University:
Michigan State University
Course:
PHM 813 | Cardiovascular Pharmacology and Toxicology
Academic year:

2021
Views:

332

Pages:

53
Author:

Dixie Summers

Drugs used in the treatment of Angina Pectoris Coronary Heart Disease (CHD) Coronary Heart Disease (CHD) or Coronary Artery Disease (CAD): also known as Ischemic heart disease (IHD), atherosclerotic heart disease. Atherosclerotic and cardiovascular disease; is a group of heart diseases that includes: stable angina, unstable angina, myocardial infarction, and sudden coronary death. Ischemic heart disease (IHD); is the most common cardiovascular disease in developed countries and angina pectoris is the most common condition involving tissue ischemia. The heart regulates the amount of vasodilation or vasoconstriction of the coronary arteries based upon the oxygen requirements of the heart (oxygen demand). Failure of oxygen delivery caused by a decrease in blood flow in front of increased oxygen demand of the heart results in tissue ischemia, a condition of oxygen deficiency. Brief ischemia is associated with intense chest pain, known as angina. Severe ischemia can cause the heart muscle to die from hypoxia, such as during a myocardial infarction. Angina Pectoris Angina, the term derives from the Latin angere “to strangle” and pectus “chest”, and can therefore be translated as “ a strangling feeling in the chest”, commonly known as angina. Definition; Chest pain caused by transient myocardial ischemia due to an imbalance between myocardial oxygen supply and oxygen demand. Angina is not a disease. It is a symptom of an underlying heart problem and is usually a symptom of coronary heart disease (CHD). Angina pectoris Angina pectoris refers to sudden, severe, pressing chest pain radiating to the neck, jaw, back, and arms caused by cardiac ischemia Other symptoms: Nausea, fatigue, shortness of breath, sweating and dizziness Occurs due to an imbalance in the myocardial oxygen supplydemand relationship caused by: ✓ An increase in myocardial oxygen demand (determined by heart rate, ventricular contractility, and ventricular wall tension) ✓ A decrease in myocardial oxygen supply (primarily determined by coronary blood flow) ✓ Both Heart Rate Contractility Preload Afterload Oxygen Oxygen = demand supply > ischemia Coronary blood flow Regional myocardial blood flow Angina Risk Factors ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ ➢ Coronary heart disease Family history of heart disease Unhealthy cholesterol levels Unhealthy diet (high fat and high salt) Smoking Diabetes Inactivity High blood pressure Overweight or obesity Stressful lifestyle Menopause Age (Men>45 years- Women >55 years) Types of angina 1. Atherosclerotic or typical angina • The most common form of angina • Caused by the reduction of coronary blood flow produced by coronary atherosclerosis • Symptoms of angina occurs when myocardial oxygen demand increases, as with physical activity, emotional excitement, or any other cause of increased cardiac workload 2. Unstable angina or acute coronary syndrome • It lies between stable angina on the one hand and myocardial infarction on the other • Characterized by pain with increased frequency that occurs with less and less exertion, culminating in pain at rest • Cause: abrupt reduction in blood flow, as might result from coronary thrombosis or rupture of an atherosclerotic plaque, with consequent platelet adhesion and aggregation • Requires hospital admission and more aggressive therapy to prevent death and progression to MI 3. Vasospastic or variant angina: • Occurs at rest, even during sleeping and is due to vasospasm of large epicardial coronary vessels or one of their major branches • Symptoms are caused by decreased blood flow to the heart muscles Therapeutic objectives The major therapeutic goals are aimed at: ✓ Slow the progression of the disease;Terminating or preventing an acute attack and reduce the possibility of future events, especially myocardial infarction (MI) and future death. ✓ Relieve the symptoms; Increasing the patient’s exercise capacity Can be achieved by: ✓ Reducing overall myocardial oxygen demand (Ꞵ- Adrenergic receptor antagonist) ✓ Increasing oxygen supply to ischemic areas (Nitrates and Ca channel blockers) ✓ Lifestyle modification ✓ Treat coronary artery disease (Decrease bad cholesterol level (LDL) and surgical procedures e.g., angioplasty) Therapeutic objectives • Reducing myocardial O2 demand can be achieved by decreasing heart rate/ myocardial contractility, reducing preload/cardiac filling, reducing afterload/ arterial pressure, & by shifting myocardial metabolism to substrates that require less oxygen per unit of adenosine triphosphate (ATP) produced • Increasing O2 supply can be achieved by dilating the coronary vasculature Therapeutic objectives • Drugs used in typical angina function principally by reducing myocardial O2 demand by decreasing heart rate, myocardial contractility, and/or ventricular wall stress • The principal therapeutic aim in variant angina is to prevent coronary vasospasm by nitrate or calcium channel-blocking vasodilators Therapeutic objectives • In unstable angina, vigorous measures are taken to achieve both—increase oxygen delivery and decrease oxygen demand • strategies include the use of antiplatelet agents and heparin to reduce intracoronary thrombosis, often accompanied by efforts to restore flow by mechanical means, including percutaneous coronary interventions using coronary stents, or (less commonly) emergency coronary bypass surgery Classification of treatments Lifestyle modifications Stop smoking Reduce weight Treat hypertension Treat hypercholesterolemia and diabetes Drug treatment Four types of drugs, used either alone or in combination, are commonly used to manage patients with stable angina Antiplatelet therapy and lipid-lowering therapy are needed to prevent clot formation and decrease atherosclerosis plaque formation Antianginal drugs, such as, nitrates, calcium channel blockers (CCBs), -blocking drugs, and others new anti-anginal drugs….) Coronary artery revascularization Organic Nitrates Agents: Nitroglycerine (NotromAck®), Isosorbide Mononitrate (Effox®), Isosorbide Dinitrate (Isordil®), and Amyl Nitrate Nitroglycerin (Glyceryl Trinitrate; GTN) is the prototype of these groups. Organic Nitrates Nitrates are available as oral tablets, transdermal patches, sublingual tablets, and intravenous infusion Nitrates exert their effect by intracellular conversion to nitric oxide (NO) NO activates guanylate cyclase and increases the cells' cyclic guanosine monophosphate (cGMP), which leads smooth muscle relaxation by dephosphorylation of myosin light chain phosphate ❑ Depletion of SH group----→ Lead to nitrate tolerance ❑ Sildenafil; is selective inhibitors of Phosphodiesterase type 5 (PDE-5) which is responsible for degradation of cGMP into GMP-→ accumulation of cGMP→vasodilatation of penis-→ Erection Organic Nitrates/Pharmacokinetic Time to peak effect and duration of action for some common organic nitrate preparations Onset of action Duration of action Key: Isosorbide dinitrate Nitroglycerin Sublingual tablet or spray 2 min 25 min Oral, sustainedrelease 35 min 4-8 hrs Transdermal 30 min 8-14 hrs 5 min 1hr Sublingual Oral, slowrelease 30 min 8 hrs Isosorbide mononitrate Oral, extendedrelease 30 min 12 hrs Organic Nitrates/Pharmacokinetic ❑Nitroglyerine: ❑ Rapid onset of action (2-5 mins) ❑ Maximal effect observed at 3 to 10 minutes ❑ Short half-life (1-3 mins) ❑ Significant first-pass metabolism (F < 10-20%) ❑ Commonly administered either sublingually, transdermal patch ❑ Isosorbide IV or via a mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown ❑ Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity Organic Nitrates/Pharmacokinetic Amyl nitrite and related nitrites: are highly volatile liquids. Amyl nitrite is available in fragile glass ampules packaged in a protective cloth covering. The ampule can be crushed with the fingers, resulting in rapid release of vapors inhalable through the cloth covering. The inhalation route provides very rapid absorption and, like the sublingual route, avoids the hepatic first-pass effect. Because of its unpleasant odor and short duration of action, amyl nitrite is now obsolete for angina Pharmaceutical preparation Nitroglycerin ❑ Sublingual nitroglycerin: is the most frequently used agent for the immediate treatment of angina b/c of its rapid onset of action (1–3 minutes). Because its duration of action is short (not exceeding 20–30 minutes), it is not suitable for maintenance therapy (Short acting/Acute attacks) ❑ IV nitroglycerine: has a rapid onset of action of intravenous nitroglycerin (minutes), but its hemodynamic effects are quickly reversed when the infusion is stopped. Clinical application of intravenous nitroglycerin