Anti Anginal Drugs

Slide 1: 

Antianginal drugs

Angina pectoris: 

Angina pectoris Angina pectoris is a recurrent severe crushing pain in the chest, neck, shoulder or arm . It is caused by transient episodes of myocardial ischemia due to an imbalance in oxygen supply & demand . The coronary blood flow is inadequate for the needs of the heart.

Main types of Angina: 

Main types of Angina Types of Angina: Stable Angina (Classic, Angina of effort, Atherosclerotic Angina).The most common type. The angina occurs whenever the oxygen demand increases due to increased physical activity or sympathetic stimulation.

Slide 5: 

Variant Angina ( Angiospastic or Prinzmetal’s Angina).Uncommon ,occurs at rest & is due to reversible coronary artery spasm. Unstable Angina (Acute coronary syndrome)The chest pain occurs with increased frequency & precipitated by progressively less effort. It is a medical emergency, if untreated may progress to myocardial infarction. Mixed form of Angina: seen in advanced coronary artery disease (CAD) .

Slide 7: 

Pathophysiology of Angina: Determinants of myocardial oxygen demand. Major: Wall stress: depends upon Intraventricular pressure Ventricular radius (volume) Wall thickness Heart rate Contractility Minor: Activation energy Resting metabolism.

Slide 8: 

Determinants of coronary blood flow & myocardial oxygen supply: Perfusion pressure (aortic diastolic pressure). Duration of diastole. Coronary vascular bed resistance.

Slide 9: 

Determinants of vascular tone: Smooth muscles of blood vessels may be relaxed by: Increasing cGMP. Decreasing intracellular Ca ++. Stabilizing or preventing depolarization of the vascular smooth muscle cell membrane. Increasing cAMP

Slide 11: 

Antianginal drugs improve the balance of myocardial oxygen demand & supply by  demand by reducing cardiac work load.  supply by dilating the coronary vasculature. Combination of both

Slide 12: 

Anti anginal drugs: Main groups are Organic nitrites & nitrates Calcium channel blockers  - Adrenoceptor Blockers

Classification of anti anginal drugs: 

Classification of anti anginal drugs A. Organic nitrites & nitrates 1. Short Acting (D.O.A: 3 – 60 min) Nitroglycerin (sublingual) 10-30 min Isosorbide dinitrate (sublingual) 10-60 min Amylnitrite (inhalant) 3-5 min

Slide 14: 

2. Long Acting: (5 – 10 hrs) Nitroglycerin , 2% ointment, transdermal: 3-6 hrs Nitroglycerin, slow-release, buccal: 3-6 hrs Nitroglycerin, oral sustained-action 6-8 hrs Nitroglycerin, slow-release patch, transdermal: 8-10 hrs Isosorbide dinitrate , sub lingual: 1.5–2 hrs Isosorbide dinitrate, Chewable oral : 2- 3 hrs Isosorbide dinitrate, oral: 4 - 6 hrs Isosorbide, mononitrate oral 6-10 hrs

B.Calcium channel blockers : 

B. Calcium channel blockers Dihydropyridines : Nifedipine , Nicardipine Nimodipine , Amlodipine Nisoldipine , Nitrendipine Felodipine , Isradipine Miscellaneous: Diphenylalkylamine : Verapamil Benzothiazepine : Diltiazem

Slide 16: 

C.  - Adrenoceptor Blockers Cardioselective (  1 ) blockers Atenolol , Bisoprolol , Metoprolol , Betaxolol Non-selective (  1 ,  2 ) blocker Propranolol --- prototype D. Newer Anti- Anginal Drugs: Potassium - Channel Activators: Nicorandil Metabolic modulators: Ranolazine , Trimetazidine Direct bradycardic agent: Ivabradine

Slide 17: 

Newer Anti-Anginal Drugs Under Investigation: Rho-Kinase inhibitors,eg, fasudil. Sulfonylureas, eg, glibenclamide. Vasopeptidase inhibitors. Nitric oxide donors, eg, L- arginine. Capsaicin Amiloride.

Slide 18: 

Organic Nitrites & Nitrates: They are nitrous oxide/nitric oxide esters of glycerol. Nitroglycerin is the Prototype drug .

Structure: 

Structure 0

Slide 20: 

Pharmacokinetics: Ph. K factors govern the choice of agent & mode of therapy . Liver contains high capacity organic nitrate reductase that can remove nitrate group in a step wise fashion from parent molecule & ultimately inactivates the drug. DOA is determined by: Rate of absorption form site of administration. Rate of metabolism.

