Angina pectoris and anti-anginal drugs Angina pectoris is a characteristic sudden, severe, pressing chest pain radiating to the neck, jaw, back, and

arms resulting from myocardial Ischemia, i.e. the coronary blood flow (which feed the heart) is insufficient

to meet the oxygen demands of the myocardium, leading to ischemia. This imbalance between oxygen

delivery and utilization may result either from the followings:

1-Narrowing of coronary blood vessels caused by atherosclerosis (coronary artery disease, CAD); This

results in effort angina , also known as classic angina; In effort angina, the imbalance occurs when the

myocardial oxygen requirement increases, especially during exercise, and coronary blood flow does not

increase proportionately. This is most common cause.

2- Transient spasm of localized portions of coronary blood vessels; This results in ( vasospastic or variant

angina ). Variant angina is also called Prinzmetal angina. so, oxygen delivery decreases as a result of

reversible coronary vasospasm.

* In some individuals, the ischemia is not always accompanied by pain, resulting in “silent” or “ambulatory”

ischemia.

* Unstable angina , an acute coronary syndrome , is said to be present when episodes of angina occur at rest

and when there is an increase in the severity, frequency, and duration of chest pain in patients with previously

stable angina.

In theory, the imbalance between oxygen delivery and myocardial oxygen demand can be corrected by

by increasing delivery (by increasing coronary flow) or by decreasing oxygen demand (by decreasing pre-

and after- load);

1- Increasing coronary delivery; The organic nitrates, e.g., nitroglycerin , are the mainstay of therapy for

the immediate relief of angina. Another group of vasodilators, the calcium channel blockers , are useful in

prophylaxis.

2- Decreasing myocardial oxygen demand; β-blockers , which are not vasodilators, are useful in

prophylaxis.

ORGANIC NITRATES

Organic nitrates (and nitrites) used in the treatment of angina pectoris are simple nitric and nitrous acid esters

of glycerol. They are effective in stable and unstable angina as well as in variant angina pectoris.

Mechanism of action

Organic nitrates, such as nitroglycerin, which is also known as glyceryl trinitrate, relax vascular smooth

muscle by increasing intracellular nitrite ions which are converted to nitric oxide, which, in turn, activates

guanylate cyclase and increases the cells’ cyclic guanosine monophosphate (cGMP). Elevated cGMP

ultimately leads to dephosphorylation of the myosin light chain, resulting in vascular smooth muscle

relaxation. (Figure).

Nitrates inhibit coronary vasoconstriction or spasm, increasing perfusion of the myocardium and, thus,

relieving vasospastic angina. In addition, nitrates relax the veins (venodilation), decreasing preload (mainly

Intraventricular pressure), leading to decreasing myocardial oxygen consumption and, thus, relieving effort-

induced angina (classic angina).

Pharmacokinetics

Three drugs are most commonly used; nitroglycerin, isosorbide dinitrate, isosorbide mononitrate.

The time to onset of action varies from 1 minute for nitroglycerin to more than 1 hour for isosorbide mononitrate (Figure). Significant first-pass metabolism of nitroglycerin occurs in the liver. Therefore, it is common to take the drug either sublingually or via a transdermal patch, thereby avoiding this route of elimination. Isosorbide mononitrate owes its improved bioavailability and long duration of action to its stability against hepatic breakdown. Oral isosorbide dinitrate undergoes denitration to two mononitrates, both of which possess antianginal activity. Significant first-pass metabolism of isosorbide dinitrate also occurs in the liver necessitating sublingual administration.

Adverse effects

The most common adverse effect of nitroglycerin, as well as of the other nitrates, is headache. From 30 to 60 percent of patients receiving intermittent nitrate therapy with long-acting agents develop headaches. High doses of organic nitrates can also cause postural hypotension, facial flushing, and tachycardia.

Tolerance

Tolerance to the actions of nitrates develops rapidly (The mechanisms by which tolerance develops are not completely understood.). The blood vessels become desensitized to vasodilation. Tolerance can be overcome by providing a daily “nitrate-free interval” to restore sensitivity to the drug. This interval is typically 10 to 12 hours, usually at night, because demand on the heart is decreased at that time. Nitroglycerin patches are worn for 12 hours, then removed for 12 hours. Patients who continue to have angina despite nitrate therapy may benefit from addition of another class of agent especially calcium blockers.

β-ADRENERGIC BLOCKERS

The β-adrenergic–blocking agents lowering both the rate and the force of contraction of the heart, i.e. lowering the heart work and thus the myocardial demand for oxygen is reduced both during exertion and at rest. Because of these effects, β-blockers are the drugs of choice as prophylaxis in effort-induced angina. They reduce the frequency and severity of angina attacks. Propranolol is the prototype for this class of compounds, but it is not cardioselective. Thus, other β-blockers, such as metoprolol and atenolol, are preferred. [Remember: All β-blockers are nonselective at high doses and can inhibit β2 receptors. This is particularly important to remember in the case of asthmatic patients.]

- Agents with intrinsic sympathomimetic activity (for example, pindolol ) are less effective and should be avoided in angina.

-In patients with classic angina (effort-induced angina), β-blockers can be used with nitrates to increase exercise duration and tolerance.

-β-blockers are, however, contraindicated in patients with asthma, diabetes, severe bradycardia, peripheral

vascular disease, and chronic obstructive pulmonary disease.

-[Remember: It is important not to discontinue β-blocker therapy abruptly. The dose should be gradually tapered off over 2 to 3 weeks to avoid rebound angina, myocardial infarction, and hypertension].

CALCIUM-CHANNEL BLOCKERS

The calcium-channel blockers inhibit the entrance of calcium into the smooth muscle cells of the cardiac ,coronary and systemic arterial beds, so;

1- They reduce the force of cardiac muscle contraction (negative inotropic) thus reduce heart work and myocardial oxygen consumption.

2- They reduce afterload thus reduce heart work and myocardial oxygen consumption.

3- They increasing delivery (by increasing coronary flow). [Remember: Verapamil mainly affects the myocardium, whereas nifedipine exerts a greater effect on smooth muscle in the peripheral vasculature. Diltiazem is intermediate in its actions.]