Pharmacology for dentistry phần 41

188 Section 4/ Drugs Acting on Cardiovascular & Urinary System act by inhibiting the uptake and degradation of adenosine (a local mediator involved in auto regulation of coronary flow in response to ischemia) It has also weak platelet inhibiting action It reversibly inhibits platelet phosphodiesterase hence cAMP concentration is increased and there is reduction of platelet reactivity Adverse effects include nausea, dizziness, skin rash and headache Though it is not useful as an antianginal drug, but it has been employed for prophylaxis of coronary and cerebral thrombosis in post MI and post stroke patients, as well as to prevent thrombosis in patients with prosthetic heart valves tterer p p a h CCh 4.4 1.4 Antiarrhythmic Pharmacodynamics (ModeAgents of Action of Drugs) CARDIAC ARRHYTHMIAS Cardiac arrhythmias is a group of disorder characterized by an abnormal cardiac rhythm and arise as a result of disorders of impulse formation or conduction or both Tachyarrhythmias (sinus rate more than 100 per minute) are produced by a disturbances of impulse generation or of impulse conduction in the heart Tachyarrhythmias due to disturbed impulse formation are associated with irregular and rhythmic discharge from ectopic pacemaker activity in areas of the heart other than the SA node The characteristic of myocardial cells, which enables them to generate spontaneous depolarization, is called automaticity Bradycardia can be due to depressed sinus automaticity and AV block Bradyarrhythmias manifest as slow heart rate (less than 50 to 60 beats per minute in sleep) Depressed SA nodal automaticity lead to missing beats and bradycardia AV block can be due to high vagal activity and side effect of certain drugs e.g digitalis and β-blockers Antiarrhythmic drugs can be classified as in table 4.4.1 SODIUM CHANNEL BLOCKERS By limiting the conductance of Na+ (and K+) across cell membrane, they interfere with depolarization and decrease responsiveness to excitation thereby reducing rate of phase of phase depolarisation in automatic cells QUINIDINE It is an alkaloid obtained from the bark of cinchona and is a dextro isomer of anti-malarial drug ‘quinine’ Its sodium channel blocking property results in an increased threshold for excitability and decreased automaticity As a consequence of its potassium channel blocking properties, it prolongs action potential in most cardiac cells Pharmacological Actions Cardiac actions: a Excitability: Quinidine depresses the excitability of cardiac tissues 190 Section 4/ Drugs Acting on Cardiovascular & Urinary System Table 4.4.1: Classification of antiarrhythmic agents I Class I: Sodium channel blockers Quinidine (NATCARDINE) 200-400 mg TDS-QID Procainamide (PRONESTYL) 50 mg/kg/day oral, 50 mg/min slow IV Disopyramide (NORPACE) 100-200 mg TDS-QID, mg/kg slow IV Lignocaine (XYLOCARD) mg/kg slow IV (bolus) then 1-3 mg/min IV infusion Phenytoin sodium (DILANTIN) 100-400 mg/day oral, 100 mg IV (max 600 mg/day) II Class II: Beta adrenergic blockers Propranolol, etc (Detailed pharmacology is discussed in chapter ‘Antihypertensive agents’ and Adrenergic blocking agents’) III Class III: Drugs that prolong effective refractory period by prolonging action potential Amiodarone (ALDARONE) 200 mg TDS Bretylium 5-10 mg/kg bolus IV then 0.5-2 mg/min IV infusion IV Class IV: Calcium channel blockers Verapamil, diltiazem etc (Detailed pharmacology is discussed in chapter ‘Antihypertensive agents’) V Miscellaneous Adenosine (ADENOCOR) 6-12 mg IV bolus Atropine 0.6-2 mg IM (Used for AV block) Sympathomimetics (e.g adrenaline, isoprenaline and orciprenaline are also used for AV block) Digitalis (DIGOXIN) 0.25-0.5 mg IV for paroxysmal supraventricular tachycardia (PSVT), atrial flutter and atrial fibrillation b Automaticity: Quinidine decreases the slope of slow diastolic depolarisation (phase of action potential) and thus decreases the spontaneous rate of firing of pacemakers By depressing the entry of sodium into the cell during depolarization, quinidine depresses diastolic depolarization and ultimately automaticity c Conductivity: Quinidine depresses interventricular and atrioventricular conductivity PR and QRS intervals are also prolonged Also decreases the rate of rise of action potential d Effective refractory period: Quinidine depresses the potassium efflux during repolarization and prolongs repolarization The refractory period increases due to its antivagal action Its antivagal action prolongs the refractory period of atrium and shortens that of AV node The antivagal action on the AV node causes paradoxical tachycardia in a patient of atrium fibrillation e Contractility: Quinidine produces a negative inotropic action on the heart and contractility is depressed with toxic doses f AV conduction: Quinidine depresses the conduction in atrium and Purkinje system g Electrophysiological effect (effect on ECG): It reduces the rate of rise of action potential i.e phase zero of action potential which is due to depolarisation Antiarrhythmic Agents Increase in the duration of ventricular systole (QT interval) Decrease in amplitude of T waves Depression of ST segment Reduction in conduction velocity (widening of QRS complex) Extracardiac actions: a Quinidine in normal individuals produce a decrease in blood pressure after oral and IV administration b Quinidine has got antimalarial, antipyretic, oxytocic and skeletal muscle relaxant activity also It is well absorbed orally, undergoes extensive hepatic oxidative metabolism 90% quinidine is bound to plasma