Slide 21: 

Low oral bioavailability due to extensive 1 st pass hepatic metabolism Nitroglycerin & Isorbide dinitrate ---- oral bioavailability < 10-20% . ROA: S/L , Buccal , Oral, Transdermal , IV Sustained-action / slow -release preparations available. Amylnitrate : Inhalant

Slide 22: 

Plasma half life of parent drugs—2-8min. Partially denitrated compounds have longer half life Metabolism: by denitration & conjugation Some drugs have active metabolites. Nitroglycerin ---- 2 di-nitroglycerin → 2 Mono-nitroglycerins Isorbide dinitrate----- Isorbide mononitrate. Excretion: glucuronide conjugation → renal excretion

Slide 23: 

Pharmacodynamics : A. MOA in smooth muscles: B.  Mechanism of Clinical Effects (  Oxygen Demand) :

Slide 25: 

A: MOA in smooth muscles: Denitration of nitrates by glutathion S - transferase Release of free Nitrite ion Conversion of Nitrite ion into nitric oxide OR A different enzyme reaction releases nitric oxide directly from the drug. Activation of Guanylyl cyclase Accumulation of cGMP.

Slide 26: 

Activation of cGMP dependent Kinases De- phosphorylation of myosin light chains No interaction between Myosin & Actin So relaxation of SM. Vasodilattion ----- Mainly Venular Production of PGE & PGI 2 ( Prostacyclin ) & membrane hyper polarization may increase vascular SM relaxation.

Slide 27: 

B. Mechanism of Clinical Effects: (  Oxygen Demand) Venodilatation   venous capacitance  (venous return) Preload   wall tension   work load   oxygen consumption   oxygen demand  relief of classical angina Some arteriolar dilatation   After load also  oxygen demand

Slide 28: 

Contributory Mechanism : Redistribution of blood from normal to ischemic areas due to vasodilation of large epicardial arteries. Production of PGE , PGI 2-- vasodilation .

Slide 29: 

Relief of Vasospastic Angina: Relief of spasm of coronary arteries (Calcium channel blockers are preferred) Relief of Unstable Angina : Precise mechanism not clear Reduced myocardial oxygen demand. Relaxation of epicardial coronary arteries Decrease in platelet aggregation: Stimulation of Guanylyl cyclase-- ↑cGMP ---↓ in platelet aggregation

Slide 30: 

Pharmacological Effects Vascular smooth muscles: Different segments vary in their ability to release nitric oxide. All segments of vascular system are relaxed. Veins respond at lowest conc. Arteries at higher conc. Arterioles & pre-capillary sphincters are less dilated.

Slide 31: 

Direct effects: The primary effect is marked relaxation of veins   venous capacitance   Preload  pulmonary vascular pressure &  heart size CO  in normal subjects ,  in heart failure. Marked orthostatic hypotension ---- syncope.

Slide 32: 

Dilation of larger arteries Temporal artery dilatation may produce pulsation . Meningeal artery dilation ---- throbbing headache. Relaxation of epicardial arteries. Redistribution of blood from normal to ischemic areas of heart.

Slide 33: 

Indirect effects: due to compensatory responses evoked by baroreceptors & hormonal mechanisms. Tachycardia.  contractility. Salt & water retention ---- with intermediate & long acting nitrates Tolerance:

Slide 35: 

Other smooth muscles: Relaxation of SM of bronchi, GIT, GUT, used as recreational drugs. Effect on platelets: ↓ Platelets aggregation due to ↑ cGMP. Other effects: Nitrate ion can form methemoglobin, Toxicity in nursing infants large doses can produce Pseudocyanosis, tissue hypoxia & death

Slide 36: 

Therapeutic Uses: 1: Angina: Classical Angina: a) For treatment of acute attack: S/L Nitroglycerine 0.15-1.2 mg. OOA: 1-2 min DOA:10-20 min b) For prophylaxis & maintenance therapy: Long acting prep · Treatment of  Variant angina. ( DOC are CCBs) · Treatment of Unstable angina I/V Nitroglycerine along with drugs of other groups --- antiplatelet drugs,Heparin thromobolytics.Beta blockers may also be combined. Stenting may be required.

Slide 37: 

2. . Chronic Heart failure & Acute Heart failure due to Myocardial Infarction. Reduces preload & ventricular stretch. 3. In interventional cardiac procedures ( percutaneous coronary angioplasty) to dilate coronary arteries. 4. Cyanide poisoning (Sodium nitrite).

