Antiarrhythmic and Antianginal Drugs PDF

State Medical and Pharmaceutical University “N. Testemiţanu” Department of Pharmacology and clinical pharmacology Associate professor Ianoș Corețchi Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs: class I, II, III...

State Medical and Pharmaceutical University “N. Testemiţanu” Department of Pharmacology and clinical pharmacology Associate professor Ianoș Corețchi Electrophysiology of the heart Arrhythmia: definition, mechanisms, types Drugs: class I, II, III, IV etc Guides to treat some types of arrhythmia Normal conduction pathway: 1- SA node generates Other types of action potential and conduction that occurs delivers it to the atria between myocardial and the AV node cells: When a cell is depolarized → 2- The AV node delivers adjacent cell the impulse to purkinje depolarizes along fibers 3- purkinje fibers conduct the impulse to the ventricles Action potential of the heart: In the atria, purkinje, In the SA node and and ventricles the AV node, AP curve AP curve consists of consists of 3 phases 5 phases Non-pacemaker action potential Phase 1: partial repolarization Due to rapid efflux of K+ Phase 2: plateu Phase 0: fast Due to Ca++ influx upstroke Due to Na+ influx Phase 3: repolarization Due to K+ efflux Phase 4: resting membrane potential N.B. The slope of phase 0 = conduction velocity Also the peak of phase 0 = Vmax Pacemaker AP Phase 0: upstroke: Phase 3: Due to Ca++ influx repolarization: Due to K+ efflux Phase 4: pacemaker potential Na influx and K efflux and Ca influx until the cell reaches threshold and then turns into phase 0 Pacemaker cells (automatic cells) have unstable membrane potential so they can generate AP spontaneously Effective refractory period (ERP) In this period the cell can’t be excited Takes place between phase 0 and 3  Causes of If the arrhythmia arrhythmia arises from atria, SA node, or AV node it is called arteriosclerosis supraventricular arrhythmia Coronary artery spasm If the arrhythmia Heart block arises from the ventricles it is called ventricular Myocardial arrhythmia ischemia  1- Abnormal impulse generation Automatic Triggered rhythms rhythms Enhanced normal Ectopic focus Delayed Early automaticity afterdepolarization afterdepolarization AP arises from sites other than SA node ↑AP from SA node  2-Abnormal conduction Conduction block Reentry Circus 1st degree 2nd degree 3rd degree movement Reflection 1-This This is when the pathway is impulse is not blocked conducted from the atria to the ventricles 3-So the cells here will be reexcited (first by the original pathway and the 2-The impulse from other from the retrograde) this pathway travels in a retrograde fashion (backward) Abnormal anatomic conduction Here is an accessory pathway in the heart called Bundle of Kent Present only in small populations Lead to reexcitation → Wolf-Parkinson-White Syndrome (WPW)  In case of abnormal generation: In case of abnormal conduction: Decrease of phase 4 ↑ERP ↓conduction velocity slope (in pacemaker (so the cell (remember phase 0) cells) won’t be reexcited again) Before drug Raises the threshold after phase4  Supraventricular Arrhythmias ✓Sinus Tachycardia: high sinus rate of 100-180 beats/min, occurs during exercise or other conditions that lead to increased SA nodal firing rate ✓Atrial Tachycardia: a series of 3 or more consecutive atrial premature beats occurring at a frequency >100/min ✓Paroxysmal Atrial Tachycardia (PAT): tachycardia which begins and ends in acute manner ✓Atrial Flutter: sinus rate of 250-350 beats/min. ✓Atrial Fibrillation: uncoordinated atrial depolarizations. AV blocks A conduction block within the AV node , occasionally in the bundle of His, that impairs impulse conduction from the atria to the ventricles.  ventricular Arrhythmias ✓Ventricular Premature Beats (VPBs): caused by ectopic ventricular foci; characterized by widened QRS. ✓Ventricular Tachycardia (VT): high ventricular rate caused by abnormal ventricular automaticity or by intraventricular reentry; can be sustained or non-sustained (paroxysmal); characterized by widened QRS; rates of 100 to 200 beats/min; life-threatening. ✓Ventricular Flutter - ventricular depolarizations >200/min. ✓Ventricular Fibrillation - uncoordinated ventricular depolarizations  PHARMACOLOGIC RATIONALE & GOALS ❑ The ultimate goal of antiarrhythmic drug therapy: o Restore normal sinus rhythm and conduction o Prevent more serious and possibly lethal arrhythmias from occurring. ❑ Antiarrhythmic drugs are used to: ✓ decrease conduction velocity ✓ change the duration of the effective refractory period (ERP) ✓ suppress abnormal automaticity  ANTYARRHYTHMIC DRUGS Most antiarrhythmic drugs are pro-arrhythmic (promote arrhythmia) They are classified according to Vaughan William into four classes according to their effects on the cardiac action potential class mechanism action notes Can abolish Change the slope of tachyarrhythmia I Na+ channel blocker phase 0 caused by reentry circuit ↓heart rate and Can indirectly alter K II β blocker conduction velocity and Ca conductance 1. ↑action potential duration (APD) or Inhibit reentry III K+ channel blocker effective refractory tachycardia period (ERP). 2. Delay repolarization. Slowing the rate of rise in ↓conduction velocity in IV Ca++ channel blocker phase 4 of SA node(slide SA and AV node 12)  A. Classification of antiarrhythmics used in tachyarrhythmias and extrasystoles. I. Medicines blocking the ion channels of cardiomyocytes  Class I. Na channel blockers or membranostabilisers  Class I A: quinidine, procainamide, disopyramide,aprindine, imipramine, ajmaline.  Class I B: lidocaine, mexiletine, phenytoin, tocainide,  Class I C: flecainide, moracizine, propafenone,encainide, lorcainide.  Class II. Calcium channel blockers:  verapamil,diltiazem. galopamil, bepiridil,  Class III. Potassium channel blockers (preparations whic hprolong the effective refractory period and the potential foraction):  amiodarone, sotalol, bretylium, ibutylide,dofetilide. II. Medicines influencing the efferent innervation of the heart.  Medicines which reduce the tone of adrenergic innervation  beta-adrenoblockers:  Non-selective: propranolol, pindolol, timolol, sotalol.  Selective (beta1>>>beta2): metoprolol, atenolol, bisoprolol, acebutolol etc.  Cholinergic agonists (acetylcholinesterase inhibitor)  Edrophonium 17  A. Classification of antiarrhythmics used in tachyarrhythmias and extrasystoles. III. Medicines of different groups  Potassium salts  Potassium chloride, asparcam, panangine  Magnesium salts  Magnesium sulphate, magnesium chloride, magnesium orotate, magnesium aspartate, asparcam, panangine  Cardiac glycosides  Digoxin, strophanthin  Nucleoside analogues  Adenosine 18  B. Classification of antiarrhythmics used in bradyarrhythmias and AV block. Medicines that increase the tone of adrenergic innervation.  alpha-beta-adrenomimetics - epinephrine, ephedrine  beta-1-adrenomimetics - dobutamine, dopamine  beta-1,2-adrenomimetics - isoprenaline, orciprenaline Medicines that decrease cholinergic innervation tone  M-cholinoblockers - atropine 19 Have moderate K+ channel Class I blockade IA IB IC They ↓ conduction velocity in non-nodal tissues They act on open Na+ (atria, ventricles, and purkinje fibers) channels or inactivated only So they are used when many Na+ channels are opened or inactivated (in tachycardia only) because in normal rhythm the channels will be at rest state so the drugs won’t work  Quinidine Procainamide Slowing of the rate of rise in phase 0 → ↓conduction velocity ↓of Vmax of the cardiac action potential They prolong muscle action potential & ventricular (ERP) They ↓ the slope of Phase 4 spontaneous depolarization (SA node) → decrease enhanced normal automaticity They make the slope more horizontal  CLASS IA DRUGS  They possess intermediate rate of association and dissociation (moderate effect) with sodium channels. Pharmacokinetics: procainamide quinidine Good oral Good oral bioavailability bioavailability Used as IV to Metabolized in avoid hypotension the liver Procainamide metabolized into N-acetylprocainamide (NAPA) (active class III) which is cleared by the kidney (avoid in renal failure)  CLASS IA DRUGS USES  Supraventricular and ventricular arrhythmias  Quinidine is rarely used for supraventricular arrhythmias  Oral quinidine/procainamide are used with class III drugs in refractory ventricular tachycardia patients with implantable defibrillator  IV procainamide used for hemodynamically stable ventricular tachycardia  IV procainamide is used for acute conversion of atrial fibrillation including Wolff-Parkinson-White Syndrome (WPWS) defibrillator CLASS IA DRUGS TOXICITY quinidine procainamide AV block Asystole or ventricular Torsades de pointes arrhythmia arrhythmia because it ↑ ERP (QT interval) Hypersensitivity Shortens A-V nodal : fever, refractoriness (↑AV agranulocytosis conduction) by antimuscarinic like effect Systemic lupus erythromatosus (SLE)-like ↑digoxin symptoms: arthralgia, fever, pleural-pericardial concentration by : inflammation. 