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3. CARDIOVASCULAR SYSTEM3.1 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 SMCDenitration by glutathione S-transferaseFree nitrite ions released and form NONO 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 requirementWhat 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 painToxicityAcute averse effects: orthostatic hypotension, (reflex) tachycardia, throbbing headacheContraindications: increased ICP (not in glaucoma as was once believed)Tolerance w/ continuous exposure (sulphydryl groups +?O2 free radicals)Carcinogenicity - no evidence in anti-anginal useMethemoglobinaemia – caused by nitrites, Hb contains ferric iron -> pseudocyanosis, even high doses of nitrates are unlikely to cause this, may be useful in cyanide poisoning2008-1Outline the pharmacokinetics of sublingual GTNPharmacokineticsLow bioavailability (liver has high-capacity organic nitrate reductase)Thus given sublingualShort t?: only 2-8 minutes for the unchanged compounds, but partially denitrated metabolites have much longer half lives (up to 3 hours)Duration of action 15-30minsDenitrated metabolites conjugated to glucuronide and excreted in urine3.2.2 Calcium channel blockers (1) 3.2.3 Beta blockers (1)3.3 Antiarrhythmic agents3.3.1 Sodium channel blockers3.3.1.1 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.PharmacodynamicsClass 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 cellsAffects 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 ischaemiaRoutine prophylactic use not recommended as increased mortality b/c incidence of asystoleDescribe the adverse effects of lignocaine.ToxicityOne of the least cardiotoxic Na blockers and most common adverse effects are CNSCNS: 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? 2005-1As a class Ib antiarrhythmic: shortens the APD and dissociates with rapid kineticsIs selective for tissue that is depolarized (e.g. ischaemic tissue)It is the least toxic of the class I sodium channel blocking agentsWhat are the clinical uses of lignocaine? 2005-1Antiarrhythmic (termination of VT and prevention of VF post cardioversion with acute iscahemia)Local AnaestheticPost herpetic neuralgia3.3.1.3 Class 1c (2)2008-2What is flecainide’s mechanism of action?Class Ic antiarrhythmic: sodium channel blockade, no effect on APD, slow kineticsPotent INa (and K blocker) w/ slow unblockingDespite certain K channel blocking, doesn’t prolong AP or QTVery effective for supraventricular arrhythmias and for PVCsDescribe flecainide’s pharmacokinetics. Prompt Usual oral dose Tambocar trade nameWell 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 dailyIn which patients is it contraindicated?CAST trial showed increased mortality in patients on 1C drugsIncreases exacerbation of arrhythmia in those with ventricular tachyarrhythmia, post MI or ventricular ectopyContraindicated 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?PharmacodynamicsPrimarily 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 rhythmBlocks depolarized cells > normal cellsUsed for serious ventricular arrhythmias and supraventricular arrhythmiasCauses peripheral vasodilation by -blocking effectsWhat are some important drug interactions with amiodarone?Drug interactionsSubstrate for CYP3A4 and inhibits other cytochrome metabolizing enzymesWarfarin (inhibits metabolism -> INR)Digoxin (inhibits metabolism - toxicity)Phenytoin (increased plasma concentration)Increased cardiac effects of other antiarrhythmic agents; Cimetidine (H2 blocker) blocks CYP3A4 -> amiodarone levelsRifampicin induces CYP3A4 -> amiodarone levelsInteracts 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, magnesiumWhat are the clinical uses of amiodarone? 2006-1Used for serious ventricular arrhythmias and supraventricular arrhythmiasMaintaining normal sinus rhythm in AF Prevention of Recurrent VTDescribe the potential adverse effects of amiodarone? 