Slide 38: 

Haemoglobin  Methaemoglobin  Cyanomethaemoglobin  Methaemoglobin + Sod. thiocyanate  Sodium thiocyanate--Excreted in urine Sod. Nitrite (10 ml of 3% solution i.v) Sod. thiosulfate (50 ml of 25% solution i.v) Cyanide

Slide 40: 

Adverse Effects: A. Acute A/E:- Orthostatic hypotension , weakness, dizziness, syncope Tachycardia. It can be overcome by combination therapy with Calcium Channel or Beta blockers Throbbing headache Drug rash B. Tolerance: C. Drug interactions D. Carcinogenicity

Slide 41: 

B. Tolerance: Loss of effect of nitrate when exposure is prolonged beyond 10-12 hrs. The possible mechanisms are  release of nitric oxide due to  tissue thiol compounds. Systemic compensatory mechanisms. Monday disease in workers of chemical/ explosives industry .On starting the work week due to volatile vapours , workers have throbbing headache. After a day or so due to tolerance the symptoms disappear. Over the weekend ,there is no exposure ,tolerance disappears ;so symptoms recur on Monday.

Slide 42: 

D. Interaction of Nitrates with drugs used in erectile dysfunction ---- marked hypotension Sildenafil & other vasodilators

Slide 43: 

C. Carcinogenicity. In humans correlation between esophageal & gastric carcinoma & the nitrate content of food. Nitrates can combine with amines to form nitrosamines Nitrosamines are converted to reactive derivatives & are powerful carcinogens in animals.

Slide 44: 

 - Blockers Mechanism of anti-anginal effect:  - Blockers are extremely useful in management of EFFORT ANGINA as prophylactic agents 1. Prevent angina mainly by ↓ Oxygen consumption. Block  1 receptors in the heart, JGA. ↓ HR and force of contraction ↓ Blood pressure ↓ in cardiac work & double product . (HR x Blood pressure) ↓ in oxygen consumption & demand at rest & during exercise ---- relief angina & improve exercise tolerance.

Slide 45: 

2. ↑ Oxygen supply: lower HR --- ↑ in diastolic perfusion time ---- ↑ coronary perfusion ---- ↑ Oxygen supply. Therapeutic Uses: : Propranolol—the prototype,is non-cardioselective , Atenolol or metoprolol preferred as they are cardioselective.  - Blockers with intrinsic sympathomimetic activity ---Pindolol are not used as they are less effective

Slide 46: 

 - Blockers are useful in: Prophylaxis of classical Angina , of no value in acute attack May be combined with nitrates to avoid undesirable compensatory effects ( Should not be given in variant angina ---- can worsen) 2. Silent or ambulatory angina which causes no pain

Slide 47: 

3. In patient with recent MI to ↓ mortality ,as they prevent arrhythmias. 4. In patients of angina with associated hypertension, improve survival & prevent stroke.

Slide 48: 

A/E: An ↑ in end-diastolic volume & ↑ in ejection time ---- ↑ oxygen requirement off sets the beneficial effects in angina , can be avoided by combination of nitrates . Other A/E : Already discussed. Contraindications: Already discussed .

Calcium channel blockers(CCBs): 

Calcium channel blockers(CCBs) A group of drugs which block the entry of Calcium ions through voltage sensitive L- type calcium channels in heart & smooth muscles of BV.

Calcium channel blockers : 

Calcium channel blockers Dihydropyridines: Nifedipine , Nicardipine Nimodipine , Amlodipine Nisoldipine , Nitrendipine Felodipine , Isradipine Clevipidine Miscellaneous: Diphenylalkylamine: Verapamil Benzothiazepine: Diltiazem

Slide 52: 

CCBs are orally active drugs, variable low bioavailability due to first pass effect in liver, high PPB, & extensive metabolism. Verapamil & Diltiazem are also used I/V. Clevipidine is a newer drug; only for I/V use (used in acute hypertension during surgery as infusion)

Slide 53: 

Chemistry & Pharmacokinetics:

Slide 55: 

Type of Voltage activated Calcium Channels. L Type: Cardiac & Smooth muscles , Neurons T Type: Heart & Neurons N & R Type: Neurons , sperms P/Q Type: Neurons

Slide 56: 

Pharmacodynamics : MOA of calcium channel antagonists : They block the entry of calcium ions through the L Type voltage activated calcium channels in heart, smooth muscles of coronary & peripheral vasculature mainly in arterioles. Cardiac calcium channels, more sensitive to Verapamil B.V calcium channels --- more sensitive to Dihydropyridines —the prototype drug is Nifedipine .

