Dr. Mariam Yousif Pharmacology & Toxicology Dept 17/10/2006

1. Definition of angina pectoris. 2. Identify the 3 types of angina with their underlying pathophysiology. 3. What is the aim/rationale of therapy? 4. What are the 3 main classes of antianginal drugs? 5. Identify the mechanism of action, main pharmacological actions, major side effects and main drug examples for each class. 6. What anti-thrombotic therapies are available for the treatment of unstable angina. 7. What are the new emerging anti-anginal drugs?

Angina pectoris is the clinical syndrome of transient cardiac ischaemia resulting from inadequate coronary blood flow. It is characterized by severe retrosternal chest pain or pressure that radiates to the left shoulder, left arm or to the back.

It occurs when the oxygen supply to the myocardium is insufficient for its needs.  Imbalance in myocardial oxygen supply-demand relationship results from spasm or obstruction of the coronary blood vessels.

Types of Angina
1- Stable (Classic / Typical / Angina of Effort) 2- Unstable Angina 3- Variant (Prinzmetal's Angina)

1- Stable
 Characterized by predictable pain on exertion.  Occurs due to a fixed narrowing of the coronary

arteries by atherosclerosis.

2- Unstable Angina
 Characterized by pain that occurs with less

exertion, can occur at rest.
 Occurs due to disruption of an atherosclerotic

plaque with subsequent cascade of platelet activation and aggregation, and thrombosis leading to a decrease in coronary blood flow.

3- Variant (Prinzmetal's Angina)
 Cardiac pain that occurs exclusively at rest.  Caused by coronary artery vasospasm (vasospastic) which reduces coronary flow leading to reduction of blood flow to the myocardium.

Aim of Therapy
To improve the balance between myocardial oxygen demand and supply.

Supply = Demand
Coronary Blood Flow Systolic Wall Tension Contractility Heart rate

How to achieve the aim? A. Coronary vasodilators
Increase blood flow to the myocardium by dilating the coronary arteries.

B. Drugs that ⇓ work load of the heart

Decrease oxygen demand by reducing cardiac work.

Types of Therapy for Angina # Prevention # Medical Therapy Using Anti-Anginal Drugs # Revascularization PTCA: Percutaneous Transluminal Coronary Angioplasty CABG: Coronary Artery Bypass Graft Surgery

     

Quit smoking Lose weight Reduce cholesterol levels Exercise Better control of diabetes Better control of hypertension

Medical Therapy
Anti-Anginal Drugs # Beta-adrenoceptor blocking drugs # Nitrates # Calcium channel blockers Can be used alone or in combination

1. β -Adrenergic Blocking Agents
e. g. Propranolol, Atenolol, Metoprolol # Predominant receptor subtype in the myocytes is β 1-receptor, its blockade minimizes the influence of endogenous catecholamines.

Molecular mechanism of action of beta1-adrenoceptor antagonists. Stimulation of beta1-adrenoceptors by catecholamines leads to activation of adenylyl cyclase and an elevation of cAMP. This process is inhibited by beta1-adrenoceptor antagonists.

Beta-blockers Negative chronotropic effect ( negative inotropic effect ( HR) and


therefore reduce the oxygen demand by the heart. # Cardioselective β1-blockers may be used to minimize bronchospasm in asthmatic patients. # Contraindicated in variant angina.

2. Organic Nitrates and Nitrites Esters of nitric and nitrous acid.  Nitroglycerin (GTN) is the prototype drug.  Isosorbide dinitrate  Amyl nitrite

-Nitrates are extremely important agents for the treatment of angina.

Nitroglycerin concentrations are affected by the route of administration Preparations Sublingual, Tablet forms, Topical. Peak concentrations Sublingual: 2-4 minutes Oral route: 15-30 minutes Transdermal route: 1-2 hours

-Nitroglycerin is rapidly inactivated by hepatic metabolism. Given sublingually to avoid the first pass effect and to achieve a therapeutic blood level rapidly.

- Oral and transdermal products are acceptable for the long-term prophylaxis.

Mechanism of Action Organic nitrates nitric oxide (NO) [activates guanylyl cyclase] ⇑ synthesis of cGMP vascular smooth muscle relaxation

Molecular and cellular mechanisms of action of nitrate and nitrite vasodilators. The product, phosphorylated protein kinase, leads to de-phosphorylation of myosin light chain and causes vascular smooth muscle relaxation.


-Relax vascular smooth muscle and cause vasodilation of vessels, both veins and arteries.

-The effect on veins is more pronounced than on the arteries (starts at lower doses).

