bile). Ie It reduces the bioavailability of a drug.
35
How can you increase bioavailability?
1. Different route of administration - IV, IM/SC, SL, PR (50% bypass), Inh, TD 2. Increase absorption (depending on properties of drug) - hydrophilic, lipophilic, actively pumped into gut
36
Define drug clearance
1. Volume of plasma/blood cleared per unit time, or rate of elimination 2. CL systemic = CL renal + CL liver + CL other
37
What is the relationship between clearance and the dosing frequency of a drug?
1. Knowing the clearance of a drug will allow the dosage to be worked out to achieve the target concentration (to maintain steady state, the dosing rate must equal the rate of elimination). 2. Maintenance dose needs to be adjusted for disease states which affect clearance (eg renal failure). 3. Dosing rates (mg/hr) = rate of elimination (steady state) = CL x target conc
38
Give an example of dosage adjustment for impaired clearance.
Gentamicin, digoxin in renal failure. Loading dose not affected, maintenance dose reduced or dosage interval increased.
39
With respect to the biotransformation of drugs, please distinguish between Phase 1 & Phase 2 reactions.
Phase 1 - converts the parent drug to a more polar metabolite by introducing or unmasking functional groups (-OH, -NH2, -SH) - eg: oxidations including cytochrome p450 dependent and independent, deaminations, desulfurations, reductions, hydrolysis Phase 2 - involves conjugation with an endogenous substrate to form a highly polar conjugate - eg: glucuronidation, acetylation, sulfation, methylation, conjugation Both types of reactions result in more polar compounds that are more amenable to urinary excretion.
40
Does biotransformation generally result in more or less active metabolites?
Usually less active. Detoxification may frequently result in metabolites with residual pharmacological activity or even enhanced activity (activation).
41
Variables influencing the extent & rate that drugs are absorbed
1. Route of administration 2. Nature of absorbing surface - cell membrane (single layer of intestinal epi cells compared to several layers of skin cells) - surface area (lung, small intestine, stomach) 3. Blood flow - blood flow enhances absorption (SL v SC) 4. Drug solubility - lipid soluble drugs 5. Drug formulation - enteric coatings
42
Explain why aspirin absorption is enhanced by the low pH in the stomach.
Aspirin is an acidic drug (pKa 2.98), relatively unionised in the stomach and more ionised in the small intestine. Ie it is more lipid soluble in the stomach and therefore more easily absorbed.
43
How does ionisation of a drug affect it's solubility?
Drugs exist as weak acids or weak bases and in the body they are either ionised or un-ionised. Ionised (charged polar) more water soluble. Un-ionised (non-polar) more lipid soluble
44
Describe Phase 1 and Phase 2 reactions in drug metabolism.
Process of chemical modification of a drug leading to more hydrophilic, more polar, readily excreted compound. Phase 1 (functionalization): converts parent drug to more polar, often inactive metabolite. Oxidation, reduction, hydrolysis - majority of reaction via cytochrome P450 enzymes. Phase 2 (conjugation): metabolites combine with endogenous glucuronic a, sulphate, acetylcoenzyme A, or glutathione to form more polar metabolite. Phase 1 & 2 can occur alone, sequentially, or simultaneously. Metabolites can be more active or toxic than the parent drugs.
45
Define bioavailability.
Fraction of unchanged drug reaching systemic circulation following administration by any route. AUC (conc-time) is a common measure of the extent of bioavailability.
46
Factors that affect bioavailability
Extent of absorption - too hydrophilic/too lipophilic, reverse transporter ass with P-glycoprotein (pumps drug back to gut lumen), gut wall metabolism First pass metabolism - metabolism by liver before it reaches systemic circulation, small additional effect if drug has biliary excretion Rate of absorption - determined by site of administration and drug formulation
47
How can the effect of first pass metabolism be overcome?
Change route of administration to SL, TD, PR, Inh, IV, IM Increase dose
48
How does Hartmann's differ from normal saline?
- addition of sodium lactate, potassium chloride, calcium chloride (+pH adjustment) - Hartmann's Na 131, K 5, Cl 112, Ca 2, Lactate/bicarb 28mmol - N/saline Na 150, Cl 150
49
What are the potential advantages of Hartmann's in resuscitation?
- closer to physiologic re potassium, calcium - less hyperchloraemic - effective bicarbonate (?some slow good effect on acidosis)
50
Potential complications of IV therapy
- overload/under resuscitation - hypothermia - extravasation - acidosis - electrolyte abnormalities - osmo changes - air embolism - infection - cerebral oedema - haemodilution
51
What is drug clearance?
- Measure of the ability of the body to eliminate a drug - Rate of elimination in relation to drug concentration - CL = rate of elimination/conc
52
What factors affect drug clearance?
Concentration - dose & bioavailability Elimination - specific organ function/blood flow & protein binding Organ specifics - major sites of elimination are kidneys and liver, therefore factors that affect these organs' function/blood flow will have most effect
53
What is the difference between capacity-limited and flow-dependent drug elimination?
Capacity limited - saturable, zero order kinetics - eg aspirin, phenytoin, ethanol Flow dependent - non-saturable, first order kinetics, organ blood flow, protein binding - eg amitriptyline, isoniazid, labetalol, lignocaine, morphine, propranolol, verapamil
54
What is the difference between a competitive and irreversible antagonist?
Competitive (naloxone, flumazenil, propranolol, isoprenaline) - in fixed conc of agonist, inc conc of antagonist will lead to progressively inhibited response, but an inc agonist conc can overcome to still evoke max response (agonist conc/effect curve R) - high competitive antagonist conc can prevent response completely if agonist conc fixed Irreversible (MAOI, phenoxyenzamine) - bind so tightly/covalently to receptor makes it unavailable to agonist - number of remaining receptors may then be too low to allow maximal response to occur regardless of agonist conc (unless spare receptors) - length of effect will reflect turnover of receptors involved rather than rate of elimination of antagonist
55
Define drug elimination half-life
- time required to change the amount of drug in the body by 1/2 during elimination - T1/2 = 0.7 x Vd/clearance - 50% after 1, \>90% after 4
56
How does knowledge of a drug's half life help us clinically?
- dosing regimes - decay after dose/overdose - time to steady state after dose change
57
What disease states can affect elimination half-life?
- liver - renal - cardiac disease - eg morphine affected by liver and renal disease
58
Outline the mechanism of action for aspirin.
Irreversible non-selective cyclooxygenase inhibition (COX 1 & 2) - in platelets, irreversible inhibition of COX 1 results in reduction in thromboxane A2 and inhibition of platelet aggregation for the life of the platelet (10 days) - in tissues, inhibits prostaglandin synthesis (COX 2) resulting in anti-inflammatory action, analgesic and anti-pyretic effects
59
Describe the pharmacokinetics of aspirin.
- rapidly absorbed from stomach and intestine, aspirin hydrolysed to salicyclic acid in plasma/blood, peak plasma level within 1-2hrs - serum half-life of aspirin is 15 mins, low protein binding, saturable metabolism with increasing doses (switches from first to zero order metabolism) - urinary alkalinisation increases excretion of salicylate and its conjs
60
Outline the adverse effects of aspirin
- GI upset, GI bleeding (gastritis, peptic ulceration) - Hepatotoxicity - Hypersensitivity reactions (asthma, angioedema, rash) - Prolonged bleeding time from platelet inhibition
61
Describe the mechanism of action of glyceryl trinitrate
- taken up by vascular smooth muscle - interacts with tissue sulfhydryl groups - releases free radical nitric oxide - activates cGMP - dephosphorylates myosin light chains - reduces intracellular Ca levels - smooth muscle relaxation & vasodilation
62
What are the clinical effects of nitrates?
- low doses: venodilation leads to decreased preload & stroke volume - higher doses: arterial dilation leads to dec blood pressure as well as dec cardiac output & dec myocardial oxygen demand + dilation of coronary arteries/redistribution of perfusion - improved oxygen delivery to myocardium & resolution of ischaemic pain - adverse effects: postural hypotension, tachycardia, dizziness, headache, flushing, blurred vision, dry mouth, rash
63
Describe the mechanism of action of ACE inhibitors.
- competitive block conversion of angiotensin 1 to 2 - dec vascular tone from prevention of vasoconstrictor effects of AT2 (main effect) - inhibition of aldosterone secretion caused by AT2 leading to reduced Na & H2 resorption resulted in dec BP
64
What are the adverse effects of ACE inhibitors?
- dizziness, hypotension - cough - headaches, weakness - loss of taste, nausea, diarrhoea - rash, fever, joint pain - mild hyperK due to dec in aldosterone secretion, ARF
65
What are some drug interactions that occur with ACE inhibitors?
Diuretics - hypotension General anaesthetics - hypotension Lithium - lithium toxicity NSAIDs - hyperkalaemia & reduced effects of ACE inhibitor K sparing diuretics/K supplements - hyperkalaemia
66
Describe the pharmacodynamics of therapeutic drugs that modulate the effect of angiotensin
- ACE inhibitors - bind ACE reversibly preventing conversion of AT1 to AT2 - inhibitory action on the renin-angiotensin system stimulating action on kallikrein-kinin system
67
What are the advantages of AT2 receptor antagonists over ACE inhibitors?
- AT2 inhibitors - competitive antagonists at AT2 receptor - as AT2 inhibitors do not result in production of bradykinins, there is a dec incidence of cough and angioedema - potentially greater effect as enzymes other than ACE can generate AT2
68
What is the cellular mechanism of action of GTN?
- denitration by glutathione S-transferase - free nitrite ions released and form NO - NO activates guanylyl cyclise leading to increased cGMP and dephosphorylation of myosin and smooth muscle relaxation (precise mechanism unknown)
69
How does GTN relieve angina pain?
- venodilation leads to reduced venous return, reduce ventricular volume and reduced heart wall tension - this reduces myocardial O2 requirement
70
Outline the pharmacokinetics of sublingual GTN.
- oral bioavailability is low due to extensive first pass hepatic metabolism by high capacity organic nitrate reductase - rapid and efficient absorption by sublingual or intranasal routes but rapid elimination (t1/2 2-8mins) and duration of action (15-30mins) due to high capacity hepatic metabolism - denitrited metabolites conjugated to glucuronide and excreted in urine
71
How does GTN exert its effect on smooth muscle?
- nitrite -\> NO -\> increased cGMP -\> relaxation - prostaglandins also involved
72
What are the clinical effects of GTN?
- venodilation -\> reduced venous return -\> reduced LVEDV -\> reduced LV wall tension -\> reduced myocardial oxygen consumption (-\> reduced cardiac output in normal people, possibly inc in pathological conditions where pretreatment preload is abnormally high) - arterial dilation -\> throbbing headache (relatively ineffective on resistance vessels) - other smooth muscle relaxation (eg amyl nitrate + enhanced erection) - dec platelet aggregation, but no apparent beneficial therapeutic effect in this regard - methaemoglobinaemia from nitrite, but not from GTN
73
What are the pharmacokinetic features of B-blockers?
- well absorbed - low bioavailability - large volume of distribution - most are metabolised in liver
74
What are the effects of beta blockers?
- dec in hypertension - negative chronotrope and negative ionotrope - AV block - increased survival after AMI - bronchospasm - dec IO pressure
75
What are the effects of B-blocker in overdose?
- hypotension, bradycardia, cardiogenic shock, bronchospasm, seizures (cerebrotoxic) - NB propranolol causes arrhythmias through Type 1 antiarrhythmic effects (Na channel block)
76
What is the mechanism of action of atropine?
Reversible block of cholinergic muscarinic receptors.
77
Examples of organ effects of atropine.
CNS: dec tremor & rigidity in Parkinson's disease Eye: mydriasis (pupil dilation) & cycloplegia (ciliary m paralysis - loss of accommodation) CVS: SA (and AV) node, blocks vagal slowing -\> rel tachycardia and inc conduction (shorten PR), block coronary vasodilation Resp: blocks M receptors on sm m & secretions GI: blocks motility & secretions GUT: relaxes sm m in ureters & bladder wall (spasm) and slows voiding (retention) Skin: decreases sweating
78
What are the features of atropine poisoning?
- agitation & delirium - raised temp - blurred vision/mydriasis - dry mouth/flushed skin - tachycardia
79
At a cellular level, describe the action of Ca channel blockers
Bind at intracellular L type Ca channel
80
1. What are the differences in pharmacodynamics between dihydropyridines and other Ca channel blockers? 2. How are these differing pharmacodynamics reflected in their side effect profile?
1. Dihydropyridines (amlodipine) are vascular sm m selective. Verapamil/diltiazem greater effect on cardiac/conducting tissue. 2. Dihydropyridines cause flushing, headaches, & tachycardia. Verapamil causes bradycardia. Both can cause hypotension.
81
What is the mechanism of action of captopril?
