Pharmacology (12) Flashcards
What are the objectives of anti-arrhythmic drugs?
Taken all he time to prevent
→ reduce morbidity
→ reduce mortality
Ventricular arrhythmias lead to 70,000 deaths /year in the UK
Treatment of chronic/episodic arrhythmias is notoriously difficult
What are the phases of a cardiac cation potential in ventricular myoctyes?
Phase 0 → rapid depolarisation, Na+ channels open, rapid influx into myocytes
Phase 1 → short depolarisation, K+ channels open, K+ efflux
Phase 2 → delay in repolarisation (Ca2+ entry via L-type channels) - small plateau
Phase 3 → rapid repolarisation, K+ channels open, K+ efflux, brings membrane potential back down
Phase 4 → automatically slow depolarisation - relatively flat as not peacemaker cells
What are the phases of a cardiac action potential in SA nodes?
Phase 4 → slow depolarisation - causes pacemaker activity - mediated by if channels
Phase 0 → rapid influx of Ca via L type Ca channels
Phase 3 → repolarisation ik channels - back to baseline
What is the refractory period?
Play crucial role in regulation of electrical impulses in heart, preventing arrhythmias
Absolute refractory period → when there is an AP being fired, myocytes unresponsive to electrical stimulation
→ voltage-gated sodium channels inactivated
Relative refractory period (vulnerable period) → followed ARP, could get an extra AP, could drive arrhythmias
Supranormal period → excitable due to which channels are open - high chance of an extra beat
What are afterdepolarisations?
Extra depolarisations - not a full AP
Early → during repolarisation
Delayed → following complete repolarisation
If they get big enough can cause arrhythmias
Can occur if you don’t have enough K+ - ce;;s hyper excitable
What are the major modes of action to block arrhythmias?
- Decreases slope of phase 4 → reduce gradient of slow automatic depolarisation
- Increase threshold potential → slow phase 0
- Increase refractory period → lengthen action potential - make cardiac AP longer
Aim: prevent re-entrant circuit loops
What is the Vaughan-Williams classification of anti-arrhythmic drugs?
Class I → sodium channel blockade
Class II → catecholamine blockade
Class III → lengthening of refractoriness
Class IV → calcium channel blockade
What do sodium channel (class I) blockade anti-arrhythmic drugs do?
Restrict rapid inflow of Na+ during phase 0
→ slow depolarisation
→ slow conduction
→ can also block K+ channels - do many things
3 subtypes:
1a → sodium channel blockade with lengthened refractoriness - make AP longer, slow repolarisation
→ (also block K+ currents) - quinidine, disopyramide, procainamide
1b → sodium channel block with reduced refractoriness - don’t change rising phase, stop premature beats by holding channel inactivated, block voltage gated Na+ channels
→ local anaesthetics like lidocaine, supresses premature beats
1c → sodium channel block with little effect on refractory period, slows rising phase, slows QRS
→ flecainide, bind and unbinds slowly, general reduction in excitability, suppress re-rentrant rhythms
What do beta-andrenoceptor antagonist (class II) anti-arrhythmia drugs do?
Used for ventricular dysrhythmias following MI often due to increases sympathetic activation
→ inhibit the effects of catecholamines like epinephrine and noradrenaline
→ reduce delayed afterdpolarisations due to symptoms activity - membrane stabilising activity makes less excitable
→ some ectopic pacemakers depend on adrenergic drive - useful for ectopic beats
→ increases refractory period of AV node - prevent re-entrant tachycardia
What do class III anti-arrhythmia drugs do?
Block K+ channels - lengthen refractory period
e.g. amiodarone - prolongs cardiac action potential
→ useful in re-entrant tachycardias, suppress ectopic activity
On ECG: prolongs QT, widens QRS
Long elimination half life (10-100 days)
Given as loading dose
Adverse effects: photosensitive rash, thyroid abnormalities, pulmonary fibrosis
Sotalol → non-selective beta-adrenoceptor blocker, prolongs cardiac AP
→ delays slow outward K+ current
→ not as effective as amiodarone but less adverse effects
How can class III anti-arrhythmia drugs be pro-arrhythmic?