2006-1ToxicityBradycardia and heart block, hypotension, negative inotropyDrug interactionsAccumulates in many tissues incl. heart, lung, liver and skinDose related pulmonary toxicity – fatal pulmonary fibrosis in 1%Abnormal liver function (tests) and hepatitisPhotodermatitis and gray-blue skin in sun-exposed areas (malar)Asymptomatic corneal microdeposits, halos, optic neuritis (rarely)Blocks T4 -> T3, can cause hypo or hyperthyroidism3.3.4 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 effectsRelax smooth muscle especially vascular smooth muscle Arterioles more sensitive than veins (less orthostatic hypotension)Does effect bronchiolar, GIT and uterineAnti-anginal effectsDecrease myocardial contractilityDecrease afterload by relaxing vascular smooth muscle (decrease PVR)Decrease oxygen demandVerapamil/ diltiazem have a non-specific antiadrenergic effect and decrease heart rate Relieve and prevent coronary artery spasm (in variant angina)Anti-arrhythmic effectsClass IV (the dihydropyridines do not have anti-arrhythmic efficacy, and may be pro-arrhythmic)SA pacemaker, AV node: slower conductionBlockade of L-channels more marked in tissues that fire frequently More marked effects on tissues that depend on Ca channels for activation, SA & AV nodesMore marked on tissues with tissues less polarized at restNote: Do not affect skeletal muscle b/c it uses an intracellular Ca2+ pool c.f. transmembrane influxWhat are the differences in pharmacodynamics between dihydropyridines and other Ca channel blockersDihydropyridines (amlodipine, felodipine, nifedipine) are vascular smooth muscle selectiveVerapamil / Diltiazem greater effect on cardiac/conducting tissueHow are these differing pharmacodynamics reflected in their side effect profileDihydropyridines more likely to cause flushing, headache & (reflex) tachycardiaVerapamil and diltiazem cause bradycardia and rarely: serious cardiac depression, cardiac arrest, AV block, heart failureBoth 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 nucleosideActivates inward rectifier IK and blocks ICa -> marked hyperpolarization and Ca-dependent AP suppressionBolus -> direct inhibition of AV node conduction and AV node refractory periodLesser effects on SA nodeDescribe the pharmacokinetics of adenosine.Rapidly metabolised in the blood with a elimination t? <10secIs less effective w/ adenosine receptor blockers e.g. theophylline or caffineWhat are the clinical implications of this pharmacokinetic profile?Only suitable for IV use (larger more proximal vein)Must be given by rapid bolusing to achieve therapeutic effects.Repeat doses must be escalatedWill not be effective for supraventricular tachyarrhymthias caused by adenosine-blockers such as theophyllineName 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 consentToxicityFlushing (20%), dyspnea (10%), AF, rarely headache, hypotension, nausea, parasthesias3.4 Cardiac glycosides (1)2009-1, 2006-1What are the actions of digoxin on the heart at therapeutic levelsPhamacodynamicsMultiple direct and indirect cardiovascular effectsInhibit Na/K ATPase (aka the sodium pump) -> positive inotropyCardiac effectsMechanical effectsIncrease contraction of cardiac sarcomere by increasing free calcium concentrationResult of 2 steps:Increase of intracellular Na (Na/K ATPase inhibition)Relative reduction of calcium expulsion (caused by increase in intracellular sodium)Electrical effectsMixture of direct and autonomicDirect: initially early brief prolongation of APD, followed by shortening (esp short plateau)likely due to increased K+ conductance because of high intracellular Caif toxicity -> delayed after depolarization’s (DADs) w/ overloading of intracellular Cacan cause premature depolarization’s -> bigeminy -> self-sustaining tachycardia -> VFAutonomic: (involved both parasympathetic and sympathetic)Low dose range: cardioselective parasympathetomimetic dominate (atropine blockable)Sensitization of baroreceptorsCentral vagal stimulationFacilitation of muscarinic transmission at cardiac muscle cellToxic range: sympathetic outflow increased -> sensitized myocardium exaggerates toxicityAre 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, diarrhoeaCNS: vagal, chemoreceptor trigger zone stimulation (nausea/vomiting), disorientation, hallucinationsOther: Gynacomastia (rare)What factors might predispose patients towards digoxin toxicity?Electrolyte imbalance (Interactions w/ K, Ca and Mg)Hypo K+ -> increased toxicity (increases binding, stimulates cardiac automaticity)Hyper Ca2+ -> increased toxicityHypo Mg2+ -> increased toxicityOrgan disease: Renal impairment, hypothyroidism,Other drugs: Amiodarone, calcium channel blockers, potassium depleting drugsWhat is the specific antidote for digoxin toxicity ? What are the indications? 2004-2Digibind, aka digoxin immune fab (digitalis antibodies)Indications: Acute ingestion w/ high digoxin or potasium levels, life-threatening arrhythmiasCaution for potential allergic response i.e. anaphylaxisDescribe the pharmacokinetics of digoxin? 2006-1Pharmacokinetics65-80% absorbed after oral administration10% population with enteric bacteria that reduce oral bioavailability20-40% plasma protein boundWidely distributedModerate Volume of Distribution (6.3 L/kg)Moderate metabolism w/ 2/3 excreted unchanged by kidneysClearance proportional to CrClt? 