3. CARDIOVASCULAR SYSTEM

3.1 Emergency drugs (cardiac) (1)

3.1.1 Drugs used in cardiac arrest (1)

3.1.2 Inotropes (1)

3.2 Antianginal drugs (1)

3.2.1 Nitrates (1)

2010-2, 2008-1, 2007-1, 2004-2Describe the mechanism of action of glyceryl trinitrate.- Taken up in SMC- Denitration by glutathione S-transferase- Free nitrite ions released and form NO- NO activates guanylyl cyclase leading to increased cGMP and dephosphorylation of myosin and

smooth muscle relaxation (precise mechanism unknown)- Venodilation leads to reduced venous return, reduce ventricular volume and reduced heart wall

tension. This reduces myocardial O2 requirement

What are the clinical effects of nitratesTherapeutic effects:Low doses: venodilation -> ↓ preload & stroke volumeHigher doses: arterial dilation -> ↓ blood pressure↓ cardiac output -> ↓ myocardial oxygen demandDilation of coronary arteries/redistribution of perfusion -> improved oxygen delivery to myocardium & resolution of ischaemic pain

Toxicity1. Acute averse effects: orthostatic hypotension, (reflex) tachycardia, throbbing headache

Contraindications: increased ICP (not in glaucoma as was once believed)2. Tolerance w/ continuous exposure (sulphydryl groups +?O2 free radicals)3. Carcinogenicity - no evidence in anti-anginal use4. Methemoglobinaemia – caused by nitrites, Hb contains ferric iron -> pseudocyanosis, even high

doses of nitrates are unlikely to cause this, may be useful in cyanide poisoning

2008-1Outline the pharmacokinetics of sublingual GTNPharmacokinetics- Low bioavailability (liver has high-capacity organic nitrate reductase)- Thus given sublingual- Short t½: only 2-8 minutes for the unchanged compounds, but partially denitrated metabolites

have much longer half lives (up to 3 hours)- Duration of action 15-30mins- Denitrated metabolites conjugated to glucuronide and excreted in urine

3.2.2 Calcium channel blockers (1)

3.2.3 Beta blockers (1)

3.3 Antiarrhythmic agents

3.3.1 Sodium channel blockers

3.3.1.1 Class 1a (2)

3.3.1.2 Class 1b (1)2011-1, 2005-1, 2004-2Describe the mechanism of action of lignocaine on the heart.Pharmacodynamics- Class Ib antiarrhythmic (shortens the APD and has rapid kinetics)- Blocks both activated and inactivated Na channels w/ rapid kinetics (at normal RMP)- Increased inactivation and slower unbinding w/ higher RMP (sick/depolarized tissue)- Thus selective depression of conduction in depolarized cells- Affects cells with the longest APs, such as purkinje and ventricular cells (c.f. atrial cells)- Agent of choice for termination of VT and prevention of VF post cardioversion and in acute

ischaemia- Routine prophylactic use not recommended as increased mortality b/c incidence of asystole

Describe the adverse effects of lignocaine.Toxicity- One of the least cardiotoxic Na blockers and most common adverse effects are CNS- CNS: parasthesia, tremor, nausea, slurred speech, convulsions (respond to diazepam)- CVS: hypotension ( contractility), pro-arrhythmic incl. SA node arrest (rare)

What features distinguish lignocaine from other Class 1 Antiarrythmics? 2005-1- As a class Ib antiarrhythmic: shortens the APD and dissociates with rapid kinetics- Is selective for tissue that is depolarized (e.g. ischaemic tissue)- It is the least toxic of the class I sodium channel blocking agents

What are the clinical uses of lignocaine? 2005-11. Antiarrhythmic (termination of VT and prevention of VF post cardioversion with acute iscahemia)2. Local Anaesthetic3. Post herpetic neuralgia

3.3.1.3 Class 1c (2)2008-2What is flecainide ’ s mechanism of action? - Class Ic antiarrhythmic: sodium channel blockade, no effect on APD, slow kinetics- Potent INa (and K blocker) w/ slow unblocking- Despite certain K channel blocking, doesn’t prolong AP or QT- Very effective for supraventricular arrhythmias and for PVCs

Describe flecainide ’ s pharmacokinetics. Prompt Usual oral dose Tambocar trade name Well absorbed orally, half life ~ 20 hours, Peak plasma drug levels at ~ 3 hours (range 1-6 hrs), Vd ranges from 5 to 13.4 L/kg (mean 8.7 L/kg), 30% of a single oral dose (range 10 to 50%) is excreted in urine as unchanged drug –– remainder by hepatic metabolism. Usual dose 100- 200 mg daily

