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

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

3. 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.

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

7. 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

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

10. 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

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

12. 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

13. 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%

14. 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

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

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

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

18. Adverse effects:
From % 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.

19. 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

20. 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.

21. 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 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.

22. 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.

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

24. 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

25. 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.

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

27. 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

28. 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.

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

30. Potassium-Channel Activators

31. 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

33. 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.