protein The drug is distributed to most tissues except brain About 20% is excreted unchanged by the kidney Adverse effects include SA block or arrest, high grade AV block, ventricular tachycardia, arrhythmia or ventricular asystole, polymorphic ventricular tachyarrhythmia, hypotension (particularly when given IV), cinchonism, tinnitus, loss of hearing, gastrointestinal upset, severe headache, diplopia, photophobia, etc It is indicated in prevention of atrial arrhythmia, atrial fibrillation or flutter, paroxysmal supraventricular tachycardia, ventricular premature beats and ventricular tachycardia PROCAINAMIDE It has got quinidine like cardiac property It depresses the excitability of both atria and ventricles Contractility and conductivity are also depressed It has got minimal vagolytic action 191 It decreases the rate of rise of action potential and prolongs the effective refractory period After oral administration it is absorbed quickly, about 20% is bound to plasma protein up to and 70% of a dose is excreted in urine in unchanged form Adverse effects include renal failure, hypotension (when given IV), anorexia, nausea, vomiting, Q-T prolongation Rarely there is diarrhoea, giddiness, psychosis, hallucination, mental depression, hypersensitivity, agranulocytosis, myalgia, angioedema, skin rash, digital vasculitis Procainamide can cause syndrome that resembles SLE, which is reversible on discontinuation of procainamide; leukopenia and thrombocytopenia It is indicated in ventricular arrhythmia, ventricular premature depolarization and paroxysmal ventricular tachycardia, supra-ventricular tachycardia and atrial arrhythmia DISOPYRAMIDE It has got anticholinergic and membrane depressant properties and like quinidine, it is effective against most of the atrial and ventricular arrhythmias It has no effect on sinus rate Adverse effects include dry mouth, constipation, blurred vision, urinary urgency and occasional urinary retention, nausea, vomiting, diarrhoea, abdominal pain, hypoglycaemia, jaundice, coronary heart failure and hypotension It is indicated in atrial and ventricular arrhythmias in digitalised and non- 192 Section 4/ Drugs Acting on Cardiovascular & Urinary System digitalised patients, arrhythmias associated with Wolff-Parkinson-White (WPW) syndrome LIGNOCAINE It is an amide local anaesthetic and has rapid onset of action It depresses diastolic depolarization and automaticity in ectopic foci in ventricular tissue Phase depolarization in partially depressed Purkinje fibres and after depolarizations are antagonised It does not depress AV conduction and decreases action potential duration, effective refractory period It has no effect on BP Adverse effects include ventricular fibrillation, hypotension or massive cardiac arrest due to overdose, dizziness, paraesthesia, drowsiness, seizures, disorientation, respiratory arrest, nausea, vomiting, circulatory collapse and blurred vision It is indicated in prophylaxis or treatment of ventricular arrhythmias associated with Ml, digitalis intoxication, ventricular tachyarrhythmia, in patients predisposed to ventricular arrhythmias during general anaesthesia PHENYTOIN SODIUM It is a anticonvulsant drug and depresses the ventricular automaticity and accelerates the AV conduction It also reduces the duration of action potential like quinidine It also shortens the QT interval It mainly blocks inactivated Na+ channels It is used for the suppression of ectopic beats and for prophylaxis of recurrent paroxysmal tachycardia and also for the treatment of rapid supraventricular or ventricular tachycardia It is also used in digitalis induced ventricular arrhythmia as it reverse the conduction block while accentuating the depression of automaticity (The detailed pharmacology is discussed in chapter ‘Antiepileptic agents’) BETA-ADRENEGIC BLOCKERS The detailed pharmacology of beta blockers is discussed in chapter ‘Adrenergic blocking agents’ and ‘Antihypertensive agents’ The antiarrhythmic action is due to cardiac adrenergic blockade It decreases the slope of phase depolarization and automaticity in SA node, Purkinje fibres and other ectopic foci It also prolongs the effective refractory period of AV node and impedes AV conduction ECG shows prolonged PR interval It is useful in sinus tachycardia, atrial and nodal extrasystoles It is also useful in sympathetically mediated arrhythmias in pheochromocytoma and halothane anaesthesia DRUGS PROLONGING ACTION POTENTIAL By prolonging repolarization, AP is widened and ERP is increased, so the tissues remain refractory even after full repolarization AMIODARONE It is a long acting antiarrhythmic drug It contains iodine and may cause disorders of thyroid function It blocks inactivated sodium channels It also decreases calcium current and transient outward, delayed rectifier and inward rectifier potassium currents It is a potent inhibitor of abnormal automaticity It prolongs duration of action potential, refracto- ... mainly blocks inactivated Na+ channels It is used for the suppression of ectopic beats and for prophylaxis of recurrent paroxysmal tachycardia and also for the treatment of rapid supraventricular or... Sympathomimetics (e.g adrenaline, isoprenaline and orciprenaline are also used for AV block) Digitalis (DIGOXIN) 0.25-0.5 mg IV for paroxysmal supraventricular tachycardia (PSVT), atrial flutter and... diltiazem etc (Detailed pharmacology is discussed in chapter ‘Antihypertensive agents’) V Miscellaneous Adenosine (ADENOCOR) 6-12 mg IV bolus Atropine 0.6-2 mg IM (Used for AV block) Sympathomimetics