is therefore restricted to the treatment of severe, recurrent rest angina (Short acting/Acute attacks) ❑ Slowly absorbed preparations of nitroglycerin: such as buccal form, oral preparations, and several transdermal forms have been shown to provide blood concentrations for long periods but, this leads to the development of tolerance (Long acting/ Angina prophlaxis) Pharmacological action Nitrovasodilators relaxes all types of smooth muscle and promote vascular smooth muscle relaxation. It has no direct effect on cardiac or skeletal muscle. Nitrated cause dilation of veins predominates over that of arterioles. This result in marked relaxation of veins with increased venous capacitance, decreased venous return to the heart (reduce preload), and reduces the work of the heart (decreases myocardial oxygen consumption)……This is believed to be their main mechanism of action in the treatment of angina Pharmacological action Because methemoglobin has a very low affinity for oxygen, large doses of nitrites can result in pseudocyanosis, tissue hypoxia, and death The plasma level of nitrite resulting from even large doses of organic and inorganic nitrates is too low to cause significant methemoglobinemia in adults Vasodilation related Adverse effects ❑ Orthostatic hypotension (dizziness and syncope) ❑ Tachycardia ❑ Throbbing headache (Cerebral vasodilation) ❑ Reflux tachycardia ❑ Facial flushing ❑ Nitrate edema (Pulmonary edema) -→Due to vasodilation which increase permeability of blood vessels -→ Due to increase Angiotensin II which increases aldosterone hormone (Na and water retention) Sildenafil potentiates the action of the nitrates. To preclude the dangerous hypotension and inadequate perfusion of critical organs that may occur, this combination is contraindicated Nitrate tolerance ❑ Repeated and frequent exposure to organic nitrates is accompanied by the development of tissue tolerance: the blood vessels become desensitized to the vasodilating action of nitrates ❑ The magnitude of tolerance is a function of dosage and frequency of use Nitrate Tolerance Hpothesis Depletion of SH group Excessive generation of free radicals Dysfunction of endothelial nitric oxide synthase (NOS) Decrease sensitivity of guanylate cyclase Activation of renin-angiotensin-aldosterone axis Avoid of tolerance Monday Syndrom Beneficial and deleterious effects of nitrates in treatment of angina Beta-blockers β-blockers are the Drug of choice to treat exercise-induced angina, but are ineffective and should not be used against vasospastic angina Calcium channel blockers Binding of the drug results in a marked decrease in transmembrane calcium current. In smooth muscle which in turn results with a long-lasting relaxation In the vascular system, arterioles appear to be more sensitive than veins. Therefore, orthostatic hypotension is not a common adverse effect In cardiac muscle with a reduction in contractility throughout the heart and decreases in sinus node pacemaker rate and AV node conduction velocity CCBs are vasodilators and effective in both effort angina (reduction in myocardial oxygen consumption) and vasospastic angina (relaxation of coronary arteries) Calcium channel blockers Important differences between the available CCBs arise from the differences in their relative smooth muscle versus cardiac effects 1. Diphenylalkylamines (e.g.Verapamil): is the least selective and has significant effects on both cardiac and vascular smooth muscle cells 2. Benzothiazepines (e.g. diltiazem): it affects both cardiac and vascular smooth muscle cells; however, it has a less pronounced negative inotropic effect on the heart compared to that of verapamil. 1 and 2 called Non- Dihydropyridines 3. Dihydropyridines: nifedipine, amlodipine, felodipine, isradipine ,nicardipine , and nisoldipine. They have a much greater affinity for vascular calcium channels than for calcium channels in the heart Calcium channel blockers Organ system effects All the Ca2+ channel blockers approved for clinical use decrease coronary vascular resistance and increase coronary blood flow The dihydropyridines (e.g. nifedipine) are more potent vasodilators and have a greater ratio of vascular smooth muscle effects relative to cardiac effects than do diltiazem and verapamil The dihydropyridines may cause reflex tachycardia if peripheral vasodilation is marked The non-dihydropyridines Verapamil and diltiazem reduce cardiac