CARDIOVASCULAR AGENTS

Contents

• Description of Cardiovascular agents

• Anti-angina agents – Coronary artery diseases

• Intermediary myocardial metabolism

• Ischemic glucose metabolism

• Nitrovasodilators - Smooth muscle Contraction/relaxation

• Mode of action of nitrovasodilators

• Metabolism of nitrovasodilators

• Study of individual compounds

Learning Objectives

At the end of this lecture, student will be able to

• Describe various cardiovascular diseases

• Discuss intermediary myocardial metabolism and ischemic glucose metabolism

• Explain the mode of action of nitrovasodilators

• Discuss the metabolism of nitrovasodilators

• Emphasize the utility of nitrovasodilators in curing angina pectoris

Cardiovascular Agents

• Cardiovascular agents (drugs) are used for their action on the heart or other parts of the vascular system, to modify the total output of the heart or the distribution of blood to the circulatory system

• These drugs are employed in the treatment of

v  Angina

v  Cardiac arrhythmias

v  Hypertension

v  Hyperlipidemias and

v  Disorders of blood coagulation

THERAPY FOR ANGINA

• Pharmacological therapy to prevent myocardial infarction and death is with antiplatelet agents (aspirin, clopidogrel) and lipid lowering agents. Recently, angiotensin-converting enzyme (ACE) inhibitors have also reported to reduce the risk from coronary artery disease. In unstable angina and non-STsegment elevation myocardial infarction, and in coronary stenting, antilipid drugs, heparin, and antiplatelet agents are recommended.

• Angina of effort: For therapy of chronic stable angina, long-acting nitrates, calcium channel blockers, or β blockers are chosen. The combination therapy has shown to be more effective than individual drugs used alone.

• Vasospastic angina: Nitrites and calcium channel blockers are effective drugs for reducing and preventing ischaemic episodes in patients with variant angina. In approximately 70% of the patients treated with nitrites or calcium channel blockers, angina attacks are completely abolished.

• Unstable and acute coronary syndromes: In patients with unstable angina with recurrent ischaemic episodes at rest, recurrent thrombotic occlusions of the offending coronary artery occur as the result of fi ssuring of atherosclerotic plagues and platelet aggregation. Anticoagulant and antiplatelet drugs play an important role in these cases.

Nitrites and Nitrates

• Mode of action: These types of drugs are rapidly denitrated enzymatically in the smooth cells to release the reactive free radical nitric oxide (NO), which activates cytostolic guanyl cyclase and increases the cyclic guanosine mono phosphate (cGMP) that causes dephosphorylation of myosin light chain kinase (MLCK) through cGMP dependent protein kinase.

• The reduction in phosphorylated MLCK interferes with myosin and fails to cause contraction. Relaxation also occurs due to reduced Ca2+ entry.

Calcium channel blockers

• Mode of action: Calcium channel blockers act on the Ca2+ channel receptors, block the release of calcium, and, therefore, the calcium interaction with a protein calmodulin to form calcium calmodulin complex is decreased. This leads to the decreased activation of myosin light chain phosphorylation, which promotes muscle contraction by interacting between actin and myosin.

SAR of Dihydropyridines

• 1, 4-Dihydro pyridine ring is essential for activity. Substitution at N or oxidation or reduction of the ring reduces or abolishes the activity.

• A phenyl substitution at the 4th position is optimum for the activity. Substitution at para or unsubstituted phenyl ring reduces the activity.

• The 3rd and 5th position ester group optimizes activity. Placement of electron withdrawing substitution results in agonistic activity.

• When the ester at C3 and C5 are nonidentical, the C4 become chiral and stereo selectivity is observed.

• S-enantiomers found to be more effective

Nitro glycerine

Synthesis of Nitro glycerine

Properties and Use of Nitro glycerine:

• It is a colourless, odourless liquid with a sweet taste.

• Glyceryl trinitrate is the trinitrate ester of glycerol.

• Nitroglycerine is used in angina pectoris and extensively as an explosive in dynamite.

• A solution of the ester, if spilled or allowed to evaporate, will leave a residue of nitroglycerine.

• To prevent an explosion of the residue, the ester must be decomposed by addition of alkali.

• Even then the material dispensed is so dilute that the risk of explosions does not exist.

Isosorbide dinitrite

Synthesis of Isosorbide dinitrite

Properties and Uses: it is a fine white crystalline powder, slightly soluble in water, well soluble in acetonr, but sparingly soluble in alcohol.

It is effective in the treatment of acute angina attack.