ANGINA PECTORIS

The angina pectoris is a cardiovascular disease which denotes the chest pain caused by accumulation of metabolites resulting from myocardial ischemia. The angina pectoris is generated by the imbalance between the oxygen requirement of the heart and the oxygen supplied to it via the coronary vessels.

PATHOPHYSIOLOGY OF ANGINA:

• Determinants of Myocardial Oxygen Demand
• Determinants of Coronary Blood Flow &Myocardial Oxygen Supply
• Determinants of Vascular Tone

Determinants of Myocardial Oxygen Demand:

The requirement of myocardial oxygen increases when there is an increase in arterial pressure, contractility, or ventricular volume and heart rate. These hemodynamic alterations frequently occur during physical exercise and sympathetic discharge.

Determinants of Coronary Blood Flow &Myocardial Oxygen Supply:

            Increased demand for oxygen in the normal heart is met by augmenting coronary blood flow. The Coronary blood flow related to the duration of diastole and aortic diastolic pressure. Coronary blood flow is inversely proportional to coronary vascular resistance.

Determinants of Vascular Tone:

Arteriolar tone controls peripheral vascular resistance and arterial blood pressure. Venous tone will determines the venous circulation capacity and controls the amount of blood segregate in the venous system and the amount of blood returned to the heart. Venous tone thereby determines the diastolic wall stress.

The major drugs are nitro vasodilators, beta adrenergic receptor antagonists, Ca2+ channel antagonists, and in stable and unstable angina, antiplatelet agents as well as statins (HMG CoA-reductase inhibitors), which may have a role in stabilizing the vulnerable plaque.

DRUG ACTION IN ANGINA:

ORGANIC NITRATES:

Introduction:

Organic nitrates are prodrugs of nitric oxide (NO) derivatives. Nitric oxide activates the isoform of guanylyl cyclase, by increasing intracellular levels of cyclic GMP. This promotes the dephosphorylation of the myosin light chain and the reduction of Ca2+ and that leads to the relaxation of smooth muscle cells in a broad range of tissues. The relaxed nitric oxide dependent vascular smooth muscle leads to vasodilation. NO-mediated guanylyl cyclase activation inhibited the platelets aggregation and relaxes the smooth muscles in the bronchi and gastrointestinal (GI) tract.

Mechanism of Action:

Organic nitrates, Nitrites, and other nitrogen oxide-containing substances (including nitroprusside) lead to the formation of the reactive free radical NO. NO can activate guanylyl cyclase, increase the cellular level of cyclic GMP, activate PKG (the cyclic GMP-dependent protein kinase), and modulate the activities of cyclic nucleotide phosphodiesterases (PDEs 2, 3, and 5) in a variety of cell types. One important consequence of the NO-mediated increase in intracellular cyclic GMP is the activation of PKG, which catalyzes the phosphorylation of various proteins in smooth muscle. Another important target of this kinase is the myosin light-chain phosphatase, which is activated on binding PKG and leads to de-phosphorylation of the myosin chain and thereby promotes vaso-relaxation, Phosphorylation of the myosin light chain regulated the maintenance of the contractile state in smooth muscles. The pharmacological and biochemical effects of the nitro vasodilators appear to be identical to those of an endothelium-derived relaxing factor now known to be NO. Although the soluble isoform of guanylyl cyclase remains the most extensively characterized molecular "receptor" for NO, it is increasingly clear that NO also forms specific adducts with thiol groups in proteins and with reduced glutathione to form nitrosothiol compounds with distinctive biological properties. The enzyme mitochondrial aldehyde dehydrogenase has been shown to catalyze the reduction of nitroglycerin to yield bioactive NO metabolites providing a potentially important clue to the biotransformation of organic nitrates in intact tissues.

Toxicity & Tolerance:

The acute toxicity of organic nitrates is extensions of therapeutic vasodilation. Orthostatic hypotension, tachycardia, headache, Glaucoma.

Therapeutic Uses: Angina

CA2+ CHANNEL ANTAGONISTS:  

Mechanisms of Action:

An increased concentration of cytosolic Ca2+ causes increased contraction in cardiac and vascular smooth muscle cells. The entry of extracellular calcium is more important in the contraction of cardiac myocytes (Ca2+-induced Ca2+ release). The release of calcium ions from the intracellular storage sites contribute to the contraction of vascular smooth muscle, particularly in some vascular beds. Cytosolic Ca2+ concentrations may be increased by various contractile stimuli. Thus many hormones and neurohormones increase Ca2+ influx through so-called receptor-operated channels, whereas high external concentrations of K+ and depolarizing electrical stimuli increase Ca2+ influx through voltage-sensitive channels. The calcium ion channel antagonists produces their effects by binding to the alpha1 subunit of the L-type Ca2+ channels and reducing Ca2+ flux through the channel.

Toxicity and Untoward Responses:

 The most common adverse effects caused by the calcium channel antagonists are dizziness, headache, flushing, hypotension, digital dysesthesia, and nausea, some Patients may also get constipation, coughing, peripheral edema, somnolence, wheezing, and pulmonary edema, rash, and occasional minor elevations of liver function tests.

Therapeutic Uses: Variant Angina, Exertional Angina, Unstable Angina, Myocardial Infarction, as antiarrhythmic agents, hypertension, treatment of heart failure. Verapamil also has been used in the prophylaxis of migraine headaches.

BETA ADRENERGIC RECEPTOR ANTAGONISTS:  

These agents are effective in reducing the severity and frequency of attacks of exertional angina and it improves the survival in patients who have an MI. Most beta-adrenergic receptor antagonists are effective in the treatment of exertional angina. Timolol, atenolol, metoprolol, and propranolol have been shown to exert cardioprotective effects. The effectiveness of b adrenergic receptor antagonists in the treatment of exertional angina is attributable primarily to a fall in myocardial oxygen consumption at rest and during exertion, although there also is some tendency for increased flow toward ischemic regions. The decrease in myocardial oxygen consumption is due to a negative chronotropic effect (during exercise), a negative inotropic effect, and a reduction in arterial blood pressure during exercise. Not all actions of b adrenergic receptor antagonists are beneficial in all patients. The decreases in contractility and heart rate cause increases in the systolic ejection period and left ventricular end-diastolic volume; these alterations tend to increase O2 consumption.

Therapeutic Uses: Unstable Angina, Myocardial Infarction.

Angina pectoris, radiant angina, oxygen supply