Slide 57: 

The drugs bind from the inner side of the membrane. The drugs bind more effectively to open channels & inactivated channels . They ↓ the frequency of opening in response to depolarization. Reduce transmembrane calcium current. These channels contains several drug receptors. Affinity of different drugs differ for these receptors & binding of one drug can affect the other drug.

Slide 58: 

Pharmacological Actions / Effects Cardiac calcium channels, more sensitive to Verapamil B.V calcium channels --- more sensitive to Dihydropyridines Different drugs produce variable effects by different effects on: Vascular smooth muscle: Heart– SA node , AV node & Myocardium.

Slide 59: 

Due to effect on heart & vasculature the group actions produced are: Anti-hypertensive. Anti- anginal . Anti-arrhythmic. Myocardial infarction To prevent cerebral vasospasm & infarct following sub- arachenoid hemorrhage:

Slide 60: 

Other effects: Anti-Platelet effect ---- ↓ PA. Effect on other smooth muscles ----bronchiolar , GIT,uterine Skeletal muscles---- not depressed. Decreased secretion of exocrine glands at high doses. Verapamil blocks reverse transporter p-170 glycoprotein. In vitro it can reverse the drug resistance of cancer cells to chemotherapy.

Slide 61: 

Mechanism of anti anginal effect: CCBs relieve angina by acting on blood vessels & heart . L type Ca ++ channels in vascular smooth muscle are more sensitive to blockade by Dihydropyridines than the miscellaneous group. L type Ca ++ channels in heart are mainly sensitive to blockade by Verapamil & Diltiazem.

Mechanism of action in stable / classical angina : 

Mechanism of action in stable / classical angina In B.V mainly arterioles & arteries (All CCBs): Blocking of voltage gated L type calcium channels. Reduced Ca ++ influx in smooth muscle cells. Reduced formation of Ca ++ /calmodulin complex. No activation of myosin light chain kinase.

Slide 63: 

No Phosphorylation of myosin light chains. So interaction b/w actin & myosin can not occur--- no contraction--- relaxation of smooth muscles Vasodilatation  Reduced PVR &  Reduced after load. -- reduced workload of heart Reduced oxygen requirement  Relief of angina.

Slide 65: 

On Heart (Verapamil and diltiazem) Blockade of voltage gated calcium channels Reduced Ca ++ influx into cardiac cells  impulse generation in SA node --- HR  conduction in AV node.  myocardial contraction CO may . Less work load Less Oxygen consumption  R elief of angina

Slide 66: 

Mechanism of action in vasospastic angina Removal of spasm of coronary arteries (DOC). Mechanism of action in unstable angina Inhibition of platelet aggregation.

Slide 67: 

Anti-hypertensive Effect: In B.V --mainly arterioles & arteries (All CCBs ): Blocking of voltage gated L type calcium channels. Reduced Ca ++ influx in smooth muscle cells. Reduced formation of Ca ++ / calmodulin complex. No activation of myosin light chain kinase .

Slide 68: 

No Phosphorylation of myosin light chains. So interaction b/w actin & myosin can not occur--- no contraction--- relaxation of smooth muscles Vasodilatation  Reduced PVR &  Reduced blood pressure.

Slide 69: 

On Heart (only Verapamil & Diltiazem ) Blockade of voltage gated calcium channels Reduced Ca ++ influx into cardiac cells  impulse generation in SA node --- HR  conduction in AV node.  myocardial contraction  CO---- reduced blood pressure.

Slide 70: 

Useful in Myocardial infarction . Calcium influx is ↑in ischemia b/c hypoxia produces membrane depolarization. ↑activity of ATP consuming enzymes Depletion of energy stores Worsening of ischemia CCBs protect the tissue, limit infarct size

Slide 71: 

Anti-arrhythmic effect : Will be discussed with Anti-arrhythmic drugs. To prevent cerebral vasospasm & infarct following sub- arachenoid hemorrhage: Nimodipine .—withdrawn Nicardipine & Verapamil —by I/V or intracerebral arterial infusion. CCBs may also decrease cerebral damage after thromboembolic stroke.

