Antidysrhythmic drugs

• ANTIDYSRHYTHMIC DRUGS

  • Dysrhythmia = an abnormal heart rhythm
  • risk factors for dysrhythmias include:

  1. excessive alcohol consumption
  2. smoking
  3. genetics
  4. congenital abnormalities
  5. obesity
  6. existing damage to the heart

  • can also be triggered by medications, caffeine, stress, exercise, posture and recreational drugs
• DYSRHYTHMIA CLASSIFICATION

  • Cardiac arrhythmias/ dysrhythmias: any order of heart rate or rhythm

  1. disruptions of the normal electrical conduction system of the heart

  
• DYSRHYTHMIA MECHANISMS

  
• RE-ENTRY CIRCUITS

  • Electrical signals go round and round in circles
  • occurs due to damage , or abnormalities in conduction (local, nodal, global)
  • unidirectional conduction block can happen because of tissue death

  
• EG OF DYSRHYTHMIAS- ATRIAL FIBRILLATION

  • re-entry circuits or ectopic pacemakers
  • most common dysrhythmia 14% of over 80s
  • atrial rate up to 600 bpm (locally)
  • occasional conduction to ventricles- irregular
  • fatigue, 'palpitato'/ racing heart sensation
  • increases risk of stroke
  • risk factors for AF: heart disease, high BP, congenital heart disorders, genetics
• EG OF DYSRHYTHMIAS- PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA

  • most commonly a re-entry circuit through AV node
  • about 0.2% of population: starts at a young age (teens-40s)
  • ventricular rate 250 bpm
  • palpitations, shortness of breath, chest pain
  • attacks can be haltered (sometimes) by valsalva manoeuvre (increases BP so triggers baroreceptors)
  • causes unknown but triggered by anxiety, stress, caffeine, smoking
• VENTRICULAR FIBRILLATION

  • ventricular re-entry circuits or ectopic foci
  • ventricles cease beating in co-ordinated way
  • no QRS waves on ECG
  • rapidly fatal
  • DC shock (defibrillation) may be only way of restoring contraction
  • common as a complication following a heart attack
• HEART BLOCK

  • form of bradycardia
  • damage to AV node impairs atrial to ventricular conduction
  • FIRST DEGREE: slowed conduction, PQ increased but you get a QRS for every P wave
  • SECOND DEGREE (several different types): miss QRS complexes
  • THIRD DEGREE BLOCKS: impulses do not get from atria to ventricles

  1. ventricles or AV node can take over as pacemaker, so many get some ventricular contractions (rate will be slower)
• WOLFF-PARKINSON-WHITE SYNDROME

  • congenital abnormality = accessory AV pathway (Kent Bundle)
  • global re-entry circuit = re-entry AV tachycardia
  • no rate-limiter in Kent bundle, so AF --> very fast ventricular rate --> ventricular fibrillation

  
• TREATMENT- VAUGHAN WILLIAMS CLASSIFICATION

  • Weakness of the Vaughan Williams systems:

  1. many drugs have multiple sites of action (amiodarone could be class III, II or IV)
  2. sites of action may be different in disease state vs healthy tissue
  3. many useful drugs are not included (adenosine, digoxin, atropine)
  4. more modern approach: Lei et al system (seven classes)
  5. Individual dysrhythmias can be treated with drugs from more than one class
  6. Alternative is to prioritise clinical utility over mechanisms
• EFFECT OF ANTIDYSRHYTHMIC DRUGS ON THE CARDIAC ACTION POTENTIAL

  
• CLASS I- sodium channel blockers

  • CLASS 1A (e.g. disopyramide)

  1. moderate Na+ channel block
  2. increased effective refractory period (ERP)
  3. increase action potential duration (APD)

  • Class IB (e.g. lidocaine)

  1. weak Na+ channel block (stronger in ischaemic tissue)
  2. decreased ERP, shortened APD

  • Class IC (e.g. flecainide)

  1. strong Na+ channel block
  2. no change in ERP and APD

  
• DISOPYRAMIDE: CLASS 1A

  • intermediate dissociation rate, increased ERP, increased APD
  • suppresses re-entry circuits but can increase TPD risk
  • useful for preventing ventricular and supra ventricular dysrhythmias, WPW
  • can be used after heart attack and after defibrillation
  • side effects:

  1. GI tract problems, arrhythmias, cognitive problems, visual problems, urinary disorders, hypotension, depresses force of contraction

  • contradicted in heart blocks and severe heart failure
• LIDOCAINE: CLASS 1B

  • binds to inactivated sodium channel;s
  • use dependent: fast dissociation
  • also a local anaesthetic
  • given intravenously to suppress ventricular dysrhythmias
  • given after defibrillation
  • no longer given after heart attack
  • adverse effects (systemic):

  1. CNS excitation + depression
  2. bradycardia, hypotension, dysrhythmias

  • lots of drug interactions
  • contradicted in WDW, severe heart block
• FLECAINIDE: CLASS 1C

  • blocks sodium channel but much slower dissociation than lidocaine
  • used for supraventricular, ventricular arrhythmias
  • side effects include:

  1. dysrhythmias
  2. oedema
  3. visual disturbances

  • narrow therapeutic window
• ATENOLOL: CLASS II

  • β1 adrenoceptors are class II antidysrhythmic drug's target
  • reduces automaticity: slows SA node, AV node conduction
  • many other beta blockers also used: bisoprolol, metopolol
  • useful in dysrhythmias where sympathetic activation is a trigger:

  1. atrial fibrillation
  2. supraventricular tachycardias

  • useful in preventing dysrhythmias after heart attack
• ATENOLOL CLASS II cont.

