Cardiovascular Pharmacology Professor Doctor: Abd Al Rahman Abd Al Fattah Yassin Professor and head of clinical pharmacology department Mansura university

DRUG THERAPY OF ANGINA PECTORIS

Definition It is a clinical syndrome characterized by sudden severe pressing sub sternal pain that often radiate to the left shoulder and along the flexor surface of the left arm that occurs when coronary blood flow is inadequate to supply the oxygen required by the heart.

Angina occurs when the myocardial oxygen demands exceed the oxygen requirement.

Types of Angina Stable angina: (Effort, typical angina): The pain is commonly induced by exercise, emotion or heavy meals. Variant angina: (Prinzmetal's angina,  - receptor–mediated vasoconstriction): Patient develope pain even at rest. Unstable angina: (accelerated angina): There is a change in pattern, increase in frequency, severity and/or duration of pain.

Treatment of Angina Pectoris Includes: A. General Measures Alteration of life style: avoid intolerable effort, stress, heavy meals, and smoking. Correct obesity and reduce fat intake. Treatment of predisposing factors e.g. hyperlipidemia, hypertension, heart failure, arrhythmias, anemia and diabetes mellitus.

B. Drugs Drugs used during the acute attack: nitrites or nitrates. Sedative, analgesics and tranquilizers. Drugs used in between the attacks: Long acting nitrates. Beta adrenoceptor blockers. Calcium channel blockers. Cytoprotective drugs(trimetazidine,ranolazine) Antiplatelets:aspirin,clopidogril. statins. C. Surgical Treatment: (Myocardial revascularization)

NITRITES AND NITRATES Organic nitrates are ester of nitric acid whereas organic nitrites are esters of nitrous acid.They are potent vasodilators.

Pharmacologic Characteristics of Currently Available Nitrates

Pharmacokineticsa It is absorbed through mucous membrane, gastrointestinal tract, skin and from tracheobronchial tree by inhalation. Sublingual administration produces rapid onset (2-5 minutes) and short duration (less than 30 minutes) It is metabolized by the liver. Oral preparations provide more prolonged prophylaxis. Excretion of nitrates is largely via the kidney.

Mechanism of action  Nitrates converted to NO(nitric oxide) which increase cGMP,which cause V.D of vein more than artery.  SH group is required for this conversion.

Pharmacological Effects Cardiovascular system Blood vessels Nitrites are dilators of venous and to less extent arterial smooth muscle. They increase coronary blood flow due to coronary vasodilatation Arteriolar dilatation of the face and neck lead to flushing Vasodilatation of the meningeal arteries leads to throbbing headache. Heart The effects on the heart are secondary to the peripheral effects. They produce tachycardia, decreased venous return and so the cardiac output (COP) and cardiac work are decreased.

Blood pressure Rapid administration of high doses decreases systolic and diastolic blood pressure and COP resulting in palpitations, weakness, dizziness and tachycardia. Systemic venous capacity is increased due to venular dilatation and this reduces both the venous return and the pulmonary pressure.

Pharmacolgical effect Action on smooth muscle: They relax biliary, G.I.T,bronchial and uterine smooth muscles. Action on respiration Reflex increase in the respiratory rate through the carotid body or secondary to hypotension. Smooth muscle relaxation in bronchospastic disorders. Action on blood : Nitrate ions readily oxidize to methaemoglobin.

Therapeutic Uses 1. Angina pectoris Nitrates are effective in the different types of angina: [A] Reduction of myocardial oxygen demand via: Venodilatation leading to decreased preload. Arteriodilatation leading to decreased afterload. [B] Enhancement of myocardial perfusion Through: Coronary vasodilatation Redistribution of coronary flow to the ischaemic subendocardium

. 2. Congestive heart failure: Due to: mainly reduction of pre-load. And reduction of afterload. 3. Acute myocardial infarction: Nitroglycerine (NG) may reduce the area of myocardial damage and may preserve viable tissues. 4. Other uses Biliary colic. Management of constriction ring of uterus. Treatment of cyanide.poisoning.

Adverse Reactions Throbbing headache. Postural hypotension, dizziness and even syncope. Tachycardia and palpitations. Flushing in the face. Methaemoglobinaemia. Tolerance especially during chronic exposure.

Precautions Start with the smallest possible dose in order to minimise side effects. Nitrate therapy should not abruptly stop to avoid withdrawal symptoms. The patient should consult his doctor when more than 3 tablets sublingually taken over 15 minutes without improvement for fear of MI. Nitroglycerine tablets should not be put in sunlight, or with cotton. The expiry date should be checked (active tablets have burning taste).

CALCIUM CHANNEL BLOCKERS (CCBs) pharmacologyThe of (CCBs) was discussed before. They are effective in the management of variant angina, chronic stable angina and in some subsets of unstable angina. What are the underlying mechanisms of CCBs in angina?

BETA BLOCKERS Beta-blockers are useful in the management of stable and unstable angina. However, they may worsen variant angina due coronary spasm. Sudden cessation of  -blockers may worse the angina due to up regulation of  -receptors. The beneficial effects of beta-blockers in angina are:

Mechanism of action of beta blockers as an anti ischemic: They slow the heart rate..They decrease force of cardiac contraction. Beta blockers may exert cytoprotective effect. Combined use of beta-blockers and nitrates are very effective in the treatment of typical angina.why Because some of the negative aspects of the effects of each drug are reduced. For example, the reflex tachycardia and increased contractility induced by nitrates are blocked by B-blockers.

Effects of  - blockers, nitrates and their combinations in therapy of angina

CYTOPROTECTIVE AGENTS This cytoprotection is obtained by providing enough energy to maintain an efficient myocardial contraction during ischemia e.g. TRIMETAZIDINE: It produces a metabolic switch via inhibition of fatty acid oxidation toward activation of glucose oxidation during ischemia It preserves contractile function and limit cytolysis. It limits membrane damage induced by oxygen free radical

Anti-platelete drugs: Aspirin small dose.  Ticlopidine-clopidogre.  Abciximab-tirofiban

Other antianginal drugs: Nicorandil ranolazine

Selection of Anti anginal drugs for patients with angina pectoris and concomitant diseases

Beneficial anti anginal combinations Nitrate plus beta blockers Nitrate plus verapamil Unfavorable antianginal combinations Nitrate plus nifidipine. Beta blocker plus verapamil.

DRUG THERAPY OF ACUTE MYOCARDIAL INFARCTION (AMI) Myocardial infarction is coagulative necrosis of a part of the cardiac muscles as a result of sudden and persistent cessation of its blood supply. All patients should be admitted to the coronary care unit..

DRUG THERAPY OF A. M.I Oxygen: To increase PO2. Relief of pain: Morphine sulfate or Mepridine. Sedation: by diazepam Measures to limit the size of infarction: Beta- blockers, NG or CCBs

DRUG THERPY OF A.M.I. Fibrinolytic therapy: e.g. Streptokinase Anticoagulants Treatment of arrhythmias, heart failure and cardiogenic shock: Control of risk factors: Stop smoking; physical activity, control hypertension, obesity, diabetes mellitus and correction of plasma lipids.