- inhibit converting enzyme peptidyl dipeptidase (which hydrolysis AT1 to AT2 - get dec peripheral vasc resistance; CO & HR same - inactivates bradykinin -\> vasodilation, dec peripheral vasc resistance & dec BP
82
Clinical uses of captopril
- CCF, after MI (better preservation of LVF - reduce post MI remodelling) - hypertension - diabetic nephropathy: diminish protein urea, stabilise renal function - improved intrarenal haemodynamics
83
Adverse effects of captopril
- hypotension after 1st dose if hypovolaemic, diuretics, NaCl restriction, GI loss - ARF (bilateral renal a stenosis) - hyperkalaemia if renal insufficiency, DM - dry cough, angioedema (bradykinin, substance P) - foetal problems if 2nd/3rd trimester - neutropaenia, proteinuria from high dose captopril - minor: taste change, skin rash, drug fever
84
1. What is the mechanism of action of adenosine? 2. What effect does this have on cardiac conduction?
1. - enhanced K+ conduction -\> marked hyperpolarisation - inhibition of cAMP induced Ca2+ influx -\> suppression of Ca dependant action potential 2. - inhibits AV node conduction (at least) - increases AV node refractory period - lesser effect on SA node
85
What are the cardiac effects of amiodarone at a cellular level?
- prolongs AP duration (by blocking K+ channels) - blocks inactivated Na channels, the AP prolonging action reinforces this effect - blocks depolarised cells \> normal cells - mild antisympathetic, no competitive inhibitor of B receptors - weak adrenergic blocker -\> slows HR and AV node conduction - weak Ca channel blocker -\> inhibits abnormal automaticity, slows sinus rate, increase PR interval
86
What are the mechanisms of pharmacokinetic drug interaction with amiodarone? Give 2 examples.
Inhibits liver cytochrome metabolising enzymes - digoxin, warfarin levels increase - cimetidine increases amiodarone toxicity by dec hepatic clearance - interacts with statins (atorvastatin/simvastatin, use pravastatin as not P450) - concentration and effects of phenytoin, anaesthetics, cyclosporins, theophylline, procainamide, flecainide, quinidine are increased by amiodarone
87
Describe the pharmacokinetics of metoprolol
- oral or IV, well absorbed - bioavailability 50% due to first-pass effect - large volume of distribution - Half life 3-4hrs - metabolised in the liver
88
How does metoprolol differ from propranolol in its action at beta receptors?
- B1 equipotent - B2 50-100 x less potent
89
How do B-blockers control hypertension?
- not fully understood - negative inotropic and chronotropic effects - slow AV node conduction - antagonises release of renin caused by sympathetic nervous system
90
Pharmokinetics of atropine
- oral (well absorbed) or IV (usual), neb, topical - widely distributed (including CNS) - half life 2 hours - elimination: 60% excreted renally unchanged - 40% phase 1 & 2 metabolism and renally excreted
91
At which receptors does atropine act?
- muscarinic (equipotent at M1, M2, & M3) - nicotinic (minimal potency)
92
Effects of atropine on heart rate
Dose dependant - at lower doses often an initial bradycardia -\> blocks prejunctional M1 receptors - tachycardia
93
Mechanism of action of Calcium Channel Blockers
CCBs bind to receptors on alpha 1/2, gamma, delta subunits of L-type Ca channel - dec freq of opening of Ca channels in response to depolarisation - dec transmembrane Ca current - dec Ca influx -\> vascular sm m relaxation, dec contractility in cardiac m, dec SA node pacemaker rate, dec AV node conduction velocity
94
Toxic effects of CCBs
- CVS: cardiac arrest, bradycardia, AV block, heart failure, hypotension - Minor: flushing, dizziness, nausea, constipation, peripheral oedema
95
Mechanism of action of atropine
Antimuscarinic at cholinergic receptors
96
Toxic effects of atropine
Tachycardia, flushing, dry skin/mucous membranes, mydriasis, ileus, urinary retention, acute angle glaucoma, central anticholergic syndrome (delirium with visual hallucinations)
97
Therapeutic uses for atropine
- symptomatic bradycardias, esp when vagally mediated - OGP poisoning/inocybe mushroom poisoning, drying of secretions - adjunct to reversal of non-depolarising muscle relaxants and sux administration in young infants - antispasmodic - mydriatic (dilation of pupil)
98
Regarding B agonists, by what cellular mechanism do they exert their effects?
- bind to specific receptor - G-protein activation - stimulate adenyl cyclase - increased cyclic AMP - increased free intracellular Ca - activate protein kinase
99
Compare the cardiovascular effects of adrenaline and dobutamine
Adrenaline: - has B1, B2 and alpha effects - increased inotrope and chronotrope - peripheral vasoconstriction in most vascular beds - vasodilation in skeletal m beds (B2), may reduce TSVR Dobutamine: - is a selective B1 agonist - increases cardiac output with less reflex tachycardia as it has fewer B2 effects - comes as racemic mixture of +ve and -ve isomers, one isomer has B agonist and alpha antagonist effects, the other has alpha agonist effects
100
What is flecainide's mechanism of action?
Na channel blockade (class effect) - predominant action is to inhibit the fast, or sodium, channel which is largely responsible for the rapid upstroke of the myocardial action potential in cardiac conducting tissue Class 1C action - minimal effect on the action potential duration and dissociates from the Na channel with slow kinetics (no effect on QT interval) Decrease the rate of rise of the action potential with little effect on duration
101
Describe flecainide's pharmacokinetics.
- well absorbed orally, half life ~ 20hrs - peak plasma drug levels at ~ 3hrs (range 1-6hrs) - Vd ranges from 5 - 13.4L/kg (mean 8.7L/kg) - 30% of a single oral dose (range 10 - 50%) is excreted in urine as unchanged drug, remainder by hepatic metabolism - usual dose 100-200mg daily - SE: hypotension, LV dysfunction
102
What are the effects of adrenaline on the blood vessels in different tissues? What receptors mediate these effects?
Vascular resistance - cutaneous (alpha) - mucous membranes (alpha) - skeletal muscle (B2, alpha) - renal (alpha, delta) - splanchnic (alpha, B), venous tone (alpha, B)
103
Describe the effects of adrenaline on other organs besides the heart
Resp - bronchodilation Eyes - pupillary dilation, dec intraocular pressure, dec prod aqueous H GI - relaxation of gastric sm m, dec salivary production GUT - uterine sm m relaxation, bladder relaxation, bladder sphincter contraction, ejaculation Skin - apocrine sweat glands (hands) Liver - enhanced glycogenolysis Lipolysis - inc fatty acids & glycerol in circulation Metabolic acidosis Dec extracellular potassium Leucocytosis Insulin - inhibits or stimulates insulin secretion
104
The actions of digoxin on the heart at therapeutic levels
Mechanical: Na-K ATPase Electrical: - direct: alters action potential - indirect: autonomic, parasympathetic effects predominate Sensitisation of baroreceptors Central vagal stimulation Facilitation of muscarinic transmission
105
Are the parasympathetic effects of digoxin uniform throughout the heart?
No. Affect atrial and AV nodal function more than Purkinje or ventricular function.
106
Sites of action of anti hypertensive drugs (with examples)
Vasomotor centre - clonidine, methyldopa Sympathetic ganglia - trimethaphan Sympathetic nerve terminals - guanethidine, reserpine \* B receptors of the heart - B blockers \* Angiotensin receptors of blood vessels (?by) - AT2 receptor blockers Alpha receptors of blood vessels (?by) - prazosin \* Vascular sm m - hydrallazine, SNP, Ca blockers, GTN \* Kidney tubules - diuretics B receptors juxtaglomerular cells - B-blockers \* ACE
107
Describe the molecular action of digoxin
Na+/K+ ATPase (sodium pump) inhibition - binds to alpha subunit which has different isoforms - differing affinities for digoxin in various tissues - low concentration occasionally stimulate the enzyme
108
What are the cardiac effects of digoxin?
Mechanical: increased contractility due to increased intensity of interaction of actin and myosin filaments due to inc free calcium during systole. Electrical: - Direct: shortening of action potential and therefore shortened atrial & ventricular refractoriness - at toxic levels, resting membrane potential reduced, then as toxicity progresses depolarising afterpotentials - Autonomic: at lower doses parasymp effects predominate
109
What are the non-cardiac manifestations of digoxin toxicity?
At toxic levels, sympathetic outflow inc - all excitable tissue including smooth muscle and CNS. Relative low sens compared to cardiac. GIT: nausea, vomiting, diarrhoea, anorexia CNS: nausea, vomiting, disorientation, hallucinations, visual disturbances, agitation, convulsions Gynaecomastia
110
Pharmacokinetics of digoxin
- well absorbed orally - moderate Vd (6.3L/kg) - not extensively metabolised, 2/3 excreted unchanged by the kidneys - 10% population with enteric bacteria that reduce oral bioavail - 20-40% plasma protein bound
111
Describe succinylcholine and its metabolism
- depolarising neuromuscular blocking drug - hydrolysed by plasma cholinesterase (to succinic acid & choline) - action at motor end plate terminated by diffusion away into ECF
112
What are the adverse effects of depolarising neuromuscular blockade?
Hyperkalaemia: renal failure, burns \>24hrs, demyelination, spinal cord injury, muscular dystrophies, CVA Increased IOP, intragastric & ICP Paralysis & prolonged apnoea CVS: negative inotrope & chronotrope Muscle pain
113
Describe the mechanism of action of amiodarone
Potassium channel blocker (Class 3) Prolongs refractory period by prolonging action potential duration Na channel blockade (Class 1), blocks inactivated Na channels Weak Ca channel (Class 4) & adrenergic (Class 2) blocking Vasodilator
114
What are the clinical uses of amiodarone?
Atrial & ventricular arrhythmias Maintaining sinus rhythm in AF Prevention of recurrent VT
115
Describe the potential adverse effects of amiodarone
Cardiac: bradycardia, heart block, hypotension, negative inotropy. Pulmonary fibrosis Abnormal LFTs & hepatitis Skin and corneal deposits Hypo/hyperthyroidism (blocks peripheral conversion of T4 to T3)
116
What are the organ effects of nitrous oxide?
CNS: analgesic, amnesic, inc CBF Renal: decreased GFR, inc filtration fraction & inc renal vasc resistance CVS: dose dependant myocardial depression Resp: reduced resp response to CO2 & hypoxia
117
Mechanism of action of nitrous oxide
Directly activate GABA A receptors - GABA A receptor Cl channel, facilitates GABA mediated inhibition at GABA receptor sites - membrane hyperpolarisation - dec duration of opening of nicotinic receptor activated channels, dec excitatory effect of Ach
118
Describe the pharmacodynamics of propranolol
- non selective action on beta receptors - membrane stabilising action - antagonises renin release from sympathetic ns - competitive, pure antagonist - others: inhibits sympathetic ns stimulation of lipolysis, inhibits liver glycogenolysis, reduces aqueous humour production, inc VLDL, dec HDL, blocks B2 receptor in bronchial sm m inc airway resistance
119
How does carvedilol differ from propranolol?
- carvedilol has no local anaesthetic action - causes A1 adrenoceptor block, but effect on beta \> alpha - stereoselective metabolism of its 2 isomers occurs
120
What are the effects of nitric oxide?
- smooth muscle relaxant - platelet inhibitor - immune regulator - neurotransmitter
121
Potential therapeutic applications of nitric oxide
1. Vascular effects - vasc sm m tone & BP, inhibits neutrophil adhesion to vasc endothelium 2. HTN ass with pregnancy - resemble deficiency of NO & PG 3. Resp disorders - via inh for newborns with pulm HTN & ARDS, dec pulm a pressure, improves blood O2, adults with ARDS, poss bronchodilator 4. Septic shock - urinary excretion of NO3, bacterial infection 5. Atherosclerosis - poss antioxidant, block LDL prev foam cell form 6. Platelets - potent inhibitor of platelet adhesion & aggregation 7. Organ transplantation - dec free radical toxicity, inhibits platelet/neutrophil aggregation/adhesion to vasc wall 8. CNS - modifies neurotransmitter release, also negative effects 9. PNS - NO promotes relax of sm m in corpora cavernous a
122
What is the mechanism of action of glyceryl trinitrate in smooth muscle?
NO release, cGMP increases
123
How do nitrates relieve angina?
Preload reduction decreases myocardial work
124
Describe the pharmacokinetics of propranolol.
- high 1st pass liver metabolism - high lipid soluability - B-blockade with variable selectivity - negative inotropic and chronotropic
125
What B-receptor types are there?
B1, B2, B3
126
What cellular processes do B-agonist-B-receptor coupling initiate?
Activation of all 3 receptor types results in stimulation of adenylyl cyclase and increased conversion of ATP to cAMP. Mediated by stimulatory coupling protein (Gs) via GDP & GTP
127
What are the clinical uses of B2 selective agonists?
Respiratory, uterine, and vascular smooth muscle relaxation Skeletal muscle K+ uptake
128
What is the mechanism of action of warfarin?
- inhibits reduction of inactive Vit K epoxide (KO) to active hydroquinone (KH2) form - blocks gamma-carboxylation of glutamate residues in prothrombin (factor 2) and factors 7, 9, 10 as well as endogenous anticoagulant protein C & S
129
Why is there a delay in the onset of action of warfarin?