In which patients is it contraindicated?- CAST trial showed increased mortality in patients on 1C drugs- Increases exacerbation of arrhythmia in those with ventricular tachyarrhythmia, post MI or

ventricular ectopy- Contraindicated in: structural heart disease (ventricular dysfunction or hypertrophy, symptomatic

ischaemic heart disease or valvular heart disease), unpaced 2nd or 3rd DHB, shock, children3.3.2 Beta blockers – class 2 (1)

3.3.3 Potassium channel blockers – class 3 (1)

2011-1, 2010-1, 2006-1What are the mechanisms of action of amiodarone?Pharmacodynamics- Primarily blocks IKr, also inactivated INa channels and weakly ICa-L and and -blocker- APD over a wide range of HR (other class III have “reverse use-dependance” – i.e. AP duration

increase least at high HR – where needed, and most at low HR – contributes to risk of TDP)- Thus, prolongs APD and QT, slows HR and AV node conduction (decreases automaticity)- I.e. effects on both rate and rhythm- Blocks depolarized cells > normal cells- Used for serious ventricular arrhythmias and supraventricular arrhythmias- Causes peripheral vasodilation by -blocking effects

What are some important drug interactions with amiodarone?Drug interactions- Substrate for CYP3A4 and inhibits other cytochrome metabolizing enzymes

1. Warfarin (inhibits metabolism -> INR)2. Digoxin (inhibits metabolism - toxicity)3. Phenytoin (increased plasma concentration)4. Increased cardiac effects of other antiarrhythmic agents; 5. Cimetidine (H2 blocker) blocks CYP3A4 -> amiodarone levels6. Rifampicin induces CYP3A4 -> amiodarone levels7. Interacts with statins (artorvastatin and simvastatin – instead use pravastatin as not P450)

2011-1What anti arrhythmic drugs can be used in the management of atrial fibrillationIC: Sodium channel blockers, e.g. flecainideII: Beta-blockers, e.g. metoprololIII: Potassium channel blockers, e.g. amiodaroneIV: Calcium channel blockers, e.g. diltiazemV: Unclassified/others, e.g. digoxin, magnesium

What are the clinical uses of amiodarone? 2006-1- Used for serious ventricular arrhythmias and supraventricular arrhythmias- Maintaining normal sinus rhythm in AF Prevention of Recurrent VT

Describe the potential adverse effects of amiodarone? 2006-1Toxicity- Bradycardia and heart block, hypotension, negative inotropy- Drug interactions- Accumulates in many tissues incl. heart, lung, liver and skin- Dose related pulmonary toxicity – fatal pulmonary fibrosis in 1%- Abnormal liver function (tests) and hepatitis- Photodermatitis and gray-blue skin in sun-exposed areas (malar)- Asymptomatic corneal microdeposits, halos, optic neuritis (rarely)- Blocks T4 -> T3, can cause hypo or hyperthyroidism

3.3.4 Calcium channel blockers – class 4 (1)

Sample viva, 2011-2, 2009-2, 2006-2At a cellular level, describe the action of calcium channel blockersBind at intracellular side of L type calcium channel -> reduces frequency of opening in response to depolarization -> decreased transmembrane calcium current ->

Anti-hypertensive effects- Relax smooth muscle especially vascular smooth muscle - Arterioles more sensitive than veins (less orthostatic hypotension)- Does effect bronchiolar, GIT and uterine

Anti-anginal effects- Decrease myocardial contractility- Decrease afterload by relaxing vascular smooth muscle (decrease PVR)- Decrease oxygen demand- Verapamil/ diltiazem have a non-specific antiadrenergic effect and decrease heart rate - Relieve and prevent coronary artery spasm (in variant angina)

Anti-arrhythmic effects- Class IV (the dihydropyridines do not have anti-arrhythmic efficacy, and may be pro-arrhythmic)- SA pacemaker, AV node: slower conduction- Blockade of L-channels more marked in tissues that fire frequently - More marked effects on tissues that depend on Ca channels for activation, SA & AV nodes- More marked on tissues with tissues less polarized at rest

Note: Do not affect skeletal muscle b/c it uses an intracellular Ca2+ pool c.f. transmembrane influx

What are the differences in pharmacodynamics between dihydropyridines and other Ca channel blockers1. Dihydropyridines (amlodipine, felodipine, nifedipine) are vascular smooth muscle selective2. Verapamil / Diltiazem greater effect on cardiac/conducting tissue