36-40 hoursDose adjustment needed for renal impairment3.5 Antihypertensives2009-1What 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-i3.5.1 Beta blockers (1)2010-1, 2007-1 (beta blockers), 2004-2 (propranolol)Describe the pharmacokinetics of metoprololOral or IV, Well absorbedBioavailability 50% due to first-pass effectLarge volume of distributionHalf-life, 3-4 hoursMetabolised in the liver (P450)Generally prolonged in liver disease, reduced hepatic blood flow, hepatic enzyme inhibitionHow does metoprolol differ from propranolol in its action at beta receptors1 selective (50-100x less 2 potent c.f. propranolol)May be safer than propranolol in patients who have asthma, diabetes or PVDWhat are the effects of beta blockers? 2007-1, 2005-1 (propranolol)How do b-blockers control hypertension 2010-1, 2004-2 (cardiovascular effects)MechanismMost are pure competitive antagonists at -adrenoceptorsSome have selectivity for 1 vs 2: this tends to diminish at higher concentrationsCardicovascularChronically lower BP in hypertensive patients (do not cause hypotension in normotensives)Probably via suppression of rennin release by CNSNegative inotrope and negative chronotrope -> Rx for angina, CHF, post MIAV node adrenoceptor blockade -> slowed AV conduction -> increased PR2 mediated vasodilation blockade -> unopposed effects -> increased acute PVR in response to decreased CO -> possible acute rise in BP -> chronically lowered PVR in hypertensive’sRespiratory2 blockade of bronchial SMC -> bronchoconstrictioncurrently no drug selective enoughavoid in asthma, but may still be well tolerated and beneficial in COPD patientsEye - IOP via aqueous humor productionMetabolic and endocrineTreatment 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 understoodWhat are the effects of beta blocker in overdose? 2007-1Hypotension, 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 receptorsHow does carvedilol differ from propranolol? 2005-1Carvedilol has no local anaesthetic action1 adrenoceptor block, but effect on Beta receptor > Alpha receptorCauses vasodilation in addition to b-blockadeStereoselective metabolism of its 2 isomers occurs Polymorphism influenced Cytochrome P450 2D6 affects R isomer metabolism3.5.2 ACE inhibitors (2) 2010-2Describe the mechanism of action of ACE inhibitors, 2005-2 & 2003-1 (captopril)MechanismCompetitively block angiotensin converting enzyme, preventing angiotensin I -> angiotensin II vascular tone from prevention of vasoconstrictor effects of Ang II (main effect)aldosterone secretion (by Ang II) -> Na & H2O resorptionAlso 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 liverWhat are the adverse effects of ACE inhibitors, 2005-2 & 2003-1 (captopril)ToxicityHypotension (esp if hypovolaemic)Acute renal failure (esp renal artery stenosis)Hyperkalaemia (interact with K+ sparing diuretics)CoughAngioedema (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 captoprilCHF, after MI (better preservation of LVF – reduce post MI remodeling)Diabetic nephropathy – diminish proteinuria, stabilize renal function – improved intrarenal hemodynamicsHypertension2008-1Describe the pharmacodynamics of therapeutic drugs that modulate the effect of angiotensinAs above for ACE-iAngiotensin 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 angioedemaPotentially greater effect as enzymes other than ACE can generate angiotensin IIExamples: losartan, candesartan3.5.3 Vasodilators (2) 2011-1List some drugs used in hypertensive emergencies.GTN , nifedipine , diazoxide , hydrallazine , sodium nitroprusside , esmolol , labetalolTell us about the pharmacokinetics of Na nitroprusside.PharmacokineticsParenterally administered by IVI (sensitive to light)Onset minutes, peak effect minutes, t? 2 minutes (thiocyanate 3 days)Duration of action 1-10 minutesElimination: By RBC's -> cyanide, then liver -> thiocyanate -> renally excretedWhat 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, unconsciousness3.5.4 Sympatholytics (2)3.6 Diuretics3.6.1 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 limbReduces reabsorption of NaClAlso reduces K+ recycling -> reduces lumen +ve potential that drives Mg2+/Ca2+ reabsorptionUltimately leads to loss of counter-current mechanism -> reduced ability to concentrate the urine2. 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 pressuresWhat are the toxic effects of FRUSEMIDE?ToxicityElectrolyte 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? 