Antianginals - pharmacology

principle action of drugs,types of angina classification of drugs ,nitrates,calcium channel blockers pharmacological actions ,combination therapy and its sid effects

1. Anti- anginal drugs

2. content Anti anginal drugs Angina pectoris Types Classification Nitrates Calcium channel blockers b blockers Combination therapy

3. Angina pectoris It is the principal symptoms of patient with ischemic heart disease. Manifested by sudden, severe, pressing substernal pain that often radiates to the left shoulder and along the flexor surface of the left arm. Usually precipitated by exercise, excitement or a heavy meal.

4. Anti-anginal drugs Antianginal drugs may relieve attacks of acute myocardial ischemia by increasing myocardial oxygen supply or by decreasing myocardial oxygen demand Three groups of pharmacological agents have been shown to be effective in reducing the frequency, severity, or both of primary or secondary angina. These agents include the nitrates, adrenoceptor antagonists, and calcium entry blockers . To understand the beneficial actions of these agents, it is important to be familiar with the major factors regulating the balance between myocardial oxygen supply and demand.

5. Types of angina pectoris

6. nitrates Classification of nitrates : Rapidly acting nitrates * used to terminate acute attack of angina * e.g.- Nitroglycerin and Amyl nitrate * usually administered sublingually Long acting nitrates * used to prevent an attack of angina * e.g. – Tetranitrate , Iso sorbide di nitrate, Penta erythritol tetra nitrate * administered orally or topically

7. Organic nitrates Organic nitrates & nitrites are simple nitric & nitrous esters of glycerol. Activation of guanylate cyclase increases cGMP activating a cGMP kinase leading to dephosphorylation of myosin light chains decreasing contractile force.

8. 1 st mechanism of action Coronary artery dilatation Decrease coronary bed resistance (Relieved coronary vasospasm) Increase coronary blood flow Increase oxygen supply

9. 2 nd mechanism of action Reduction on peripheral resistance (Secondary to dilatation of aorta) Decrease blood pressure Decrease after load Decrease workload Decrease oxygen consumption

10. 3 rd mechanism of action Reduced venous return (Due to dilatation of the veins) Decrease left ventricular volume Decrease preload Decrease workload Decrease oxygen consumption

11. Route of administration 1. Sublingual route – rational and effective for the treatment of acute attacks of angina pectoris. Half-life depend only on the rate at which they are delivered to the liver. 2. Oral route – to provide convenient and prolonged prophylaxis against attacks of angina 3. Intravenous Route – useful in the treatment of coronary vasospasm and acute ischemic syndrome. 4. Topical route – used to provide gradual absorption of the drug for prolonged prophylactic purpose .

12. Drug Usual single dose Route of administration Duration of action Short acting Nitroglycerin 0.15-1.2 mg sublingual 10 - 30 min Isosorbide dinitrate 2.5-5 mg sublingual 10 – 60 min Amyl nitrite 0.18 – 3 ml inhalation 3 – 5 min Long acting Nitroglycerin sustained action 6.5 – 13 mg q 6-8 hrs oral 6 – 8 hrs Nitroglycerin 2% ointment 1 – 1.5 inches q hr topical 3 – 6 hrs Niroglycerin slow released 1 –2 mg per 4 hrs Buccal mucosa 3 – 6 hrs Nitroglycerin slow released 10 – 25 mg /24hrs (one patch/day} transdermal 8 –10 hrs Isosorbide dinitrate 2.5 – 10 mg per 2 hrs sublingual 1.5 – 2 hrs Isosorbide dinitrate 10 –60 mg per 4-6 hrs oral 4 – 6 hrs Isosorbide dinitrate chewable 5 – 10 mg per 2-4 hrs oral 2 – 3 hrs Isosorbide mononitrate 20 mg per 12 hrs oral 6 –10 hrs

13. effects 1. Coronary artery dilatation 2. Reduction of peripheral arterial resistance – decrease after load 3. Reduce venous return – decrease preload

14. pharmacokinetics The difference between nitrate preparations is mainly in time of onset of action. Nitroglycerin suffers marked 1st pass metabolism so administration is sublingual. t1/2 ~10 minutes. Occasionally as nitroglycerin is metabolized anginal symptoms will return. Transdermal administration either as patch or paste provides a depot of agent for a steady availability. Nitro-Bid is an oral or topical preparation which saturates the hepatic catabolic pathways allowing a prolonged level of nitroglycerine. Isosorbide mono nitrate & Isosorbide di nitrate are long acting nitrates that are relatively resistant to hepatic catabolism ……t1/2 ~ 1 hour.