How are these differing pharmacodynamics reflected in their side effect profile1. Dihydropyridines more likely to cause flushing, headache & (reflex) tachycardia2. Verapamil and diltiazem cause bradycardia and rarely: serious cardiac depression, cardiac arrest,

AV block, heart failure3. Both can cause hypotension (and constipation, but particularly common with verapamil)

Miscellaneous antiarrhythmic agents (1)

2011-1, 2005-2, 2003-1What are the principal effects of adenosine on cardiac conduction?- Endogenous nucleoside- Activates inward rectifier IK and blocks ICa -> marked hyperpolarization and Ca-dependent AP

suppression- Bolus -> direct inhibition of AV node conduction and AV node refractory period- Lesser effects on SA node

Describe the pharmacokinetics of adenosine.- Rapidly metabolised in the blood with a elimination t½ <10sec- Is less effective w/ adenosine receptor blockers e.g. theophylline or caffine

What are the clinical implications of this pharmacokinetic profile?1. Only suitable for IV use (larger more proximal vein)2. Must be given by rapid bolusing to achieve therapeutic effects.3. Repeat doses must be escalated4. Will not be effective for supraventricular tachyarrhymthias caused by adenosine-blockers such as

theophylline

Name some indications and contraindications to its use.- Used for SVT -> SR w/ high efficacy 90-95%, also diagnostic (to determine underlying atrial

rhythm)- Contraindications: AV block, sick sinus, acute asthma, lack of consent

ToxicityFlushing (20%), dyspnea (10%), AF, rarely headache, hypotension, nausea, parasthesias

3.4 Cardiac glycosides (1)

2009-1, 2006-1What are the actions of digoxin on the heart at therapeutic levelsPhamacodynamics- Multiple direct and indirect cardiovascular effects- Inhibit Na/K ATPase (aka the sodium pump) -> positive inotropy

Cardiac effects1. Mechanical effects

1. Increase contraction of cardiac sarcomere by increasing free calcium concentration2. Result of 2 steps:

i. Increase of intracellular Na (Na/K ATPase inhibition)ii. Relative reduction of calcium expulsion (caused by increase in intracellular sodium)

2. Electrical effectsMixture of direct and autonomic Direct: initially early brief prolongation of APD, followed by shortening (esp short plateau)

- likely due to increased K+ conductance because of high intracellular Ca- if toxicity -> delayed after depolarization’s (DADs) w/ overloading of intracellular Ca- can cause premature depolarization’s -> bigeminy -> self-sustaining tachycardia -> VF

Autonomic: (involved both parasympathetic and sympathetic)- Low dose range: cardioselective parasympathetomimetic dominate (atropine blockable) Sensitization of baroreceptors Central vagal stimulation Facilitation of muscarinic transmission at cardiac muscle cell

Toxic range: sympathetic outflow increased -> sensitized myocardium exaggerates toxicity

Are the parasympathetic effects uniform throughout the heartAtrial and AV function > Purkinje or ventricular b/c cholinergic innervation richer in atria

2011-1, 2004-2What are the features of digoxin toxicity?Toxic cardiac effects: features of bradycardia (progressing AV block, slow AF) and increased automaticity (PVCs and bigeminy, SVT with AV block, VT/VF)

Effects on other organs (2006-1)- Gastrointestinal: anorexia, nausea, vomiting, diarrhoea- CNS: vagal, chemoreceptor trigger zone stimulation (nausea/vomiting), disorientation,

hallucinations- Other: Gynacomastia (rare)

What factors might predispose patients towards digoxin toxicity?1. Electrolyte imbalance (Interactions w/ K, Ca and Mg)- Hypo K+ -> increased toxicity (increases binding, stimulates cardiac automaticity)- Hyper Ca2+ -> increased toxicity- Hypo Mg2+ -> increased toxicity2. Organ disease: Renal impairment, hypothyroidism,3. Other drugs: Amiodarone, calcium channel blockers, potassium depleting drugs

What is the specific antidote for digoxin toxicity ? What are the indications? 2004-2- Digibind, aka digoxin immune fab (digitalis antibodies)- Indications: Acute ingestion w/ high digoxin or potasium levels, life-threatening arrhythmias- Caution for potential allergic response i.e. anaphylaxis