1- displace from tissue binding sites Symptoms are dose and time dependent 2- ↓renal clearance Common in patients with slow hepatic Ventricular acetylation tachycardia  Notes: Torsades de pointes: twisting of the point. Type of tachycardia that gives special characteristics on ECG At large dosesof quinidine → cinchonism occurs:blurred vision, tinnitus, headache, psychosis and gastrointestinal upset Digoxin is administered before quinidine to prevent the conversion of atrial fibrillation or flutter into paradoxical ventricular tachycardia CLASS IB DRUGS They shorten Phase 3 repolarization ↓ the duration of the cardiac action potential They suppress arrhythmias caused by abnormal automaticity ❑They show rapid association & dissociation (weak effect) with Na+ channels with appreciable degree of use-dependence ❑No effect on conduction velocity AGENTS OF CLASS IB Lidocaine Mexiletine  Used IV because of extensive 1st pass  These are the oral analogs of lidocaine metabolism  Lidocaine is the drug of choice in  Mexiletine is used for chronic treatment of emergency treatment of ventricular ventricular arrhythmias associated with arrhythmias previous myocardial infarction  Has CNS effects: drowsiness, numbness, convulstion, and nystagmus Adverse effects: 1- neurological effects 2- negative inotropic activity Uses ✓They are used in the treatment of ventricular arrhythmias arising during myocardial ischemia or due to digoxin toxicity ✓They have little effect on atrial or AV junction arrhythmias (because they don’t act on conduction velocity)  CLASS IC DRUGS  They markedly slow Phase 0 fast depolarization  They markedly slow conduction in the myocardial tissue  They possess slow rate of association and dissociation (strong effect) with sodium channels  They only have minor effects on the duration of action potential and refractoriness  They reduce automaticity by increasing the threshold potential rather than decreasing the slope of Phase 4 spontaneous depolarization.  Uses: Refractory ventricular arrhythmias. Flecainide is a particularly potent suppressant of premature ventricular contractions (beats) Toxicity and Cautions for Class IC Drugs: They are severe proarrhythmogenic drugs causing: 1. severe worsening of a preexisting arrhythmia 2. de novo occurrence of life-threatening ventricular tachycardia In patients with frequent premature ventricular contraction (PVC) following MI, flecainide increased mortality compared to placebo. Notice: Class 1C drugs are particularly of low safety and have shown even increase mortality when used chronically after MI Compare between class IA, IB, and IC drugs as regards effect on Na+ channel & ERP  Sodium channel blockade: IC > IA > IB  Increasing the ERP: IA>IC>IB (lowered) Because of K+ blockade  CLASS II ANTIARRHYTHMIC DRUGS (Β-ADRENERGIC BLOCKERS) Mechanism of action Uses  Negative inotropic and  Treatment of increased sympathetic chronotropic action. activity-induced arrhythmias such as stress- and exercise-induced arrhythmias  Prolong AV conduction (delay)  Atrial flutter and fibrillation.  Diminish phase 4 depolarization → suppressing  AV nodal tachycardia. automaticity(of ectopic focus)  Reduce mortality in post-myocardial infarction patients  Protection against sudden cardiac death CLASS II ANTIARRHYTHMIC DRUGS Propranolol (nonselective): was proved to reduce the incidence of sudden arrhythmatic death after myocardial infarction Metoprolol selective reduce the risk of bronchospasm Esmolol: Esmolol is a very short-acting β1-adrenergic blocker that is used by intravenous route in acute arrhythmias occurring during surgery or emergencies  CLASS III ANTIARRHYTHMIC DRUGS K+ BLOCKERS  Prolongation of phase 3 repolarization without altering phase 0 upstroke or the resting membrane potential  They prolong both the duration of the action potential and ERP  Their mechanism of action is still not clear but it is thought that they block potassium channels  Class III sotalol amiodarone ibutilide Uses: Ventricular arrhythmias, especially ventricular fibrillation or tachycardia Supra-ventricular tachycardia Amiodarone usage is limited due to its wide range of side effects  Sotalol (Sotacor) Sotalol also prolongs the duration of action potential and refractoriness in all cardiac tissues (by action of K+ blockade) Sotalol suppresses Phase 4 spontaneous depolarization and possibly producing severe sinus bradycardia (by β blockade action) The β-adrenergic blockade combined with prolonged action potential duration may be of special efficacy in prevention of sustained ventricular tachycardia It may induce the polymorphic torsades de pointes ventricular tachycardia (because it increases ERP) Ibutilide ❖Used in atrial fibrillation or flutter ❖IV administration ❖May lead to torsade de pointes ❖Only drug in class three that possess pure K+ blockade  AMIODARONE (CORDARONE) Amiodarone is a drug of multiple actions and is still not well understood It is extensively taken up by tissues, especially fatty tissues (extensive distribution) t1/2 = 60 days Potent P450 inhibitor Amiodarone antiarrhythmic effect is complex comprising class I, II, III, and IV actions Dominant effect: Prolongation of action potential duration and refractoriness It slows cardiac conduction, works as Ca2+ channel blocker, and as a weak β-adrenergic blocker  Amiodarone – side effects Peter S. Fischbach. Clinical Cardiac Electrophysiology in the Young. Pharmacology of Anti-arrhythmic Agents Amiodarone – side effects Peter S. Fischbach. Clinical Cardiac Electrophysiology in the Young. Pharmacology of Anti-arrhythmic Agents  CLASS IV ANTIARRHYTHMIC DRUGS (CALCIUM CHANNEL BLOCKERS) ❖Calcium channel blockers decrease inward Ca2+ currents resulting in a decrease of phase 4 spontaneous depolarization (SA node) ❖They slow conductance in Ca2+ current-dependent tissues like AV node. ❖Examples: verapamil & diltiazem Because they act on the heart only and not on blood vessels. ❖Dihydropyridine family are not used because they only act on blood vessels  MECHANISM OF ACTION  They bind only to depolarized (open) channels → prevention of repolarization So they act only in cases of arrhythmia because many Ca2+ channels are depolarized while in normal rhythm many of them are at rest  They prolong ERP of AV node → ↓conduction of impulses from the atria to the ventricles Uses ❑More effective in treatment of atrial than ventricular arrhythmias. ❑Treatment of supra-ventricular tachycardia preventing the occurrence of ventricular arrhythmias ❑Treatment of atrial flutter and fibrillation  contraindication ❑Contraindicated in patients with pre-existing depressed heart function because of their negative inotropic activity Adverse effects ❑Cause bradycardia, and asystole especially when given in combination with β-adrenergic blockers  MISCELLANEOUS ANTIARRHYTHMIC DRUGS Adenosine oAdenosine activates A1-purinergic receptors decreasing the SA nodal firing and automaticity, reducing conduction velocity, prolonging effective refractory period, and depressing AV nodal conductivity oIt is the drug of choice in the treatment of paroxysmal supra-ventricular tachycardia oIt is used only by slow intravenous bolus oIt only has a low-profile toxicity (lead to bronchospasm) being extremly short acting for 15 seconds only class ECG QT Conduction Refractory velocity period IA ++ ↓ ↑ IB 0 no ↓ IC + ↓ no II 0 ↓In SAN and ↑ in SAN and AVN AVN III ++ No ↑ IV 0 ↓ in SAN and ↑ in SAN and AVN AVN  1st: Reduce thrombus formation by using anticoagulant warfarin 2nd: Prevent the arrhythmia from converting to ventricular arrhythmia: First choice: class II drugs: After MI or surgery Avoid in case of heart failure Second choice: class IV Third choice: digoxin Only in heart failure of left ventricular dysfunction 3rd: Conversion of the arrhythmia into normal sinus rhythm: Class III: IV ibutilide, IV/oral amiodarone, or oral sotalol Class IA: Oral quinidine + digoxin (or any drug from the 2nd step) Use direct current in case of Class IC: unstable hemodynamic Oral propaphenone or IV/oral flecainide patient  Premature ventricular beat (PVB) First choice: class II IV followed by oral Early after MI Avoid using Second choice: amiodarone class IC after MI → ↑ mortality First choice: Lidocaine IV Repeat injection Second choice: procainamide IV Adjust the dose in case of renal failure Third choice: class III drugs Especially amiodarone and sotalol  CLINICAL PHARMACOLOGIC PROPERTIES OF ANTIARRHYTHMIC DRUGS 1-May suppress diseased sinus nodes. 