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.

NitratesDrug Fast GTN Slow GTN Isosorbide

dinitrateIsosorbide mononitrate

Nicorandil

Route Sublingual Transdermal Oral/sublingual Oral 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

NicorandilAlso opens KATP channels in smooth muscle, dilating arterial as well as venous vessels.Can cause ulcers, often in the mouth.

NitratesGIT availability Route Onset Duration

Glyceryl trinitrate

poorsublingual (tablet, spray) <5 minutes <1 hourpatch 30–60 minutes prolongedIV infusion <10 minutes

Isosorbide dinitrate

20–25%oral tablet 15–40 minutes 4–6 hourssublingual tablet <10 minutes 1–2 hours

Isosorbide mononitrate

100% controlled release tablet 1–2 hours prolonged

Australian Medicines Handbook

β-blockers• Competitively antagonise beta adrenergic

receptors• Blunt sympathetic stimulation• Reduce contractility and rate• No reflex rise in peripheral resistanceβ-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 anginaDrug Receptors Elimination Daily

dosesTrade 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 blockersDrug Duration Example dose Trade name

Verapamil 80mg bid Anpec, Isoptin, Cordilox, Veracps

Diltiazem 30mg tid180mg daily LA

Cardizem, Coras, Dilzem, Vasocardol, Diltahexal

Amlodipine Long 5mg daily Amlo, Nordip, Norvapine, Norvasc

Felodipine Short 5mg daily (LA) Felodur, Felodil, PlendilNifedipine Short 20mg bid Adalat, Adefin, NifexalLercandipine 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 Unclear. Calcium channel blocker?Carnitine palmitoyltransferase 1 inhibitor?

Adverse effects

Peripheral neuropathyHepatotoxicity

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 IvabradineAustralian Medicines Handbook

Mechanism Inhibits If (not so funny now)

Lowers heart rate

Side effects Prolongs QT interval

“Luminous phenomena” (Retinal Ih current)

Trade name CoralanPBS Not subsidised