Week 1: Antiarrhythmic drugs Flashcards
What is the difference between pacemaker potentials and non pacemaker potentials?
Pacemaker potentials are slow- no true resting membrane potential, but influx via If “funny” currents, mixed Na+/K+ current, that slowly depolarises cell to threshold (phase 4) , opening of T type (transient Ca2+ ), depolarisation then by L type Ca2+ channel, repolarisation by K+ channels.
Cardiac AP - specific resting Vm (-90mv), AP arrives, opening Na+ channels, fast depol by Na+, transient repol by K+ current, then plateau by influx Ca2+ through L type Ca channels, then Na+ and Ca2+ channels close, repolarisation by K+ outflow.
What are the mechanisms of cardiac arrhythmias?
What are some common causes of cardiac arrhythmias?
Result from disorder of impulse formation, conduction or both.
Causes:
Cardiac ischaemia
Excessive discharge or sensitivity to autonomic transmitters
exposure to toxic substances
What are the classes of arrythmic mechanisms?
Automaticity:
- Enhanced
- Abnormal
Triggered activity:
- Early afterdepolarisation
- Delayed afterdepolarisation
Re-entry
Pathophysiology of enhanced automaticity?
Pathophysiology of abnormal automaticity?
Enhanced cardiac automaticity refers to the accelerated generation of an action potential by either normal pacemaker tissue (enhanced normal automaticity) or by abnormal tissue in mycardium (abnormal automaticity).
Enhanced normal automaticity –> accounts for sinus tachycardia
Abnormal automaticity –> results in atrial or ventricular arrhythmias
Under normal circumstances the SA node is responsible for the generation of AP’s in the heart, and is the primary pacemaker. This automaticity increases during exercise - normal physiological increase in automaticity. In other circumstances the automaticity in SA and other latent pacemakers can increase without physiological motivation –> E.g. ischaemia during MI increasing automaticity in purkinje cells. Under pathological circumstances, atrial and ventricular myocardium (does not posses normal automaticity) can start discharging AP’s –> abnormal automaticity. Can cause extra beats.
Other conditions that induce abnormal automaticity –> MI/hypoxia/ Hypokalaemia/ lung disease/ digoxin (alter resting membrane of the cell bringing it closer to threshold for depolarisation).
Pathophysiology of triggered activity?
AP may induce an after depolarisation –> is a depolarisation occurring either during or after the repolarisation phase. After depolarisation occuring during repolarisation = early depolarisation. After depolarisation occurring after repolarisaton = late depolarisation.
Early and late depolarisation may be strong enough to reach threshold for eliciting another AP –> this is triggered activitiy
EAD -> typically in bradycardia, hypokalaemia, hypoxia, acidosis, hypocalcaemia, drug SE.
DAD –> digoxin overdose and SNS stimulation
Pathophysiology of re-entry?
For re-entry to occur you need 1) a unidirectional block within a conducting pathway 2) critical timing -> in that the AP travelling down one conducting pathway can come back on itself as it finds tissue that is re-excitable. This is related to the effective refractory period of this tissue.
AP travels down one branch of excitable tissue in the conducting pathway, but cannot travel down the other due to conduction block (e.g. scar tissue),it can then travel retrograde up this pathway and re-enter the circuit –> circular pathway of high freq impulses (tachyarrhythmia).
This can happen locally i.e within atria (e.g. AV nodal re-entry or AV re-entrant tachycardia) or globally, i.e between atria and ventricles. E.g. in WPW syndrome accessory pathway (bundle of kent) exists which allows AP to travel from atria to ventricles and back up the AV node back into the atria –> SVT.
What are the principles of cardiac pharmacotherapy?
- Change heart rate
- Increase force of cardiac muscle contraction
- Alter depolarisaton/repolarisation of the myocardium
- Change the flow through the coronary arteries
What are the components of heart rate control?
Intrinsic pacemaker - SAN, if that fails AVN takes over, if that fails escape rhythm (but at slower rate) from other tissues in conducting pathway.