4-May be effective in atrial arrhythmias caused by digitalis. 2-Anticholinergic effect and direct depressant action. 5-Half-life of active metabolites much longer. 3-Especially in Wolff-Parkinson-White syndrome.  Antianginal medicines Department of Pharmacology and Clinical Pharmacology  Chronic Ischemic Heart Disease also known as Coronary artery disease (CAD). It is a is a group of diseases that includes: stable angina, unstable angina, myocardial infarction, sudden coronary death.  Ischemic heart disease According to the new International Classification of Diseases, announced by the WHO in 2018, ischemic heart disease includes: Acute diseases: Angina Acute myocardial infarction – acute MI Subsequent myocardial infarction Coronary thrombosis without MI Acute nonspecific ischemic heart disease Chronic diseases: ❖ Old MI ❖ Ischemic heart disease ❖ Nonspecific chronic ischemic heart disease Current complications after acute myocardial infarction: ❑ Dressler syndrome ❑ Complications after acute MI: pericarditis, rupture of the heart wall, ventricular aneurysm, pulmonary embolism, arrhythmia, cardiogenic shock Unspecified ischemic heart disease.  FACTORS AFFECTING MYOCARDIAL OXYGEN SUPPLY AND DEMAND Varvinskiy, Andrey & Yuan, Shuai & Felicidad, Bo. (2023). UPDATE IN ANAESTHESIA. Goodman and Gilman's The Pharmacological Basis of Therapeutics 12th Ed. (2011) David Golan, Armen H. Tashjian, Ehrin J. Armstrong - Principles of Pharmacology, The Pathophysiologic Basis of Drug Therapy- 2011  According to the MOA I. Remedies that reduce the oxygen demand by the myocardium and increase its delivery. 1. Nitrovasodylators a) Organic nitrates Short acting: Nitroglycerine (Glyceryl trinitrate) Long acting: Nitroglycerine (Nitrong, Trinitrolong, Sustac), Isosorbide dinitrate (short acting by sublingual route), Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate b ) Sydnonimine: molsidomine c) Nitrate-like drug (NO donator): Sodium nitroprusside 2. Ca 2+ channel blockers: Nifedipine, Diltiazem, Verapamil, Amlodipine, Felodipine, Lercanidipine 3. Potasium channel activators (oppeners): Nicorandil, Pinacidil 4. If-channel inhibitors: Ivabradine 5. Late sodium influx inhibitors: Ranolazine 6. Various preparations with anti-anginal action: Amiodarone II. Remedies that reduce myocardial oxygen demand β- adrenoblockers: Propranolol, Talinolol, Metoprolol, Atenolol III. Remedies that increase myocardial oxygen delivery: 1. Musculotropic coronarodilators : a) with adenosine mechanism: Dipyridamole, Lidoflazine b) Inhibitors of phfosphodiesteraze: Aminophylline, Carbocromen, Xantinol nicotinate c) other spasmolytics: Drotaverine, Baralgin 2. Remedy that removes reflectory coronarospasm: Validol. IV. Cardioprotectors Trimetazidine V. Antithrombotic preparations: Antiplatelet agents: acetylsalicylic acid, clopidogrel, prasugrel Anticoagulants: heparin, enoxaparin, bemiparin,rivaroxaban, fondaparinux VI. Preparations that inhibit atherosclerosis: Lipid-lowering agents: atorvastatin, rosuvastatin,pravastatin, fenofibrate  Clinical classification A.Used to abort or terminate attack GTN, Isosorbide dinitrate (sublingually). B.Used for chronic prophylaxis All other drugs.  Molecullar mechanism of action of nitrates da Silva GM, da Silva MC, Nascimento DVG, Lima Silva EM, Gouvêa FFF, de França Lopes LG, Araújo AV, Ferraz Pereira KN, de Queiroz TM. Nitric Oxide as a Central Molecule in Hypertension: Focus on the Vasorelaxant Activity of New Nitric Oxide Donors. Biology. 2021; 10(10):1041. https://doi.org/10.3390/biology10101041 Systemic mechanism of action of nitroglycerin  Antiplatelet action of nitroglycerin 1. Activates soluble guanylate cyclase (sGC) ⇒ GTP into cGMP⇒ ⇑ intracellular cGMP and ⇑ of S-nitrosothyols ⇒ inhibitors of platelet aggregation. 2. Activation of sGC inhibits Ca2+ flow ⇒ reduces the binding of fibrinogen to the glycoproteic receptor GPIlb/IIIa of platelets.  Indications of nitrates Cessation of angina pectoris attacks: Nitroglycerin: in the form of tablets, aerosol, capsules with oily solution; Isosorbide dinitrate – sublingual tablets; Prophylaxis of angina pectoris accesses: Nitroglycerin: in the form of tablets, aerosol, capsules with oily solution; Isosorbide dinitrate – sublingual tablets; Treatment of angina pectoris: isosorbide dinitrate, isosorbide mononitrate Treatment of congestive heart failure: isosorbide dinitrate, isosorbide mononitrate, nitroglycerin (TTS); Acute myocardial infarction: nitroglycerin (aerosol, sublingual tablets, intravenous solutions); Treatment of left acute heart failure – nitroglycerin (sublingual tablets, intravenous solutions);  Contraindications of nitrates Shock states, including cardiogenic; Collapse, hypotension; Acute myocardial infarction with low filling pressure of the LV; Intracranial hemorrhage, recent craniocerebral trauma; Intracranial hypertension; Combination with phosphodiesterase V inhibitors (sildenafil, etc.) Toxic pulmonary edema; Hypertrophic aortal stenosis; Isolated mitral stenosis; Angle-closure glaucoma; Severe anemia, hyperthyroidism; Tamponade of the heart; Hemorrhagic CVA; Constrictive pericarditis; Hypovolemia, allergy to nitrates  Adverse reactions of nitrates Very common: headache, hyperemia of the face, nausea, vomiting; Common: dizziness, asthenia, drowsiness, reflex tachycardia, hypotension, orthostatic collapse. Rare: worsening of symptoms of angina pectoris; Rarely: allergic reactions, skin vasodilation with erythema, exfoliative dermatitis Exceptional: collapse with bradycardia and syncope; hypotension with cerebral ischemia. Prolonged treatment with high doses: tachyphylaxis, acute tolerance High doses of nitroglycerin can cause: vomiting, cyanosis, restlessness, methemoglobinemia, respiratory failure, transient hypoxemia Goodman and Gilman's The Pharmacological Basis of Therapeutics 12th Ed. (2011) Molsidomine - molecular mechanism of action: As a result of biotransformation, an active metabolite ( N-nitrozoamino-acetonitrile) is formed, which directly releases physiologically active NO. NO stimulates GC with increased concentration of cGMP that promotes vasodilation - antianginal effect Pharmacodynamic advantages: The mechanism of action is not thiol-dependent and tachyphylaxis does not develop Does not induce reflex tachycardia and positive inotropism The main side effects: moderate headache , mild hypotension.  Molsidomine Indications: Jugulation of bouts of angina pectoris (at ineffectiveness of nitrates); Prophylaxis of angina pectoris bouts (at ineffectiveness of nitrates); Treatment of angina pectoris (in case of nitrates intolerance). Calcium channel blockers Phenylalkylamines Verapamil Calcium channel blockers Benzothiazepines Diltiazem Nifedipine Amlodipine Dihydropyridines Nicardipine Lercanidipine Nitrendipine  Mechanism of action of calcium channel blockers Sueta, D., Tabata, N. & Hokimoto, S. Clinical roles of calcium channel blockers in ischemic heart diseases. Hypertens Res 40, 423–428 (2017). https://doi.org/10.1038/hr.2016.183  Calcium channel blockers Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.  