8-12hr delay due partially inhibited synthesis and unaltered degradation of 4 Vit K dependent clotting factors and depends on degradation 1/2 in circulation - eg factor 7 (6hrs), 9 (24hrs), 10 (40hrs), 2 (60hrs)
130
What pharmacological agents are used in the reversal of warfarin?
- vitamin K - FFP - prothrombin complex - recombinant factor 7a
131
Describe the mechanisms of drug interactions with warfarin
Pharmacokinetic - enzyme induction and inhibition - altered protein binding Pharmacodynamic - synergism - competitive antagonism (Vit K)
132
List the classes of drugs used for the management of AF in the ED
1. B-blockers (class 2) 2. Ca channel blockers (class 4) 3. Cardiac glycosides (eg digoxin) 4. Class 1c antiarrhythmics (eg flecainide) 5. Class 3 antiarrhythmics (eg amiodarone, sotolol)
133
Describe the pharmacodynamics of sotolol
Class 2 - non-selective B-blocker Class 3 - prolongs plateau phase
134
Main side effects of sotolol
Pro-arrhythmic - esp prolongation of QT Torsades CCF Asthma AV blockade
135
What drug interactions with sotalol prolong the QT?
Drugs with prolong QT - phenothiazines, macrolides (erythromycin), quinolones Anti-depressants - increased risk of torsades Drugs which cause hypokalaemia/hypomagnesaemia inc risk of Torsades Myocardial depressant drugs - inc LVF CCB, class 1a antiarrhythmics - may increase refractory time & contraction
136
Describe the mechanisms by which drugs interact with warfarin
PK: enzyme inhibition (maj), enzyme induction, altered plasma protein binding,altered abs PD: synergism (impaired homeostasis), competitive antagonism (clotting factor synthesis/concentration)
137
Give some examples of drugs that increase INR
Aspirin, heparin, corticosteroids, metronidazole, fluconazole, trimethoprim-sulfamethoxazole, 3rd gen cephalosporins, macrolides, amiodarone, SSRIs, tramadol.
138
Give some examples of drugs that decrease the INR
Vit K, diuretics, barbiturates, phenytoin, carbamazepine, rifampicin, dicloxacillin, azathioprim.
139
1. What are the indications for use of adenosine? 2. How does it work?
1. Conversion of paroxysmal SVT to sinus rhythm. 2. Activation of inward rectifier K+ currents and inhibition of calcium currents. Leads to marked hyperpolarisation and suppression of calcium-dependent APs. Effect is direct inhibition of AV nodal conduction and increase in AV node refractory period. This interrupts re-entry pathway through AV node.
140
How do the specific pharmacokinetic properties of adenosine influence the method of administration?
- very rapid metabolism by adenosine deaminase in red cells and vessel walls = very short elimination t1/2 (\<10sec) and duration of action (30sec) - must be given by rapid IV bolusing - if initial dose is ineffective then subsequent dose should be increased (no accumulation occurs)
141
Describe the mechanism of action of tissue plasminogen activator (tPA)?
- activates plasminogen to form plasmin, resulting in fibrin digestion - preferentially activates plasminogen bound to fibrin by several hundred fold, therefore is considered clot specific - short half life therefore heparin is essential adjunct - naturally occurring
142
What are the clinical uses of tPA?
- AMI - unstable PE - acute ischaemic stroke - severe DVT, peripheral limb intra-arterial clot
143
What are the complications of tPA?
Haemorrhage - physiological haemostatic thrombi at site of vascular injury eg GIH - systemic lytic state resulting from formation of plasmin, producing fibrinogenolysis and destruction of other coagulation factors esp 5 and 8.
144
What is the mechanism of action of atropine?
A reversible muscarinic antagonist. Binds to muscarinic receptor, preventing release of inositol triphosphate (IP3) and the inhibition of adenyl cyclase which are caused by the muscarinic agonists.
145
Describe the organ effects of atropine.
CNS: decreased tremor in Parkinson's disease, delirium EYE: mydriasis & cycloplegia CVS: tachycardia RESP: bronchodilation and dec secretions GIT: inc salivary secretion, dec gastric secretion of acid/pepsin/mucin, dec gastric emptying, dec gut transit time GUT: relaxes ureteric & bladder wall sm m and slows voiding Decreased sweating
146
Describe the mechanism of action of heparin.
- binds to endothelial cell surfaces & plasma proteins - its activity depends on antithrombin - heparin binds to antithrombin, causes a conformational change in the inhibitor, exposing its active site for more rapid interaction with proteases - heparin acts as a cofactors for the antithrombin-proteases reaction - antithrombin inhibits proteases esp thrombin 2a, 9a, 10a by forming stable complexes with them and the presence of heparin accelerates this reaction 1000 x - the binding of AT3 and unfractionated heparin -\> degradation of both factor 10a and thrombin
147
How is heparin reversed?
Stop the drug. Administer antagonist protamine (100 units heparin - 1mg protamine) which binds heparin to form a complex devoid of anticoag activity. Excess protamine anticoag effect.
148
What are the potential adverse effects of heparin?
Bleeding - elderly women, renal failure more prone Thrombocytopaenia - 1-4%, rare pregnancy, lower rates in paediatrics Allergy Reversible alopecia Accelerates clearing of post prandial lipaemia Long term: OP, spont #, mineralocorticoid deficiency
149
What are the principle effects of adenosine on cardiac conduction?
1. Inhibits AV nodal conduction (inc PR interval) 2. Increases AV nodal refractory period 3. These effects are a result of enhanced K conduction and inhibition of cAMP-induced Ca influx resulting in hyperpolarisation and suppression of Ca-dependent action potentials
150
How do the unusual pharmacokinetics of adenosine influence its use in therapeutics?
1. Rapidly metabolised in the blood with elimination half-life of less than 10 sec 2. Only suitable for IV use 3. Must be given by rapid blousing to achieve therapeutic effects 4. Repeat doses must be escalated 5. Not effective for SVTs caused by adenosine-blockers (theophylline)
151
What is the mechanism of action of captopril?
- angiotensin converting enzyme inhibitor - stops conversion of AT1 to AT2 - AT2 is potent vasoconstrictor, AT2 also increases aldosterone secretion -\> increased salt & water retention - ACE (kinase2) also metabolises bradykinin into its inactive form - increase in bradykinin causes vasodilation -\> dec PVR -\> dec BP
152
Potential adverse effects of captopril
1. Profound hypotension 2. ARF - esp with renal a stenosis 3. Hyperkalaemia 4. Cough, wheeze 5. Angioedema 6. Foetal abnormalities - inc malformations, hypotension, anuria, ARF
153
Describe the effects of an IV adrenaline infusion
Predictable physiological effects from a combination of alpha and beta stimulation - increased cardiac output (chronotropy + inotropy) - (low dose: beta \> alpha) vasodilation with widened pulse pressure - (higher dose: alpha \> beta): vasoconstriction with narrowing of pulse pressure
154
What are the potential side-effects or complications of an adrenaline infusion?
1. General - anxiety, tremor, nausea, vomiting, pallor 2. CVS - palpitations and/or arrhythmias, myocardial ischaemia, HTN 3. Metabolic (beta effect) - hyperglycaemia, metabolic (lactic) acidosis, hypokalaemia
155
How does the effect of adrenaline differ from noradrenaline?
1. Noradrenaline peripheral alpha effect -\> vasoconstriction 2. Adrenaline mixed peripheral alpha and beta 3. Noradrenaline lesser cardiac effect 4. Slightly different side-effect profile (metabolic effects due predominantly to beta receptor activation)
156
Describe the mechanisms for drug interactions with warfarin and give examples.
PK - enzyme inhibition (maj), enzyme induction, altered plasma protein binding, altered abs (cholestyramine p157) PD - bioavailability for Vit K, influencing Vit K dependant clotting factors, drugs affecting haemostasis
157
What anti arrhythmic drugs can be used in the management of atrial fibrillation?
- Beta-agonists (class 2) - calcium-antagonists (class 4) - flecainide (class 1c) - amiodarone (class 3) - digoxin (cardiac glycoside) - magnesium
158
What are the mechanisms of action of amiodarone?
Blocks Na, K, Ca channels Blocks B adrenoreceptors - prolongs AV conduction - decreases automaticity - decreases automaticity of purkinje fibres (Actions on both rhythm and rate)
159
What are some important drug interactions with amiodarone?
Warfarin - inc anticoagulant effect by inhibiting metabolism Digoxin - inc plasma conc leading to toxicity Increased cardiac effects of other antiarrhythmic agents Phenytoin - inc plasma conc
160
Describe the mechanism of action of lignocaine on the heart.
Blocks activated & inactivated Na channels - class 1B antiarrhythmic action - greater effect on ischaemic tissue - no vagal effects
161
Describe the adverse effects of lignocaine.
CNS: dizziness, anorexia, N & V, tinnitus, tremor, visual disturbance, paraesthesia (perioral), slurred speech, seizure, resp depression CVS: bradycardia, CVS collapse, uncommon proarrhythmia, can get SA arrest, impaired conduction my worsen/precipitate pre existing CCF, dec BP from myocardial depression Allergy, GI as above
162
What are the features of digoxin toxicity?
GI: anorexia, nausea, vomiting, diarrhoea CNS: visual disturbances, confusion, nightmares, agitation, drowsy Cardiac: bradycardia (progressing AV block, slow AF) and inc automaticity (VEBs/bigeminy, SVT with AV block, VT/VF)
163
What factors might predispose patients towards digoxin toxicity?
Electrolyte imbalance - hypokalaemia, hypercalcaemia, hypomagnesaemia Organ disease - renal impairment, hypothyroidism, other drugs - amiodarone, CCBs, K depleting drugs
164
1. What are the principal effects of adenosine on cardiac conduction? 2. Describe the pharmacokinetics? 3. What are the clinical implications of this pharmacokinetic profile? 4. Indications/contraindications to its use?
1. Inhibits AV nodal conduction 2. Rapidly metabolised by red cells and endothelial cells, very short elimination half-life (seconds) 3. Rapid IV bonus, side effects short-lived, no prolonged action to prevent further arrhythmia, prox IV site preferable 4. Ind: SVT, diagnostic. Contraind: AV block, sick sinus, acute asthma
165
List some drugs used in hypertensive emergencies.
GTN Nifedipine Hydrallazine Nitroprusside Esmolol Labetalol
166
Describe the pharmacokinetics of Na nitroprusside.
- IV administration, onset minutes, peak effect minutes - T1/2 life 2 mins (this cyanate 3 days, duration of action 1-10 mins - Elimination: RBCs to cyanide, liver to thiocyanate - Excretion: renal
167
What are the potential toxicities of Na nitroprusside?
Cyanide toxicity - hypotension, metabolic acidosis, pink skin, tachypnoea, decreased reflexes, dilated pupils, coma Thiocyanate toxicity - ataxia, blurred vision, headache, nausea, vomiting, tinnitus, SOB, delirium, unconsciousness
168
What are the effects of Ca channel blockers on smooth muscle?
Relax smooth muscle, esp vascular smooth muscle - arterioles more sensitive than veins - does affect bronchiolar GIT and uterine
169
By what mechanisms do CCBs control angina?
- decrease myocardial contractility - decrease oxygen demand - decrease afterload by relaxing vascular smooth muscle - verapamil/diltiazem have a non-specific antiadrenergic effect and decrease heart rate - relieve and prevent coronary artery spasm
170
Why is verapamil more efficacious than dihydropyridines in the treatment of arrhythmias?
- blockade of L-channels more marked in tissues that fire more frequently - more marked effects on tissues that depend on Ca channels for activation -\> SA and AV nodes - more marked on tissue with cells less polarised at rest
171
What is the adrenoreceptor selectivity of noradrenaline?
Alpha 1 = alpha 2, beta 1 \> \> beta 2 Alpha 1: post synaptic effector cells, esp smooth muscle Alpha 2: pre synaptic nerve terminals, platelets, lipocytes, smooth m Beta 1: post synaptic effector cells, esp heart, lipocytes, brain
172
Describe the cardiovascular effects of infused noradrenaline
- increases peripheral vascular resistance - increases SBP and DBP - positive inotropy - little chronotropy
173
What are the mechanisms of action of frusemide
Inhibits a luminal Na+/K+/2Cl co-transporter of thick ascending limb of Loop of Henle -\> decreased reabsorption of NaCl -\> diuresis Increased prostaglandin synthesis -\> inhibition of salt transport in thick ascending limb -\> inc renal blood flow, dec pulmonary congestion, dev LV filling press
174
What are the toxic effects of frusemide?
- hypokalaemia, hyponatraemia, hypomagnesaemia - metabolic alkalosis - dehydration - allergy: rash, eosinophilia, interstitial nephritis - hyperuricaemia - ototoxicity
175
Describe the pharmacokinetics of metoprolol
- oral or IV - large Vd - half life 3-4hrs - metabolised in liver - bioavailability 50% due to 1st pass effect
176
How does metoprolol differ from propranolol in its action at beta receptors?