contractility & oxygen requirement in a dose-dependent fashion Mechanisms of clinical effects Angina of Effort ❑ The beneficial effect is decrease in O2 demand and increase in coronary flow Variant angina ❑ The beneficial effect is to relieve and prevent the focal coronary artery spasm involved in variant angina ❑ Use of these agents has thus emerged as the most effective prophylactic treatment for this form of angina pectoris Calcium channel blockers Adverse effects ✓ Excessive inhibition of calcium influx can cause serious cardiac depression, including cardiac arrest, bradycardia, atrioventricular block, and heart failure (rare effects) ✓ Minor toxicities include flushing, dizziness, nausea, constipation, and peripheral edema ✓ Constipation is particularly common with verapamil ✓ Patients receiving β-blocking drugs are more sensitive to the cardio-depressant effects of calcium channel blockers Newer Antianginal Drugs Sodium channel blocker: Ranolazine Ranolazine is a newer anti-anginal drug, classified as Na channel blocker. It is indicated for the treatment of chronic angina, and may be used alone or in combination with other traditional therapies Mechanism of Action: ➢ It reduces contractility resulting from the blockade of a late sodium current (late INa) in myocardial cells that facilitates calcium entry via the sodium-calcium exchanger ➢ The decrease in intracellular sodium causes and increase in calcium expulsion via the Na-Ca+2 exchanger Adverse Drug Effect: ➢ The most common ADRs are constipation, nausea, and weakness Ranolazine: Mechanism of action Metabolic modulation (pFOX): Trimetazidine Trimetazidine: Is a first cytoprotective anti-ischemic agent. Is clinically effective anti-anginal agent that has no negative inotropic or vasodilator properties. Mechanism of Action: ➢ Trimetazidine is metabolic modulator that does not reduce oxygen demand or increase blood supply ➢ It act by shifting myocardial metabolism to substrates that require less oxygen per unit of ATP produced Metabolic modulation (pFOX): Trimetazidine • • Myocytes O2 requirement of glucose pathway is lower than FFA pathway During ischemia, oxidized FFA levels rise, blunting the glucose pathway Glucose FFA Acyl-CoA Pyruvate β-oxidation Trimetazidine Adverse Drug Effect: ➢ GIT disturbance, dizziness, and headache. ➢ Trimetazidine use can result in movement disorders such as parkinsonian symptoms (tremor, akinesia, hypertonia), gait instability, and restless legs Acetyl-CoA Energy for contraction pFOX = partial fatty acid oxidation FFA = free fatty acid Contraindications: Parkinson disease and sever renal impairment (creatinine clearance <30 ml/min.) Nicorandil Nicorandil is a new organic nitrate with vasodilator properties. It is an anti-anginal drug that has the dual properties of a nitrate and potassium channel activators. Mechanism of Action: a) K channel opener: It opens ATP-sensitive K+ channels, causing K efflux. This hyperpolarizes the cell, which inactivates voltage-gated calcium channels and reduce free intracellular Ca; thereby causing dilatation of peripheral and coronary resistant arterioles b) Nitrate: It contains an NO2-moiety, it stimulates guanylate cyclase to increase formation of cyclic GMP, decreasing the calcium influx, leads to smooth muscle vasodilation-→which dilates systemic veins and epicardial coronary arteries Most common adverse drug effect: Headache, dizziness, flushing and reflex tachycardia Ivabradine It is indicated for the symptomatic treatment of chronic stable angina pectoris Mechanism of action: Ivabradine is the first selective sinus node If channel inhibitor, slowing the heart rate and allowing more time for blood to flow to the myocardium, decreasing the myocardial oxygen demand without effect on inotropic or blood pressure. Heart rate is determined by spontaneous electrical pacemaker activity in the sinoatrial (SA) node controlled by the If current (If channel, f for “funny”) Most common adverse effect: Luminous phenomena or phosphenes (seeing light without light actually entering the eye; visual “flashing lights” which are usually only mild to moderate in intensity and transient ), dizziness and/or blurred vision. Coronary artery revascularization Coronary artery revascularization Coronary artery revascularization Strategy of treatment of angina

Drugs Used in the Treatment of Angina Pectoris

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