ANTI – ANGINAL DRUGS 7.7.23.pptx nitrates

classification, drugs used and ADR

1. ANTI – ANGINAL DRUGS NITRATES AND CALCIUM CHANNEL BLOCKERS Dr. S.Santhosh Post - Graduate

2. OVERVIEW It is the chest pain caused due to inadequate blood flow to the heart muscles. Anginal pain is often described as squeezing, pressure, heaviness, tightness or pain in the chest.

3. ANTIANGINAL DRUGS Classified into Drugs used to terminate the attack. (Isosorbide dinitrate) Drugs used for chronic prophylaxis. (All other drugs)

4. NITRATES Short acting Glyceryl trinitrate Isosorbide dinitrate Long acting Isosorbide mononitrate Erythrityl tetranitrate Pentaerythritol tertranitrate The major action is non – specific smooth muscle relaxation.

5. MECHANISM OF ACTION

6. PHARMACOLOGICAL ACTIONS Preload reduction: dilate veins more than arteries – peripheral pooling of blood – decreased venous return – reduction in preload. this reduction in preload reduces end diastolic volume and pressure. this reduces the ventricular radius and thus the O 2 needed is reduced. Thus subendocardial crunch is abolished by restoring the pressure gradient across the ventricular wall which ensures subendocardial perfusion during diastole.

7. Afterload reduction: some extent of arteriolar dilatation seen – reduces the total peripheral resistance – decrease in systolic and diastolic BP – reduction in cardiac work.

8. Redistribution of coronary flow: nitrates preferentially relax bigger coronary arteries. favor by redistribution of blood to ischemic areas. The blood flow to ischemic areas increased by autoregulatory function of ischemic resistance vessels improving the ischemia. The resistance vessels in other areas maintain their tone compensating for the blood flow to the ischemic zone.

9. Role in angina: relaxation of larger coronary vessels. reduction in cardiac work by action on peripheral vessels.

10. Heart and peripheral blood flow: no direst stimulant or depressive effect on heart. dilate cutaneous vessels over face and neck dilate meningeal vessels Splanchnic and renal blood flow reduced to compensate vasodilatation in other regions.

11. Smooth muscles: relaxation of bronchi, biliary tract, and esophagus.

12. PHARMACOKINETICS Well absorbed from buccal mucosa, intestines and skin. Undergo extensive first pass metabolism. Denitrated by glutathione reductase and mitochondrial aldehyde dehydrogenase.

13. GLYCERYL TERTRANITRATE Sublingual route is used to terminate or abort an attack. Tablet may be crushed under the teeth and spread over buccal mucosa for absorption. Acts within 1 – 2 mins. Plasma half – life is 2 min. When anginal pain is relieved the remaining tablet may be spit out.

14. Other formulations: Spray: recently being marketed. Acts rapidly. Transdermal patch: provides steady drug delivery for 24 hrs. bioavailability is around 70 – 90 percent. can be taken off for 8 – 10 hrs daily to overcome tolerance and provide drug free intervals. Intravenous infusion: provides steady titrable concentrations in blood. used in unstable angina, coronary vasospasm, LVF, hypertension during cardiac surgery.

15. ISOSORBIDE DINITRATE Used sublingually at the time of the attack. Plasma half life is 40 mins. Sustained release formulation may afford relief for 6 – 10 hrs. Last dose should be taken before 6 pm to give drug free interval to avoid tolerance.

16. ISOSORBIDE MONONITRATE Longer acting Half life 4 – 6 hrs.

17. ERYTHRITYL TETRANITRATE & PENTAERYTHRITOL TERTRANITRATE Longer acting. SR formulations available for twice or thrice daily dosing. Duration of action – 4 – 6 hrs

18. USES Angina pectoris: increase exercise tolerance and postpone ECG changes of ischemia. Acute coronary syndrome: useful in reducing preload increase coronary flow sublingual GTN given; i.v infusion started if pain persists.