Calcium channel blockers Effects: antihypertensive (hypotensive); cardioprotective, nephroprotective; antiarrhythmic; decrease the tone and contractile activity of the uterus (tocolytic effect); antiatherogenic; Antiplatelet. Indications: Stable and vasospastic angina pectoris Angina pectoris with supraventricular arrhythmias (verapamil, diltiazem); Angina pectoris with heart failure and hypertension (dihydropyridines)  Side effects Nausea Phenylalkyl- Constipation amines, Bradycardia, hypotension Benzo- Flushing, headache and ankle edema thiazepines Worsening of A-V block and HF Cardiac arrest (when IV in SSS) Palpitation, flushing, ankle edema, hypotension, headache, drowsiness and nausea Dihydro- Increased frequency of angina in some patients pyridines Increase urine voiding difficulty in elderly males Gastroesophageal reflux may be worsened  IVABRADINE Mechanism of action – Block If current in SA node ‘funny’ cation channels that open during early part of slow diastolic depolarization Effects – Decrease HR – decrease myocardial oxygen demand – Prolongation of the diastole – improve myocardial oxygen delivery improve exercise tolerance in stable angina and reduce angina frequency  IVABRADINE Indications – chronic stable angina in patients with sinus rhythm – chronic stable angina in patients who are intolerant to β blockers – chronic stable angina in patients when the β blockers are contraindicated – inappropriate sinus tachycardia. Side effects – excess bradycardia – visual disturbance – extrasystoles – prolongation of P-R interval – Headache, dizziness, nausea  Contraindications Contraindications – Heart rate 100 beats/min chronic nitrate therapy in angina does not decrease Right ventricular infarction is suspected Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.  ANTIANGINAL AND OTHER ANTI-ISCHAEMIC DRUGS 545 Hypotension caused by nitrate limits the Haemoglobin administration of β blockers which have more Sod. nitrite (10 ml of 3% solution i.v.) powerful salutary effects.* Methaemoglobin Patient has taken sildenafil in the past 24 Cyanide hours. Cyanomethaemoglobin 4. CHF and acute LVF The role of vasodilators Sod. thiosulfate (50 ml of 25% solution i.v.) in CHF is described in Ch. 37. Nitrates afford relief by venous pooling of blood (which can Methaemoglobin + Sod. thiocyanate ↓ be aided by sitting posture while managing acute Excreted in urine LVF or severe chronic CHF) → reduced venous Sodium nitrite is used for this purpose because it is return (preload) → decreased end diastolic volume a very weak vasodilator; large doses (>300 mg) → improvement in left ventricular function by sufficient to generate enough methaemoglobin can be Laplace law and regression of pulmonary injected i.v. without producing hypotension. congestion. Intravenous GTN is the preparation of choice for emergency use. Rate of infusion β BLOCKERS (see Ch. 10) CHAPTER 39 must be guided by continuous haemodynamic monitoring. These drugs do not dilate coronaries or other blood vessels; total coronary flow is rather reduced 5. Biliary colic due to disease or morphine— due to blockade of dilator β2 receptors. However, responds to sublingual GTN or isosorbide flow to the ischaemic subendocardial region is dinitrate. not reduced because of favourable redistribution and decrease in ventricular wall tension. β blockers 6. Esophageal spasm Sublingual GTN act by reducing cardiac work and O2 consumption promptly relieves pain. Nitrates taken before a as a consequence of decreased heart rate, inotropic meal facilitate feeding in esophageal achalasia state and mean BP. This is marginal at rest. More by reducing esophageal tone. importantly, β blockers limit increase in cardiac work that occurs during exercise or anxiety by 7. Cyanide poisoning Nitrates generate met- antiadrenergic action on heart. haemoglobin which has high affinity for cyanide All β blockers are nearly equally effective radical and forms cyanomethaemoglobin. in decreasing frequency and severity of attacks However, this may again dissociate to release and in increasing exercise tolerance in classical cyanide. Therefore, sodium thiosulfate is given angina, but cardioselective agents (atenolol, to form Sod. thiocyanate which is poorly metoprolol) are preferred over nonselective β1 dissociable and is excreted in urine. + β2 blockers (e.g. propranolol). The latter are Cytochrome and other oxidative enzymes are particularly prone to worsen variant angina due thus protected from cyanide; even that which has to unopposed α receptor mediated coronary complexed CN is reactivated. However, early constriction that may accentuate the coronary treatment is critical. The antidotes should be spasm. Long term β blocker therapy clearly lowers repeated as required. risk of sudden cardiac death among ischaemic heart disease patients. In angina pectoris, β-blockers are to be taken on a regular schedule; not on ‘as and when * American Heart Association/American College of Cardiology guidelines for the management of patients required’ basis. The dose has to be individua- with acute myocardial infarction. Circulation 2004, 110, lized. Abrupt discontinuation after chronic use 588-636. may precipitate severe attacks, even MI. Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical. 546 CARDIOVASCULAR DRUGS Voltage sensitive calcium channels L-type T-type N-type (Long lasting current) (Transient current) (Neuronal) 1. Conductance 25 pS 8 pS 12–20 pS 2. Activation threshold High Low Medium 3. Inactivation rate Slow Fast Medium 4. Location and Excitation-contraction SA node—pace- Only on neurones function coupling in cardiac and maker activity in CNS, sympathetic smooth muscle ‘T’ current and and myenteric plexuses SA, A-V node—con- repetitive spikes —transmitter release ductivity in thalamic and Endocrine cells— other neurones hormone release Endocrine cells— Neurones—transmitter hormone release release Certain arteries— constriction 5. Blocker Nifedipine, diltiazem, Mibefradil, flunari- ω-Conotoxin verapamil verapamil zine, ethosuximide SECTION 8 Unstable angina (UA)/Non-ST-elevation MI Calcium channels (NSTEMI) Unless contraindicated, β blockers Three types of Ca 2+ channels have been described in smooth are routinely used in UA/NSTEMI. However, they muscles (other excitable cells as well): should be given only after starting nitrate ± (a) Voltage sensitive channel Activated when membrane potential drops to around –40 mV or lower. calcium channel blocker to counteract coronary (b) Receptor operated channel Activated by Adr and vasospasm, if present (β blockers carry the risk other agonists—independent of membrane depolarization (NA of worsening coronary vasospasm). β blockers contracts even depolarized aortic smooth muscle by promoting reduce myocardial O 2 demand and afford influx of Ca2+ through this channel and releasing Ca2+ from additional benefit by reducing risk of impending sarcoplasmic reticulum). MI/sudden cardiac death. (c) Leak channel Small amounts of Ca2+ leak into the resting cell and are pumped out by Ca2+ATPase. Mechanical stretch promotes inward movement of Ca2+, through the leak CALCIUM CHANNEL BLOCKERS channel or through separate stretch sensitive channel. Verapamil was developed in Germany in 1962 as a coronary dilator. It had additional cardiodepressant property, but its The voltage sensitive Ca2+ channels are heterogeneous: three mechanism of action was not known. Fleckenstein (1967) major types have been identified (see box): showed that it interfered with Ca2+ movement into the cell. All voltage sensitive Ca2+ channels are membrane spanning In the subsequent years, a large number of chemically diverse funnel shaped glycoproteins that function as ion selective Ca2+ channel blockers (CCBs) with different pharmacological valves. They are composed of a major α 1 subunit which profiles have been produced. encloses the ion channel and other modulatory subunits like Three important classes of calcium channel α 2 ,β , γ and δ. In L-type Ca 2+ channels each subunit exists in multiple isoforms which may be site specific, e.g. blockers are examplified by: Skeletal muscle L-channels are: α1s. α2/δa. β1. γ Verapamil—a phenyl alkylamine, hydrophilic Cardiac muscle L-channels are: α 1ca. α2/δc. β2 papaverine congener. Smooth muscle L-channels are: α1cb. α 2/δ. β3 Nifedipine—a dihydropyridine (lipophilic). Even smooth muscle L-channels differ between vascular and nonvascular. Moreover, distribution may be heterogeneous Diltiazem—a hydrophilic benzothiazepine. in different parts of the vascular bed. The dihydropyridines (DHPs) are the most potent Only the voltage sensitive L-type channels are blocked Ca2+ channel blockers, and this subclass has by the CCBs. The 3 groups of CCBs viz. phenylalkylamines proliferated exceptionally. (verapamil), benzothiazepine (diltiazem) and dihydropyridines Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.  