Pharmacological Actions At low doses:
Venodilation (pooling of blood in veins) ⇑ Venous capacitance ⇓ preload (⇓ venous return) ⇓ work on the heart ⇓ Oxygen consumption.

At higher doses: Nitroglycerin dilates arterioles ⇓ peripheral resistance ⇓ after-load ⇓ myocardial O2 demand
 ⇓ Blood pressure → reflex tachycardia → ⇑ HR → ⇑ O2 consumption (combination therapy with β blockers).

# Nitroglycerin dilates the coronary arteries Blood supply to the heart muscle # Nitroglycerin diverts blood from normal to ischaemic areas of the myocardium through dilatation of collateral vessels (redistribution).

Development of Tolerance
Continuous exposure to high doses of organic nitrates ⇒ ⇓ most of their pharmacological effects.

 Caused by depletion of tissue sulfhydryl groups, can be partially reversed by sulfhydryl group donors, e.g. N- acetylcysteine.

Organic Nitrates Tissue thiols NO2Smooth muscle cell H+ NO Thiols R-SH Nitrosothiols R-SNO

Guanylate cyclase cGMP GTP




Mode of action of nitrates (L-Arg=L-arginine; GTP=guanosine 5’-triphosphate; cGMP=cyclic guanosine 3’5’monophosphate; PKG=cGMP-dependent protein kinase

 The offset of tolerance is as rapid as its onset. Therefore, one alternative dosing strategy to minimize tolerance is to provide a daily nitrate-free interval of 6-8 hours.

Adverse Effects & Toxicity  Postural hypotension  Headache  Reflex tachycardia

3. Ca2+ Channel Blockers
Nifedipine (smooth muscle selective) Verapamil (cardioselective) Diltiazem (intermediate)

-Their main action is to interfere with the entry of calcium into the myocytes and vascular smooth muscle cells.

 Vasodilator effects (nifedipine) on resistance

vessels: ⇓ after-load.
 Coronary arterial dilation ⇒ ⇑ coronary blood

flow (variant angina).  Effects on the heart: Calcium channel block in myocardium ⇒ impaired AV conduction and ⇓ myocardial contractility (-ve inotropic effect).

Side Effects

Constipation, heart failure.

Other antianginal & Vasodilator drugs 3. Dipyridamole. 4. Molsidomine. 5. Hydralazine. 6. Sodium nitroprusside. 7. Nicorandil :K+ channel activator and nitrovasodilator (NO donor) actions.

Antithrombotic Therapy In Unstable Angina
-Platelet aggregation and thrombosis play a major role in acute phase of unstable angina. -Both aspirin and heparin are extremely effective. -They reduce the occurrence of recurrent angina and the occurrence of MI or death. -Alternative antiplatelet agents available are clopidogrel and ticlopidine.

Mechanism of action of Aspirin. Aspirin blocks the activity of cyclooxygenase and reduces the formation of prostacyclin and thromboxane A2. PGG2 and PGH2 are both prostaglandin cyclic endoperoxides and are unstable intermediated.

The molecular mechanism of aspirin is a selective inhibition of thromboxane synthesis. This is achieved because platelets do not possess a cell nucleus and are therefore unable to resynthesize cyclo-oxygenase, whereas endothelial cells can resynthesize cyclo-oxygenase within a few hours.

Low dose aspirin (30 mg/day) is insufficient to block the activity of cyclo-oxygenase completely, so its use can achieve a maintained suppression of thromboxane synthesis, with only a transient inhibition of prostacyclin synthesis, and an overall effect of reduced platelet aggregation.

Emerging Drugs Ranolazine: Acts on mitochondria to inhibit fatty acid oxidation, stimulate glucose oxidation and improve oxygen metabolism. Dalteparin and enoxaparin: low molecular weight heparin fragments, under investigation for treatment of unstable angina. Dalteparin is already approved in many countries.

Revascularization Coronary artery bypass and percutaneous interventions such as angioplasty are alternatives to pharmacological treatment in some patients. PTCA: Percutaneous Transluminal Coronary Angioplasty CABG: Coronary Artery Bypass Graft Surgery

Recommended reading from your text book (Integrated Pharmacology by Page et al)

(Fig. 18.19 page: 378): Diseases that cause unstable angina (Fig. 18.20 page: 378): Clinical features of variant angina pectoris.


LIST OF ANTIANGINAL DRUGS Nitroglycerin, Isosorbide dinitrate Propranolol, Atenolol, Verapamil, Nifedipine, Diltiazem Aspirin, heparin, Clopidogrel, Ticlopidine

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