Antianginal Drugs Ass. Prof. Naza M. Ali Lec 3-4 G2 21 April 2019

Objective and Outlines Definition and types of angina Drugs used in Angina Mechanism of antianginal drugs Newer Anti-anginal drug

Angina Pectoris: Refers to a strangling or pressure –like pain caused by cardiac ischemia. Due to imbalance between the oxygen requirement of the heart & the oxygen supply to it.

Drugs used in angina exploit two main strategies: Reduction of oxygen demand 2. Increase of the oxygen delivery to the myocardium

Types of Angina: 1. Atherosclerotic angina (classic angina or angina of effort) 2. Vasospastic angina ( Prinzmetal΄s , Variant angina) occur at rest caused by coronary artery spasm 3. Unstable angina it is thought to be the immediate precursor of MI

Drugs used in Angina: Nitrates and Nitrites β-adrenergic blocking agents Calcium-Channel blockers Potassium-Channel Activators 5. Newer antianginal drugs

1. Nitrates and Nitrites Mechanism of action Denitration of the nitrates within smooth muscle cells releases nitric oxide NO Which stimulates guanyly cyclase and increase cGMP This cGMP lead to smooth muscle relaxation by dephosphoylation of myosin light chain phosphate

Effects of nitrates and nitrites on smooth muscle. cGMP = cyclic guanosine 3', 5'-monophosphate.

Effects on the CVS Nitroglycerin has 2 major effect: First It causes dilation of the large veins, Resulting in pooling of blood in the veins. This diminishes preload &reduces the work of the heart. Second Nitroglycerin dilates the coronary vasculature providing an increased blood supply to heart muscle

Classification and Pharmacokinetics Nitrates differ in their onset of action and rate of elimination Nitroglycerin ( glyceryl trinitrate) Is rapidly denitrated in the liver & in smooth muscle First to glyceryl dinitrate which retain a significant vasodilating effect Then more slowly to mononitrate which is much less active First –pass effect for nitroglycerin is 90%

Nitrates according to their half-life 1.Short duration: Sublingual/ rapid onset of action 2. Intermediate duration: Oral, Sustained Release 3. Long duration / transdermal patch

Types I. Nitroglycerin ( glyceryl trinitrate) II. Isosorbide dinitrate (oral ,sublingual) III. Isosorbide mononitrate (oral ) IV. Amyl nitrite is a volatile by inhalation

Time to peak effect & duration of action for some common nitrate

For relief of an ongoing attack of angina due to exercise or emotional stress, sublingual (or spray form) nitroglycerin is the drug of choice.

Adverse effects: From 30 -60% of patients receiving intermittent nitrate therapy with long-acting agents develop throbbing headaches. High doses of organic nitrates can also cause postural hypotension, facial flushing, and tachycardia. Monday disease Phosphodiesterase V inhibitors like sildenafil potentiate action of nitrates.

Nitrates interact with sildenafil and similar drugs promoted for erectile dysfunction. These agents inhibit PDE5 enzyme that metabolizes cGMP in smooth muscle The increased cGMP in erectile smooth muscle relaxes it , allowing for greater inflow of blood and more effective This effect also occurs in vascular smooth muscle

As a result , the combination of nitrates ( increased production of cGMP ) and PDE5 inhibitors ( decreased breakdown of cGMP) causes a synergistic relaxation of vascular smooth muscle with potentially dangerous hypotension. Nitrites cause methemoglbinemia at high blood concetrations but Nitrates not.

The blood vessels become desensitized to vasodilation. Tolerance 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 10 - 12 h , 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. Variant angina worsens early in the morning, due to circadian catecholamine surges.

2. The β-adrenergic–blocking agents decrease the oxygen demands of the myocardium by lowering both rate & force of contraction of heart. by blocking of β1 receptors, reduce the work of the heart , decreasing heart rate, contractility, COP & BP So the demand for oxygen by the myocardium is reduced both during exertion and at rest.

β-blockers are the drugs of choice to treat effort- induced angina. Are ineffective against in vasospastic angina. Metoprolol , Atenolol, are preferred

Agents with intrinsic sympathomimetic activity Pindolol are less effective & should be avoided in angina. In patients with classic angina , β-blockers can be used with nitrates

3. Calcium -Channel Blockers Amlodipine , Felodipine , Nifidipine, Verapamil, Diltiazem Calcium is essential for muscular contraction. All calcium-channel blockers are, arteriolar vasodilators that cause a decrease in smooth muscle tone and vascular resistance.

Amlodipine and Nifedipine Arteriolar vasodilator. useful in the treatment of variant angina caused by spontaneous coronary spasm.

Verapamil Verapamil affects the myocardium Slows AV conduction directly decreases heart rate, contractility, BP , and oxygen demand. Verapamil causes greater negative inotropic effects than nifedipine

Diltiazem Diltiazem can relieve coronary artery spasm is useful in patients with variant angina. Verapamil mainly affects the myocardium, whereas amlodipine exerts a greater effect on smooth muscle in the peripheral vasculature. Diltiazem is intermediate in its actions.

4. Potassium-Channel Activators Nicorandil Combines the activation of the potassium channel with nitric oxide action It is both arterial and a venous dilator

Potassium-Channel Activators

5. Newer Anti-Anginal Drug Ranolazine Inhibits the late phase of the sodium current INa Reduces calcium entry, so reduce contractility Approve for use in USA for chronic angina

Ivabradine The first sinus node inhibitor to be marketed. This agent inhibits the If channel and slows the heart rate by closing the If channel, thus delaying depolarisation and sinus node activation.