ANTIANGINAL AND OTHER ANTI-ISCHAEMIC DRUGS 547 (nifedipine) bind to their own specific binding sites on the through binding to troponin—allowing interaction α1 subunit; all restricting Ca2+ entry, though characteristics of myosin with actin (see Fig. 37.3). The CCBs of channel blockade differ. Further, different drugs may have differing affinities for various site specific isoforms of the would thus have negative inotropic action. L-channels. This may account for the differences in action The 0 phase depolarization in SA and A-V exhibited by various CCBs. The vascular smooth muscle nodes is largely Ca2+ mediated. Automaticity and has a more depolarized membrane (RMP about –40 mV) conductivity of these cells appear to be dependent than heart. This may contribute to vascular selectivity of certain CCBs. on the rate of recovery of the Ca2+ channel. The L-type Ca2+ channels activate as well as PHARMACOLOGICAL ACTIONS AND inactivate at a slow rate. Consequently, Ca2+ depo- ADVERSE EFFECTS larized cells (SA and A-V nodal) have a The common property of all three subclasses of considerably less steep 0 phase and longer CCBs is to inhibit Ca2+ mediated slow channel refractory period. The recovery process which component of action potential (AP) in smooth/ restores the channel to the state from which it cardiac muscle cell. The two most important can again be activated (Fig. 39.4) by membrane actions of CCBs are: depolarization is delayed by verapamil and (i) Smooth muscle (especially vascular) relaxa- diltiazem (resulting in depression of pacemaker CHAPTER 39 tion. activity and conduction), but not by DHPs (they (ii) Negative chronotropic, inotropic and dromo- have no negative chronotropic/dromotropic tropic action on heart. action). Moreover, channel blockade by verapamil is enhanced at higher rates of stimulation, that Smooth muscle Smooth muscles depolarize by nifedipine is independent of frequency, while primarily by inward Ca2+ movement through diltiazem is intermediate. Thus, verapamil slows voltage sensitive channel. These Ca2+ ions trigger sinus rate and A-V conduction, but nifedipine does release of more Ca2+ from intracellular stores and not. Effect of diltiazem on sinus node automaticity together bring about excitation-contraction and A-V conduction is similar to that of verapamil. coupling through phosphorylation of myosin light chain as depicted in Fig. 39.3. The CCBs cause relaxation by decreasing intracellular availability of Ca2+. They markedly relax arterioles but have mild effect on veins. Extravascular smooth mus- cle (bronchial, biliary, intestinal, vesical, uterine) is also relaxed. The dihydropyridines (DHPs) have the most marked smooth muscle relaxant and vasodilator action; verapamil is somewhat weaker followed by diltiazem. Nitrendipine and few other DHPs have been shown to release NO from endothelium and inhibit cAMP-phosphodiesterase resulting in raised smooth muscle cAMP. These additional mechanisms may account for their predominant smooth muscle relaxant action. Released endothelial NO may exert antiatherosclerotic action. Heart In the working atrial and ventricular fibres, Ca2+ moves in during the plateau phase of AP and releases more Ca2+ from sarcoplasmic Fig. 39.4: Activation–inactivation–recovery cycle of reticulum. This Ca2+ surge causes contraction cardiac Ca2+ channels Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical. 548 CARDIOVASCULAR DRUGS TABLE 39.2 Comparative properties of representative calcium channel blockers Verapamil Nifedipine Diltiazem 1. Channel blocking potency ++ +++ + 2. Frequency dependence of ++ – + channel blockade 3. Channel recovery rate Much delayed No effect Delayed 4. Cardiac effects (In vivo at usual clinical doses) Heart rate ↓ ↑ ↓, – A-V conduction velocity ↓↓ – ↓↓ Contractility –, ↓ ↑ ↓,↑ Output –, ↓ ↑ –, ↑ 5. Vascular smooth muscle ++ +++ + relaxation 6. Clinical use in Arrhythmia Angina Angina Angina Hypertension Hypertension (Hypertension) Arrhythmia SECTION 8 The relative potencies to block slow channels CCBs, while flushing, headache and ankle edema in smooth muscle do not parallel those in the are less common. Hypotension is occasional and heart. The DHPs are more selective for smooth tachycardia (common with DHPs) is absent. It muscle L channels. At concentrations which cause can accentuate conduction defects (contraindicated vasodilatation they have negligible negative in 2nd and 3rd degree A-V block) and precipitate inotropic action which is most prominent in CHF in patients with preexisting disease. Cardiac verapamil. Diltiazem causes less depression of arrest has occurred on i.v. injection and when contractility than verapamil. Important differen- it is given to patients with sick sinus. ces between the three representative CCBs are Interactions Verapamil should not be given summarized in Table 39.2. Their cardiac electro- with β blockers—additive sinus depression, physiological effects are compared in Table 38.1. conduction defects or asystole may occur. Verapamil It dilates arterioles and has some It increases plasma digoxin level by decreasing α adrenergic blocking activity—decreases t.p.r. its excretion: toxicity can develop. but BP is only modestly lowered. The pronounced It should not be used along with other cardiac direct cardiodepressant effect is partially offset depressants like quinidine and disopyramide. in vivo by reflex effects of peripheral vasodilata- tion. The HR generally decreases, A-V conduc- Diltiazem It is somewhat less potent vasodilator tion is slowed, but c.o. is maintained by reflex than nifedipine and verapamil, and has modest sympathetic stimulation and reduction in aortic direct negative inotropic action, but direct impedance. However, ventricular contractility may depression of SA node and A-V conduction are be markedly impaired in CHF patients. Coronary equivalent to verapamil. Usual clinical doses flow is increased. produce consistent fall in BP with little change Dose: 40–160 mg TDS oral, 5 mg by slow i.v. injection. or decrease in HR. Large dose or i.v. injection CALAPTIN 40, 80 mg tabs, 120, 240 mg SR tabs, 5 mg/2 ml decreases t.p.r. markedly which may elicit reflex inj. VASOPTEN 40, 80, 120 mg tab. cardiac effects. Diltiazem dilates coronaries. Dose: 30–60 mg TDS–QID oral; DILZEM, 30, 60 mg tabs, Adverse effects Nausea, constipation and 90 mg SR tab; 25 mg/5 ml inj; ANGIZEM 30, 60, 90, 120, bradycardia are more common than with other 180 mg tab, DILTIME 30, 60 mg tab; 90, 120 mg SR tab. Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.  ANTIANGINAL AND OTHER ANTI-ISCHAEMIC DRUGS 549 Adverse effects Side effects are milder, but selectivity and major differences in pharmaco- the profile is similar to verapamil. Like verapamil, kinetic characteristics exhist (Table 39.3). The it also increases plasma digoxin level. slower and longer acting ones induce less reflex Diltiazem should not be given to patients with sympathetic stimulation. Tachycardia, propensity preexisting sinus, A-V nodal or myocardial to increase cardiac work, flushing, headache, disease. Only low doses should be given to patients dizziness are subdued. They are the favoured on β blockers. DHPs because of milder side effects and because Nifedipine It is the prototype DHP with a rapid increased mortality among post-MI patients is onset and short duration of action. The overriding reported with the regular short-acting nifedipine action of nifedipine is arteriolar dilatation → t.p.r. formulation. decreases, BP falls. The direct depressant action Felodipine It differs from nifedipine in having on heart requires much higher dose, but a weak greater vascular selectivity, larger tissue distribu- negative inotropic action can be unmasked after tion and longer t½. The extended release prepara- β blockade. As described above, it does not tion is suitable for once daily administration. depress SA node or A-V conduction. Reflex Dose: 5–10 mg OD, max. 10 mg BD. sympathetic stimulation of heart predominates FELOGARD, PLENDIL, RENDIL 2.5, 5, 10 mg ER tab. CHAPTER 39 producing tachycardia, increased contractility and Amlodipine Pharmacokinetically it is the most c.o. No decrease in venous return along with lowering of afterload aids increase in c.o. distinct DHP and the most popular. Oral Coronary flow is increased. absorption is slow, but complete; peak blood level Dose: 5–20 mg BD–TDS oral. occurs. after 6 to 9 hr—the early vasodilator side CALCIGARD, DEPIN, NIFELAT 5, 10 mg cap, also 