Title 17. ANTI-ANGINAL DRUGS.pdf ✅

PHARMD GURU Page 1 DEFINITION: Angina Pectoris is a symptom of myocardial ischemia and occurs due to an imbalance between oxygen demand and oxygen supply of myocardium.  Characteristic abrupt, severe, pressing-like substernal chest pain radiating towards neck, jaw, back, and arms. Patients may also experience dyspnea or atypical symptoms such as indigestion, nausea, vomiting, or diaphoresis.  Usually precipitated by exercise, excitement or a heavy meal.  Transient episodes (15 seconds to 15 minutes) of myocardial ischemia (stable angina) do not results cellular death; as occurs in myocardial infarction (MI). TYPES OF ANGINA: TYPICAL ANGINA (CLASSICAL ANGINA):  Pain is commonly induced by exercise, excitement or a heavy meal.  Secondary to advanced atherosclerosis of coronary vessels.  Associated with ST-segment depression on ECG.  Usually lasts 1-15 minutes. VARIANT ANGINA (PRINZMETAL ANGINA):  Pain is induced while at rest.  Symptoms are caused by decreased blood flow to the heart muscle from the spasm of the coronary artery.  Although individuals with this form of angina may have significant coronary atherosclerosis, the angina attacks are unrelated to physical activity, heart rate, or blood pressure.  Associated with ST-segment elevation on ECG.  Generally responds promptly to coronary vasodilators, such as nitroglycerin and calcium-channel blockers.  But β-blockers are contraindicated. ANTI-ANGINAL DRUGS
PHARMD GURU Page 2 UNSTABLE ANGINA (ACUTE CORONARY SYNDROME):  May involve coronary spasm and may also have the component of atherosclerosis.  The duration of manifestation is longer than the first two and has the manifestation of myocardial infarction (MI).  Lies between stable angina and MI.  The pathology is similar to that involved in MI: a platelet-fibrin thrombus associated with a ruptured atherosclerotic plaque but without complete occlusion of the blood vessel. CLASSIFICATION OF ANTI-ANGINAL DRUGS: NITRATES/ORGANIC NITRATES: Ex: Nitroglycerine, Isosorbide dinitrate, Isosorbide mononitrate.  Preload reduction: Peripheral pooling of blood → decreased venous return (preload reduction).  After load reduction: Nitrates also produce some arteriolar dilation → slightly decrease total peripheral resistance or after load on the heart.  Redistribution of coronary flow: In the arterial tree, nitrates preferentially relax bigger conducting coronary arteries than arterioles or resistance vessels. MECHANISM OF ACTION: The organic nitrate agents are prodrugs that are sources of NO. NO activates the soluble isoforms of guanylyl cyclase, thereby increasing intracellular levels of cGMP.
PHARMD GURU Page 3 In turn, cGMP promotes the dephosphorylation of the myosin light chain and the reduction of cytosolic Ca++ and leads to the relaxation of smooth muscles cells in a broad range of tissues. ADVERSE EFFECTS:  Headache is the most common adverse effect of nitrates. High doses of nitrates can also cause postural hypotension, facial flushing and tachycardia.  Phosphodiesterase type 5 inhibitors such as sildenafil potentiate the action of the nitrates. To preclude the dangerous hypotension that may occur, this combination is contraindicated. TOLERANCE: Tolerance to the action of nitrates develops rapidly as the blood vessels become desensitized to vasodilation. Tolerance can be overcome by providing a daily “nitrate free interval” to restore sensitivity to the drug. DEPENDENCE: Sudden withdrawal after prolonged exposure has resulted in spasm of coronary and peripheral blood vessels. Withdrawal of nitrates should be gradual.
PHARMD GURU Page 4 β-BLOCKERS: Ex: Atenolol, Bisoprolol, Metoprolol, Proranolol.  Atenolol, metoprolol, propranolol, bisoprolol are used only for prophylactic therapy of angina; they are of no value in an acute attack.  Effective in preventing exercise-induced angina.  But are ineffective against the vasospastic form.  Cardioselective β-blockers, such as metoprolol or atenolol, are preferred. Thus, Propranolol is not preferred.  Agents with intrinsic sympathomimetic activity (for example, pindolol) are less effective and should be avoided in angina. The dose should be gradually tapered off over 5 to 10 days to avoid rebound angina or hypertension. MECHANISM OF ACTION: Suppress the activation of the heart by blocking B1 receptors. I. Decrease the heart rate, resulting in: 1) Decreased myocardial oxygen demand. 2) Increased oxygen delivery to the heart. II. Decrease myocardial contractility, helping to conserve energy/ decrease demand. III. Reduce the work of the heart by decreasing COP and causing a slight decrease in BP  ↓ HR,  ↓ contractility,  ↓ systolic wall tension,  ↑ perfusion time Reasons for Using Nitrates and β-Blockers in Combination in Angina:  β-Blockers prevent reflex tachycardia and contractility produced by nitrate- induced hypotension.  Nitrates prevent any coronary vasospasm produced by β- Blockers.  Nitrates prevent increases in left ventricular filling pressure or preload resulting from the negative inotropic effects produced by β-Blockers.