Beta 1 - full agonist Beta 2 - 50-100 fold less potent (Beta 1 selective)
177
How do B-blockers control hypertension?
- negative inotropic and chronotropic effects - slow AV node conduction - antagonises release of renin (not fully understood)
178
1. How does heparin act? 2. How may heparin by administered?
1 - heparin binds endogenous antithrombin and enhances its activity - antithrombin inhibits factors 2a, 9a, and 10a by completing with them and inducing a conformational change 2 - IV vs SC, continuously (following bolus) vs intermittent, therapeutic vs prophylactic
179
What are the potential adverse effects of heparin?
- bleeding - heparin-induced thrombocytopaenia - allergy - alopecia - osteoporosis - mineralocorticoid deficiency
180
What are the advantages of low molecular weight heparins compared to unfractionated heparin?
- have equal efficacy - increased SC bioavailability - require less frequent dosing - less monitoring - shorter chain heparin with less effect on thrombin (factor 2a)
181
How does frusemide exert its action?
- selectively inhibits Na+/K+/2Cl- transporter in thick ascending limb of loop of Henle thus preventing resorption of Na+ & Cl- - abolishes counter-current concentrating mechanism leading to dilute urine - increased prostaglandin synthesis -\> inhibition of salt transport in thick ascending limb -\> inc renal blood flow, dec pulmonary cong, dec LV filling pressures
182
What are the pharmacokinetic properties of frusemide?
- rapid absorption after oral administration - oral bioavailability 50% (range 10-100%) - highly protein bound (\>95%) - 50% conjugated in kidney & 50% excreted in urine (tubular sec) - elimination t1/2 1.5-2hrs - peak effect 30mins IV/1hr oral
183
What are the potential adverse effects of frusemide?
Electrolyte disturbances - hypokalaemia, hyponatraemia, hypomagnesaemia, hyperuricaemia Postural hypotension and dizziness Metabolic alkalosis Allergy - rash, eosinophilia, interstitial nephritis Increased LDL & trigs, dec HDL Hyperglycaemia Ototoxicity (high dose IV)
184
What is the mechanism of action of captopril?
- angiotensin converting enzyme (kinase 2) inhibitor -\> inhibits hydrolysis of AT1 to AT2 - hence inhibits AT2 effects (potent vasoconstrictor and inc aldosterone secretion - salt & water retention) and dec pulmonary vasc resistance, blood pressure - also inhibits bradykinin inactivation to cause vasodilation and decreased pulmonary vascular resistance, blood pressure
185
What are the adverse effects of captopril?
Hypotension - 1st dose esp if hypovolaemic, diuretics, salt res, GI loss ARF - esp with bilateral renal artery stenosis Hyperkalaemia - esp if renal insufficiency, diabetes Cough, angioedema - (bradykinin, substance P), wheeze Foetal abnormalities - 1st teratogenesis, 2nd/3rd hypotension ARF Altered taste, allergic skin rash, drug fever (10%)
186
What drugs interact with captopril?
K+ supplements, K+ sparing diuretics - inc hyperkalaemia NSAIDs - impair blood pressure reduction (block bradykinin) Other antihypertensives Haemaccel
187
What are the indications for amiodarone?
- treatment of atrial and ventricular tachyarrhythmias - used both to revert VT & prevent recurrence - used in VF/VT cardiac arrest (after 3 shocks and adrenaline)
188
Describe the mechanism of action of amiodarone
Prolongs the AP duration (hence QT interval) by K channel blockade - has class 1, 2, 3, and 4 effects
189
Short and long term adverse effects of amiodarone
Acute - bradycardia & heart block - hypotension Chronic - pulmonary fibrosis - liver dysf/hepatitis, skin/corneal dep, hypo/hyperthyroidism
190
1. By what routes can GTN be administered? 2. Why are parentral routes favoured?
1. Sublingual, Transdermal, IV, Oral, Buccal, Inhaled 2. To avoid hepatic first pass effect which significantly decreases bioavailability
191
1. What is meant by the term tachyphylaxis as it relates to GTN? 2. What is the implication of this for the dosing and administration of GTN? 3. What is the theoretical basis for this phenomenon?
1. Continuous exposure to nitrates -\> smooth m may develop tolerance. Particularly seen with continuous IV infusion or long acting preparations (oral, TD) 2. Concept of 'drug-free' interval - at least 8hr between doses 3. A) Diminished release of nitric oxide resulting from reduced bio activation 2nd to depletion of tissue thiol compounds, dec tissue sulphyl dryly groups, inc generation of 02 free radicals, dec availability of CGRP. B) Systemic compensation - after \>1 day of therapy salt & water retention reverse favourable haemodynamic change
192
When should GTN be used with caution?
Hypotension Inferior/posterior MI, RV infarct Fixed cardiac output (AS, tamponade etc) Raised ICP Significant tachy/brady Allergy, Those on sildenafil
193
1. What anti-arrhythmic class does amiodarone belong to? 2. What are the effects of amiodarone on the heart?
1. Class 3 Also has class 1, 2, and 4 effects 2. Increases action potential duration due to blockage of rapid component of delayed K+ current. Chronic use also blocks slow K+ rectifier. Prolongs QT. Blocks inactivated Na+ channels. Weak adrenergic and CCB.
194
1. What other arrhythmias is amiodarone used for? 2. What arrhythmias can amiodarone cause?
1. Atrial fibrillation, VT/VF, supra ventricular (re-entrant/accessory) 2. Torsades de pointes (rare \<1%), bradycardia, heart block
195
What is the mechanism of action of metaraminol?
Direct alpha 1 receptor agonist - some indirect effect through increased noradrenaline
196
What are the effects of metaraminol on the cardiovascular system?
Vaso and arterioconstriction in vascular beds Arterioconstriction -\> increased blood pressure Direct cardiac effects less important Heart rate slows due to vagal feedback Cardiac output unchanged or slight dec as inc venous return and hence stroke volume
197
What role do sympathomimetics have in management of shock?
- temporising only while other treatment instituted (fluids etc) - efficacy not proven - useful in 'failure' of sympathetic nervous system (eg spinal injury or anaesthesia)
198
What is the mechanism of action of GTN?
- Nitrite -\> NO -\> increased cGMP -\> smooth muscle relaxation - prostaglandins may be involved
199
What are the clinical effects of GTN?
Beneficial - VENODILATION, reduced venous return, dec ventricular pre-load, reduced LVEDV, reduced LV wall tension, REDUCED MYOCARDIAL O2 CONSUMPTION, vasodilation of epicardial coronary arteries, inc coronary collateral flow, DEC SYSTEMIC BP Adverse - hypotension, tachycardia, headache
200
What are the indications for GTN use in ED?
- angina - acute coronary syndrome - hypertensive urgencies/emergencies - acute pulmonary oedema - aortic dissection (with beta-blockade)
201
What is digoxin's mechanism of action in heart failure?
Ca accumulation in cells (due to Na+/K+ ATP block, Na in cells drive Na/Ca exchange) leads to: - increased contraction strength - more stroke volume/CO per beat -\> smaller EDSV, small heart, reduced R heart pressures/volume - slower HR -\> greater stroke volume (particularly if AF), via effects on parasympathetic fibres/AV node
202
Why are patients in heart failure prone to digoxin toxicity?
- poor renal function from low CO - potential dehydration and/or other drug interactions - ie:ACE/diuretics/sprionolactone/CCBs - low K+ from other heart failure meds - esp diuretics (makes patients higher risk from dig toxicity) - poor cardiac reserve/output, altered digoxin handling during acute HF/fluid distribution changes/other major illnesses
203
What are the feature of digoxin toxicity?
- High K (strongly with mortality) - Yellow/green (or other) colour vision - GI: diarrhoea, N & V, malaise, anorexia - Arrhythmias from greater automaticity and also AV node block (particularly brady, but R on T as well) - Severe heart blocks, particularly if previous blocks, worsening failure, low BP - CNS: tiredness, lethargy, headaches, parasthesias
204
Describe the mechanism of action of verapamil.
- block voltage-gated L-type Ca channels (a1 subunit) - reduced freq of opening when depolarised - resulting in dec transmembrane Ca current and Ca influx -\> vascular smooth m relaxation (\< dihydropyridines) - Cardiac: dec AVN conduction, contractility, CO
205
1. What are the toxic effects of verapamil? 2. What antidotes can be used to treat verapamil toxicity?
1. CVS: bradycardia, AV block, cardiac arrest, heart failure, hypotension Minor: flushing, dizziness, nausea, constipation, peripheral oedema 2. IV calcium, high-dose insulin (euglycaemic therapy)
206
Describe the mechanism of action of gentamicin.
- irreversible inhibitor of protein synthesis (possible mechanism) - passive diffusion via porin channels across outer memb, then active transport into cytoplasm by an O2 dependant process - inside the cell, binds 30S ribosome & inhibits protein synthesis by 1. Inducing misreading of mRNA thus producing toxic or nonfunctional protein 2. Interfere with initiation complex of peptide formation 3. Cause break up of polygons into non-functional monosomes
207
What are the benefits of once daily dosing of gentamicin?
- Concentration-dependant killing (at inc conc kill inc no of bacterial at a more rapid rate) - Postantibiotic effect - activity lasts longer than detectable serum levels - Reduced toxicity (tox is time & conc dependant) - time above critical level will be longer with multi dose than single dose schedule - Less nursing time, OPD therapy possible - Drug level not required unless \>3 day therapy. Dosage still needs to be adjusted according to renal function
208
How do penicillins enhance the efficacy of gentamicin?
Low ECF pH & anaerobic conditions inhibits transport Transport enhanced by cell wall active drugs eg penicillin
209
How are cephalosporins classified?
Class 1 - gram positives Class 2 - haemophilus & klebsiella Class 3 - gram positives & gram negatives Class 4 - pseudomonas
210
1. Why are 3rd generation cephalosporins used in CNS infection? 2. Are there any bacteria responsible for CNS infection that cephalosporins do not cover?
1. Expanded gram neg activity, cross the blood brain barrier, penetrate body fluids well, good toxicity profile. 2. Listeria, resistant pneumococci may need vancomycin, resistant E Coli (use with aminoglycoside to cover pseudomonas)
211
Describe the pharmacokinetics of metronidazole
Class - nitroimidazole antiprotozoal drug Pharmacokinetics - well absorbed orally (99% oral bioavailability), oral/IV/suppository - metabolised in liver (can accumulate in hepatic insufficiency) - low protein binding (10-20%) - dosage: 500mg TDS or single dose 2g for vaginitis - half life 7.5hrs
212
What are the adverse effects of metronidazole?
- nausea, diarrhoea, dry mouth, hairy black tongue - headache, parasthesia, dizziness, insomnia - dysuria, dark urine - disulfiram-like effect - hence avoid alcohol - potentials the effect of anticoagulants, lithium - teratogenic effect on mice, but not proven in humans
213
How are cephalosporins classified and give examples?
1st generation - cephalexin, cephazolin, cephalothin - very active against gram pos cocci (pneumococci, strep, staph) - gram neg org (E.coli, K pneumoniae, proteus mirabilis) often sensitive, but not against gram neg aerobes (P aeruginosa, indole-pos proteus, enterobacter, serration marcescens, citrobacter) & acinetobacter 2nd generation - cefaclor, cefamandole, cefuroxime - active against organisms inhibited by 1st gen drugs but has extended gram neg coverage, klebsiellae are usually sensitive - some anaerobic 3rd generation - ceftriaxone, cefotaxime, ceftazidime - have expanded gram neg coverage & cross blood brain barrier (BBB) - less active against staph than earlier cephalosporins but are active against citrobacter, S marcescens, & Providencia - also effective against lactamase-producing strains of haemophilus & neisseria - some anaerobic None of the above active against MRSA, enterococci, or P aeruginosa 4th generation - cefepime - extended spectrum of activity covering the majority of the enteric gram neg rods, including pseudomonas and enterobacter - also active against S aureus & S pneumoniae - more resistant to hydrolysis by chromosomal lactamases (eg those produced by enterobacter)
214
What are the adverse effects of the cephalosporins?
Hypersensitivity reactions identical to penicillins - anaphylaxis, fever, skin rashes, nephritis, granulocytopaenia, & haemolytic anaemia - frequency of cross-allergenicity uncertain, prob around 5-10% Severe pain with IMI Thrombophlebitis with IVI Renal toxicity - interstitial nephritis & ATN Cephalosporins with a methylthiotetrazole group (cefotetan) may cause hypoprothrominaemia, bleeding (preventable with Vit K) Severe disulfiram-like reactions with alcohol
215
Describe the mechanism of action of gentamicin.