  • used in thyrotoxicosis (increased catecholamine release); angina; anxiety (hypertension) and heart failure
  • adverse effects include:

  1. bronchoconstriction (non-selective)- asthma, bronchitis, emphysema
  2. precipitation of heart failure, blocks
  3. diabetes
  4. cold extremities, Raynaud's phenomenon
• AMIODARONE: VW CLASS III

  1. inhibits beta adrenoceptors (class II)
  2. blocks calcium channels (class IV)
  3. inhibits sodium channels (class Ia)

  • blocking potassium channels delays depolarisation

  1. prolonged action potential, refractory period
  2. decreased AV node conduction velocity
  3. decreases re-entry tendency

  • useful in a wide range of dysrhythmias

  1. atrial fibrillation/ flutter
  2. ventricular and supraventricular tachycardias
  3. Wolff-Parkinson-white syndrome

  • can be administrated orally or IV
  • oral has variable bioavailability
• AMIODARONE: VW CLASS III cont.

  • Adverse effects includes:

  1. can make bradycardias or AV node block worse
  2. can cause TDP
  3. can interfere with thyroid function
  4. causes lung fibrosis
  5. is depolarised in the eye (visual problems)
  6. liver toxicity
  7. deposited into the skin: blue-grey colouration under UV light

  • metabolised by CYP3A4 so many interactions with drugs
  • very long plasma half-life (up to 100 days)
  • takes a long time to reach steady state- binds to tissues
  • use IV into central vein for CV emergencies
• VERAPAMIL: VW CLASS IV

  • oral, IV formulations
  • used to prevent PSVT (or terminate)
  • helps keep ventricular rate under control in AF
  • angina, hypertension, cluster headaches
  • contradicted in Wolff-parkinson-white, bradycardia, heart block (exacerbates)
  • side effects: headache, constipation, flushing, hypotension
  • many drug interactions, metabolism partially via CYP3A4 so avoid grapefruit
• VW UNCLASSIFIED DRUGS- ADENOSINE

  • there's 4 GPCR subtypes of adenosine receptors: A1, A2a, A2b, A3

  1. A1: Gi, βγ via GIRK kAch
  2. A2a: A2b: Gs
  3. A3: Gi/ Gq

  • very short plasma half-life (10s)
  • rapid uptake by red blood cells and metabolism
  • given as rapid IV bolus: effects last 20-30s
  • suppression of:

  1. PSVT
  2. Ventricular tachycardia with WPW structure
  3. supraventricular tachycardias during surgery

  • has largely replaces verapamil: short duration of a action is an advantage
• VW UNCLASSIFIED DRUGS- ADENOSINE cont.

  • Adverse effects include:

  1. can cause bradycardia (but short duration)- avoid in heart block, heart failure, facial flushing
  2. chest pain
  3. bronchospasm and dyspnoea - avoid in asthma
  4. dangerous interactions with some local aesthetics
  5. caffeine and theophylline are adenosine antagonists
• VW UNCLASSIFIED DRUGS- DIGOXIN

  • blocks sodium pump directly
  • indirectly blocks sodium/ calcium exchange
  • increases calcium in stores: more contraction force
  • stimulates parasympathetic nervous system

  1. AV node conduction, SA node firing rates decrease

  • increases AV node refractory period, but decreases it in myocytes
  • increases force of contraction, slows ventricles --> better filling
  • membrane potential is more positive

  1. digoxin CAUSES dysrhythmias at higher doses
  2. increases automatically

  • used in heart failure and in atrial fibrillation
• VW UNCLASSIFIED- DIGOXIN cont.

  • Adverse effects include:

  1. very narrow therapeutic window (nausea, vomitting, visual disturbances, ventricular tachyarrhythmias)
  2. may need to monitor plasma levels
  3. digoxin binds to K+ site on sodium pump so toxicity increased by hypokalaemia
  4. contradicted in ventricular dysrhythmias, Wolff-parkinson-white, heart block
  5. interacts a lot with other drugs
  6. overdose treatment: stop digoxin, correct hypokalaemia, give beta blockers to control dysrhythmias,
• VW NCLASSIFIED- ATROPINE (M2 muscarinic receptors)

  • atropine is a competitieve antagonist at M2
  • M2 receptor decreases heart rate
  • atropine blocks this: increases HR
  • used IV in bradycardia, some forms of heart block

  1. low doses: causes bradycardia via central effects

  • contradicted in glaucoma, certain GI tract disorders, urinary retention
  • causes dizziness, drowsiness, photophobia, constipation, headache, nausea, palpitations, tachycardias
  • severe interactions with phenylephrine (hypertension), interacts with any drug with muscarinic actions