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 9/18/2018 MEDC 604 Anti-anginals

Angina Pectoris Development of Angina QRS Complex ST Segment PR Segment QT Interval PR Interval 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) 9/18/2018 MEDC 604 Anti-anginals

Nitrovasodilators 9/18/2018 MEDC 604 Anti-anginals

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. 9/18/2018 MEDC 604 Anti-anginals

Duration of Action (min) Pharmacokinetics of Nitrate Esters 330 20 Pentaerythritol tetranitrate 180 15 Erythrityl tetranitrate Active 60 3 Isosorbide dinitrate 30 2 Nitroglycerin 1 0.25 Amyl nitrite Metabolites Duration of Action (min) Onset (min) 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!! 9/18/2018 MEDC 604 Anti-anginals

Biochemical Mechanism of Action Nitrate Ester NO Guanylate Cyclase 9/18/2018 MEDC 604 Anti-anginals

Mechanism of Action of __________!! Another less-known use of this drug is in the treatment of pulmonary arterial hypertension!! 9/18/2018 MEDC 604 Anti-anginals

Biochemical Mechanism of Action Nitrate Ester NO Guanylate Cyclase 9/18/2018 MEDC 604 Anti-anginals

Calcium channel blockers Types of Calcium Channel Blockers Dihydropyridines  Nifedipine and others Phenylalkylamines  Verapamil and Bepridil Benzothiazipines  Diltiazem Extensive hydroxylation to inactive species 9/18/2018 MEDC 604 Anti-anginals

Structure of Ca+2 channel blockers NOR: ~20% Active O-deMe gives inactive species Des-Ac gives ~50% 9/18/2018 MEDC 604 Anti-anginals

phenyl hydroxylations, inactive Protein Binding of Calcium Channels Blockers 24 h >90% Bepridil 6 h iv ~80% Diltiazem phenyl hydroxylations, 1 active <1% 3 h 95% Nicardipine phenyl hydroxylations, inactive >95% Amlodipine Metabolites Duration of Action Protein Binding 8 h 90% Verapamil desacetyl derivative, ~ 50 % active Extensive inactive metabolites N-demethyl derivative, ~ 20 % active 9/18/2018 MEDC 604 Anti-anginals

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 9/18/2018 MEDC 604 Anti-anginals