Angina pharmacology

Summary Drugs Stable angina management: reduce heart O2 demand Nitrates (reduce venous return) Beta blockers (reduce sympathetic drive) Calcium channel blockers (reduce inotropic state) Refractory stable angina options Perhexiline, Ivabradine Preventative agents Thrombosis prophylaxis (Aspirin, clopidigrel, dipyrimadole, heparins) Statins ACE inhibitors Diuretics

Triple Whammy ACE Inhibitor, diuretic, and NSAID: a dangerous combination (TGA.gov.au, Australian Adverse Drug Reactions Bulletin 2003) NSAID + Diuretic + ACE inhibitor Correlation with Renal failure ADRAC wishes to remind prescribers that the combination of ACE inhibitors (or angiotensin receptor antagonists), diuretics and NSAIDs (including COX-2 inhibitors) should be avoided if possible, and great care should be taken with ACE inhibitors and NSAIDs in patients with renal impairment.

Nitrates Mechanism Release nitric oxide (NO) NO dilates venules and coronary arteries Increases venous capacitance Decreases preload Decreases contractility (Frank-Starling mechanism)

Nitrates Adverse effects Contraindications Precautions Headaches, hypotension, flushing, palpitations, orthostatic hypotension, fainting, peripheral oedema, contact dermatitis Contraindications Hypovolemia or hypotension Raised intracranial pressure Significant anemia G6PD deficiency (risk of hemolytic anemia) Recent (1-5 days) use of PDE5 inhibitors (excacerbates hypotension) hypertrophic obstructive cardiomyopathy cardiac tamponade Aortic stenosis, mitral stenosis, cor pulmonale. Precautions Tolerance. 10-12 hour nitrate free interval recommended each day. Withdrawal. Reduce dose gradually.

Nitrates Drug Fast GTN Slow GTN Isosorbide dinitrate Isosorbide mononitrate Nicorandil Route Sublingual Transdermal Oral/sublingual Oral Example Dose 500 mcg prn 10mg daily 10mg q.i.d 60mg daily 10mg b.i.d Trade name Nitrolingual, Lycinate, Anginine Minitran, Nitro-dur Sorbidin, Isordil Imtrate, Duride, Imdur, Monodur Ikorel Nicorandil Also opens KATP channels in smooth muscle, dilating arterial as well as venous vessels. Can cause ulcers, often in the mouth.

Nitrates GIT availability Route Onset Duration Glyceryl trinitrate poor sublingual (tablet, spray) <5 minutes <1 hour patch 30–60 minutes prolonged IV infusion <10 minutes Isosorbide dinitrate 20–25% oral tablet 15–40 minutes 4–6 hours sublingual tablet 1–2 hours Isosorbide mononitrate 100% controlled release tablet Australian Medicines Handbook

β-blockers Competitively antagonise beta adrenergic receptors Blunt sympathetic stimulation Reduce contractility and rate No reflex rise in peripheral resistance β-1 receptors mainly in heart muscle β-2 receptors mainly in lungs and peripheral vessels β-3 receptors mainly in heart and adipose tissue

β-blockers Contraindications Adverse effects Precautions Reversible airway disease Cardiogenic and hypovolemic shock Prinzmetal (vasospasm) angina Bradycardia, 2nd and 3rd degree Heart block, Sick sinus Adverse effects nausea, diarrhoea, bronchospasm, dyspnoea, cold extremities, exacerbation of Raynaud's syndrome, bradycardia, hypotension, orthostatic hypotension (carvedilol, labetalol), heart failure, heart block, fatigue, dizziness, abnormal vision, decreased concentration, hallucinations, insomnia, nightmares, depression, alteration of glucose and lipid metabolism, oedema (carvedilol) Precautions Diabetes: hypoglycemia sign can be masked Hyperthyroidism: signs masked Anaphylaxis risk: Reduces epipen effect Phaeochromocytoma: aggravates hypertension Myasthenic symptoms: aggravated Peripheral vascular disease or Raynaud’s phenomenon: aggravated Renal or hepatic impairment: Choose drug with appropriate elimination route

β-blockers for angina Drug Receptors Elimination Daily doses Trade name Metoprolol beta1 hepatic 1–2 Betaloc, Lopressor, Metohexal, Minax, Metrol Propanolol beta1, beta2 2–3 Deralin, Inderal Atenolol renal 1 Noten, Tensig, Tenormin Oxyprenolol beta1, beta2, symp Hepatic 2-3 Corbiton Pindalol Renal Barbloc, Visken Australian Medicines Handbook

L-type Calcium channel blockers Dihydropyridines Strong vasodilation (arterial) Decreases afterload Phenylalkylamine Verapamil (less) Vasodilation and (more) cardiac depression Decreases afterload, heart rate, and contractility Benzothiazepine Diltiazem (more) Vasodilation and (less) cardiac depression

L-type Calcium channel blockers Contraindications Cardiogenic shock, Heart failure, Aortic stenosis Adverse effects Transient worsening of angina symptoms Reflex tachycardia (short acting dihydropyridines) Bradycardia (Diltiazem, Verapamil) Headache, flushing, peripheral oedema (especially dihydropyridines) Gingival hyperplasia Constipation (Verapamil) Rash, fatigue, dizziness, nausea, abdominal pain Precautions Myasthenia-like disease – exacerbated symptoms Avoid β blockers with Verapamil Use β blocker with dihydropyridines? (Murtagh) CCB related oedema may not respond to diuretics

L-type Calcium channel blockers Drug Duration Example dose Trade name Verapamil 80mg bid Anpec, Isoptin, Cordilox, Veracps Diltiazem 30mg tid 180mg daily LA Cardizem, Coras, Dilzem, Vasocardol, Diltahexal Amlodipine Long 5mg daily Amlo, Nordip, Norvapine, Norvasc Felodipine Short 5mg daily (LA) Felodur, Felodil, Plendil Nifedipine 20mg bid Adalat, Adefin, Nifexal Lercandipine 10mg daily Zanidip Australian Medicines Handbook Nimodipine is a CCB indicated for subarachnoid hemorrhage management

Refractory stable angina options Perhexiline Australian Medicines Handbook Mechanism Unclear. Calcium channel blocker? Carnitine palmitoyltransferase 1 inhibitor? Adverse effects Peripheral neuropathy Hepatotoxicity Precautions CYP2D6 saturable metabolism. Identify slow metabolizers Monitor plasma levels Titrate dose when changing other drugs Trade name Pexsig

Saturable hepatic metabolism Australian Medicines Handbook – Drugs and CYP enzymes Cytochrome P450 enzyme family CYP1A2 CYP2B6 CYP2C8 CYP2C9 CYP2C19 CYP2D6 CYP3A4/5 Interactions Grapefruit, Starfruit , St John’s Wort, Nicotine, Watercress Pharmaceuticals

Refractory stable angina options Ivabradine Australian Public Assessment Report for Ivabradine Australian Medicines Handbook Mechanism Inhibits If (not so funny now) Lowers heart rate Side effects Prolongs QT interval “Luminous phenomena” (Retinal Ih current) Trade name Coralan PBS Not subsidised