- irreversible inhibitor of protein synthesis - passive diffusion via porin channels across outer memb, then active transport into cytoplasm by O2 dependant process; transmembrane electrochem gradient supplies the E, transport coupled to proton pump - low ECF ph & anaerobic conditions inhibits transport as reduces gradient; transport enhanced by cell wall active drugs (eg penicillin) - binds 30S ribosome & inhibits protein synthesis by simultaneously 1 inducing misreading of mRNA thus producing non toxic protein 2 interfere with initiation complex of peptide formation 3 cause break up of polysomes into non-functional monosomes
216
Outline the pharmokinetic properties of gentamicin.
- poor oral absorption, well absorbed IM, and usually given IV - highly polar and thus does not enter cells well, water soluble - CSF - 20% plasma levels - bile - 30% plasma levels - pleural/synovial 50-90% plasma levels - most tissues low except renal cortex - not metabolised, cleared by kidney - may be activated by bacteria - half life 2-3hrs - 40-60% removed by HD - dosage adjustment needed for renal impairment
217
What are the reasons for once daily dosing of gentamicin?
- concentration dependant killing - post antibiotic killing effect - toxicity is both time & concentration dependant - numerous clinical studies suggest once daily dosing is just as effective and no more (possibly less) toxic - more convenient, outpatient administration possible - no need to obtain serum levels unless \>4-5 days
218
How do tetracyclines exert their antimicrobial activity?
- bacteriostatic - enter cells by diffusion and active transport - bind irreversibly to 30S sub-unit of the ribosome - block binding of tRNA to mRNA - ribosome complex, stop addition of amino acids to peptide
219
Describe the pharmacokinetics of the tetracyclines
- Variable oral absorption, generally greater than 60% (depending on drug) - Absorption occurs mainly in upper small intestine - Food, calcium, dairy, and alkaline pH impair absorption - 40-80% protein bound - Distributed widely to tissues except CSF, crosses placenta - Chelate to Ca and are bound to growing teeth & bones - Excreted in bile and in urine, concentrated in bile (up to 10x serum conc) - Undergo enterohepatic circulation - Depending on drug 10-50% urine or biliary excretion - Doxy is the exception, no renal elimination
220
Are there any groups of patients where tetracyclines are contraindicated?
- pregnancy - children \< 8 years - breast feeding
221
Regarding penicillins, what is their mechanism of action?
- interfere with bacterial wall synthesis - high intracellular osmotic pressure bursts weakened cell wall - inhibits transpeptidase reaction -\> inhibits cross linkage
222
How do bacteria become resistant to penicillins?
- beta lactamase - modification of PBPs - impaired penetration - efflux pump
223
1. How are penicillins eliminated? 2. How does probenicid alter the elimination of some penicillins?
1. Renal excretion and secretion. Biliary secretion. 2. Inhibits secretion of weak acids from the proximal tubule.
224
What is the mechanism of action of erythromycin?
- inhibits RNA-dependent protein synthesis by binding to the 50S ribosomal subunit - bacteriostatic (at high conc with selected organisms can bacteriocidal)
225
What is the mechanism for the drug interactions associated with erythromycin? Give some examples.
Inhibits hepatic CYP3A4 - usually inhibits metabolism of other drugs causing increased activity Examples - benzodiazepines, carbamazepine, cisapride (cardiotoxicity), digoxin, warfarin, theophylline, cyclosporin, tacrolimus
226
What are the adverse effects of erythromycin?
Common - GIT: abdo cramps, diarrhoea, N&V, candida (oral/vag) Rare - hypersensitivity, hearing loss, pancreatitis, hepatotoxicity Rapid IV may cause ventricular arrhythmias
227
What is the mechanism of action of cephalosporins?
- inhibit bacterial cell wall synthesis, cell division and growth (similar to penicillins) - bactericidal - most effective in rapidly dividing cells
228
How does the spectrum of microbiological activity for the 4th generation cephalosporins compare to that of earlier generations?
- Gram neg as for 3rd gen eg E Coli, H influenza, Klebsiella - Some gram pos (S pneumoniae) but less than 1st generation - More resistant to B lactamases than earlier generations
229
What is the relationship between penicillin allergy and cephalosporin allergy?
5-15% possibility of cross-reaction with penicillin allergy.
230
What are the organ system effects of theophylline?
CNS: Mild cortical arousal with inc alertness & deferral of fatigue. Bronchodilation. Nervousness & tremor. Overdose causes medullary stimulation, convulsions & death. CVS: Positive chronotropic & inotropic effects by inhibiting presynaptic adenosine receptors in sympathetic nerves & increasing catecholamine release at nerve endings. Produces tachycardia, inc cardiac output & BP. May cause arrhythmias. GIT: Stimulates gastric acid & digestive enzymes secretion. Kidney: Weak diuretic from inc glomerular filtration & reduced tubular sodium reabsorption. Lung: Bronchodilation by relaxing airway smooth m & inhibits antigen-induced release of histamine from lung tissue.
231
How do the organ effects of theophylline correlate to its serum concentrations?
Theophylline has a narrow therapeutic window, and its therapeutic and toxic effects are related to its blood level: 5-20mg/L - Improvement in pulm function. Anorexia, nausea. 15-20mg/L - Vomiting, abdominal discomfort, headache, & anxiety occur in some patients. \> 40mg/L - Cause seizures or arrhythmias.
232
How does penicillin exert its action?
Interferes in bacterial cell wall synthesis by binding to penicillin-binding-protein (PBP) & preventing removal of terminal d-alanyl-d-alanine from peptides preventing cross linking & formation of peptidoglycan.
233
What are the mechanisms of resistance to B lactam antibiotics?
1. Inactivation of B-lactamase 2. Modification of target PBPs 3. Impaired penetration of drug to target PBPs 4. Presence of efflux pumps
234
1. Why is once-daily dosing advocated for gentamicin? 2. Why is gentamicin usually used in combination with another antibiotic?
1. Concentration-dependent killing & post antibiotic effect vs toxicity proportional to time over threshold concentration...... Practical advantages. 2. Usually combined with a cell-wall active drug that enhances gentamicin transport into the cell, eg B-lactam or vancomycin
235
What is the mechanism of action of gentamicin & how does resistance develop?
Aminoglycoside that binds to specific ribosomal proteins and inhibits protein synthesis. Resistance by - transferase that inactivates drug, carried by plasmids - impaired cell entry (cell wall) - altering ribosomal receptor protein
236
What are the adverse effects of chloramphenicol?
GIT - nausea, vomiting, & diarrhoea Bone marrow suppression - reversible RBC suppression, idiosyncratic aplastic anaemia (1/24000 - 1/40000) Newborn - gray baby syndrome Drug interaction - phenytoin, chlorpropamide, warfarin prolongs half life and raises concentration
237
What bacteria does chloramphenicol affect?
- Aerobic and anaerobic - Gram positive and negative - Rickettsia but NOT chlamydia
238
What is the mechanism of action of chloramphenicol?
- Potent inhibitor of microbial protein synthesis - Binds to 50S subunit of bacterial ribosome by inhibiting peptidyl transferase - Bacteriostatic
239
Describe the mechanism of action of penicillin?
- Penicillin Binding Protein (PBP) binding - Block peptidoglycan/cell wall synthesis
240
What are the important mechanisms of resistance to penicillins?
1. B-lactamase 2. Altered PBPs 3. Reduce penetration 4. Efflux pump
241
Describe the pharmacokinetics of penicillin?
- oral absorption food impaired - wide distribution - renal excretion and tubal secretion
242
What is the mechanism of action of trimethoprim?
- Inhibits bacterial dihydrofolic acid reductase - Converts dihydrofolic acid to tetrahydrofolic acid (purine synthesis & DNA)
243
Why are sulphonamides synergistic with trimethoprim?
- Sulphonamides are a structural analog of p-aminobenzoic acid (PABA) - Inhibit synthesis of dihydrofolic acid, therefore sequential blocking of sequence (Trimethoprim inhibits bacterial dihydrofolic acid reductase)
244
What are the mechanisms of bacterial resistance to trimethoprim?
- Reduced cell permeability - Increased droid unction of dihydrofolic reductase - Alteration in dihydrofolic reductase with reduced binding
245
What is the mechanism of action of the tetracyclines?
1. Bacteriostatic drug 2. Inhibits protein synthesis 3. Enters bacteria by passive diffusion and active transport. Once inside binds reversibly to 30S subunit of ribosome, blocking the binding of aminoacyl-tRNA to the acceptor site on mRNA ribosome complex, preventing the addition of a.acids to growing peptide.
246
What mechanisms of resistance affect the tetracyclines?
1. Dec intracellular accumulation due to impaired influx or increased efflux by an active transport protein pump. 2. Production of proteins that interfere with the tetracycline binding to the ribosome. 3. Enzymatic inactivation with production of efflux pump. 4. Resistance is plasmid mediated.
247
What are their adverse reactions?
1. GIT: N, V, & D due to local irritation. 2. Enamel dysphasia, bony deformity, and growth retardation due to deposition in children \< 8yr and pregnancy. 3. Liver toxicity. 4. RTA if medicine is outdated. 5. Venous thrombosis if given IV. 6. Photosensitisation. 7. Vertigo from vestibular dysfunction.
248
What is the mechanism of action of ciprofloxacin?
1. Synthetic flourinated analogs of nalidixic acid - earlier forms not systemic antibacterial levels - flourinated derivatives improved serum activity 2. Block bacterial DNA synthesis by inibiting bacterial topoisomerase 2 (DNA gyrase) and topoisomerase 4 - T2 -\> prevent relaxation of positively supercoiled DNA needed for normal transcription and replication - T4 -\> interferes with separation of replicated chromosomal DNA into daughter cells during cell division
249
What are the uses of ciprofloxacin?
- UTIs (norflox, cipro, oflox) - Bacterial diarrhoea (shigella, salmonella, Ecoli, campyl) - Soft tissue, bone, joint, intra-abdominal, resp - gonococcal (cipro, oflox), chlamydia (cipro)
250
What are the adverse effects of ciprofloxacin?
- nausea, vomiting, diarrhoea \> headache, dizziness, insomnia, rash, LFT abnormalities - may damage growing cartilage, cause arthropathy not \<18yrs - tendinitis in adults -\> risk tendon rupture - avoid during pregnancy and lactation
251
What is an antiseptic?
A chemical disinfectant applied to living tissue (skin, mucous membranes, and wounds) which decreases the number of organisms by killing, removing, diluting and has generally low toxicity to tissues.
252
Describe the actions and uses of chlorhexidine. When is chlorhexidine contraindicated?
1. Low skin sensitising or irritating capacity. Oral toxicity low (poorly absorbed from the alimentary tract). 2. Active against bacteria (most effective against G pos cocci), mycobacteria, moderate against fungi & viruses. 3. Not inhibited by blood or organic products. Contraindicated: middle ear surg, neurosurg, allergy.
253
1. Name some macrolide antibiotics. 2. What is their mechanism of action? 3. What organisms are usually sensitive to macrolides?
1. Erythromycin, azithromycin, clarithromycin, roxithromycin. 2. Inhibits protein synthesis via binding to SOS ribosomal RNA and blocks aminoacyl translocation and the formation of initiation complexes. 3. G pos: pneumococci, staph, mycoplasma, legionella, chlamydia. G neg: neisseria, pertussis, campylobacter. Treponema palladium
254
Describe suxamethonium.
Rapid onset depolarising skeletal muscle relaxant with short duration. Acts by mimicking acetylcholine at neuromusc junction. - Contraindicated: FHx malignant hyperthermia, severe liver disease, hyperkalaemia. - Side effects: muscle pain, fascicles ion, myoglobinaemia, brady/tachycardia, hyper/hypotension, anaphylaxis, bronchospasm, prolonged apnoea, hyperkalaemia (0.2-0.4mmol), hyperthermia, inc intragastric pressure, dec lower oesophageal tone, inc salivation & gastric secretions, transient inc in intraocular pressure.
255
What are the pharmacokinetics of suxamethonium?
Distribution: Initial rapid redistribution phase. Protein-bound to unknown extent. Metabolism: Hydrolysed by plasma cholinesterase (80%) of administered dose hydrolysed before reaching NMJ. Excretion: Liver 75-90%, kidney, duration of action \<8mins, half life 3-5 mins.
256
Drug/condition interactions with suxamethonium?
Conditions that may dec plasma cholinesteras (prolonging action of sux): pregnancy, liver disease, cardiac or renal failure, hypoproteinaemia, thyrotoxicosis, muscular dystrophy, burns, carcinomatosis. Drugs that dec plasma cholinesterase: procaine, lignocaine, lithium, ketamine, OCP, cytotoxic agents.
257
Describe suxamethonium.
Mechanism of action: Agonist at nicotinic ACh receptors, especially at neuromusc junctions, depolarises, may stimulate ganglionic nicotinic ACh & cardiac muscarinic ACh receptors. Effects: Initial depolarisation causes transient contractions, followed by prolonged flaccid paralysis. Depolarisation is then followed by depolarisation also accompanied by paralysis. Clinical App: Placement of ETT, control of muscle contractions in status epilepticus. PK, Tox: Rapid metabolism by plasma cholinesterase, normal duration ~5min. Tox - arrhythmias, hyperkalaemia, transient inc intra-ab/intraocular pressure, post op muscle pain.