10 mg, effects (palpitation, flushing, headache, postural 20 mg S.R. (RETARD) tab; ADALAT RETARD 10, 20 mg dizziness) are largely avoided. Because of less SR tab. extensive and less variable first pass metabolism, Adverse effects Frequent side effects are palpi- its oral bioavailability is higher and more tation, flushing, ankle edema, hypotension, consistent. Volume of distribution and t½ are headache, drowsiness and nausea. These are exceptionally long: diurnal fluctuation in blood related to peaks of drug level in blood: can be level is small and action extends over the next minimized by low starting dose or fractionation morning. of dose or use of retard formulation. Ankle edema Dose: 5–10 mg OD; AMLOPRES, AMCARD, AMLOPIN, is not due to fluid retention, but because of greater MYODURA 2.5, 5, 10 mg tabs. dilatation of precapillary than postcapillary S(–)Amlodipine The single enantiomer prepa- vessels. Nifedipine has paradoxically increased ration is effective at half the dose and is claimed the frequency of angina in some patients. Higher to cause less ankle edema. mortality among post MI patients has been con- Dose: 2.5–5 mg OD; firmed. However, it has been safely administered S-NUMLO, S-AMCARD, ASOMEX, ESAM 2.5, 5 mg tabs. with β blockers and digoxin. By its relaxant effect on bladder nifedipine Nitrendipine A DHP with oral bioavailability can increase urine voiding difficulty in elderly of 10–30% and elimination t½ of 4–12 hours. males. Gastroesophageal reflux may be worsened It has been shown to release NO from the by all DHPs due to relaxation of lower esophageal endothelium and inhibit cAMP phosphodiesterase. sphincter. It has also been reported to hamper These may be the additional mechanisms of diabetes control by decreasing insulin release. vasodilator action. The endothelial NO may retard atherosclerosis. Ventricular contractility and Other dihydropyridines (DHPs) A-V conduction are not depressed. Nitrendipine All DHPs have pharmacodynamic profile similar is indicated in hypertension and angina pectoris. to nifedipine. However, minor differences in organ Dose: 5–20 mg OD; NITREPIN, CARDIF 10, 20 mg tabs. Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical. 550 CARDIOVASCULAR DRUGS Lacidipine A highly vasoselective newer DHP All are 90–100% absorbed orally, peak occurring suitable for once daily administration. It is claimed at 1–3 hr (except amlodipine 6–9 hr). The oral to attain higher concentration in vascular smooth bioavailability of Ca 2+ channel blockers is muscle membrane, and is approved only for use incomplete with marked inter- and intra-individual as antihypertensive. variations. This is due to high first pass metabolism Dose: 4 mg OD, increase to 6 mg OD if required. (modest and less variable for amlodipine). All LACIVAS, SINOPIL 2, 4 mg tabs. are highly plasma protein bound (min.: diltiazem Nimodipine It is a short-acting DHP which 80%, max.: felodipine 99%). penetrates blood-brain barrier very efficiently due The Ca2+ channel blockers are high clearance to high lipid solubility. As such, it is believed drugs with extensive tissue distribution. All are to selectively relax cerebral vasculature and is > 90% metabolized in liver and excreted in urine. approved for prevention and treatment of Some metabolites are active. The elimination t½ neurological deficit due to cerebral vasospasm are in the range of 2–6 hr, but that of amlodipine following subarachnoid haemorrhage or ruptured is exceptionally long; followed by lacidipine, congenital intracranial aneurysms. Side effects are nitrendipine and felodipine. headache, flushing, dizziness, palpitation and On chronic use verapamil decreases its own metabolism—bioavailability is nearly doubled and SECTION 8 nausea. Dose: 30–60 mg 4–6 hourly for 3 weeks following t½ is prolonged. subarachnoid haemorrhage; VASOTOP, NIMODIP, NIMOTIDE 30 mg tab; 10 mg/50 ml inj. USES Lercanidipine Another DHP similar to nifedi- Calcium channel blockers can be safely given pine, but with longer duration of action. Peak to patients with obstructive lung disease and plasma concentrations occur at 1.5–3 hrs; t½ is peripheral vascular disease in whom β blockers 5–10 hours. It is indicated in hypertension at a are contraindicated. The problem of rebound dose of 10–20 mg OD. worsening of angina on withdrawal after chronic LEREZ, LERKA 10, 20 mg tabs. use is less marked with CCBs than with β blockers. Benidipine A long-acting DHP that owes its 1. Angina pectoris All CCBs are effective in long duration of action to slow dissociation from reducing frequency and severity of classical as the DHP receptor on the smooth muscle cell. well as variant angina. Benefit in classical angina Marketed only in India and Japan, it is indicated appears to be primarily due to reduction in cardiac in hypertension and angina pectoris. work: mainly as a result of reduced afterload and Dose: 4–8 mg OD; CARITEC 4, 8 mg tab. the BP × HR product. Though, they can increase coronary flow in normal individuals, this is PHARMACOKINETICS unlikely to be significant in patients with fixed The pharmacokinetic parameters of representative arterial obstruction. Exercise tolerance is Ca2+ channel blockers are tabulated in Table 39.3. increased. TABLE 39.3 Pharmacokinetic characteristics of calcium channel blockers Drug Bioavailability Vd CL Active Elimin. (L/Kg) (L/hr/Kg) metabolite t½ (hr) 1. Verapamil 15–30% 5.0 0.9 Yes 4–6 2. Diltiazem 40–60% 3.0 0.7 Yes 5–6 3. Nifedipine 30–60% 0.8 0.42 Minor 2–5 4. Felodipine 15–25% 10.0 1.0 None 12–18 5. Amlodipine 60–65% 21.0 0.42 None 35–45 Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.  ANTIANGINAL AND OTHER ANTI-ISCHAEMIC DRUGS 551 Many controlled studies and metaanalysis of ventricular rate in supraventricular arrhythmias have concluded that myocardial ischaemia may (see Ch. 38). be aggravated by short-acting DHPs. This may 4. Hypertrophic cardiomyopathy The negative be due to decreased coronary flow secondary to inotropic action of verapamil can be salutary in fall in mean arterial pressure, reflex tachycardia this condition. and coronary steal. The direct cardiac effect of verapamil and diltiazem to reduce O2 requirement. 5. Other uses Nifedipine is an alternative drug In addition, less marked reflex sympathetic stimu- for premature labour (see p. 333). Verapamil has lation makes them unlikely to aggravate ischaemia. been used to suppress nocturnal leg cramps. The Trials using high dose regular short-acting DHPs reduce severity of Raynaud’s episodes. nifedipine formulation have reported increased mortality among MI patients. The sudden rush DRUG COMBINATIONS IN ANGINA of sympathetic activity evoked by each dose of these preparations has been held responsible for Along with any of the drugs used for chronic the deleterious effect. The slow and long-acting prophylaxis of angina, sublingual short-acting DHPs do not share this disadvantage. There is nitrate is allowed on ‘as and when’ required basis CHAPTER 39 some evidence that verapamil and diltiazem reduce to abort and terminate anginal attacks when they reinfarction and mortality in MI patients (similar occur. In addition to the symptomatic treatment to that achieved by β blockers) with uncom- with antianginal drugs, therapy aimed at modifying promised ventricular function. course of coronary artery disease (CAD), and at cardioprotection with antiplatelet drugs, statins Myocardial infarction: The concensus opinion and ACE inhibitors is advised by professional is against use of CCBs in evolving MI as well guidelines. The β blockers ward-off attacks of as to prevent further attacks, but verapamil/diltia- angina as well as afford cardioprotection. zem may be employed for secondary prophylaxis Of the three major classes of antianginal drugs when β blockers are contraindicated. described above, generally one agent is used The capacity of CCBs to prevent arterial initially; choice depends on the stage and severity spasm is undoubtedly responsible for the of disease, associated cardiac/other medical beneficial effect in variant angina. Reduction of conditions and individual acceptability of side cardiac O2 demand would also work in the same effects. The antianginal efficacy and tolerability direction. No significant difference in efficacy of long-acting nitrates (including transdermal among different CCBs has been noted in angina GTN), β blockers and long-acting CCBs is similar. pectoris. However, direct comparative studies have found CCBs are not a first line treatment of unstable β blockers to achieve greater reduction in the angina, but may be used as add on therapy to number of anginal attacks than CCBs, but nitrates when coronary vasospasm is prominent objective measurements and outcome were not and is not counteracted by nitrate alone. Antiplatelet different. When monotherapy is unable to provide drugs and β blockers + a nitrate are the primary adequate relief in tolerated doses, concurrent use drugs which reduce infarction and mortality in of 2 or 3 drugs may be required. UA. Use of nifedipine/DHPs in non β blocked I. β blocker + long-acting nitrate combination patients is to be avoided. is rational in classical angina because: (a) Tachycardia due to nitrate is blocked by β 2. Hypertension All DHPs, diltiazem and blocker. verapamil are among the first line drugs for (b) The tendency of β blocker to cause ventri- hypertension (see Ch. 40). cular dilatation is counteracted by nitrate. 