Describe the pharmacokinetics of digoxin? 2006-1 Pharmacokinetics- 65-80% absorbed after oral administration- 10% population with enteric bacteria that reduce oral bioavailability- 20-40% plasma protein bound- Widely distributed- Moderate Volume of Distribution (6.3 L/kg)- Moderate metabolism w/ 2/3 excreted unchanged by kidneys- Clearance proportional to CrCl- t½ 36-40 hours- Dose adjustment needed for renal impairment

3.5 Antihypertensives

2009-1What are the sites of action of antihypertensive drugs (with examples)

Vasomotor centre - 2-blocker clonidine, mefhyldopaSympathetic ganglia - trimethaphan Sympathetic nerve terminals - guanethidine, reserpine 1 receptors of heart - -blockers Angiotensin receptors of blood vessels - AT II receptor blockers receptors of bv - prazosin Vascular smooth muscle - hydrallazine, SNP, Ca blockers, GTN Kidney tubules - diuretics receptors of juxtaglomerular cells - -blockers ACE – ACE-i

3.5.1 Beta blockers (1)

2010-1, 2007-1 (beta blockers), 2004-2 (propranolol)Describe the pharmacokinetics of metoprolol- Oral or IV, Well absorbed- Bioavailability 50% due to first-pass effect- Large volume of distribution- Half-life, 3-4 hours- Metabolised in the liver (P450)- Generally prolonged in liver disease, reduced hepatic blood flow, hepatic enzyme inhibition

How does metoprolol differ from propranolol in its action at beta receptors- 1 selective (50-100x less 2 potent c.f. propranolol)- May be safer than propranolol in patients who have asthma, diabetes or PVD

What are the effects of beta blockers? 2007-1, 2005-1 (propranolol)How do b-blockers control hypertension 2010-1, 2004-2 (cardiovascular effects)Mechanism- Most are pure competitive antagonists at -adrenoceptors- Some have selectivity for 1 vs 2: this tends to diminish at higher concentrations

1. Cardicovascular- Chronically lower BP in hypertensive patients (do not cause hypotension in normotensives)

Probably via suppression of rennin release by CNS- Negative inotrope and negative chronotrope -> Rx for angina, CHF, post MI

AV node adrenoceptor blockade -> slowed AV conduction -> increased PR- 2 mediated vasodilation blockade -> unopposed effects -> increased acute PVR in response

to decreased CO -> possible acute rise in BP -> chronically lowered PVR in hypertensive’s

2. Respiratory- 2 blockade of bronchial SMC -> bronchoconstriction- currently no drug selective enough- avoid in asthma, but may still be well tolerated and beneficial in COPD patients

3. Eye - IOP via aqueous humor production

4. Metabolic and endocrine- Treatment of hyperthyroidism esp. propranolol in thyroid storm- ?impair glycogenolysis via 2 blockade -> impair recovery after hypoglycaemia -> use w/ caution

in insulin-dependents esp those with frequent hypoglycaemia- VLDL and HDL w/ HDL-chol/LDL-chol ratio – poorly understood

What are the effects of beta blocker in overdose? 2007-1- Hypotension, bradycardia, cardiogenic shock, bronchospasm, seizures (cerebrotoxic)- NB Propanolol causes arrhythmias through Type 1 (Na channel block) antiarrhythmic effects - Life threatening adverse cardiac effects of -> Rx w/ glucagon that stimulates via glucagon

receptors

How does carvedilol differ from propranolol? 2005-1 - Carvedilol has no local anaesthetic action- 1 adrenoceptor block, but effect on Beta receptor > Alpha receptor- Causes vasodilation in addition to b-blockade- Stereoselective metabolism of its 2 isomers occurs - Polymorphism influenced Cytochrome P450 2D6 affects R isomer metabolism3.5.2 ACE inhibitors (2)

2010-2

Describe the mechanism of action of ACE inhibitors, 2005-2 & 2003-1 (captopril)Mechanism- Competitively block angiotensin converting enzyme, preventing angiotensin I -> angiotensin II

i. vascular tone from prevention of vasoconstrictor effects of Ang II (main effect)ii. aldosterone secretion (by Ang II) -> Na & H2O resorption

- Also prevents the inactivation of bradykinin (potent vasodilator via NO and prostacyclin, thus NSAIDs may block due to prostaglandin mediated effect)

- Useful in chronic kidney disease -> proteinuria, stabilize renal function (even w/out lowering BP, thus useful in normotensive diabetics)