2010-2PharmacokineticsRapid absorption after oral adminOral bioavailability 50% (range 10 –100%)Highly protein-bound (>95%)Small Vd <10L/70kg50% conjugated in kidney & 50% excreted in urine unchanged (tubular secretion)Elimination t1/2 1.5 – 2 hoursPeak effect 30 minutes IV / 1 hour oralWhat effects do they have on renal handling of Ca and Mg ? 2004-2Reduces K+ recycling -> reduces lumen +ve potential that drives Mg2+/Ca2+ reabsorptionToxic effect is hypomagnesemiaUsually 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 inhibitorsWork by inhibiting NaCl co-transport (NCC) in DCTUsed for HTN, CHF, renal stones, nephrogenic diabetes insipidusEnhance 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, hyperlipidaemiaAllergic reactions: sulfonamides alsoOther: 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 PTAlso oppose the actions of ADH in the CT via osmotic effect (and counter-current failure)High urine output, approaching osmolality of plasmaWater diuresis > natriuereisWhat are the clinical uses of Mannitol?ICP (and IOP) – alters the Starling’s forces so water leaves cells: intracellular volumeIncrease 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, vomitingDehydration, K+, Na+ - as water extracted from cells intracellular K+ rises -> cellular losses, and the water diuresis is > than the electrolyte lossNa+ in renal failure3.6.Extra Carbonic Anhydrase Inhibitors2007-2 What are the actions of acetazolamideInhibition of carbonic anhydrase, found predominantly in the luminal brush border of the PCTCarbonic 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 acidosisRenal 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 encephalopathy3.7 Drugs affecting haemostasis, thrombosis and the haemopoietic system3.7.1 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 activationManufactured as alteplase by means of recombinant DNA technologyShort half life means heparin is an essential adjunctWhat are the indications for TPA use?PE with haemodynamic instabilitySevere 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 hoursAcute 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 hourHow does tPA differ from streptokinase?t-PA is a naturally occurring human enzyme, 10x the cost of streptokinaseStreptokinase is not an enzyme itself- it is a bacterial product that combines with plasminogen to form an enzymatic complex catalyses conversion of plasminogen to plasminStreptokinase 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 resistanceStreptokinase has been shown to increase bleeding risk in acute ischaemic stroke and is not recommended3.7.3 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 blockersPrevents the ADP mediated platelet aggregation Unlike aspirin, no effect on PG metabolismClopidogrel: after 300mg po -> at 5 hours 80% platelet activity inhibtionHow long is this effect?7-10 days, the life of the plateletWhat are the indications for clopidogrel?IHDPre/post stentStroke prevention2005-1How does it differ from aspirin?Aspirin: Irreversible acetylation -> inhibition of cyclooxygenase, prevents AA -> thromboxane A2Unlike aspirin, no effect on PG metabolismWhat 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 activityMinimal 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 aggregationAbciximab, eptifibatide and tirofiban – all administered parenterally3.7.5 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 3.5Rapidly absorbed from stomach, peak levels 1-2 hoursSmall Vd, capacity limited metabolism (zero order elimination in higher doses)Aspirin t ? 15mins -> hydrolysed tissue esterases to salicylate t ? 2-19 hoursLess than 2% aspirin excreted unchanged, 2-30% of salicylateSalicylate is non-linearly bound to albuminSalicylate conjugated with glucuronide or glycine to form salicyuric acidRenally 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, proteinuria2007-2What is the mechanism of action of aspirin?Irreversible acetylation -> inhibition of cyclooxygenase (I & II)Prevents AA -> thromboxane A2Platelet effects last 8-10 days (the life of the platelet)Other tissues generate more COX so ordinary doses have duration of action 6-10 hoursThromboxane 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 morePoorly 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 absorbedWith 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 areaWhat are its therapeutic indications? 