15. Adverse effects 1. Throbbing headache 2. Flushing of the face 3. Dizziness – especially at the beginning of treatment 4. Postural Hypotension – due to pooling of blood in the dependent portion of the body

16. contraindications 1. Renal ischemia 2. Acute myocardial infarction 3. Patients receiving other antihypertensive agent

17. UsES of NITRATES Angina Pectoris Myocardial Infarction CHF and Left VF Esophageal Spasm Cynaide Poisoning

18. Beta- blockers β-Blockers decrease oxygen demands of the myocardium by lowering the heart rate and contractility (decrease CO) particularly the increased demand associated with exercise. They also reduce PVR by direct vasodilatations of both arterial & venous vessels reducing both pre- and after load. These effects are caused by blocking β 1 receptors, selective β 1 antagonists (atenolol, metoprolol ) lose their selectivity at high doses and at least partially block β 2 receptors.

19. β 1 antagonists reduce the frequency and severity of anginal episodes particularly when used in combination with nitrates. β 1 antagonists have been shown to improve survival in post MI patients and decrease the risk of subsequent cardiac events & complications. There are a number of contraindications for β blockers: asthma, diabetes, bradycardia, PVD & COPD. β-Blockers in combination with nitrates can be quite effective

20. Hemodynamic effect 1.   Decrease heart rate 2. Reduced blood pressure and cardiac contractility without appreciable decrease in cardiac output

21. Mechanism of action Decrease heart rate & Contractility Increase duration of diastole Decrease workload Increase coronary blood flow Decrease oxy.consumption Increase oxygen supply

22. contraindications 1. Congestive heart failure 2. Asthma 3. Complete heart block

23. Calcium channel blockers Ca +2 channel blockers protect tissue by inhibiting the entrance of Ca +2 into cardiac and smooth muscle cells of the coronary and systemic arterial beds. All Ca +2 channel blockers produce some vasodilation (↓ PVR) and (-) inotropes. Some agents also show cardiac conduction particularly through the AV node thus serving to control cardiac rhythm. Some agents have more effect on cardiac muscle than others but all serve to lower blood pressure. CHF patients may suffer exacerbation of their failure as these are (-) inotropes. They are useful in Prinzmetal angina in conjunction with nitrates.

24. agents Nifedipine: This Ca+2 channel blocker works mainly on the arteriolar vasculature decreasing after load it has minimal effect of conduction or HR. It is metabolized in the liver and excreted in both the urine & the feces. It causes flushing, headache, hypotension and peripheral edema. It also has some slowing effect on the GI musculature resulting in constipation. A reflex tachycardia associated with the vasodilatation may elicit myocardial ischemia in tenuous patients, as such it is generally avoided in non-hypertensive coronary artery disease.

25. verapamil The agents has its main effect on cardiac conduction decreasing HR and thereby O2 demand. It also has much more (-) inotropic effect than other Ca+2 channel blockers It is a weak vasodilator. Because of its focused myocardial effects it is not used as an antianginal unless there is a tachyarrhythmia. It is metabolized in the liver. It interferes with digoxin levels causing elevated plasma levels; caution and monitoring of drug levels are necessary wit concomitant use.

26. diltiazem This agent function similarly to Verapamil however it is more effective against Prinzmetal angina. It has less effect on HR. It has similar metabolism and side effects as Verapamil.

27. Drugs Onset of action Peak of action Half-life Nifedipine 20 minutes 1 hour 3-4 hours Verafamil 1-2 hours 5 hours 8-10 hours Diltiazem 15 minutes 30 minutes 3-4 hours Nicardifine 20 minutes 45 minutes 2-4 hours Felodipine 2-5 hours 6-7 hours 11-16 hour pharmacokinetics

28. Adverse effect Nausea and vomiting Dizziness Flushing of the face Tachycardia – due to hypotension

29. contraindications Cardiogenic shock Recent myocardial infarction Heart failure Atria-ventricular block

30. Combination therapy 1. Nitrates and B-blockers The additive efficacy is primarily a result of one drug blocking the adverse effect of the other agent on net myocardial oxygen consumption B-blockers – blocks the reflex tachycardia associated with nitrates Nitrates – attenuate the increase in the left ventricular end diastolic volume associated with B-lockers by increasing venous capacitance

31. Calcium channel blockers +beta blockers Useful in the treatment of exertional angina that is not controlled adequately with nitrates and B-blockers B-blockers – attenuate reflex tachycardia produce by nifedipine These two drugs produce decrease blood pressure

32. Calcium channel blocker+nitrates Useful in severe vasospastic or exertional angina (particularly in patient with exertional angina with congestive heart failure and sick sinus syndrome) Nitrates reduce preload and after load Ca channels reduces the after load Net effect is on reduction of oxygen demand

33. Triple drugs:- nitrates+calcium channel blockers+beta blocker Useful in patients with exertional angina not controlled by the administration of two types of anti-anginal agent Nifidipine – decrease after load Nitrates – decrease preload B-blockers – decrease heart rate & myocardial contractility