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
9/18/2018
MEDC 604 Anti-anginals

2. 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

3. Nitrovasodilators
9/18/2018
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.
9/18/2018
MEDC 604 Anti-anginals

5. 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

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

7. 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

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

9. 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

10. 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

11. 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

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
9/18/2018
MEDC 604 Anti-anginals