- Most are prodrugs (except captopril) converted by hydrolysis in liver

What are the adverse effects of ACE inhibitors, 2005-2 & 2003-1 (captopril)Toxicity- Hypotension (esp if hypovolaemic)- Acute renal failure (esp renal artery stenosis)- Hyperkalaemia (interact with K+ sparing diuretics)- Cough- Angioedema (via bradykinin and substance P)- Contraindicated in 2nd and 3rd trimesters (fetal hypotension, anuria, renal failure)- NSAIDS may impair the hypotensive effects by blocking the blocking the bradykinin mediated

vasodilation (in part prostaglandin mediated)

2003-1What are the clinical uses of captopril- CHF, after MI (better preservation of LVF – reduce post MI remodeling)- Diabetic nephropathy – diminish proteinuria, stabilize renal function – improved intrarenal

hemodynamics- Hypertension

2008-1Describe the pharmacodynamics of therapeutic drugs that modulate the effect of angiotensin- As above for ACE-i- Angiotensin II inhibitors are competitive antagonists at angiotensin II receptor (type 1)

What are the advantages of Angiotensin 2 receptor antagonists over ACE inhibitors? - Do not result in production of bradykinins -> cough and angioedema- Potentially greater effect as enzymes other than ACE can generate angiotensin II- Examples: losartan, candesartan

3.5.3 Vasodilators (2)

2011-1List some drugs used in hypertensive emergencies.GTN , nifedipine , diazoxide , hydrallazine , sodium nitroprusside , esmolol , labetalol

Tell us about the pharmacokinetics of Na nitroprusside.Pharmacokinetics- Parenterally administered by IVI (sensitive to light)- Onset minutes, peak effect minutes, t½ 2 minutes (thiocyanate 3 days)- Duration of action 1-10 minutes- Elimination: By RBC's -> cyanide, then liver -> thiocyanate -> renally excreted

What are the potential toxicities of Na nitroprusside?ToxicityCyanide toxicity - hypotension, metabolic acidosis, pink skin, tachypnoea, decreased reflexes, dilated pupils, coma Thiocyanate toxicity - ataxia, blurred vision, headache, nausea, vomiting, tinnitus, SOB, delirium, unconsciousness

3.5.4 Sympatholytics (2)

3.6 Diuretics

3.6.1 Loop diuretics (1)

2011-2, 2010-2, 2008-1 2004-2What are the mechanisms of action of FRUSEMIDE?Pharmacodynamics1. Inhibit the NKCC2, i.e. the luminal Na-K-2Cl co-transporter in the thick ascending limb- Reduces reabsorption of NaCl- Also reduces K+ recycling -> reduces lumen +ve potential that drives Mg2+/Ca2+ reabsorption- Ultimately leads to loss of counter-current mechanism -> reduced ability to concentrate the urine

2. Increased prostaglandin synthesis (induce COX-2: AA -> PG)- inhibition of salt transport in thick ascending limb (PGE2)- increased renal blood flow, decreased pulmonary congestion, decreased LV filling pressures

What are the toxic effects of FRUSEMIDE?Toxicity- Electrolyte disturbances: K+/H+, Na+ (esp in patients H2O), Mg2+, hyperuricaemia (-> gout)- Postural hypotension & dizziness (dehydration)- Ototoxicity (high dose IV, esp w/ aminoglycosides)- Drug interactions (NSAIDs may reduce efficacy, esp in nephrotic syndrome or cirrhosis)- Allergy (furosemide, bumetanide, torsemide are sulphonamides) -> rash, eosinophilia, interstitial

nephritis

What are the pharmacokinetic properties of frusemide? 2010-2 Pharmacokinetics- Rapid absorption after oral admin- Oral bioavailability 50% (range 10 –100%)- Highly protein-bound (>95%)- Small Vd <10L/70kg- 50% conjugated in kidney & 50% excreted in urine unchanged (tubular secretion)- Elimination t1/2 1.5 – 2 hours- Peak effect 30 minutes IV / 1 hour oral

What effects do they have on renal handling of Ca and Mg ? 2004-2 - Reduces K+ recycling -> reduces lumen +ve potential that drives Mg2+/Ca2+ reabsorption- Toxic effect is hypomagnesemia- Usually don’t cause hypocacaemia (because vit D influenced intestinal absorption can be

increased), and may be useful in treatment of hypercalcaemia (given with infused saline)

3.6.2 Thiazide diuretics (2) 2006-2 How do thiazides exert their diuretic action?- Emerged from attempts to create more powerful carbonic anhydrase inhibitors- Work by inhibiting NaCl co-transport (NCC) in DCT- Used for HTN, CHF, renal stones, nephrogenic diabetes insipidus- Enhance Ca2+ reabsorption (c.f. loop diuretics) -> thus may be useful in hypercalciuric renal

stones, and may unmask hypercalcaemic disorders (hyperPTH, sarcoid, Ca), rarely cause Ca2+

