Pharmacology Series (Gippsland) Treatment of CV diseases

Antihypertensives / hypertension Vasodilators / angina Inotropic agents / heart failure Antiarrhythmic agents Lipid lowering drugs Diuretics Anticoagulant drugs
Professor Robert Widdop Department of Pharmacology Monash University robert.widdop@monash.edu

Vasodilators & angina
Objectives:
• Symptoms & causes of angina • List types of angina • List major drug classes used in the treatment of angina • Describe mechanisms of action of drugs used in treatment of angina & adverse effects • Focus on nitrates
References: Pharmacology, Rang, Dale, Ritter & Moore. th Edition (2003), Chapters 17 & 18 5 Flesh & Bones of Medical Pharmacology 2008 (D Spina)

Symptoms: Pain, severe, crushing, sub-sternal, may radiate + Shortness of breath lasts a few minutes (usually relieved by rest &/or sublingual nitrate) Causes: Coronary artery disease, coronary vasospasm due to insufficient O2 supply to heart i.e. imbalance: myocardial O2 demand >> O2 supply Urgent medical attention required for: • worsening angina (unstable angina) • chest pain lasting more than a few minutes

Angina pectoris

Types
• Chronic, stable angina (atherosclerosis +/++)
caused by exercise, coronary artery disease

• Unstable angina (atherosclerosis +++)
unpredictable, thrombi formation

• Variant angina (no atherosclerosis)
spasm of coronary artery

Risk factors: Hypertension, cholesterol, smoking etc Precipitated by: Exertion, cold, stress, large meals

Treatment of angina
• Modification of risk factors: smoking, obesity, hypertension, hyperlipidemia, diabetes • Surgery/angioplasty/stents • Drug treatment

ST depression during angina: indicates myocardial ischaemia, as might occur on exercise testing

Drugs for angina: mechanisms
•  coronary perfusion to  oxygen supply •  metabolic demand • Combination of both Determinants of myocardial oxygen requirement: • heart rate • contractility • ventricular volume • arterial pressure

Balloon angioplasty

 Venodilatation  CO   oxygen consumption  Arterial dilatation   peripheral resistance   oxygen consumption  coronary dilatation  increase oxygen supply

Nitrates
Result in release of nitric oxide in vascular smooth muscle with consequent vasodilatation, particularly in veins (smooth muscle relaxants) They have no effect on cardiac or skeletal muscle

Mechanism of action of Nitric Oxide
Endothelial cell
NOS L-arginine L-citrulline

NO NO

guanylate cyclase

cGMP

Ca2+

Vascular smooth muscle

RELAXATION

Nitrovasodilators can donate NO from their structure
Endothelial cell
NOS L-arginine L-citrulline

Nitrates: mechanism in angina
Venous dilatation reduces venous pressure and preload, with consequent fall in cardiac oxygen consumption Arteriolar dilatation reduces peripheral resistance and after-load with consequent fall in cardiac oxygen consumption Coronary dilatation- e.g. variant angina Limitation: blood pressure is associated with a reflex tachycardia  tendency to increase cardiac oxygen consumption

NO
Glyceryl trinitrate (GTN) nitrates

NO

guanylate cyclase Vascular smooth muscle

cGMP

Ca2+

RELAXATION

Nitrates - metabolism
• Large hepatic “first pass” metabolism (eg. > 90%) • Nitroglycerin inactive orally (give sublingually or transdermally)

Examples of nitrates
Nitroglycerin (glyceryl trinitrate): • sub-lingual (tablet or spray, lasts<30 min) • transdermal (patch or ointment, < 24 hr) Isosorbide dinitrate: • sub-lingual (lasts < 2 hr) • oral (lasts < 6 hr)

Nitrates - adverse effects Use of sublingual nitroglycerin
• Treatment of acute attack of angina • Immediate prophylaxis • If using tablets rather than spray, they must be kept in a closed non-plastic container as they lose activity (volatile) • Hypotension (fainting): should not be combined with Viagra or similar drugs • Tachycardia • Headache • Flushing

Nitrates – tolerance:
• Develops after continual exposure • A nitrate-free period (e.g. for 8 hours per 24 hours when using transdermal patches) reduces tolerance

Sildenafil (VIAGRA)
•PDE5 inhibitor (many isoforms) •Potentiate ‘NO donours’   BP • Contraindicated with nitrates

Side effects- mainly CVS

Deaths Associated with Sildenafil Therapy in the United States. From: Lue: N Engl J Med, Volume 342(24).June 15, 2000.1802-1813

Ca channel blockers
Cause: • Vasodilatation (arterial > venous) • Reduced cardiac contractility & reduced atrioventricular conduction (verapamil > diltiazem > nifedipine) Indications: Angina, hypertension, tachyarrhythmias (SVT) Angina: TPR & cardiac work  reduce cardiac oxygen demand • coronary vasodilation can help variant angina (angina due to vessel spasm, not fixed block)

Ca blockers: adverse effects
-cardiac depression, bradycardia (contraindicated in heart failure) -flushing, edema, dizziness, headache -constipation, nausea Contraindications: heart failure -blockers (with verapamil or diltiazem)

Uses of -blockers
e.g. propranolol- nonselective 1 & 2 antag atenolol, metoprolol- 1 selective antag
• • • • angina hypertension arrhythmias clinically stable heart failure (carvedilol- blocker)

Variant angina
• Nitrates and calcium antagonists also reduce coronary artery spasm in variant angina (not due to fixed block) • In addition, beta blockers, by slowing heart rate, can increase coronary artery perfusion time • Variant angina: beware -blockers

Angina:  cardiac oxygen demand  heart rate increases coronary artery perfusion time during diastole (relaxation phase)  oxygen supply to the heart

Unstable angina
• Dipyridamol :  adenosine- vasodilator (variant) - antiplatelet (unstable) • Aspirin - antiplatelet

Points about anti-anginal drugs
• Chest pain lasting more than a few minutes or worsening (unstable) angina require urgent medical attention • Drugs can be used for stable angina • Nitrates can be used prophylactically (e.g. before attempting exercise) • Beta-blockers reduce exercise ability & can cause bronchoconstriction • Anti-anginal drugs can cause hypotension and faintness: to reduce this, patients can lie down whilst taking nitrates (especially on starting them)