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.