CVS 4 - Arrhythmia Flashcards
SA and AV nodal cells
Phase 0- voltage gated Ca2+ channel opens due to depolarization
Phase 4- Slow depolization
spontaneous (automatic) pacemaker mostly due to Na+ influx until membrane potential reaches threshold to open calcium channels
Ventricular myocytes
Phase 2- K+ and Ca2+ channels open Ca2+ channels inactive with time
Phase 1- Na+ channels automatically inactivate
Phase 0- voltage gated Na+ channel opens
Phase 3
Ca2+ channel close K+ channels open cell repolarizes
Refractory period
refractory period between 0-2 where the channels are already open so another action potential cannot cause another contraction tot take place. However in phase 3 if another action potential arises and is sufficiently strong it can start further depolarisation
Why does arrhythmia occur? Several potential causes:
– M.I., – heart failure, – hyperthyroidism, – electrolyte abnormalities: hypokalaemia (speeds up SA phase 4), hypomagnesemia, alkalosis, acidosis – autonomic dysfunction, – drugs: eg β antagonists slow SA phase 4 – inherited mutation in ion channels, – fever
Cardiac tissue goes through a cycle
At rest -> Response -> Refractory period -> At rest….
• Different regions respond at different times (so the pump works)
• One region may be refractory while other can respond
• abnormality in:
– automaticity: site of origin of impulse, rate and regularity of pacemaker
– conduction of impulse
• leads to non-coordinated contraction
• Goal is to restore this by fixing electrical abnormalities
Arrhythmia: electrical defects
Defects in impulse from SA /AV node
• AV sets frequency if SA node slows -extra impulse when SA node does fire
• Alternatively AV node may fire too frequently- also creates extra impulse
Bypass
• Additional pathway bypassing AV node
Conduction block
Re-entry
• Common cause of tachyarrhythmia
Afterdepolarizations
• Normal action potential triggers additional oscillations
Classes of Arrhythmia
• Supraventricular
– origin is SA, AV nodes or atria
– sinus tachycardia/ bradycardia
» faster (>100 bpm)/slower (<60 bpm) than normal but regular beat
» altered SA firing
– atrial tachycardia (supraventicular tachycardia)
» atrial pacemaker other than SA node
– atrial flutter
» atrial rate 280-300 bpm but ventricle cant respond (AV node refractory period)
– atrial fibrillation
» re-entry impulses in atrium
• Ventricular
– origin is in ventricles
– Ventricular tachycardia
» normal atrial function
» Monomorphic – ventricular pacemaker causes additional systole
» Polymorphic – eg Torsades des pointes, caused by sustained early after depolarizations
– ventricular fibrillation
» re-entry impulses in ventricle.
» Fatal if untreated. Defibrillation essential
• Heart block
– pacemaker impulse delayed or fails to reach ventricles
Arrhythmia: pharmacological treatment goals
•Treatment goals – Restore normal cardiac rhythm – Prevent recurrence of arrhythmia – Prevent more severe arrhythmia – Deal with haemodynamic consequences
Vaughan Williams classification of anti-arrhythmic drugs
– Class I Na+ channel blockers
» reduce SA rate:
– Shift threshold to higher potential – Decrease slope phase 4
» decrease re-entry in contractile tissue – slow down phase 0 so refractory for longer
– Sub-classified:
» Ia bind open Na+ channel and also block K+ channels
» Ib bind open as well as refractory Na+ channel more effective at high rates » Ic not rate dependant
– Class II β adrenergic receptor antagonists
– Class III K+ channel blockers
– Class IV Ca2+ channel blockers
Pharmacologically induced arrhythmia
– All antiarrhythmic drugs can precipitate arrhythmia
– Many drugs which prolong QT → ↑ risk torsades des pointes (twisting the points)
– Several non-cardiac drugs can induce arrhythmia
Class Ia
Mechanism
Drug Example
- prolong action potential
• Mechanism
– Block Na+ channel- slow phase 0 →↓conduction velocity
– Block K+ -prolongs repolarization →↑refractory period
– prolongs QRS duration (ECG)
– Also cholinergic antagonist so blocks parasympathetic inhibition of AV node- faster AV conduction can cause increased ventricular rate in patients with atrial flutter
• Drugs
– disopyramide
Effects of cholinergic blockade
Blurred Vision, mydriasis - (pupillary constrictor muscle) Tachycardia – relief of P-ANS inhibition of SA and AV nodes Dry mouth – P-ANS promotes salivation
Constipation –P-ANS promotes GI motility
Dry skin, less sweating – P-ANS promotes these secretions
Disopyramide contraindication in heart failure
“additive” ↓cardiac output
Class Ib
Mechanism
Drug example
- shorten action potential
• Mechanism
– Na+ channel block, although relatively weak (fast dissociation)
– Advantage – most effective on frequently depolarizing tissue
– Bind both open and refractory channel
• Drugs
– Lidocaine
Class Ic - Mechanism, drug example
- no change in duration
• Mechanism
– Most potent Na+ channel blockers – marked effect on phase 0 but no effect on duration
– slows conduction in all cardiac tissues
– Suppress “premature” ventricular contraction
– increases PR and QRS intervals
– Can cause arrhythmia!
