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Anti-Anginal Agents

Anti-Anginal Agents. Angina Disease, symptoms Types of Anti-anginal Agents Nitrovasodilators, calcium channel blockers and b -blockers Nitrovasodilators Structure, physical properties, biochemical mechanism of action, metabolism and pharmacokinetics Calcium channel blockers

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Anti-Anginal Agents

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  1. Anti-Anginal Agents • Angina Disease, symptoms • Types of Anti-anginal Agents Nitrovasodilators, calcium channel blockers and b-blockers • Nitrovasodilators Structure, physical properties, biochemical mechanism of action, metabolism and pharmacokinetics • Calcium channel blockers Types, structure, physical properties, biochemical mechanism of action • Adverse Effects/Reactions MEDC 604 Anti-anginals

  2. QRS Complex PR Segment ST Segment PR Interval QT Interval Angina Pectoris • Development of Angina • Angina is a Symptom, not a disease • Types of Angina • Stable Angina (typical, atherosclerotic; exertional) • Unstable Angina (pre-infarction; at rest) • Variant Angina (transient vasospasmatic) MEDC 604 Anti-anginals

  3. Nitrovasodilators MEDC 604 Anti-anginals

  4. Structure Nitrate Esters • Some nitrate esters are wrongly named, e.g., amylnitrite is actually isoamylnitrite, nitroglycerin is not a nitro compound • Nitrate esters are susceptible to hydrolysis! Shelf life is a concern. MEDC 604 Anti-anginals

  5. Onset (min) Duration of Action (min) Metabolites Amyl nitrite 0.25 1 Nitroglycerin 2 30 3 60 Active Isosorbide dinitrate Erythrityl tetranitrate 15 180 Pentaerythritol tetranitrate 20 330 Pharmacokinetics of Nitrate Esters • Nitrate esters act fast! Think about the size of these molecules. • They are rapidly metabolized in the liver (glutathione-nitrate reductase). Yet, can be used in oral prophylactic therapy, especially ISDN, ETN and PETN • Number of nitrate groups does not linearly correspond to potency • Nitrate esters and possibility of explosion! • Nitrovasodilators decrease the blood pressure of patients!! MEDC 604 Anti-anginals

  6. Nitrate Ester NO Guanylate Cyclase Biochemical Mechanism of Action MEDC 604 Anti-anginals

  7. Mechanism of Action of __________!! • Another less-known use of this drug is in the treatment of pulmonary arterial hypertension!! MEDC 604 Anti-anginals

  8. Nitrate Ester NO Guanylate Cyclase Biochemical Mechanism of Action MEDC 604 Anti-anginals

  9. Extensive hydroxylation to inactive species Calcium channel blockers • Types of Calcium Channel Blockers • Dihydropyridines  Nifedipine and others • Phenylalkylamines  Verapamil and Bepridil • Benzothiazipines  Diltiazem MEDC 604 Anti-anginals

  10. NOR: ~20% Active O-deMe gives inactive species Des-Ac gives ~50% Structure of Ca+2 channel blockers MEDC 604 Anti-anginals

  11. Protein Binding Duration of Action Metabolites Amlodipine >95% 24 h phenyl hydroxylations, inactive Nicardipine 95% 3 h phenyl hydroxylations, 1 active <1% Diltiazem ~80% 6 h iv desacetyl derivative, ~ 50 % active Bepridil Extensive inactive metabolites >90% 24 h Verapamil 90% 8 h N-demethyl derivative, ~ 20 % active Protein Binding of Calcium Channels Blockers MEDC 604 Anti-anginals

  12. Adverse Effects of Calcium Channel Blockers • Development of Arryhthmia …Bepridil induces new arrhythmias • Hypotension … vasodilation’s side-effect; especially with nitrovasodilators • Rebound angina … sudden stoppage of drug induces flow of Ca2+ into cells causing coronary arteries to spasm • Metabolism by liver … use with caution in patients with hepatic dysfunction • Mild to moderate edema … due to vasodilation MEDC 604 Anti-anginals

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