Autonomic nervous system:
SNS - NA is the accelerator of the heart, therefore blocking this accelerator slows the heart. NA released post synaptically onto beta adrenergic receptors in SAN/ AVN.
PNS –> the vagus nerve is the “handbrake” of the heart, therefore blocking Ach at the muscarinic receptors releases this handbreak.
Receptors - as above.
What is the mechanism of action of atropine?
What is the indiction?
How is it administered?
What are the SE’s?
Atropine
MOA–> blocks the muscarinic receptors in the SA and AVN. By blocking the PNS stimulation it allows the heart to beat faster
Indication – > emergency treatment of bradycardia
Administration –> IV bolus
SE’s –> due to other Ach receptors in the body:
- Dry mouth
- urinary retention
- dilated pupils
What is the MOA of Beta blockers?
Drug names?
Indication in arrhythmia
SE?
Contraindications?
Beta blockers:
MOA: Blocks the increase in the slope of phase 4 depolarisation in the pacemaker cells of the heart by blocking the B1 adrenergic receptors. NA cannot bind in SAN and AVN, slowing the heart rate.
Drug names: Atenolol, metoprolol, carvedilolol, bisoprolol
Indication in arrhythmia: Cardi protective drugs, rate control in atrial flutter and fibrillation. Also effectiv in ventricular arrhythmia related to SNS activation e.g. ACS, heart failure.
SE: bronchospasm, bradycardia, headache, sleep disturbance, increase insulin resistance. High degree AV block = complete contraindication. Asthma = relative contraindication, if in COPD start slow and low.
Which drugs are used to alter HR?
What is their MoA?
- Beta blockers
- Blocks B1 receptors in the SA and AV nodes, blocking sympathetic input to reduce HR
- Atropine
- Blocks Ach recceptors in SA and AV nodes, blocking parasympathetic input to increase HR
- If channel blockers
- Selective If blocker- works only in SA node
- Slows Na+ entry, slower pacemaker potential
Which drugs are used to increase the force of contraction of cardiac muscle?
- Cardiac glycoside (usually digoxin)
- Negative inotropes (usually reduce force of contraction as a side effect)
What are the If channel blockers?
what is this drug called?
MOA?
If blockers - block the “funny channel” –> the mixed Na+/K+ channel that is responsible for the slow depoalarising waves of the pacemaker potential
Drug name: Ivabradine
Slows the Na+ entry, slowing pacemaker potential, acts only in the SA node.
What is the action of a cardiac glycoside?
What is the usual agent?
What is its MOA?
Cardiac glycoside - class of drug that increases the force of contraction but decreases the rate of contractions in the heart (negative chronotrope).
Usual agent: Digoxin
MOA: Acts on Na/K+ ATPase pump. Normally moves K+ ions in and Na+ ions out, cardiac glycosides inhibit the pump so that Na+ cannot be extruded, intracellular Na+ therefore increases.
Raised IC Na+ inhibits the function of second membrane exchanger - NCX. Normally passively exchanges Ca+ out and Na+ ions in, and is reliant upon the concentration gradient of Na+ –> therefore Ca+ ion not extruded and also builds up in the cell. –> Increased force of contraction of myocytes.
Refractory period of AV node also increased, therefore cardiac glycosides reduce the heart rate.
What drugs affect the force of contraction by negative inotropy as a side effect?
Usually dont want to reduce the force of contraction but reduced contraction force may be a side effect of:
Beta blockers –> block adrenergic receptors / affect of adrenaline and therefore reduce IC Ca2+ conc –> therefore reduce force of contraction
Ca2+ antagonists - e.g. verapamil –> inhibit L type Ca2+ channels, reduce IC Ca2+ and therefore reduce the force of contraction.
What are the phases of the cardiac action potential?
