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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 – 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 Route Sublingual Transdermal Oral/sublingual Isosorbide mononitrate Nicorandil Oral Oral 10mg b.i.d Example 500 mcg prn 10mg daily Dose 10mg q.i.d 60mg daily Trade name Sorbidin, Isordil Imtrate, Duride, Ikorel Imdur, Monodur Nitrolingual, Minitran, Lycinate, Nitro-dur Anginine Nicorandil Also opens KATP channels in smooth muscle, dilating arterial as well as venous vessels. Can cause ulcers, often in the mouth. Nitrates GIT Route availability Glyceryl trinitrate sublingual (tablet, spray) poor patch IV infusion Isosorbide dinitrate oral tablet 20–25% sublingual tablet Isosorbide mononitrate 100% controlled release tablet Australian Medicines Handbook Onset Duration <5 minutes 30–60 minutes <10 minutes <1 hour prolonged 15–40 minutes <10 minutes 4–6 hours 1–2 hours 1–2 hours prolonged 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 – – – – 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 hepatic 2–3 Deralin, Inderal Atenolol beta1 renal 1 Noten, Tensig, Tenormin Oxyprenolol beta1, beta2, symp Hepatic 2-3 Corbiton Pindalol beta1, beta2, symp Renal 2-3 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 – Decreases afterload, heart rate, and contractility 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 Short 20mg bid Adalat, Adefin, Nifexal Lercandipine Long 10mg daily Zanidip Australian Medicines Handbook Nimodipine is a CCB indicated for subarachnoid hemorrhage management Refractory stable angina options Perhexiline Australian Medicines Handbook Mechanism Adverse effects Precautions Trade name Unclear. Calcium channel blocker? Carnitine palmitoyltransferase 1 inhibitor? Peripheral neuropathy Hepatotoxicity CYP2D6 saturable metabolism. - Identify slow metabolizers - Monitor plasma levels - Titrate dose when changing other drugs 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