Cardiovascular Pharmacology

Cardiovascular Pharmacology

·        For Anti-coagulation,see Anticoagulant Treatment Topic

Idiot’s guide

·        Always push non drug treatment: lifestyle, smoking, etc

·        Hypertension: Thiazides (not diabetics or gout) + b-blockers (not CORD/asthma). Maybe ACE inhibitors

·        Angina: b-blockers + aspirin + nitrates. Maybe Ca channel blockers (¯HR), statins, ACE (if hypertension/diabetes)

·        Post MI: Aspirin, b-blockers, ACE if ¯LVF +/- statin

·        Heart Failure: ACE + diuretic + aspirin. Maybe b-blockers, spironolactone, other vasodilators, statins, etc

ACE Inhibitors

·        Block the formation of angiotensin II ® diuretic, ¯peripheral vascular resistance, and better tissue remodelling/healing of damaged myocardium. But 30% of hypertensives are non-responders

·        Eg Captopril, quinapril

·        Many patients (especially the elderly) don‟t respond on its own. Synergistic effect with diuretic (ie shifts ACE inhibitor dose-response curve to the left). If it‟s not working, add in a low dose diuretic

·        Adverse effects:

o  Metabolic taste, hypotension (especially with first few doses), hyperkalaemia, angioedema, neutropenia, proteinuria.

o  ¯Renal function, especially if existing renal impairment (­efferent flow ® ¯glomerular filtration)

o  Dry cough (due to ­bradykinins). If cough a problem, then use an angiotensin II receptor antagonist (eg Losartan)

o  Rash: may be long time after starting, especially captopril due to sulphur group

·        Interactions:

o  Diuretics: hypotension + ¯renal function

o  NSAIDS: renal failure, hyperkalaemia

·        Contra-indications:

o  Bilateral renal artery stenosis

o  Pregnancy, breast feeding

o  LV outflow obstruction (eg Aortic Stenosis)

o  Marked hypotension

o  Other drugs: K supplements, Li, NSAIDs

·        Monitor for: ¯Na, ­K, Cr > 200, rare neutropenia

Diuretics

·        Common types:

o  Thiazides eg bendrofluazide. Flat dose response curve so ­dose only ­side effects. No ­effect from a dose above 2.5 mg. Effect: mainly vasodilation, also inhibit Na/K co-transport in distal convoluted tubule ® salt and water loss. VERY cheap. Take 6 – 8 weeks to work

o  Frusemide: blocks Na/K/Cl transport in Loop of Henle.  No role in lowering blood pressure

·        Interactions:

o  General: NSAIDs, lithium, digoxin, ACE inhibitors, corticosteroids

o  Loop: antibiotics

o  Thiazides: calcium supplements

·        Adverse drug reactions are dose dependent (Þ use in low dose):

o   General: dehydration, electrolytes, lipids, endocrine, skin

o   Loop: ototoxicity, ¯K, ¯Ca.  Frusemide ® water rush.  Difficult if you‟re out and about ®

o   ¯compliance

o   Thiazide:¯K, ­Ca, ¯Mg, ­urate (+/- gout), ­lipids, progressive glucose rise over years, thrombocytopenia, impotence in high doses

·        Spironolactone:

o   Acts at distal renal tubule as an aldosterone antagonist

o   Adverse effects: hyperkalaemia, diarrhoea, gynaecomastia

o   Interactions: ACE inhibitors, digoxin

b-blockers

·        Action (effect takes 2 – 4 weeks):

o   Renal effect (¯renin)

o   Pre-synaptic b-receptor blocker

o   ¯Cardiac output due to ¯rate and strength of myocardial contraction (® ¯O2 consumption). Acutely ® ­TPR (so not if peripheral vascular disease otherwise ­ischaemia). ¯CO resolves over time

o   ?Central action

·        Use in angina, hypertension, heart failure

·        Classified by:

o   Lipid vs H2O soluble

o   b-receptor selectivity

o   a-blocking activity (eg labetalol ® prone to postural hypotension)

·        Contraindications:

o   Arrhythmias: bradycardia and AV block

o   Asthma

o   Peripheral vascular disease: lead to unopposed a1 stimulation

o   Diabetes: block the symptoms of hypoglycaemia, potentiate effects of insulin and oral hypoglycaemics

o   Overt cardiac failure: negative inotropes – but still OK in heart failure at low dose

