SV_Antianginal Drugs.pdf

Antianginal Drugs Peter W. Abel, PhD Dept. of Pharmacology hnsp15antang  Angina Pectoris Angina pectoris, chest pain, is the principle symptom of ischemic heart disease. Usually associated with coronary atherosclerosis – coronary artery disease....

Antianginal Drugs Peter W. Abel, PhD Dept. of Pharmacology hnsp15antang  Angina Pectoris Angina pectoris, chest pain, is the principle symptom of ischemic heart disease. Usually associated with coronary atherosclerosis – coronary artery disease. The ischemic condition results from an imbalance between myocardial oxygen demand and myocardial oxygen supply.  Coronary Arteries Normal Increased cardiac work Normal + Exercise, Stress, etc. sed Increa work c cardia Coronary artery disease - coronary atherosclerosis + Exercise, stress, large meals etc.  Determinants of O2 Demand cardiac output = heart rate X stroke volume (contractility) – Heart Rate ↑ heart rate, ↑ cardiac work, ↑ O2 demand. – Cardiac Contractility ↑ contractility, ↑ cardiac work, ↑ O2 demand. – Preload is the volume of blood that fills the heart. Venous return to the heart. ↑ preload, ↑ cardiac work, ↑ O2 demand. – Afterload is the pressure against which the heart has to pump to eject blood. Systemic arterial blood pressure. ↑ afterload, ↑ cardiac work, ↑ O2 demand. The primary action of antianginal drugs is to decrease O2 demand. These drugs work in one or more of the following ways: – ↓ heart rate, ↓ O2 demand. – ↓ contractility, ↓ O2 demand. – ↓ preload, ↓ O2 demand. – ↓ afterload, ↓ O2 demand. Drugs Used to Treat Angina Pectoris Organic Nitrates b-Adrenergic Receptor Blockers Calcium Channel Blockers Ranolazine Coronary artery disease - coronary atherosclerosis Nitrates Nitroglycerin  Antianginal Drugs – Organic Nitrates Organic nitrates: – organic nitrates have been used for over 100 years, and are still primary drugs for the treatment of angina pectoris – cellular mechanism of action : organic nitrates are converted to nitric oxide (NO) à NO stimulates guanylate cyclase to cause an increase in the formation of cGMP à cGMP dephosphorylates myosin light chains and causes vascular relaxation Actions of organic nitrates to treat angina: – venous and arterial dilation, with dilation of veins predominating over that of arteries. Major Effect ↓ preload because veins relax and blood pools in the veins. Less blood returns to the heart so less blood to eject, ↓ cardiac work and ↓ O2 demand. Lesser Effect ↓ in afterload because arteries relax and blood pressure falls. There is less force against which the heart has to contract to eject blood. This causes ↓ cardiac work and ↓ O2 demand. – coronary blood flow organic nitrates can dilate large coronary arteries and provide some ↑ in O2 supply to the ischemic myocardium.  Nitrate Pharmacokinetics Rapid acting nitrates have low oral effectiveness due to extensive first-pass metabolism in the liver. – After sublingual administration nitrates do not immediately pass through the liver. – Sublingual nitroglycerin is used for the treatment of acute attacks of angina pectoris. – Higher dose oral (swallowed) and transdermal nitrate preparations have a slow onset and a long duration of action. Used to prevent angina. Sublingual  Organic Nitrate Drugs Immediate Treatment Prevention  1-2 Nitrate adverse effects Nitrate tolerance – a reduced effectiveness over time – may develop with long term use of oral or transdermal nitrates. An 8-10 hour nitrate free period per day is recommended to prevent tolerance. Generally, most adverse effects are related to excessive vasodilation. They include: severe headache, facial flushing hypotension – dizziness, weakness orthostatic (postural) hypotension reflex tachycardia – baroreceptor reflex  b-Adrenergic Receptor Blockers These drugs block b-adrenergic receptors and reduce responses caused by the activation of the sympathetic nervous system, thereby inhibiting cardiac work and oxygen demand. b-blockers are used to prevent angina: – Commonly used in patients with angina. Also used to treat hypertension, arrhythmias, heart failure etc. Actions of b-blockers to treat angina pectoris – b-blockers antagonize the effects of epinephrine and norepinephrine released by sympathetic stimulation during stress or exercise – They primarily ↓ heart rate and contractility β1 – They also reduce renin release leading to less of the vasoconstrictor angiotensin II which ↓ blood pressure - ↓ afterload β1 Angiotensin II – Thus cardiac work and O2 demand are reduced  b-Adrenergic Receptor Blockers Nonselective or 1st Generation Cardioselective or 2st Generation Adverse effects: – Respiratory: wheezing, bronchoconstriction in asthma patients with drugs that block b2–adrenergic receptors – Cardiovascular: bradycardia, AV block; caution in patients with conduction disturbances – Abrupt withdrawal of b blockers can worsen angina – CNS: Insomnia, depression, bizarre dreams  Calcium Channel Blockers (CCBs) Drugs include 3 classes, all used to treat angina pectoris phenylalkylamines: verapamil Cardiac and Vascular Effects benzothiazepines: diltiazem dihydropyridines: nifedipine, amlodipine, Vascular Effects Only nimodipine, felodipine, isradipine etc. Used to prevent angina. These drugs work by blocking L-type Ca2+ channels in the heart and/or blood vessels. They also have major use to treat hypertension and some are used for arrhythmias.  Calcium entry into cells occurs through voltage- dependent L-type calcium channels in the heart and blood vessels – Vascular smooth muscle contraction is dependent upon an increase in intracellular Ca 2+ – Cardiac muscle contraction, heart rate and conduction is also dependent upon an increase in intracellular Ca 2+  CCB effects on blood vessels All CCBs inhibit L-type Ca 2+ channels in arterial smooth muscle. Reducing intracellular Ca 2+ in arterial smooth muscle results in peripheral vascular relaxation, a ↓ in blood pressure, a ↓ in afterload and ↓ O2 demand. Reducing intracellular Ca 2+ in coronary arterial smooth muscle results in modest coronary vasodilation and some ↑O2 supply.  CCB effects on the heart Some CCBs also inhibit L-type Ca 2+ channels in cardiac tissues. – Verapamil and diltiazem block L-type Ca 2+ channels in the SA node and AV node to slow heart rate and conduction. This causes ↓ cardiac work and ↓ O2 demand. – These drugs also block L-type Ca 2+ channels in cardiac muscle to ↓ myocardial contractility. This also causes ↓ cardiac work and ↓ O2 demand. Comparison of Calcium Channel Blockers  Ranolazine (Ranexa®) A new drug class approved to treat angina. Mechanism of action: – Decreases cardiac muscle sodium entry which reduces Ca2+ overload, cardiac contraction is reduced which decreases O2 demand. Also some increased myocardial blood flow and O2 supply. Adverse effects: – Arrhythmias (prolonged QT interval), constipation, nausea, vomiting, dizziness, headache. Used to prevent angina. New drug with less clinical experience.  Sequence of drug use to treat stable angina Infrequent: – Nitroglycerin sublingually as needed for acute attacks. Frequent: – Nitroglycerin sublingually as needed for acute attacks. – β-blocker most common or calcium channel blocker or ranolazine or long-acting nitrate (e.g., nitroglycerin patch) to prevent angina. If 1 drug does not prevent/reduce angina use a combination of drugs: – β-blocker plus long-acting organic nitrate – β-blocker plus dihydropyridine calcium channel blocker – All of the above choices with ranolazine