3. Cardiac arrhythmias Verapamil and diltia- (c) The tendency of β blocker to reduce total zem are highly effective in PSVT and for control coronary flow is opposed by nitrate. Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical. 552 CARDIOVASCULAR DRUGS II. The above advantages may also be obtained ATP activated K+ channel by combining a slow acting DHP (in place of Ca2+ activated K+ channel Receptor operated K+ channel nitrate) with β blocker. The DHPs are particularly Na+ activated K+ channel suitable if there is an element of coronary vaso- Cell volume sensitive K+ channel spasm in classical angina. However, verapamil These channels regulate K+ movement outward as well as or diltiazem should not be used with β blocker inward, serve diverse functions and exhibit different sensitivities to drugs. As such, K+ channel openers exhibit since their depressant effects on SA and A-V node considerable diversity in action. may add up. The above mentioned drugs open ATP activated K+ III. Nitrates primarily decrease preload, while channels in smooth muscles. Their most prominent action is hyperpolarization and relaxation of vascular as well as CCBs have a greater effect on afterload and on visceral smooth muscle. The hypotensive K+ channel opener coronary flow. Their concurrent use may decrease diazoxide reduces insulin secretion, while sulfonylureas cardiac work and improve coronary perfusion to promote insulin release by blocking K+ channels in pancreatic an extent not possible with either drug alone. This β cells. Nicorandil has been introduced as an antianginal combination may be especially valuable in severe drug in the 1990s. vasospastic angina, and when β blockers are Nicorandil This dual mechanism antianginal contraindicated. drug activates ATP sensitive K+ channels (KATP) thereby hyperpolarizing vascular smooth muscle. SECTION 8 IV. In the more severe and resistant cases of classical angina, combined use of all the three The vasodilator action is partly antagonized by classes is indicated. Since their primary K+ channel blocker glibenclamide. Like nitrates mechanism of benefit is different, supraadditive it also acts as a NO donor—relaxes blood vessels results may be obtained. by increasing cGMP. Thus, arterial dilatation is Nitrates primarily decrease preload. coupled with venodilatation. Coronary flow is CCBs mainly reduce afterload + increase increased; dilatation of both epicardial conduc- coronary flow. ting vessels and deeper resistance vessels has been β blockers decrease cardiac work primarily demonstrated. No significant cardiac effects on by direct action on heart. contractility and conduction have been noted. Verapamil/diltiazem should be avoided in such Beneficial effects on angina frequency and combinations. exercise tolerance comparable to nitrates and In randomized comparative studies, combinations have been CCBs have been obtained in stable as well as found superior to monotherapy only in more severe cases, vasospastic angina. Nicorandil is believed to exert but not in mild angina. Recent evidence suggests a greater role of reflex vasospasm of arteriosclerotic segments of cardioprotective action by simulating ‘ischaemic coronary arteries in precipitating attacks of angina. As such, preconditioning’ as a result of activation of mito- coronary dilator action of DHPs/nitrates may be more relevant. chondrial KATP channels. Ischaemic precondition- ing in a phenomenon in which brief periods of POTASSIUM CHANNEL OPENERS ischaemia and reperfusion exert a cardioprotective effect on subsequent total vascular occlusion, and Minoxidil and diazoxide are K+ channel openers involves opening of mito.KATP channels. which were used earlier in severe hypertension A large ‘Impact of nicorandil in angina’ (IONA, 2002) and hypertensive emergencies. Novel K + channel randomized trial found nicorandil to reduce acute coronary events in high risk stable angina patients. openers like nicorandil, pinacidil and cromakalim have been developed in the 1990s. Nicorandil is well absorbed orally, nearly The chemical (intracellular 150 mM vs extracellular completely metabolized in liver and is excreted 4–5 mM) and electrical (inside –90 mV) gradients for K+ in urine. It exhibits biphasic elimination; the initial across the plasma membrane are in opposite directions. As rapid phase t½ is 1 hour and later slow phase such, depending on the channel, this ion can move in either t½ is 12 hours. direction. Such movement is regulated by multiple types of K+ channels, viz: Side effects of nicorandil are flushing, Voltage dependent K+ channel palpitation, weakness, headache, dizziness, nausea Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.  ANTIANGINAL AND OTHER ANTI-ISCHAEMIC DRUGS 553 and vomiting. Large painful aphthous ulcers in of coronary and cerebral thrombosis in post-MI and post- the mouth, which heal on stopping nicorandil have stroke patients, as well as to prevent thrombosis in patients with prosthetic heart valves (see Ch. 44). been reported. Nitrate like tolerance does not Dose: 25–100 mg TDS; PERSANTIN, CARDIWELL 25, 75, occur with nicorandil, but it has the potential to 100 mg tab. interact with sildenafil. 2. Trimetazidine This antianginal drug acts by Dose: 5–20 mg BD; NIKORAN, 5, 10 mg tabs, 2 mg/vial, 48 mg/vial inj; KORANDIL 5, 10 mg tabs. nonhaemodynamic mechanisms. There is no effect Though nicorandil is an alternative antianginal on determinants of myocardial O2 consumption, drug, its efficacy and long term effects are less such as HR and BP, both at rest as well as during well established. It has failed to acquire wide exercise, but angina frequency is reduced and acceptance, but may be useful in resistant angina exercise capacity is increased. In patients not when combined with other drugs. Administered adequately controlled by long-acting nitrate/β i.v. during angioplasty for acute MI, it is believed blocker/CCB, addition of trimetazidine further to improve outcome. reduced anginal attacks and increased exercise duration. The mechanism of action of trimetazidine OTHER ANTIANGINAL DRUGS is uncertain, but it may improve cellular tolerance to ischaemia by: CHAPTER 39 1. Dipyridamole It is a powerful coronary dilator; Inhibiting mitochondrial long chain 3-ketoacyl-CoA- increases total coronary flow by preventing uptake and thiolase (LC3-KAT) a key enzyme in fatty acid oxidation— degradation of adenosine which is a local mediator involved thereby reducing fatty acid metabolism and increasing in autoregulation of coronary flow in response to ischaemia. glucose metabolism in myocardium. Ischaemic myo- It dilates resistance vessels and abolishes autoregulation, but cardium shifts to utilizing fatty acid as substrate, thereby has no effect on larger conducting coronary vessels. Cardiac increasing requirement of O2 for the same amount of work is not decreased because venous return is not reduced. ATP generated. Since oxidation of fatty acid requires BP is minimally altered. Accordingly, it fails to relieve anginal more O2, shift back of substrate to glucose would reduce symptoms or avert ECG changes. O2 demand.Trimetazidine has been labelled as pFOX (fatty The pharmacological success but therapeutic failure of acid oxidation pathway) inhibitor. dipyridamole has been explained on the basis of ‘coronary Limiting intracellular acidosis and Na+, Ca2+ accumulation