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