- Also PG production, and NSAIDs may inhibit (like loop diuretics)

What are the adverse effects of thiazides?- Electrolyte/blood: K+/H+ (hypokalaemic metabolic alkalosis), Na+ (more than furosemide),

hyperglycaemia, hyperlipidaemia- Allergic reactions: sulfonamides also- Other: weakness, fatigue, paraesthesia (like carbonic anhydrase inhibitors)

3.6.3 Potassium sparing diuretics (2)

3.6.4 Osmotic (2)2007-1 How are osmotic diuretics handled by the kidney?- A sugar freely filtered by glomerulus but not reabsorbed -> osmotic load -> holding water in

the PT- Also oppose the actions of ADH in the CT via osmotic effect (and counter-current failure)- High urine output, approaching osmolality of plasma- Water diuresis > natriuereis

What are the clinical uses of Mannitol?- ICP (and IOP) – alters the Starling’s forces so water leaves cells: intracellular volume- Increase urine volume (in avid Na+ retention or pigment load in haemolysis or rhabdomyolysis)

What are the toxic effects of Mannitol?- Extracellular volume expansion and Na+ (prior to diuresis) -> heart failure, pulmonary oedema,

headache, nausea, vomiting- Dehydration, K+, Na+ - as water extracted from cells intracellular K+ rises -> cellular losses, and

the water diuresis is > than the electrolyte loss- Na+ in renal failure

3.6.Extra Carbonic Anhydrase Inhibitors2007-2 What are the actions of acetazolamide - Inhibition of carbonic anhydrase, found predominantly in the luminal brush border of the PCT- Carbonic anhydrase: H2CO3 -> CO2 + H2O (filtered bicarbonate buffers secreted H+)- The CO2 + H2O diffuse into tubular cells and CA: CO2 + H2O -> H2CO3 and then -> H+ and HCO3

-

- The HCO3- diffuses out into the interstitium, the H+ is secreted (Na-H exchange)

- Thus reabsorption of NaHCO3 is blocked (HCO3- is the main anion reabsorbed with Na)

What are the toxic effects of acetazolamide? - Hyperchloraemic metabolic acidosis- Renal stones (phosphaturia and hypercalcuria, plus salts insoluble at alkaline pH)- Renal potassium wasting (increse Na+ to DCT -> enhanced K+ secretion)- CNS: Drowsiness and parasthesiaes (esp if renal failure)- Contraindicated: cirrhosis as decreased NH4+ secretion -> hyperammonemia and hepatic

encephalopathy

3.7 Drugs affecting haemostasis, thrombosis and the haemopoietic system

3.7.1 Streptokinase (3)

3.7.2 Tissue plasminogen activator (1)2009-2, 2007-1How does TPA work? - Tissue plasminogen activator (t-PA)- Preferentially activates plasminogen that is bound to fibrin confining fibrinolyisis to area of

thrombus and avoiding systemic activation- Manufactured as alteplase by means of recombinant DNA technology- Short half life means heparin is an essential adjunct

What are the indications for TPA use?- PE with haemodynamic instability- Severe DVT (e.g. superior vena caval syndrome, or ascending thrombophlebitis of femoral vein)- STEMI (requires careful patient selection, a specific thrombolytic agent and adjuvant therapy)

Dose: 60mg over 1 hour, then 40mg over 2 hours- Acute ischaemic stroke (within 3 hours of symptoms onset, without haemorrhagic infarct and other

contraindications)Dose: 0.9mg/kg (<90mg) w/ 10% bolus and rest over 1 hour

How does tPA differ from streptokinase?- t-PA is a naturally occurring human enzyme, 10x the cost of streptokinase- 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- Streptokinase has a long half life means that heparin is not required (and may increase

bleeding risk)- Prior streptococcal infection or streptokinase administration may result in antibodies that

cause fever, allergic reactions and therapeutic resistance- Streptokinase has been shown to increase bleeding risk in acute ischaemic stroke and is not

recommended

3.7.3 Glycoprotein IIb and IIIa receptor inhibitors (3)

3.7.4 Ticlopidine and clopidogrel (3) 2006-2, 2005-1What is the mechanism of action of clopidogrel ? - Irreversible ADP receptor blockers- Prevents the ADP mediated platelet aggregation - Unlike aspirin, no effect on PG metabolism- Clopidogrel: after 300mg po -> at 5 hours 80% platelet activity inhibtion