Phase 0 - fast depolarisation due to Na+ entry
Phase 1- transient replarisation by K+ movement out
Phase 2 - plateau phase by calcium entry and K+ out
Phase 3- repolarisation by K+ movement out
Phase 4- resting membrane potential (-90mv) achieved by Na+ movement out, K+ in
What is the Vaughnan williams classification of antiarrhythmics?
What are the different classes?
What channel do they act on/ overall MOA?
What are some examples of each class?
Classification system for the classes of antiarrhythmic drugs: Class 1 - 4, Class 1 split into three subclasses (1A/1B/1C).
Class 1 - sodium channel blockers, reduce phase 0 slope and the peak of action potential. Class 1a - moderate, class 1b - weak, class 1c - strong.
- Class 1a: disopyramide: quinidine
- Class 1b: lidocaine
- Class 1c: flecainide propafenone
Class 2 - Beta Blockers –> Block SNS activity, reduce rate and conduction. Examples: Atenolol, bisprolol, metoprolol.
Class 3 - K+ channel blocker –> Delay repolarisation, therefore increase AP duration and ERP. Examples: Amiodarone, dronedarone, sotolol (some beta blocker activity)
Class 4 - Ca2+ channel blocker –> Block L type Ca2+ channel, most effect at SA/AVN, reduce rate and conduction. Examples: Verapamil, Diltiazem
What are the class 1a drugs?
What are their MOA?
What are its uses?
SE?
Class 1a: Quinidine and Disopyramide
Moderate Fast Na+ channel block, moderate reduction in phase 0 slope (delay depolarisation in fast Na+ channels), increase AP duration, increase ERP
Uses/ indication: Ventricular and supraventricular arrhythmias
SE: odema
What are the class 1b drugs?
What is the MOA?
uses/ indication?
SE?
Class Ib - Lidocaine
Weak Na+ channel block, blocking Na+ channels in actively depolarising cells/depolarising areas. Reduce the APD, decrease ERP.
Also a local anaesthetic, short duration of action (milliseconds) on the Na+ channel, greatest effect on rapidly beating/ depolarising cells. Thus rapidly beating cells are blocked from depolarising. Less effect on normally beating cells.
Uses/indication: CPR - when lidocaine used IV.
SE: Oedema
What are the class IC drugs?
MOA?
Uses?
SE?
Class Ic - Flecainide, Propafenone.
MOA: Strong effect on depolarisation, pronounced reduction in phase 0 slope (depolarisation). No effect on APD or ERP.
Uses/ Indication: Paroxysmal AF and ventricular ectopic beats “pill in pocket”.
SE: Odema
What are the class III antiarrhythmic drugs?
Class III –> K+ channel blockers
Amiodarone, Dronedarone, sotolol (some beta blocker activity).
Delay repolarisation –> prolong AP duration and ERP (prolong QT interval)
Uses: Supraventricular, nodal and ventricular arrhythmias, atrial fibrillation (CPR used IV)
SE: N&V
What are the class 4 antiarrythmic drugs?
MOA?
Uses?
SE?
Class 4: Verapamil and diltiazem
MOA: Ca2+ channel blocker (L-type), reduces amplitude and shortens phase 2 plateau phase.
Reduces IC Ca2+, therefore -ve inotropic effects on myocytes. Most effective at SA and AVN (reduce phase 0 depolarisation by slow ca2+ influx) therefore reduce chronotropy and inotropy, Reduce CO.
Uses: supraventricular tachycardia - e.g atrial fibrillation and atrial flutter. Slows conduction to the ventricles by L type Ca2+ block (block the depolarisation of the Pacemaker potential too, phase 0 Ca2+ influx.)
SE: Hypotension with verapamil, constipation with diltiazem.
What is the mechanims of action of adenosine?
What is it used for?
What is the half life?
Binds A1 receptor in pacemaker tissue, inhibits adenylyl cyclase, reduces cAMP; K+ efflux increases and cells are transiently hyperpolarised.
Used IV to diagnose and treat AV node dependent tachycardias.
It has a short half life of seconds.
