CVS 4 - Arrhythmia

Question 1

SA and AV nodal cells

Answer 1

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

Question 2

Ventricular myocytes

Answer 2

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

Question 3

Phase 3

Answer 3

Ca2+ channel close K+ channels open cell repolarizes

Question 4

Refractory period

Answer 4

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

Question 5

Why does arrhythmia occur? Several potential causes:

Answer 5

– 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

Question 6

Cardiac tissue goes through a cycle

Answer 6

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

Question 7

Arrhythmia: electrical defects

Answer 7

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

Question 8

Classes of Arrhythmia

Answer 8

• 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

Question 9

Arrhythmia: pharmacological treatment goals

Answer 9

•Treatment goals
– Restore normal cardiac rhythm
– Prevent recurrence of arrhythmia
– Prevent more severe arrhythmia
– Deal with haemodynamic consequences

Question 10

Vaughan Williams classification of anti-arrhythmic drugs

Answer 10

– 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

Question 11

Pharmacologically induced arrhythmia

Answer 11

– 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

Question 12

Class Ia
Mechanism
Drug Example

Answer 12

• 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

Question 13

Effects of cholinergic blockade

Answer 13

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

Question 14

Disopyramide contraindication in heart failure

Answer 14

“additive” ↓cardiac output

Question 15

Class Ib
Mechanism
Drug example

Answer 15

• 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

Question 16

Class Ic - Mechanism, drug example

Answer 16

• 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

Question 17

Class Ic - Indication PK

Answer 17

• Indications
– atrial fibrillation and tachycardia
» Particularly if involves AV node

• PK
– p.o or iv
– metabolised by Cyp2D6

Question 18

Class II

Answer 18

• 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.

Question 19

Class III - Mechanism and example

Answer 19

• Mechanism
– Block K+ channel – prolong repolarization
– increased refractory period – reduced re-entry
– However- prolonged plateau increases chance after- depolarization & Torsades des pointes
• Drugs
– Amiodarone

Question 20

Class III (amiodarone)

Answer 20

amiodarone prolongs action potential & QT interval

Question 21

which drug is a β adrenergic antagonist with class II and III activity

Answer 21

Sotalol

Question 22

Class IV Mechanism and drugs

Answer 22

• 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

Question 23

Class 1a - Indication

Answer 23

• Indications

– ventricular tachycardia following MI » lidocaine is first line treatment

Question 24

Class 1a - PK

Answer 24

• PK

– iv administration with continuous ECG monitoring

Question 25

Class 1a - ADR, cautions, contraindication

Answer 25

``` • 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 ```

Question 26

Class 1a - Drug interactions

Answer 26

• Drug interactions – prolongs QT – avoid giving with other drugs that do this – negatively inotropic – avoid giving with other drugs that do this

Question 27

Class 1b - Indication, PK

Answer 27

• Indications – ventricular tachycardia, local anaesthesia – Not effective supraventricular arrhythmia • PK – iv (almost complete first pass metabolism if given p.o.)

Question 28

Class 1b - ADR, cautions, contraindication

Answer 28

• 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)

Question 29

Class 1b - Drug interactions

Answer 29

• Drug interactions | – risk of arrhythmia in patients using diuretics (hypokalemia predisposes to arrhythmia)

Question 30

Class 1c - ADR, cautions, contraindication

Answer 30

• 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

Question 31

Class 1c - Drug interactions

Answer 31

• 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

Question 32

Class III - ADR, cautions, contraindication

Answer 32

• 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

Question 33

Class III - Drug interactions

Answer 33

• 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!

Question 34

Class III - Indications, PK

Answer 34

• 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.

Question 35

Action of anti-arrhythmic drugs do 1 of 4 things:

Answer 35

– 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)