19. Myocardial infarction: relieves chest pain. diverts blood to ischemic zone. reduces pulmonary congestion. contraindicated if systolic BP: <90mmHg HR <50 or >100 bpm right ventricular infarction if patient has taken Sildenafil in the past 24 hrs.

20. CHF and LVF: favor by venous pooling of blood. this ion turn reduced the venous return, preload, decreased end diastolic volume, improvement in left ventricular function. Biliary colic: Esophageal spasm: when taken before meal, they facilitate feeding in esophageal achalasia.

21. Cyanide poisoning: generate methemoglobin which hash high affinity for cyanide radical.

22. TOLERANCE Reactive oxygen species formed during denitration of organic nitrates themselves inhibit mitochondrial aldehyde dehydrogenase interferes with NO production. Activation of compensatory mechanisms like volume expansion, sympathetic and renin – angiotensin system lead to nitrate tolerance. Can be overcome by providing drug free intervals everyday as tolerance is reversible in hours. In extreme cases drugs of other class may be given.

23. INTERACTIONS Combination of sildenafil and other PDE5 inhibitors with organic nitrate vasodilators can cause extreme hypotension PDE5 inhibitors are contraindicated for patients taking organic nitrate vasodilators, and the PDE5 inhibitors should be used with caution in patients taking α- or β blockers PDE5 inhibitors and nitrates act synergistically to cause profound increases in cGMP and dramatic reductions in blood pressure >25 mm Hg No PDE5 inhibitor should be used in the 24 h prior to initiating nitrate therapy

24. CALCIUM CHANNEL BLOCKERS Phenyl alkylamine (Verapamil) Benzothiazepine (Diltiazem) Dihydropyridines (Nifedipine, Felodipine, Amlodipine, Cilnidipine, etc.,) Rationale of using calcium channel blockers in angina: Smooth muscle relaxation Negative chronotropic, dromotropic and ionotropic action o n heart.

25. ACTIONS Smooth muscle: produce relaxations by decreasing the intracellular availability of calcium ions. markedly relax the arterioles. relaxation of bronchial, biliary, intestinal, vesical, uterine musculature.

26. Heart: recovery of calcium channels is delayed by Verapamil and Diltiazem. Verapamil and Diltiazem slow down sinus rate and A – V conduction.

27. VERAPAMIL It dilates arterioles and has some alpha adrenergic blocking activity. Produces decrease in heart rate, A – V conduction is slowed. Coronary flow is increased. Adverse effects: Constipation, bradycardia, nausea, hypotension, conduction defects (heart block)

28. DILTIAZEM It produces depression of SA node and A – V conduction. Fall in blood pressure is produced. Contraindications: pre – existing sinus, A – V nodal or myocardial disease.

29. DIHYDROPYRIDINES Nifedipine: no SA or AV node depression. reduces TPR with no decrease in venous return thus increasing cardiac output. duration of action – 3 – 6 hrs. ADE: palpitation, ankle edema, hypotension, headache, drowsiness.

30. Amlodipine: absorption is slow, thus early vasodilator effect is avoided. less extensive first pass metabolism. bioavailability, volume of distribution is more and plasma half life is long. Felodipine: longer t1/2. more vascular selectivity. used in treatment of Raynaud’s disease.

31. Nitrendipine: additional mechanism of action is inhibition if cAMP Lacidipine : longer duration of action. once daily administration. approved for use only in hypertension.

32. Cilnidipine: distinct drug. inhibits N – type calcium channels. no reflex tachycardia occurs like other Dihydropyridines.

33. USES Angina pectoris: reduction in cardiac work. exercise tolerance is increased. Verapamil and Diltiazem have direct cardio depressant activity and reduce oxygen demand. Myocardial infarction: short acting drugs like Nifedipine contraindicated. Verapamil and Diltiazem can be used.

34. Hypertension: Long acting Dihydropyridines, Verapamil and Diltiazem can be used. Cardiac arrythmias: Verapamil and Diltiazem can be used. Hypertrophic cardiomyopathy: Verapamil is used. Other uses: Nifedipine in premature labour . Dihydropyridines in Raynaud phenomena.