They can drive arrhythmias themselves - can produce a polymorphic ventricular tachycardia
→ dangerous with other drugs that lengthen QT interval - some antipsychotic drugs
→ also if have disturbed electrolyte balance (hypokalaemia)
→ also if have hereditary prolonged QT
Occurs if amiodarone taken with other specific drugs
What are class IV anti-arrhythmia drugs?
Ca2+ channel antagonists → block L-type Ca2+ channels in the heart
e.g. verapamil
→ slow conduction in SA and AV nodes - as AP is carried by Ca2+ ions
→ slow the heart and terminate supra ventricular tachycardia (partial AV block)
→ shorten plateau of AP (phases 1 and 2) - less Ca2+ influx
→ reduce force of contraction
→ reduce after depolarisations
→ suppress ectopic beats
→ on ECG: PR interval prolonged - slows conduction through AV node
→ half-life 6-8 hours
→ considerable first pass metabolism
→ slow release preparation available
Diltiazem → similar to verapamil
→ more smooth muscle relaxing effects
→ produces less bradycardia
What does adenosine do?
Receptors for adenosine in the heart - AV node
→ opens K+ channels - hyperpolarises AV node - slows conduction of beat - negative dromotropic effect
→ endogenous chemical mediator in the body (vasodilator)
→ acts via A1 receptors on AV node (hyper polarises cardiac tissue)
→ slows the rate of rise of pacemaker potential
→ slows conduction through AV node (negative dromotropic)
→ terminates paroxysmal supraventricular tachycardias
→ given as IV bolus (half life 8-10 seconds) - broken down very quickly
What do digoxin and other cardiac glycosides do?
Act directly in the heart → inhibit Na+/K+ ATPase pump
→ reduction in Na+ and Ca2+ exchange - less Na+ extrusion, reduces Ca2+ extrusion
→ increase in intracellular [Ca2+] increases excitability/contractility
→ also decreases propagation and AP generation at SA and AV nodes
→ useful as slows conduction through AV node
→ also enhances vagal activity by complex - indirect action bradycardia
Useful in: atrial fibrillation, atrial flutter, heart failure
Digoxin: eliminated 85% unchanged by the kidneys - renal failure digoxin accumulates
→ half life is 36horus - persists in body
→ given orally
→ low therapeutic index - small difference between therapeutic and toxic amount
→ treatment of overdose - use FAB fragment of antibody (Digibind), collates digoxin, no FC segment - no immune response
What is electroconversion?
Electric shock to reset rhythm of the heart → depolarises all heart muscle
Direct current electric shock applied externally
→ successful shock: heart depolarised, ectopic focus extinguished, SA node resume dominant pacemaker
→ effects are immediate
→ supra/ventricular tachycardia, ventricular fibrillation, atrial fibrillation/flutter
What drugs are used to help atrial fibrillation?
Class II agents → beta-blockers can help control ventricular rate via SA node
Class IV agents → Ca2+ antagonists, verapamil - slow conduction through AV node
Anticoagulants → blood not moving through heart, prevent clotting with e.g. warfarin
What is used to help atrial flutter?
Digoxin
DC shock
Class III agents → amiodarone/sotalol for maintenance
Anticoagulants if long standing condition - to avoid emboli
What is used to help ventricular tachycardia?
Urgent treatment as can progress to ventricular fibrillation
Electrical conversion is treatment of choice if rapid hemodynamic deterioration
Patient in good health → IV lidocaine (class I agent, flailing that amiodarone
For recurrent episodes → amiodarone or sotalol
Patients considered for implantable cardioverter defibrillator (ICD)
What is the Maze procedure?
Treatment for atrial fibrillation (if they don’t response to pharmacological treatment)
Create a number of incisions in the atrium that disrupt re-entrant circuits
→ sewn together - atrium can hold blood but the electrical impulse cannot cross incisions
→ make pathway so impulse only goes in one direction - only SA to AV node
→ sinus rhythm restored
What is catheter ablation?
Applying radio-frequency energy or electrical energy, or freezing the offending area
→ creates a small scar that is electrically inactive
→ thus incapable of generating heart arrhythmias
→ i.e. ablate the ectopic foci