258
Describe rocuronium.
Mechanism of action: Competitive antagonist at nACh receptors, esp at NMJs. Non-depolarising. Effects: Prevents depolarisation by ACh, causes flaccid paralysis. Slight antimuscarinic (cardiac) effect. Clinical applications: Prolonged relaxation for surgery, securing airway. PK, Tox: Prolonged apnoea, hepatic metabolism (75-90%), duration ~20-35min.
259
Describe baclofen as a spasmolytic.
Mechanism of action: GABAb agonist, facilitates spinal inhibition of motor neurons. Effects: Pre and postsynaptic inhibition of motor output. Clinical Applications: Severe spasticity due to CP, MS, stroke. PK, Tox: Oral, intrathecal. Tox - sedation, weakness.
260
Describe diazepam as a spasmolytic.
Mechanism of action: Facilitates GABAergic transmission in CNS. Effects: Inc interneuron inhibition of primary motor afferents in spinal cord. Central sedation. Clinical applications: Chronic spasm due to CP, stroke, spinal cord injury. Acute spasm due to muscle injury. PK, Tox: Hepatic metabolism, duration ~12-24hr,
261
How do you determine a loading dose?
Loading dose = Vd x target concentration/ bioavailability
262
Starting point for a medical solution.
1% = 1000mg in 100ml solution.
263
Pharmokinetic properties of amide local anaesthetics
Bupivacaine: t1/2 dist 28min, t1/2 elim 3.5hrs, Vd 72L, CL 0.47L/min. Lignocaine: t1/2 dist 10min, t1/2 elim 1.6hrs, Vd 91L, CL 0.95L/min. Prilocaine: t1/2 dist 5min, t1/2 elim 1.5hrs, Vd 261L, CL 2.84L/min Ropivacaine: t1/2 dist 23min, t1/2 elim 4.2hrs, Vd 47L, CL 0.44L/min
264
Describe the different types of nerve fibres.
Type A Alpha - proprio, motor, 12-20um, myel, cond 70-120m/s, block + Beta - touch, pressure, 5-12um, myel, cond 30-70m/s, block ++ Gamma - musc spindles, 3-6um, myel, cond 15-30m/s, block ++ Delta - pain, temp, 2-5um, myel, cond 5-25m/s, block +++ Type B - pregang autonomic, \<3um, myel, cond 3-15m/s, ++++ Type C Dorsal root - pain, 0.4-1.2um, no myel, cond 0.5-2.3m/s, block ++++ Symp - postganglionic, 0.3-1.3um, no myel, cond 0.7-2.3m/s ++++
265
Discuss lignocaine. (Prilocaine similar)
Mechanism of action: Blockade of sodium channels. Effects: Slows, then blocks, action potential propagation. Clinical applications: Short duration procedures, topical/IV/infiltration/spinal/epidural/peripheral blocks. PK: Parentral, duration 1-2h, 2-4h with adrenaline. Tox: CNS excitation (high vol blocks) & local neurotoxicity.
266
Discuss bupivacaine. (Ropivacaine similar)
Mechanism of action: Blockade of sodium channels. Effect: Slows, then blocks, action potential propagation. Clinical applications: Longer-duration procedures (not used top/IV). PK: Parentral, duration 3-6hrs. Tox: CNS excitation, cardiovascular collapse (high-vol blocks)
267
What is the formula for bioavailability?
Bioavailability (F) can be predicted by extent of absorption (f) and extraction ratio (ER). F = f x (1 - ER)
268
Discuss naloxone.
- Pure opioid antagonist. - High affinity for mu receptors, less so for kappa & delta receptors. - Half life 1-2hrs via IV, 10hrs orally - Well absorbed orally but rapid first pass metabolism - IVI reverses opioid tox in 1-3 mins. - No tolerance to antagonistic action, no withdrawal syndrome.
269
What is efficacy? What is potency?
Efficacy - The maximum effect a drug can bring about, regardless of dose. Potency - The dose or concentration required to bring about 50% of a drug's maximal effect.
270
What is the therapeutic index?
Therapeutic index (TI) is the relationship of the dose of a drug required to produce a desired effect to that which produces an undesirable effect. TI = median toxic dose (TD50) / median effective dose (ED50) Drugs with a high TI are safer.
271
Describe sodium cromoglycate.
Used for prophylactic treatment of exercise and allergen induced asthma. It inhibits cell activation by alteration in function of cell membrane chloride channels. Prevents mast cell degranulation. No effect on bronchial smooth muscle tone.
272
Describe the sites of action of the major classes of anti hypertensive drugs.
Vasomotor centre (brain) - clonidine, methyldopa Sympathetic ganglia - trimethaphan B-receptors heart - propranolol and other B-blockers Angiotensin receptors of vessels - losartan (ARBs) A-receptors of vessels - prazosin Vascular sm m - CCBs, hydralazine, nitroprusside Kidney tubules - thiazides B-receptors of juxtaglomerular cells (release renin) - B-blockers Renin-angiotensin path - ACE inhibitors
273
What drugs are used in angina?
Nitrates B-blockers CCB
274
Describe nitroglycerin.
Mechanism of action: Releases nitric oxide in smooth m, which activates guanylyl cyclase & increases cGMP. Effects: Sm m relaxation, esp in vessels. Vasodilation dec venous return & heart size. May inc coronary flow in some areas. Clinical Apps: Angina - acute & prophylactic. PK: High first pass effect (SL dose
275
Describe propranolol.
Mechanism of action: Nonselective competitive antagonist at B-adrenoceptors. Effects: Dec heart rate, cardiac output, & blood pressure. Dec myocardial oxygen demand. Clinical apps: Prophylaxis of angina, hypertension. PK: Oral/Parentral, 4-6hr duration of action. Tox: Asthma, AV block, acute heart failure, sedation
276
How does heparin act?
- Binds endogenous antithrombin & enhances its activity. - Antithrombin inhibits factors 2a, 9a, & 10a by complexing with them and inducing a conformational change.
277
How may heparin by administered?
- IV or SC - continuously (following bolus) vs intermittent - therapeutic vs prophylactically
278
What are the potential adverse effects of heparin?
- Bleeding - Heparin-induced thrombocytopaenia - Allergy - Alopecia, osteoporosis, mineralocorticoid deficiency
279
What are the advantages of low molecular weight heparins compared to unfractionated heparin?
- Equal efficacy - Inc SC bioavailability - Require less frequent dosing - Less monitoring - Shorter chain heparin with less effect on thrombin (2a)
280
What methods are available to reverse warfarin induced anti-coagulation?
- Cease warfarin - Vitamin K -\> oral or IV 1-10mg - +/- fresh frozen plasma or prothrombinex
281
How does vitamin K reverse warfarin effect? How long does it take to work?
- Pharmacodynamic interaction with warfarin to reduce INR ie reverses the effect of warfarin. - Re-establishes normal activity of the clotting factors. Vitamin K dependent factors: 2, 7, 9, 10. - Works in 6-24 hours.
282
What is Vitamin K?
- Fat soluble substance in leafy vegetables - Usually synthesised by gut bacteria - Vit K1 (food) - Vit K2 (bacteria)
283
Describe the mechanism of Vit K's reversal of warfarin.
Warfarin - Coumarin anticoagulant - Prevents reductive metabolism of inactive Vit K to active form - Produces biologically inactive 7, 9, 10, prothrombin (2), protein C & S Vit K1 - Confers biologic activity upon prothrombin & factors 7, 9, 10 by participating in their post-ribosomal modification Onset of action 6 hours, complete by 24hrs
284
Using examples, outline the mechanism of action of the various types of laxative.
* **Irritants or Stimulants**
* (act early) castor oil
* (act late) cascara, **senna**, aloes (contain emodin alkaloids which are liberated after absorption fro the intestine & excreted in the colon)
* (prolonged action by enterohepatic circulation) phenolphthalein & biscodyl
* **Bulking agents** - hydrophylic colloids, agar, psyllium seed, **bran**
* **Osmotic** - Mg citrate & Mg hydroxide, polyethylene glycol, sorbitol, **lactulose**
* **Stool softeners** - agents that emulsify with the stool & soften it (mineral oil, **glycerine**, detergents such as docusate)
285
Explain the rationale for the use of octreotide in upper GI bleeding.
* Octreotide reduces splanchnic blood flow (by glucagon release inhibition), and therefore reduces portal venous pressure.
* This reduces blood loss from bleeding oesophageal varices & in some cases of severe duodenal ulcer related bleeding.
286
What are the pharmacokinetic differences between octreotide & somatostatin?
Octreotide is a somatostatin analogue that has a longer half life than somatostatin (1.5hrs vs 3 min), so can be given as an IV infusion or subcutaneously.
287
Name some antiemetics used in the Emergency Dept.
* **Ondansetron**
* **Metoclopramide**
* **Prochlorperazine** (Stemetil)
* Others: anti-histamines, hyoscine, benzos, chlorpromazine (largactil), droperidol
288
Compare the mechanisms of action of ondansetron & metoclopramide.
* Act at different receptors
* Ondansetron
* **Peripheral 5-HT3 blockade** (vagal & spinal afferents, reduces sensory visceral output)
* **Central 5-HT3 blockade** (vomiting centre and central trigger zone [CTZ])
* Metoclopramide
* **D2 blockade (CTZ)**
* Inc oesophageal motility, inc LOS pressure, inc gastric emptying
289
Describe the potential adverse effects of metoclopramide.
* **CNS**
* Restlessness, insomnia, anxiety, agitation (common 20%, esp elderly), drowsiness
* **Extrapyramidal effects**
* **Acute dystonia**, akathisia, Parkinsonian effects (more likely with higher doses), tardive dyskinesia (chronic dosing)
290
What different mechanisms of actions of laxatives do you know? Give examples.
* **Bulk-forming**
* Psyllium, increase bloating & flatus
* **Stool softening**
* Docusate, glycerine, permit water & lipids to penetrate
* **Osmotic 1**
* Non absorbable sugars/salts, sorbitol, lactulose
* Osmotic 2
* Polyethylene glycol
* Stimulant
* Senna, aloe, castor oil
291
Polyethylene glycol is used as a prep for endoscopic procedures. What features make it safe for all patients.
* **Balanced**
* Osmotically active sugar (PEG) with NaCl, NaHCO3, KCl
* **No significant osmotic shifts**. Best ingested rapidly for bowel cleansing
292
Describe the action of PPIs.
* **Irreversibly inactivates H+K+ATPase**
* Blocking the proton pump
* Inhibiting \>90% acid secretion for up to 24hrs (time taken for synthesis of new enzymes)
293
Why is an IV infusion preferred to a single bolus dose?
* **Only inactivates actively secreting acid pumps**
* \<10% in fasting patients, hence single dose only decreased acid secretion for a few hours
294
Regarding oral formulations of proton pump inhibitors, describe strategies used to increase their bioavailability and activity.
* **Taken as inactive pro-drugs**
* Begin as **acid resistant enteric coated** to prevent gastric elimination
* Take on **empty stomach** as food dec bioavailability
* Weak bases, so pass into acidified parietal cells where conc 1000x, becomes activated & binds to H+K+ATPase
* **Take 1 hr prior to meal** so peak drug dose occurs when most pumps are active
295
What is the mechanism of action of Ondanstron?
* **5-HT3 receptor antagonist**
* Effect brought about as peripheral (gut) \> central receptors
* Chemoreceptor trigger zone (CTZ) & vomiting centre
296
What are the doses & routes of administration of ondanstron?
* 4-8mg
* SL, PO, IV, SC, IM
297
1. What are the adverse effects of ondanstron?
2. In which disease states would you need to modify the dosing?
1.
* Constipation
* Headache
* Dizziness
* QT prolongation
2.
* Hepatic failure
* Not with renal failure or age
298
What are some other classes of antiemetic drugs?
* Phenothiazines - stemetil (prochlorperizine)
* Antihistamines
* Cannabinoids
* Benzodiazapines
* Butryophenones - droperidol
* Benzamides - metoclopramide
* Neurokinin receptor antagonists
* Corticosteroids
299
How does carbimazole act in thyroid disease?
* Metabolised to methimazole
* **Major action is blocking hormone synthesis of T3 & T4**
* **Inhibits thyroid peroxidase**
* ****limits organification of iodine. Also blocks coupling of iodotyrosines
* Small action in blocking peripheral deiodination of T3 & T4. Slow onset as T4 may take weeks to become depleted.
300
Outline the groups of drugs that are used to treat hyperglycaemia in diabetes mellitis.
* **Insulin**
* **Sulfonylureas**
* **Biguanides**
* Meglitinides
* D-phenylalanine derivatives
* Thiazolidinesdiones
* Alpha-glucosidase inhibitors
301
Contrast the mechanism of action of sulfonylureas & biguanides.