Slide 73: 

Therapeutic uses: Hypertension . Angina Useful in: Vasospastic angina-- DOC Angina of effort for maintenance treatment. Long acting drugs preferred. Unstable angina – added for refractory cases. Supraventricular arrhythmias . Useful in supraventricular tachycardia Atrial fibrillation , Atrial flutter . ( Previously DOC in supraventricular tachycardia. Now Adenosine is DOC)

Slide 74: 

Hypertorophic cardiomyopathies . Myocardial Infarction- - Prevent increase in infarct size Migraine Prophylaxis Raynaud’s phenomenon Subarachnoid haemorrhage ( Nimodipine used previously , withdrawn. Now Nicardipine & Verapamil are used ). Verapamil can partially reverse the resistance of cancer cell to chemotherapeutic agents in clinical trails.

Slide 75: 

Animal research suggests future role of CCBs in Treatment of osteoprosis Fertility disorders Male contraception Immune modulation Schistosomiasis .

Slide 76: 

CCB Specially suitable for: Physically and / or mentally active patients. Patients of Angina / hypertension with Asthma / COPD Raynaud’s (and other PVD) & migraine; Post MI cases Pregnant hypertensive. Black hypertensives.

Slide 77: 

Adverse effects: Direct extensions of Therapeutic effects Cardiac A/E: Miscellaneous group Bradycardia , AV blocks. Serious Cardio depression including cardiac arrest. Cardiac failure– specially with short acting CCBs Dihydropyridines Marked Hypotension.---- Reflex sympathetic over activity--- Tachycardia ---aggravation of Angina / MI or Arrhythmia.

Slide 78: 

Non-cardiac A/E: Flushing , Dizziness , nausea Constipation Lassitude Nervousness Peripheral Edema ----specially of dependent parts D/I: With β blockers- --Verapamil & Diltiazm produce marked cardiodepression With Digoxin --- Verapamil can increase levels of Digoxin—toxicity as Digoxin has narrow margin of safety.

Slide 79: 

C/I or Cautions : Myocardial inadequacy , Chronic Heart Failure Conduction defects, sick sinus syndrome. Verapamil &Diltiazm worsen the condition. With β blockers- --Verapamil & Diltiazm produce marked cardiodepression With Digoxin --- Verapamil can increase levels of Digoxin. Short acting DHPs should be avoided in hypertensives as they can evoke angina .

Slide 80: 

Newer Anti-anginal drugs: Metabolic modulators: Ranolazine & Trimetazidine MOA : pFOX inhibitors They partially inhibit the fatty acid oxidation (pFOX) pathway in myocardium. Ranolazine also blocks late sodium current that facilitates Ca ++ entry through Na+/ Ca ++ exchanger--- reduces contractility

Slide 81: 

In ischemic myocardium: metabolism shifts from glucose to fatty acid oxidation. the oxygen requirement per unit of ATP production ↑ So improve the metabolic status of ischemic tissue as they : inhibit the fatty acid oxidation ↓ oxygen demand.

Slide 82: 

Bradycardic drug: Ivabradine: It selectively blocks, hyperpolarization - activated sodium channel --- I f in SA node Decreases heart rate No significant hemodynamic effects. Reduces anginal attacks. Efficacy similar to CCBs & Beta blockers No effect on GIT & Bronchial SM.

Slide 83: 

Potassium - Channel Activators A. Nicorandil : It is nicotinamide nitrate ester. It dilates normal coronary arteries but more complex effects in patients with angina.

Slide 84: 

MOA IN ANGINA 1. In BV Arteriolar dilation  ↓ afterload Venodilation  ↓ preload ↓ work load on heart  ↓ oxygen consumption  relief of angina 2. In myocardium Cardiac K ATP channel activation ↓ Myocardial protection Therapeutic use: Angina

Slide 85: 

Principles of therapy of Angina: Modification of risk factors for coronary arthrosclerosis. ( Arthrosclerosis is the most common cause of Angina). Smoking Hypertension Hyperlipidemia Obesity Clinical depression.

Slide 86: 

Anti-anginal drugs : Single / in combination Nitrites & Nitrate ; CCBs ;Beta Blockers : Reduce myocardial oxygen demand ↑ coronary blood flow to ischemic areas. Metabolic modulators: ↑ efficiency of oxygen utilization by shifting the energy substrate from fatty acid to glucose.

Slide 87: 

Myocardial revascularization Percutaneous coronary angioplasty Coronary Artery Bypass Grafting (CABG). 4. Prevention of MI: Lipid-lowering agents. Anti-platelet drugs β -Blockers