How long is this effect?7-10 days, the life of the platelet

What are the indications for clopidogrel?- IHD- Pre/post stent- Stroke prevention

2005-1How does it differ from aspirin?- Aspirin: Irreversible acetylation -> inhibition of cyclooxygenase, prevents AA -> thromboxane A2

- Unlike aspirin, no effect on PG metabolism

What other types of anti platelet agents are there? 2003-2Dipyridamole (Phosphodiesterase inhibitor)- Vasodilator that inhibits platelet function by inhibiting adenosine uptake and inhibition of cGMP

phosphodiesterase activity- Minimal benefit by itself, used in combination with aspirin (or warfarin)

Abciximab (Glycoprotein IIb/IIIa receptor inhibitors)- Inhibit the IIb/IIIa receptor complex function (blocking links with fibrinogen) – the “final common

pathway” for platelet aggregation- Abciximab, eptifibatide and tirofiban – all administered parenterally

3.7.5 Aspirin (1) 2010-1, 2003-2, 2007-2 (elimination)Describe the pharmacokinetics of aspirin - Simple organic acid, salicylic acid pKA 3.0, acetylsalicylic acid pKa 3.5- Rapidly absorbed from stomach, peak levels 1-2 hours- Small Vd, capacity limited metabolism (zero order elimination in higher doses)- Aspirin t ½ 15mins -> hydrolysed tissue esterases to salicylate t ½ 2-19 hours- Less than 2% aspirin excreted unchanged, 2-30% of salicylate- Salicylate is non-linearly bound to albumin- Salicylate conjugated with glucuronide or glycine to form salicyuric acid- Renally excreted with pH dependent resorption - alkanisation of the urine will increase the rate of

excretion (of salicylate and water soluble conjugates)

What are the adverse effects of therapeutic doses of aspirinAt therapeutic doses main side effects are: GI upset and formation of gastric and duodenal ulcersCNS: Headache, tinnitus, dizzinessCVS: Fluid retention, HTN, oedemaGIT: Abdo pain, N&V, Ulcers, BleedingHaematologic: Thrombocytopenia, neutropenia, Aplastic anaemiaHepatic: Abn LFTs, liver failurePulmonary: AsthmaSkin: All types of rashes, pruritisRenal: Impairment and failure, hyperkalaemia, proteinuria

2007-2What is the mechanism of action of aspirin?- Irreversible acetylation -> inhibition of cyclooxygenase (I & II)- Prevents AA -> thromboxane A2- Platelet effects last 8-10 days (the life of the platelet)- Other tissues generate more COX so ordinary doses have duration of action 6-10 hours

Thromboxane A2 produced by activated platelets and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of platelets. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot. Thromboxane A2 is also a known vasoconstrictor and is especially important during tissue injury and inflammation.

Describe what happens to aspirin in the gut following oral administration. - Absorbed in both the stomach and small intestine:

- Recall log(A-/HA) = pH – pKa, thus at low pH uncharged form more, high pH charge form more- Poorly soluble in acid environment of stomach as it is a weak acid, but because it is in it’s non-

ionized form it can be absorbed- With OD -> possibility of formation of concretions/bezoars (with delayed absorption)- Almost completely ionized in alkalai environment of small intestine, but will be mostly absorbed

here due to the vastly increased surface area

What are its therapeutic indications? 2003-2- Decreases incidence: of TIA, CVA, coronary artery thrombosis (MI), thrombus post CABG- Primary prevention (especially as adjunct to risk factor management)- Secondary preventionLess commonly now: Anti-inflammatory, Analgesia, Anti-pyretic

3.7.6 Warfarin (1)

2011-1, 2006-1, 2009-2 (increase INR)Describe the mechanisms for drug interactions with warfarin and give examples.Pharmacokinetic ( ↑ INR) - Inhibit transformation of  Warfarin:

- S- Metronidazole, Fluconazole, Bactrim- R & S- Amiodarone, Disulfiram, Cimetidine

- Displace albumin bound warfarin: phenylbutazone, sulphinpyrazone

Pharmacodynamic ( ↑ INR) Drugs- Aspirin – affects platelet function- 3rd generation Cephalosporins – reduce gut flora producing Vit K- Heparin – directly prolongs INR