·        Adverse effects (generally dose dependent):

o   Common: Lethargy, heavy legs (slowed up feeling due to ¯CO), cold extremities, ­lipids, headaches, nightmares (in lipid soluble propranolol, not water soluble atenolol)

o   Less common: GI disturbances and rashes

o   Rapid withdrawal ® angina, arrhythmias due to b1 up-regulation

·        Interactions with:

o   Verapamil: severe bradycardia

o   Cimitidine: inhibits metabolism ® potentiates effect

·        Consider a-blockers for hypertension– but not as first line agents (may exacerbate heart failure). Dilate peripheral arterioles (modern ones don‟t cause reflex tachycardia), less arterial dilation. Start low to avoid profound hypotension (especially elderly). Good for lipids

Ca Channel Blockers

·        Uses: Angina, dysrhythmias, hypertension, NOT heart failure

·        Hypertension: only in isolated systolic hypertension (eg due to hardened arteries)

·        Not better than diuretics or b-blockers for hypertension, but additive effect

·        Action: ¯myocardial work, decrease afterload, vasodilate coronary arteries

o   Verapamil (originally an anti-arrhythmic, derivative of theophylline, less effect on vasodilation but ­bradycardia) and Diltiazem: slow conduction at the AV node and cause coronary vasodilation 

o   Nifedipine: vasodilator Þ good for coronary artery spasm, but may also cause reflex tachycardia so may use with a b-blocker

·        Adverse effects:

o   All cause headache, flushing, dizziness, hypotension, ¯LV function

o   Verapamil: constipation 

o   Verapamil and diltiazem: ­ heart block

o   Nifedipine and verapamil: ­blood sugar

·        Interactions:

o  ­ plasma digoxin levels

o  Enzyme inhibitors ® ­plasma levels of carbamazepine and cyclosporin

o  Don‟t use verapamil with b-blockers: bradycardia + LVF

·        Also consider long acting nitrates

Positive Inotropes

·        Digoxin: only oral inotrope.  Slows AV conduction and increases contractility

o  Use: in AF, slows rate ® ­output.  But poor for rate control – still ­HR in response to standing up

o  Orally takes a week to reach steady state (T½ is 36 – 40 hours)

o  Shortens QT interval ® causes digitalis effect on ST interval (not a sign of toxicity) 

o  Low therapeutic index (although wide therapeutic range) ® toxicity common:

§  CV: any arrhythmia, arrest, worsening heart failure

§  GI: anorexia, nausea, vomiting, diarrhoea, abdominal pain

§  CNS: headache, drowsiness, unsteadiness, blurred/yellow vision, confusion

§  Worse if:

·        Electrolyte disturbance: hypokalaemic, hypercalcaemia, alkalosis

·        Potassium sparing diuretics, steroids, verapamil, amiodarone, spironolactone

·        Disease: hypothyroidism, hypoxia, renal failure

·        Old age

§  Management: stop digoxin, check plasma level and K, treat arrhythmias, antidote (Digibind)

·        Dopamine (precursor of nor-adrenaline)

o  In low doses ® renal vasodilation and improved renal function

o  In higher doses ® acts on cardiac b1 receptors ® inotropic effects

·        Dobutamine: acts on cardiac b1 receptors ® inotropic effects

Lipid Lowering Drugs

·        See Dyslipidaemia(Topic)

·        Lipids:

o  Cholesterol is most concentrated in LDL

o  HDL is beneficial

o  VLDL carries TAGs

·        Hypercholesterolaemia:

o  Primary: Hepatic overproduction of VLDL ® ­VLDL/LDL/Remnant lipoproteins

o  Secondary: Obesity, diabetes, hypothyroidism, nephrotic syndrome, alcohol, drugs (oestrogen, Retinoids, b-blockers, thiazides….)

·        Drug groups:

·        HMG-CoA Reductase Inhibitors (Statins):

o   Treatment: Requires health benefits approval (it‟s expensive) and is always accompanied by diet

o   More effect in lowering plasma concentrations of LDL and total cholesterol ® ¯mortality in hypercholesterolaemia + angina

o   SE: rare.  GI, headaches, ­LFTs, myopathy from ­Ck.  Potentiates warfarin

·        Fibrates: ­HDL and ¯TAGs

·        Bile-acid sequestrants: Indicated for children and women of childbearing age. SE: constipation, skin rashes. Bind fat soluble vitamins and other drugs (eg warfarin, give two hours before or 4 hours after)