steal’ phenomenon (Fig. 39.5C). By dilating resistance vessels during ischaemia. in nonischaemic zone as well, it diverts the already reduced Protecting against O free radical induced membrane blood flow away from the ischaemic zone. damage. Dipyridamole inhibits platelet aggregation. By potentiating PGI2 and increasing cAMP in platelets, it Trimetazidine is absorbed orally, partly meta- enhances antiaggregatory influences. Though not useful as bolized and largely excreted unchanged in urine; an antianginal drug, it is being employed for prophylaxis t½ is 6 hr. It is generally well tolerated; side effects Fig. 39.5: Diagrammatic representation of coronary haemodynamics. A—in classical angina, B — Selective nitrate action on conducting vessels, which along with ischaemic dilatation of resistance vessels, increases flow to the subendocardial region → relief of angina. C—Dipyridamole action on all resistance vessels increases blood flow to nonischaemic zone to the detriment of ischaemic zone → coronary steal Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical. 554 CARDIOVASCULAR DRUGS are—gastric burning, dizziness, fatigue and muscle Side effects reported are dizziness, weakness, cramps. Reversible parkinsonism has been reported constipation, postural hypotension, headache and in the elderly. dyspepsia. It should not be given to patients taking Trimetazidine has also been advocated for CYP3A4 inhibitors. visual disturbances, tinnitus, Méniére’s disease, Dose: 0.5–1.0 g BD as SR tab; RANOZEX, RANK, dizziness, etc., but conclusive evidence of efficacy CARTINEX, REVULANT, RANOLAZ 0.5 g SR tab. in these conditions is lacking. For ischaemic heart 4. Ivabradine This ‘pure’ heart rate lowering disease, it has been widely used in France, Spain, antianginal drug has been introduced recently as some other European countries and India, but not an alternative to β blockers. The only significant in the UK or USA. It is mostly an add on action of ivabradine is blockade of cardiac medication to conventional therapy in angina and pacemaker (sino-atrial) cell ‘f’ channels, which post-MI patients. are ‘funny’ cation channels that open during early Dose: 20 mg TDS. FLAVEDON, CARVIDON, TRIVEDON 20 mg tabs, 35 mg part of slow diastolic (phase 4) depolarization. modified release tab. The resulting inward current (If) determines the slope of phase 4 depolarization. Selective 3. Ranolazine This novel antianginal drug blockade of If current by ivabradine results in primarily acts by inhibiting a late Na+ current SECTION 8 heart rate reduction without any other electro- (late INa) in the myocardium which indirectly physiological or negative inotropic or negative facilitates Ca2+ entry through Na+/Ca2+ exchanger. lucitropic (slowing of myocardial relaxation) Reduction in Ca2+ overload in the myocardium effect. Heart rate reduction decreases cardiac O2 during ischaemia decreases contractility and has demand and prolongation of diastole tends to a cardioprotective effect. Sparing of fatty acid oxidation during ischaemia in favour of more O2 improve myocardial perfusion (O 2 supply). efficient carbohydrate oxidation by inhibiting Accordingly, in clinical trials, ivabradine has been LC3KAT has also been demonstrated. This was found to improve exercise tolerance in stable earlier believed to be the main mechanism of angina and reduce angina frequency. Ivabradine is well absorbed orally, 40% bioavailable due antianginal action of ranolazine, but is now to first pass metabolism; degraded by CYP3A4 and excreted considered secondary. Ranolazine has no effect in urine with a t½ of 2 hours. Apart from excess bradycardia, on HR and BP, but prolongs exercise duration the most important adverse effect is visual disturbance. in angina patient. Extrasystoles, prolongation of P-R interval, headache, dizziness The efficacy of ranolazine in decreasing frequency and nausea are the other problems. It should not be used if of anginal attacks and in prolonging exercise duration heart rate is 20 mm Hg. It decreases cardiac thrombus at the site of atherosclerotic obstruction preload. is the usual cause. About ¼ patients die before (b) Vasodilators: venous or combined dilator is therapy can be instituted. The remaining are best selected according to the monitored haemody- treated in specialized coronary care units with namic parameters. Drugs like GTN (i.v.), or continuous monitoring of the haemodynamic nitroprusside have been mainly used. parameters, biochemical markers and ECG to guide (c) Inotropic agents: dopamine or dobutamine i.v. the selection of drugs and dosage. Those who infusion (rarely digoxin if AF present) may be receive such facility can be greatly benefitted by needed to augment the pumping action of heart drug therapy, which according to individual needs and tide over the crisis. is directed to: 7. Prevention of thrombus extension, 1. Pain, anxiety and apprehension After pain embolism, venous thrombosis Aspirin is not relieved by 3 doses of GTN given 5 min (162–325 mg) should be given for chewing and apart, an opioid analgesic (morphine/pethidine) swallowing as soon as MI is suspected (if not or diazepam is administered parenterally. already being taken on a regular basis). This is 2. Oxygenation By O2 inhalation and assisted continued at 80–160 mg/day. Anticoagulants respiration, if needed. (heparin followed by oral anticoagulants) are used primarily to prevent deep vein thrombosis 3. Maintenance of blood volume, tissue (increased risk due to bed rest) and pulmonary/ perfusion and microcirculation Slow i.v. systemic arterial embolism. Its value in checking infusion of saline/low molecular weight dextran coronary artery thrombus extension is uncertain. (avoid volume overload). Any benefit is short-term; anticoagulants are 4. Correction of acidosis Acidosis occurs due not prescribed on long-term basis now (see to lactic acid production; can be corrected by Ch. 44). i.v. sod. bicarbonate infusion. 8. Thrombolysis and reperfusion Fibrinolytic 5. Prevention and treatment of arrhythmias agents, i.e. plasminogen activators—streptokinase/ Prophylactic i.v. infusion of a β blocker (unless urokinase/alteplase to achieve reperfusion of Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.  ANTIANGINAL AND OTHER ANTI-ISCHAEMIC DRUGS 557 the infarcted area (see Ch. 44). Unless 10. Prevention of future attacks thrombolysis can be started within 1–2 hours of (a) Platelet inhibitors—aspirin or clopidogrel MI symptom onset, primary percutaneous given on long-term basis are routinely prescribed coronary intervention (PCI) with stenting is now (see Ch. 44). the preferred revascularization procedure, (b) β blockers—reduce risk of reinfarction, CHF wherever available. and mortality. All patients not having any contraindication are put on a β blocker for at 9. Prevention of remodeling and subsequent least 2 years. CHF ACE inhibitors/ARBs are of proven (c) Control of hyperlipidaemia—dietary substi- efficacy and afford long-term survival benefit (see tution with unsaturated fats, hypolipidemic drugs Ch. 36). especially statins (see Ch. 45). PROBLEM DIRECTED STUDY 39.1 A 55-year-old man presented with complaints of tightness and discomfort over middle part of chest felt episodically, particularly after walking briskly or climbing stairs or during sex. CHAPTER 39 This is relieved within 5–10 minutes of rest. One or two episodes occur practically every day. He is a past smoker who quit smoking 5 years back when he was diagnosed to have chronic obstructive pulmonary disease (COPD), for which he regularly takes 2 inhalations of Ipratropium Br. 3 times a day and 2 puffs of salbutamol inhalation whenever he feels out of breath. The pulse was 90/min and BP 124/82 mm Hg. The resting ECG was normal, but stress test was positive. A diagnosis of exertional angina was made and he was prescribed—Tab glyceryl trinitrate 0.5 mg to be put under the tongue as soon as he begins to feel the chest discomfort, as well as before undertaking any physical exertion. (a) Should he be prescribed another drug to be taken on a regular basis to prevent episodes of angina? If so, which drugs can be given to him and which cannot be given? (b) Should additional medication be given to prevent long-term complications and improve survival? (see Appendix-1 for solution) Tripathi, K. D. (2018). Essentials of medical pharmacology (8th ed.). Jaypee Brothers Medical.