**Sulfonylureas**
* **Increase insulin release from pancreas**
* Reduction of serum glucagon levels
* Closure of potassium channels in extrapancreatic tissues
**Biguanides**
* **Action does not depend on functioning pancreatic B cells**
* May directly stimulate glycolysis in tissues with inc glucose removal from blood
* May reduce hepatic gluconeogenesis
* May slow absorption of glucose from the GI tract
* May reduce glucagon levels
302
What are the mechanisms of action of the sulfonylureas?
* **Increase secretion of insulin**
* Bind to pancreatic B cell receptor causing inc release of insulin
* **Reduced serum glucagon levels** - with chronic use thought to be due to indirect inhibitory effects of insulin & somatostatin on cells
* **Potentiation of insulin action on target tissues** - inc binding of insulin to tissue receptors ? due to indirect effect of reduced glycaemia or FFA levels
303
What are the adverse effects of sulphonylurea therapy?
* **Prolonged hypoglycaemia**
* Alcohol intolerance - flushing
* Dilutional hyponatraemia (genetic predisposition)
* Jaundice, leucopenia, thrombocytopaenia (ch
304
What are the major side effects of carbimazole?
* **Bone marrow suppression**
* Neutropaenia, agranulocytosis (reversible)
* **Rash** (common)
* Maculopapular, pruritis
* Others
* Urticaria, arthralgia, lupus reaction, vasculitis, jaundice/hepatitis, nausea & GI, occur early
305
How does carbimazole differ from propylthiouracil (PTU)?
* **Carbimazole is a pro drug**
* Converted to methimazole in vivo (which is 10x more potent)
* PTU has greater action in inhibiting peripheral deiodination of T4 & T3
* PTU is strongly **protein bound**, preferred in pregnancy, not secreted in breast milk
* PTU has shorter **half life** 1.5 vs 6hrs. PTU given QID, carbimazole is daily
* PTU **bioavailability** 50-80% vs carbimazole 100% (Vd = TBW)
* PTU **excreted** in urine as glucuronide metabolite \<24hrs, carbimazole in 48+ hrs
306
1. What is erythropoietin?
2. What are its clinical applications?
1. **Glycoprotein produced by the kidney.**
2.
* **Stimulates red cell precursors to proliferate & differentiate**. Also releases reticulocytes from marrow
* Main use is for the **anaemia of chronic renal failure**, where EPO production is impaired
* Helps some **marrow failure** states - aplastic anaemia, myeloproliferative/myelodysplastic disorders, multiple myeloma, AIDS, cancer
307
What toxic effects may occur with erythropoietin?
* **Toxicity mainly related to rapid Hb rise**
* Hypertension
* Thrombosis
* Allergic reactions are infrequent &mild
308
Regarding glucagon, outline its pharmacodynamic effects & relate these to its clinical use.
* **Inc glycogenolysis & gluconeogenesis** thus inc serum glucose -\> **treatment of hypoglycaemia**
* **Positive ionotropic & chronotropic effect** on the heart via glucagon receptors & cAMP -\> **treatment of B-blocker OD**
* **Relaxation of intestinal smooth muscle** -\> treatment of **food bolus obstruction** or to aid radiology of the bowel
309
Regarding sulphonylureas & bigaunides, compare their mechanisms of action.
* **Sulphonylureas increase insulin release**
* Act via a specific receptor -\> causes an inc in intracellular Ca++ -\> triggers insulin release
* There are also receptors in cells on binding proteins in secretory granules -\> may cause direct action on exocytosis of insulin
* Other peripheral effect may be **reduction of serum glucagon** & **potentiate insulin effects** on cells
* **Biguanides** are 'euglycaemic agents'
* **Do not require functional B islet cells to reduce blood sugar**
* Possible actions
* Directly stimulate glycolysis in tissues & blood
* Dec hepatic gluconeogenesis
* Dec GI absorption
* Dec plasma glucagon
310
How do the major side effects of suphonylureas and biguanides differ?
* **Biguanides can cause lactic acidosis**
* They reduce gluconeogenesis & reduce lactic acid uptake in the liver. More likely in patients with renal disease, alcoholism, liver disease, & chronic tissue hypoxia
* **Sulphonylureas more commonly cause hypoglycaemia**
* ****More likely in the elderly and with drugs that have a long T 1/2, eg chlorpropamide
311
Regarding hydrocortisone, what are its pharmacodynamics?
* Anti-inflammatory
* Immunosuppressive
* Catabolic effects (protein, fats)
* Permissive effects (catecholamines)
* Metabolic effects
* Other - endo, psych
312
Describe the anti-inflammatory and immunosuppressant effects of hydrocortisone.
What are the effects of chronic steroid use?
* **Altered leucocyte conc, distribution, & function**
* **Inhibit macrophages & antigen presenting cells**
* Reduce interleukins & other mediators (phospholipase A2 & COX 2)
* **Decrease histamine release** by mast cells etc
* Reduce Ab production
Chronic steroid use
* **Cushings**
313
What are the different types of oral hypoglycaemic agents?
1. **Insulin secretagogues**
* **sulfonylureas**, meglitinides
2. **Biguanides**
3. Thiazolidinediones
* enhance target tissue insulin sensitivity
4. Alpha-glucosidase inhibitors
* competitive inhibitors of intestinal alpha glucosidases -\> defers digestion to distal small intestine
314
1. What is the mechanism of action of the sulfonylureas?
2. How do the biguanides differ from sulfonylureas in their action?
1.
* **Increase insulin release from pancreas**
* Reduce serum glucagon levels
* Extrapancreatic effect to potentiate action of insulin on target cells
2.
* **No need of functioning pancreatic B cells**
* **Direct stimulation of glycolysis in tissue**
* Reduce hepatic gluconeogenesis
* Slowing glucose absorption from GIT
* Reduction of plasma glucagon levels
315
What are the clinical advantages of the different oral antidiabetic agents?
1. Biguanides -\> **refractory obesity** where insulin resistance
2. Combination with sulfonylureas in T2DM
3. Newer sulfonylureas are liver metabolised so can be used in renal failure
316
1. Describe the action of insulin on the liver.
2. What are the complications of insulin therapy?
1.
* Anabolic
* Anti-catabolic
2.
* Immune
* Hypoglycaemia
* Lipodystrophy
* Immune resistance
317
Describe the different types of insulin used in the routine management of Type 1 diabetes.
* **Rapid & short acting**
* clear solution, neutral pH, contain Zn rapid onset, short duration eg insulin neutral/lispro/glulusine
* **Intermediate acting**
* turbid solution, neutral pH, protamine in phosphate buffer to prolong action eg insulin isophane/aspart protamine
* **Long acting**
* clear solution, soluable, slow onset, prolonged action, daily admin mimics basal insulin secretion eg insulin glargine/detemir
* **Combination of therapies required to cover basal requirements & post prandial periods**
318
How are the properties of different types of insulin used to achieve optimum glycaemic control?
Tight glycaemic control is acheived by a combination of insulins with different durations of action with an aim of replacing the basal insulin requirements (50%) and meal requirements (50%).
This is done with **combinations of insulins with different durations of action**.
319
1. What type of insulin is used for IV infusion and why?
2. Describe the principles of operation of a subcut insulin infusion device.
1. Short acting regular soluble insulin, as it immediately dissociates on dilution and so is able to be more precisely delivered
2. External open-loop pump for insulin delivery. Delivers individualised basal & bolus insulin replacement doses based on blood glucose monitoring.
Programmed by user.
Consists of insulin reservoir, program chip, keypad & display screen attached to subcut inserted infusion set.
320
1. What class of drug is gliclazide?
2. What are the pharmacokinetic properties of gliclazide?
1. **Sulfonylurea**
2.
* Administered orally - good bioavailability (80%)
* Protein bound - Vd ~ 20L
* **Hepatic metabolism** to inactive metabolites
* **Half life approx 12hrs**
* Predominantly renally excreted (80%)
321
Describe the mechanism of action of sulfonylureas.
* **Stimulates insulin secretion from functional pancreatic beta cells**
* binding of sulfonylurea to receptor inhibits potassium efflux causing extracellular depolarisation
* results in opening of voltage gated calcium channels
* calcium influx causes release of preformed insulin
322
1. What class of drug is gliclazide?
2. What are the potential adverse effects of gliclazide?
1. **Sulfonylurea**
2.
* **Hypoglycaemia**
* **GI upset** - nausea, vomiting, abdominal pain, diarrhoea
* Rash/pruritis
323
Describe the pharmacokinetics of metformin.
* Absorption: well absorbed
* Distribution: not protein bound
* Metabolised: **not metabolised**
* Elimination: elimination T1/2 is 1.5-3hrs, **excreted by the kidney** as an unchanged compound
324
What are the side effects of metformin?
* **Lactic acidosis**
* especially in renal disease, liver disease, chronic cardiopulm disease, ETOH
* GIT most common (20%)
* Decreased absorption Vit B12
325
With regard to sufonylureas, what is the mechanism of action of glipizide?
* **Increase insulin release from the pancreas**
* Binds to receptor associated with ATP sensitive K+ channel, inhibits efflux of K+ ions, results in depolarization & opens Ca++ channels, influx of Ca++ causes release of preformed insulin
* Reduction of serum glucagon levels
* Closure of potassium channels in extrapancreatic tissues
326
What are the effects of hydrocortisone?
* Mediated by glucocorticoid receptors
* Physiologic + permissive effects
* Metabolic effects
* Catabolic and anti-anabolic effects
* **Anti-inflammatory + immunosuppressive effects**
* Other
* CNS, pituitary axis, psychiatric, renal, neonatal lung
327
Describe the anti-inflammatory & immunosuppressant effects of hydrocortisone.
* Effect concentration, distribution, & **function of peripheral leukocytes**
* **Suppress inflammatory mediators** (cytokines + chemokines, as well as PGs + leukotrienes)
* Inhibit tissue macrophages + APCs
* Suppress mast cell degranulation
* Reduce antibody production (in large doses)
328
What are the effects of chronic steroid use?
* **Cushings Syndrome**
* Metabolic effects (moon face, fat redistribution, striae, weight gain, myopathy, muscle wasting, thin skin, bruising, hyperglycaemia, osteoporosis, diabetes, aseptic necrosis, wound healing impaired)
* Other effects (peptic ulcers, psychosis, depression, cataracts, glaucoma, salt retention, hypertension)
* **Adrenal suppression** ( \> 2 weeks dosage)
329
Describe the pharmacokinetics of metformin.
* Absorption: well absorbed
* Distribution: not protein bound
* Metabolism: not metabolised
* Elimination: half life 1.5-3hrs, **excreted by kidney as unchanged compound**
330
Outline some common side effects of metformin.
* **GI most common**
* **20%, limits compliance with the drug**
* **Lactic acidosis** (high anion gap metabolic acidosis)
* Esp in patients with co-existent renal disease, ethanol, chronic cardiopulm disease
331
Contrast the mechanism of action of metformin (biguanide) & glipizide (sulfonylurea).
* Glipizide
* **Increases insulin release from pancreas** (patients more prone to hypoglycaemia with glipizide compared with metformin)
* Decreases serum glucagon levels
* Metformin
* Mechanism is unclear but:
* May reduce hepatic gluconeogenesis
* **Not dependent on functioning pancreatic B cells - so doesn't influence insulin release from pancreas**
* May directly stimulate glycolysis in tissues with inc glucose removal from blood
* Decreases glucose absorption in the gut
332
Describe the mechanism of action of corticosteroids at a cellular level.
* Most of known effects via widely distributed **glucocorticoid receptors**
* Present in blood in bound form on Corticosteroid Binding Globulin (CBG)
* Enters cell as free molecule
* Intracellular receptor bound to stabiising proteins (most important heat shock protein 90, Hsp90)
* Complex binds molecule of cortisol then actively transported into nucleus where binds to **Glucocorticoid Receptor Elements (GRE)** on the gene
* Interacts with DNA & nuclear proteins regulating transcription. Resulting mRNA exported to cytoplasm for **protein production** for final hormone response
333
How can corticosteroids be classified?
1. Length of action
* Hydrocortisone short to medium-acting, dexamethasone or betamethasone long-acting
2. **Anti-inflammatory activity**
* Potency: hydrocortisone 1, prednisolone 5, dexamethasone 30
3. **Mineralocorticoid activity**
* Ie salt retaining - fludrocortisones 250 times that of hydrocortisone
4. Topical vs non topical
334
What are the side effects of corticosteroid use?
**Short term** (\< 2 weeks)
* Insomnia
* Behaviour changes
* Acute peptic ulcer
* Acute pancreatitis
* Hyperglycaemia
**Long term** (\> 2 weeks)
* Cushing's syndrome (moon facies, fat redistribution, fine hair growth, acne) secondary to hormonal actions. Rate of development is a function of dose & genetic background.
* **Adrenal suppression**/Addisonian crisis
* Hyperglycaemia, diabetes
* Myopathy
* Osteoporosis, aseptic necrosis
* Psychiatric (hypomania, acute psychosis, depression)
* Sodium, fluid retention, potassium loss
* Poor wound healing
**Immunosuppressant**
335
What are the complications of insulin administration?