Body factors- Hepatic disease- Hyperthyroidism

Pharmacokinetic ( INR) - Barbituates, cholestyramine, rifampicin

Pharmacodynamic ( INR) Drugs- Diuretics, vitamin K

Body factors- Heriditary resistance- Hypothyroidism

2009-2What is the mechanism of action of warfarin?- Vitamin K epoxide reductase inhibitor (required for reduction of vitamin K)- Reduced vit K needed for normal post-translation modification of vit K dependant clotting factors- Blocks synthesis of Clotting Factors II (prothrombin), VII, IX, X and Anticoagulant proteins C and

S- Long half-life of these factors means that the anticoagulant effect is delayed until degradation of

normal preformed factors- Also, administration of vitamin K will have a delayed effect because new clotting factors need to

be synthesised

What drug interactions with warfarin prolong the INR?- As above

How is the action of Warfarin reversed?- Discontinuation of drug- Vitamin K, FFP, Prothrombin complex (Prothrombin X), Recombinant Factor VIIa- May need repeat administration due to the long t ½ of warfarin

2006-1What are the preferred administration routes for Vitamin K?1. Oral - Slower onset 4-6h- Bioavailability ~50%2. IV - Onset 1-3h- Slowly b/c rapid infusion -> dyspnea, chest/back pain, even death- E.g. 10 mg IV diluted in saline or glucose at a rate not exceeding 5% of the total dose per minute- Repeat doses at 6-8 hour intervals (longer t ½ of warfarin c.f. Vit K)3. IM (new born)4. SC is erratic

What are the clinical indications for prescribing Vitamin K? 1. Reversal of oral anticoagulant effect2. Management of warfarin toxicity3. Vit K deficiency4. Prevention of haemorrhagic disease of the newborn5. Treatment of haemorrhagic disease of the newborn

3.7.7 Heparin (1)

2006-1, 2003-1 (UFH)Describe the mechanism of action of heparin?- Heparin binds to endothelial cell surfaces and plasma proteins- Heparin accelerates the antithrombin equimolar complex formation with certain clotting factors- Binding of activated AT III with the activated clotting factors degrades and inactivates them- Normally slow, but 1000 fold increase by conformation change exposing the inhibitory binding site- About 1/3 of the heparin has the correct pentasaccharide sequence for this- This interaction does not consume the heparin and it can move on to catalyse more- Unfractionated heparin (MW 5000 – 30,000) will inhibit IIa (thrombin), IXa and Xa- Low molecular weight heparin predominantly inhibits Xa

2008-1, 2003-1What are the pharmacodynamic differences between LMW and unfractionated heparin?- Unfractionated heparin (MW 5000 – 30,000) will inhibit IIa (thrombin), IXa and Xa- Low molecular weight heparin predominantly inhibits Xa

What are the advantages of low molecular weight heparin over unfractionated heparin?- Single daily or divided subcutaneous doses – facilitates patient mobility and OP management- Due to predictable pharmacokinetics of weight-based LMWH dosing routine monitoring not

required (unless renal insufficiency or pregnancy)- Reduced bleeding risk- Lower incidence of HIT - Improved efficacy over unfractionated heparin in ACS- Increased bioavailability

2006-1How can heparin be reversed?- Stop the drug- Administration of antagonist: protamine sulphate, a basic protein that binds with heparin –>

stable inactive complex- For every 100 Units Heparin need 1mg Protamine, but excess protamine must be avoided as can

have anticoagulant effect

2006-1, 2003-1What are the potential adverse effects of heparin?Bleeding and other- Esp in elderly and renal failure- Of animal origin -> allergy- Reversible alopecia- Long term: osteoporosis, spontaneous fractures, mineralocorticoid deficiency

HIT (heparin induced thrombocytopaenia)- Immune response to heparin- Systemic hypercoagulable state- 1-4% of those treated >7 days (i.e. surgical)- Lower with LMWH

3.7.8 Haemopoietic agents (3)

2007-1What is erythropoietin- Glycoprotein hormone produced by kidney- By specialized peritubular cells of the renal cortex in response to low blood oxygenation- Stimulates red cell precursors to proliferate and differentiate- Also releases reticulocytes from marrow

What are its clinical applications?- Main use is for the anaemia of chronic renal failure, where erythropoietin production in impaired- Helps some marrow failure states (aplastic anaemia, myeloproliferative/myelodysplastic

disorders, multiple myeloma, AIDS and cancer)

What toxic effects may occur?Toxicity mainly related to rapid Hb rise- Hypertension- Thrombosis(Allergic reactions are infrequent and mild)

3.8 Drugs used in control of lipids (3)