• Drugs
– Flecainide
Class Ic - Indication PK
• Indications
– atrial fibrillation and tachycardia
» Particularly if involves AV node
• PK
– p.o or iv
– metabolised by Cyp2D6
Class II
• β receptor – sympathetic regulation of Na+ pacemaker current and K+ repolarization channels
• β adrenergic antagonist
– inhibit pacemaker (SA and AV nodes)
– slows packmaker current (phase 4) » decreased rate of node firing
– prolongs repolarization (phase 3)
» ↑refractory period →↓effect of re-entry
• Use
» Because decrease SA rate & AV conduction, useful for supraventricular arrhythmia eg atrial fibrillation & re-entry involving AV node
» Particularly useful if arrhythmia due to adrenergic stimulation
• Drugs
– Propanolol – Atenolol
• Have been shown to reduce sudden death post M.I.
Class III - Mechanism and example
• Mechanism
– Block K+ channel – prolong repolarization
– increased refractory period – reduced re-entry
– However- prolonged plateau increases chance after- depolarization & Torsades des pointes
• Drugs
– Amiodarone
Class III (amiodarone)
amiodarone prolongs action potential & QT interval
which drug is a β adrenergic antagonist with class II and III activity
Sotalol
Class IV Mechanism and drugs
• Mechanism
– Ca2+ channel blockers
– work mainly on SA and AV nodal tissue (Ca2+ channel used for phase 0 depolarization)
» slows SA rate
» slows phase 0 in AV node → slow conduction velocity through AV node, increasing its refractory period
» Used to treat re-entrant arrhythmia (eg supraventricular tachycardia) that involve the AV node
– high dose can cause complete AV block
• Drugs
– Verapamil
– Diltiazem
– Dihydropyridines – tend to less effective on cardiac tissue (more effective on smooth muscle) – channel subunit composition – “vascular selective”
• co admininstration with β antagonists can cause asystole
Class 1a - Indication
• Indications
– ventricular tachycardia following MI » lidocaine is first line treatment
Class 1a - PK
• PK
– iv administration with continuous ECG monitoring
Class 1a - ADR, cautions, contraindication
• ADR – negative inotropic agent – cholinergic antagonist so causes dry mouth, urinary retention, blurred vision, constipation • Cautions – avoid in pregnancy –can induce labour • Contraindications – heart failure
Class 1a - Drug interactions
• Drug interactions
– prolongs QT – avoid giving with other drugs that do this
– negatively inotropic – avoid giving with other drugs that do this
Class 1b - Indication, PK
• Indications
– ventricular tachycardia, local anaesthesia
– Not effective supraventricular arrhythmia
• PK
– iv (almost complete first pass metabolism if given p.o.)
Class 1b - ADR, cautions, contraindication
• ADR
– related to CNS toxicity:nausea, vomiting, drowsiness, convulsions
• Cautions
– lower dose in patients with hepatic impairment or heart failure (it’s a negative inotrope)
• Contraindications – AV block (Lidocaine slows AV conduction)
Class 1b - Drug interactions
• Drug interactions
– risk of arrhythmia in patients using diuretics (hypokalemia predisposes to arrhythmia)
Class 1c - ADR, cautions, contraindication
• ADR
– negative inotropic agent (see action potential! –less Ca influx)
– CNS toxicity: lightheadidness
– arrhythmia (by prolonging QT)
• Cautions
– avoid in patients with heart block, pregnancy
– reduce dose in patients with hepatic insufficiency
• Contraindications
– heart failure
– previous MI
Class 1c - Drug interactions
• Drug interactions
– risk of arrhythmia in patients using diuretics » hypokalemia predisposes to arrhythmia
– several pharmacokinetic interactions
» including amiodarone, fluoxetine
– avoid with other negatively inotropic drugs
Class III - ADR, cautions, contraindication
• Caution
– avoid bolus i.v in heart failure
• Contraindication
– bradycardia, heart block, iodine sensitivity, pregnancy, breast feeding (exception: cardiac arrest)
• ADR
– pulmonary fibrosis
– deposits of lipofuscin on cornea, can cause visual halo. Reversible, but very common
– sensitivity to sunlight- sun cream advised
– grey skin discolouration
– hyperthyroidism –amounts of iodine and inhibits conversion T4 to T3
Class III - Drug interactions
• Drug interactions
– Several !
– Cyp 3A4 substrate and inhibits some other Cyps » inhibits metabolism of warfarin
– inhibits renal excretion of digoxin by PgP
– avoid with other drugs that prolong QT interval
– several other interactions – needs careful consideration!
Class III - Indications, PK
• Indications
– arrhythmia
– requires specialist supervision
• PK
– t1/2 =50 days!
– Dose adjustment not usually required with hepatic or renal insufficency!
– V. large Vd (70L/kg - stored in tissue) – loading dose may be required to reduce slow onset (or i.v. for more rapid effect)
– i.v. or p.o.
Action of anti-arrhythmic drugs do 1 of 4 things:
– Alter the baseline/threshold potential in SA cells
– The rate of phase 4 repolarization
– Alter baseline/threshold potential in contractile cells
– Duration of action potential (alters refractory period)