* **Hypoglycaemia**
* Hypoglycaemia unawareness
* Insulin allergy (usually due to non-insulin contaminants)
* Immune insulin resistance
* Lipodystrophy at injection sites
336
1. What is passive immunisation?
2. What is passive immunisation useful for?
Passive immunisation
* Giving preformed antibodies to a recipient
* Source may be human, animal
Useful for
* Prevention of disease when time does not allow immunisation
* Treatment of disease normally prevented by immunisation
* For patients unable to form antibodies
* For treatment of conditions for which active immunisation is unavailable or not possible eg snakebite
337
What passive immunisation might we consider in ED?
* **Tetanus**
* Botulism, measles, rubella, vaccinia, varicella
* Hep B, Hep A
* Diptheria, rabies
* Antivenoms - spiders, snakes
* Rhesus incompatibility
338
Describe the pharmacokinetics of aspirin.
* **Absorption** - **pKa 3.5**, rapidly absorbed from **stomach** & upper small intestine
* **Distribution** - peak plasma level in 1-2hrs, **half life 15 mins**, salicylate non-linearly **bound to albumin, small Vd**
* **Metabolism** - rapidly **hydrolysed -\> acetic acid + salicylate** by esterases in tissue & blood, **capacity limited**
* **Elimination** - **alkalinisation of urine inc rate of excretion** of free salicylates & water soluble conjugates
339
What are the adverse effects of therapeutic doses of aspirin?
* **Allergy**
* CNS: headache, tinnitus, dizziness
* CVS: fluid retention, HTN, oedema
* **GIT: abdo pain, N & V, ulcers, bleeding**
* Haem: thrombocytopaenia, neutropaenia, aplastic a
* Hepatic: Abn LFTs, liver failure
* **Pulm: Asthma (bronchospasm)**
* Skin: all types of rashes, pruritis
* Renal: impairment & failure, hyperkalaemia, proteinuria
340
341
What are the pharmacodynamic differences between low molecular weight & unfractionated heparin?
* **Enoxaparin** predominantly binds & **inhibits factor 10a function**
* **UFH** binds to **antithrombin** that **inhibits factors 2, 9, 10**
342
What are the advantages of low molecular weight heparin over unfractionated heparin?
* Single daily or divided subcut **dosing** - facilitates patient mobility & OPD management
* Routine **monitoring** not required
* Reduced **bleeding risk**
* Lower incidence of HITP
* Inproved efficacy over UFH in ACS
* Increased bioavailability
343
What is the mechanism of action of warfarin?
* **Blocks synthesis of clotting factors 2, 7, 9, 10**, and anticoagulant proteins C & S
* Coupled to deactivation of **Vitamin K**
344
What drug interactions with warfarin prolong the INR?
* **Pharmacokinetic** (Increased INR)
* Inhibit transformation of warfarin: metronidazole, fluconazole, bactrim, amiodarone, disulfiram, cimetidine
* Displace albumin bound warfarin: phenylbutazone (NSAID), sulphinpyrazone
* **Pharmacodynamic** (Increased INR)
* Aspirin - affects platelet function
* 3rd generation cephalosporins - reduce gut flora producing Vit K
* Heparin - directly prolongs INR
345
How is the action of Warfarin reversed?
* Vitamin K
* FFP
* Prothrombin complex - Prothrombin X
* Recombinant Factor 7a
346
How does TPA work?
* **Fibrinolytic**
* Binds to fibrin in a thrombus & **converts entrapped inactive plasminogen to active plasmin** to initiate local fibrinolysis
347
What are the indications for TPA use?
* **STEMI**
* PE with haemodynamic instability
* **Acute ischaemic stroke**
* Severe DVT
348
How does tPA work?
* **TPA activates plasminogen already bound to fibrin, to form plasmin**
* Plasmin degrades fibrin to fibrin split products
* This theoretically confines fibrinolysis to formed thrombus
* **Short half life** means **heparin** is an essential adjunct
349
How does tPA differ from streptokinase?
* **TPA** is a **naturally occurring human enzyme**. **Streptokinase** is not an enzyme itself - it is a **bacterial product** that combines with plasminogen to form an enzymatic complex catalyses conversion of plasminogen to plasmin
* **Long half life** means that heparin is not required (and may increase bleeding risk). **Prior streptococcal infection** may result in antibodies that cause fever, allergic reactions & therapeutic resistance
350
What is the mechanism of action of clopidogrel?
* **Irreversible blockade of platelet ADP receptors**, leading to inhibition of platelet activity
* Note there is no anti-prostaglandin effect of aspirin
* Effect of clopidogrel is 7-10 days
351
What are the indications for clopidogrel?
* IHD
* Pre/post stent
* Stroke prevention
352
With regard to aspirin, what are its pharmacokinetic properties?
* **pKa 3.5**
* **Rapidly absorbed** from **stomach** & upper small intestine
* **Peak levels at 1-2hrs**
* ASA is absorbed as such, hydrolysed in blood to salicylate & acetate
* **Bound to plasma protein**, saturable, therefore inc free ASA with inc plasma concentration
* **Saturable metabolism & excretion; zero order**
* t 1/2 for 600mg ~ 3-5hrs, t 1/2 for 3.6g ~ 12-16hrs
* Has active metabolite with long t 1/2 (12 hrs)
* **Alkaline urine, inc ionized free salicylate excretion**
353
What are the adverse effects of aspirin?
* **GIT upset; gastritis, ulceration** (due to reduced protective PG synthesis)
* Abnormal LFTs; hepatitis
* **Bleeding**
* **Allergy**
354
What are its toxic effects in overdose?
* **Salicylism**
* Vomiting, tinnitus, vertigo, loss of hearing
* Tachypnoea
* Fever
* Dehydration
* Metabolic acidosis
* Hyperglycaemia
* Clotting disturbance
* CVS collapse
* Renal & respiratory failure
* Coma
355
1. What is the mechanism of aspirin's antiplatelet action?
2. What other types of anti-platelet agents are there?
Mechanism of action
* **Irreversible inhibition of COX**
* Inhibits synthesis of **thromboxane A2**
Other anti-platelet agents
* Inhibitors of ADP pathway (clopidogrel)
* Glycoprotein 2b,3a blockers (tirofiban)
* Beta-blockers
* Other NSAIDs
356
What are the clinical indications for anti-platelet agents?
* IHD
* TIA/CVA
* Pregnancy: prophylaxis pre-eclampsia
* Post acute coronary intervention
357
How does unfractionated heparin work?
* Heterogenous mixture of sulfated mucopolysaccharides which binds to endothelial cells surfaces
* **Binds to antithrombin 3** - conformational change so active site exposed for more active interaction with proteases to inhibit them from clotting (2a, 7a, 9a, 10a). Heparin speeds up 1000x
* Heparin not comsumed in process
358
How does the mechanism of action of LMW heparins differ from unfractionated heparin?
* **Inhibit activated factor 10** but less effect on antithrombin & coagulation
* Increased bioavailability from SC site of injection
* Need less frequent dosing (1-2/day)
* Don't need to follow APTT
359
What are the adverse effects of unfractionated heparin?
* **Bleeding** - inc in elderly, renal failure
* Transient **thrombocytopaenia** - 25% patients, severe in 5%
* Heparin induced thrombocytopaenia - heparin induced Ab against heparin platelet factor 4 complex
* Long term - osteoporosis, spontaneous fractures, mineralocorticoid deficiency
360
What is the mechanism of action of aspirin?
Irreversibly inhibits cyclooxygenase (COX 1 & 2) - reduces prostaglandin synthesis from arachidonic acid.
361
Describe what happens to aspirin in the gut following oral administration.
* **Highly soluble in acid environment of stomach as it is a weak acid** (rapidly absorbed)
* Becomes less soluble (100x less) in the alkali environment of the upper small bowel
* **Most of administered dose is absorbed in the small bowel** (due to vastly inc surface area)
* Possibility of formation of concretions/bezoars
362
How is aspirin eliminated from the body?
* Hydrolysed by tissue esterases to salicylate & acetic acid
* Salicylate conjugated with glucuronide or glycine to form salicyuric acid
* **First order kinetics at low doses - zero order kinetics at higher doses**
* Then renally excreted - **pH dependent resorption**, amount excreted related to urine volume
363
What are the adverse effects of aspirin?
Asthma - leukotriene production
Bleeding - inhibition of thromboxane production in the platelet
Peptic ulceration - reduction of PGE1 and PGE2 that increase gastroprotective mucous production by the gastric mucosa
CNS - tinnitus, nausea, vomiting, seizures, respiratory alkalosis - direct CNS toxicity
Metabolic acidosis - uncoupling of oxidative phosphorylation
Allergy - idopathic
Renal failure - inhibition of PGE1 production in renal medulla
364
Outline the clinical features of salicylate toxicity.
* **Salicylism: hearing/tinnitus**
* **Any CNS**: coma
* **GIT disturbance**
* Hyperthermia
* **Respiratory Alkalosis**
* **Metabolic Acidosis**
* Other: hypoglycaemia, coagulopathy, renal failure, uncoupling oxidative phosphorylation
365
Describe the enhanced elimination strategies employed in managing a patient with salicylate overdose.
* **pH manipulation/urinary alkalinisation**
* Forced diuresis
* **Dialysis**
* peritoneal dialysis
* haemodialysis
* haemoperfusion
366
What are the preferred administration routes for vitamin K?
* **Oral**
* **IM**
* **IV**
* SC erratic
367
What are the clinical indications for prescribing vitamin K?
* **Reversal of oral anticoagulant effect**
* **Management of warfarin toxicity** or superwarfarin toxicity (brodifacoum)
* **Vitamin K deficiency**
* Prevention of haemorrhagic disease of the newborn
* Treatment of haemorrhagic disease of the newborn
* IV indications: preferable in severe cases, slow infusion, may need repeated doses at 6-8hr intervals
368
1. Describe the mechanism of action of clopidogrel?
2. How does it differ from aspirin?
1. Irreversibly blocks the ADP receptor on platelets to inhibit platelet aggregation.
2. Aspirin inhibts the synthesis of thromboxane A2 within platelets by the irreversible acetylation of cyclooxygenase.
369
Outline the groups of drugs that might be used in asthma & give an example of each.
* Bronchodilators
* **Selective beta agonists** - salbutamol, salmeterol
* **Sympathomimetics** - adrenaline
* **Muscarinic antagonists** - ipratropium, tiotropium
* Methylxanthines - theophylline
* Other - magnesium, ketamine, CCBs
* Anti-inflammatory agents
* Release inhibitors - antihistamines
* Steroids - prednisolone, fluticasone
* Slow anti-inflammatory drugs
* Antibodies - omalizumab
* Leukotriene antagonists
* Lipoxygenase inhibitors - zileuton
* Receptor inhibitors - montelukast
* Heliox
370
Outline the mechanism of action of corticosteroids in asthma.
Corticosteroids do the following
* Reduce bronchial reactivity
* **Inhibition of (lymphocytic & eosinophilic) airway mucosal inflammation**
* Increase airway calibre
371
Describe the pharmacokinetics of salbutamol.
* **Absorption - complete all routes**
* **Gut fast, resp tract slower**
* Depends on **mechanism delivery - gut 80% with neb**
* Metabolism/Elimination
* **50% 1st pass**
* **No resp metabolism**
* T1/2 = 3-6hr (prolonged if resp)
372
What are the pros & cons of the different routes of delivery?
**Inhaled**
* Inhaler/spacer
* Targeted/low dose
* Minimal systemic effects
* Local effects
* Co-ordination & education required
* Nebulised
* Less co-ordination required
* \> dose/systemic effects
* Noisy/frighten children
* No benefit in co-ordinated patients
**Oral**
* Easier in very young/disabled
* Longer T 1/2
* \> SE profile
* Big doses, tachyphylaxis - possible inc deaths
**IV/IM/SC**
* Useful in asthma extremis or other indications
* Less 1st pass effect
* IV - pain/cost/staff use/high SE profile & high risk pts
373
1. What is the mechanism of action of fluoroquinolones?
2. What are the mechanisms of resistance to fluoroquinolones?
1. **DNA gyrase inhibitor** -\> blocks protein production
2. Mechanisms of resistance
* Point mutations in the quinolone **binding region** of the target enzyme
* **Change in permeability** of the organism
374
What are the clinical uses of ciprofloxacin (fluoroquinalone)?
* UTI
* Bacterial diarrhoea - shigella, salmonella, toxigenic E coli, campylobacter
* Soft tissue, bone, joint
* Intra-abdominal infections
* Respiratory tract infections
* Treatment against multi-drug resistant organisms (pseudomonas & enterobacter)
* Prophylaxis & treatment against anthrax
* STI - gonococcal, chlamydial urethritis/cervicitis
* TB & atypical mycobacterial infections
* Eradication of meningococcal carrier state
* Prophylaxis in neutropaenic patients
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