2003-2Decreases incidence: of TIA, CVA, coronary artery thrombosis (MI), thrombus post CABGPrimary prevention (especially as adjunct to risk factor management)Secondary preventionLess commonly now: Anti-inflammatory, Analgesia, Anti-pyretic3.7.6 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, BactrimR & S- Amiodarone, Disulfiram, CimetidineDisplace albumin bound warfarin: phenylbutazone, sulphinpyrazonePharmacodynamic (↑ INR)DrugsAspirin – affects platelet function3rd generation Cephalosporins – reduce gut flora producing Vit KHeparin – directly prolongs INRBody factorsHepatic diseaseHyperthyroidismPharmacokinetic ( INR)Barbituates, cholestyramine, rifampicinPharmacodynamic ( INR)DrugsDiuretics, vitamin KBody factorsHeriditary resistanceHypothyroidism2009-2What 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 factorsBlocks synthesis of Clotting Factors II (prothrombin), VII, IX, X and Anticoagulant proteins C and SLong half-life of these factors means that the anticoagulant effect is delayed until degradation of normal preformed factorsAlso, administration of vitamin K will have a delayed effect because new clotting factors need to be synthesisedWhat drug interactions with warfarin prolong the INR?As aboveHow is the action of Warfarin reversed?Discontinuation of drugVitamin K, FFP, Prothrombin complex (Prothrombin X), Recombinant Factor VIIaMay need repeat administration due to the long t ? of warfarin2006-1What are the preferred administration routes for Vitamin K?Oral Slower onset 4-6hBioavailability ~50%IV Onset 1-3hSlowly b/c rapid infusion -> dyspnea, chest/back pain, even deathE.g. 10 mg IV diluted in saline or glucose at a rate not exceeding 5% of the total dose per minuteRepeat doses at 6-8 hour intervals (longer t ? of warfarin c.f. Vit K)IM (new born)SC is erraticWhat are the clinical indications for prescribing Vitamin K?Reversal of oral anticoagulant effectManagement of warfarin toxicityVit K deficiencyPrevention of haemorrhagic disease of the newbornTreatment of haemorrhagic disease of the newborn3.7.7 Heparin (1) 2006-1, 2003-1 (UFH)Describe the mechanism of action of heparin?Heparin binds to endothelial cell surfaces and plasma proteinsHeparin accelerates the antithrombin equimolar complex formation with certain clotting factorsBinding of activated AT III with the activated clotting factors degrades and inactivates themNormally slow, but 1000 fold increase by conformation change exposing the inhibitory binding siteAbout 1/3 of the heparin has the correct pentasaccharide sequence for thisThis interaction does not consume the heparin and it can move on to catalyse moreUnfractionated heparin (MW 5000 – 30,000) will inhibit IIa (thrombin), IXa and XaLow molecular weight heparin predominantly inhibits Xa2008-1, 2003-1What are the pharmacodynamic differences between LMW and unfractionated heparin?Unfractionated heparin (MW 5000 – 30,000) will inhibit IIa (thrombin), IXa and XaLow molecular weight heparin predominantly inhibits XaWhat are the advantages of low molecular weight heparin over unfractionated heparin?Single daily or divided subcutaneous doses – facilitates patient mobility and OP managementDue to predictable pharmacokinetics of weight-based LMWH dosing routine monitoring not required (unless renal insufficiency or pregnancy)Reduced bleeding riskLower incidence of HIT Improved efficacy over unfractionated heparin in ACSIncreased bioavailability2006-1How can heparin be reversed?Stop the drugAdministration of antagonist: protamine sulphate, a basic protein that binds with heparin –> stable inactive complexFor every 100 Units Heparin need 1mg Protamine, but excess protamine must be avoided as can have anticoagulant effect2006-1, 2003-1What are the potential adverse effects of heparin?Bleeding and otherEsp in elderly and renal failureOf animal origin -> allergyReversible alopeciaLong term: osteoporosis, spontaneous fractures, mineralocorticoid deficiencyHIT (heparin induced thrombocytopaenia)Immune response to heparinSystemic hypercoagulable state1-4% of those treated >7 days (i.e. surgical)Lower with LMWH3.7.8 Haemopoietic agents (3)2007-1What is erythropoietinGlycoprotein hormone produced by kidneyBy specialized peritubular cells of the renal cortex in response to low blood oxygenationStimulates red cell precursors to proliferate and differentiateAlso releases reticulocytes from marrow What are its clinical applications?Main use is for the anaemia of chronic renal failure, where erythropoietin production in impairedHelps 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 riseHypertensionThrombosis(Allergic reactions are infrequent and mild)3.8 Drugs used in control of lipids (3) ................
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