Drugs Used in Cardiac Arrhythmias - lecture

Question 1

Electrical activity of the heart

Answer 1

• Excitation-contraction coupling – electrical activity controls the rhythm and rate of the heart pump
• Ions move in response to their concentration and electric gradients
• Ions move across the
membrane at specific
times of the cardiac cycle
when their specific ion
channels are open

Question 2

Cardiac action potential

Answer 2

sequence of ion fluxes through specific ion channels across the cell membrane (sarcolemma)

Question 3

Fast action potential

Answer 3

– Ventricular contractile cardiomyocytes – Atrial cardiomyocytes
– Purkinje fibers

Question 4

Slow action potential

Answer 4

pacemaker

SA node
AV node

Question 5

Fast action potential in cardiac muscle

Answer 5

• Phase 0: voltage-dependent fast Na+ channels open as a result of depolarization; Na+ enters the cells down its electrochemical gradient
• Phase 1: K+ exits cells down its gradient, while fast Na + channels close, resulting in some repolarization
• Phase 2: plateau phase results from K+ exiting cells offset by and Ca2+ entering through slow voltage- dependent Ca2+ channels
• Phase 3: Ca2+ channels close and K+ begins to exit more rapidly resulting in repolarization
• Phase 4: Resting membrane potential is gradually restored by Na+/K+ ATPase and the Na+/Ca2+ exchanger

Question 6

Phase 4 - pacemaker AP

Answer 6

Slow spontaneous depolarization
– Poorly selective ionic influx (Na+, K+) known as pacemaker current (Funny current, If) – activated by hyperpolarization
– Slow Ca2+ influx (via T-type (transient) channels)

Question 7

Phase 0 and 3 in pacemaker AP

Answer 7

• Phase 0: Upstroke of Action Potential
– Ca2+ influx through the relatively slow L-type
(long-acting) Ca2+ channels
• Phase 3: Repolarization
– Inactivation of calcium channels with increased K+ efflux

Question 8

Factors determining firing rate or automaticity of pacemaker AP

Answer 8

– Rate of spontaneous depolarization in phase 4
(i.e., slope): decreased slope – decreased rate (need more time to reach threshold potential)
– Threshold potential – the potential at which action potential is triggered
– Resting potential – if potential is less negative, less time is needed to reach the threshold – firing rate increases

Question 9

sodium channel

Answer 9

• Resting state – the channel is closed but ready to generate action potential
• Activated state – depolarization to the threshold opens m-gates greatly increasing sodium permeability
• Inactivated state – h-gates are closed, inward sodium flux is inhibited, the channel is not available for reactivation – this state is responsible for the refractory period

Question 10

State-dependent sodium channel block

Answer 10

drugs may have different affinities towards the ion channel protein while it shuttles through different states of the cycle
– Na+ channel drugs have been extensively studied
– Most useful drugs block open activated or inactivated Na+ channels, with very little affinity towards channels in a resting state

Question 11

Sympathetic effect on SA nodal cells

Answer 11

• Role of cAMP
• Effect on the Funny current – If
• Effect on Ca2+ channels – lower the threshold
• Increased slope due to effects on If and T-type Ca channels
• Reduced threshold due to effect on L-type Ca channels

Question 12

Regulation of resting potential - K+ channel

Answer 12

– Inward (electric) gradient is in equilibrium with the outward (concentration) gradient in the resting cell
– Inwardly rectifying K+ channels are open in the resting state
– No current occurs in these channels because of this equilibrium
– If extracellular K+ concentration changes, membrane potential will have to readjust to reach new equilibrium

Question 13

Regulation of AP - K+ channel

Answer 13

– Voltage-gated K+ channels contribute to the regulation of action potential
– Repolarization of cell membrane during action potential
– Limit the frequency of action potentials (regulate the duration of the refractory period)