WEEK 3: Pharmacology of the rhythm of the heart Flashcards
Review the physiology of the conduction system of the heart.
The conduction system of the heart is responsible for generating and coordinating the electrical impulses that regulate the heartbeat. This system consists of specialized cardiac muscle cells that initiate and propagate electrical signals throughout the heart. Here’s a brief overview of the physiology of the conduction system:
- Sinoatrial (SA) Node:
-The SA node is located in the right atrium near the entrance of the superior vena cava.
-It serves as the heart’s natural pacemaker, generating rhythmic electrical impulses at a regular rate (approximately 60-100 beats per minute in adults).
-The electrical impulses spread from the SA node through the atria, causing them to contract and pump blood into the ventricles.
- Atrioventricular (AV) Node:
-The AV node is located near the lower portion of the interatrial septum.
-It acts as a gateway between the atria and the ventricles, slowing down the electrical impulses to allow the atria to contract fully before the ventricles are activated.
-The delay in conduction through the AV node ensures coordinated contraction of the atria and ventricles, allowing for efficient blood pumping. - Bundle of His:
-After passing through the AV node, the electrical impulses travel along specialized conducting fibers called the bundle of His, which extends into the interventricular septum.
-The bundle of His branches into the left and right bundle branches, which transmit the electrical impulses to the respective ventricles. - Purkinje Fibers:
The bundle branches further divide into smaller fibers known as Purkinje fibers, which spread throughout the ventricles.
Purkinje fibers rapidly conduct the electrical impulses to the myocardium of the ventricles, stimulating coordinated contraction of the ventricular muscle fibers.
This rapid conduction ensures synchronized contraction of the ventricles, leading to effective ejection of blood from the heart.
What is the name of the tissue that prevents the passage of impulses from the atrium to the ventricles?
The tissue that prevents the passage of impulses directly from the atria to the ventricles, forcing them instead to pass through the atrioventricular (AV) node, is called the atrioventricular (AV) junctional tissue or simply the AV node.
This specialized tissue serves as a gateway between the atria and ventricles, slowing down the electrical impulses to allow for coordinated contraction of the heart chambers.
The delay imposed by the AV node ensures that the atria contract fully to pump blood into the ventricles before ventricular contraction begins, facilitating efficient pumping and maintaining the integrity of the cardiac cycle.
Define the following terms:
1. Membrane potential
2. Depolarization
3. Repolarization
Membrane potential is the difference in voltage (or electrical potential) between the inside and outside of a cell.. It is determined by the relative conductance’s (or permeabilities) to ions and the concentration gradients for the permeant ions.
Depolarization means the membrane potential has become less negative. It occurs when there is net movement of positive charge into the cell, which is called an inward current.
Repolarization means the membrane potential has become more negative, and it occurs when there is net movement of positive charge out of the cell, which is called an outward current.
Describe the physiology of the cardiac action potential 4 phases.
Phase 0: Rapid Depolarization:
During phase 0, the membrane potential rapidly depolarizes from its resting state (around -90 mV) to a more positive value.
This depolarization is triggered by the influx of positively charged ions, primarily sodium ions (Na+), through fast voltage-gated sodium channels that open in response to a threshold membrane potential being reached (-70 to -60 mV).
The influx of sodium ions causes a sharp increase in membrane potential, leading to the rapid upstroke of the action potential.
Phase 1: Early Repolarization:
Phase 1 is a brief period of partial repolarization immediately following phase 0.
It is characterized by the transient opening of voltage-gated potassium channels, allowing potassium ions (K+) to move out of the cell, which partially counteracts the influx of sodium ions.
This partial repolarization results in a small decrease in membrane potential, giving phase 1 its characteristic notch or plateau appearance on the action potential waveform.
Phase 2: Plateau Phase:
Phase 2 is a prolonged plateau phase where the membrane potential remains relatively stable at a slightly positive value.
This plateau phase is primarily due to a balance between inward and outward currents, particularly the influx of calcium ions (Ca2+) through voltage-gated calcium channels and the efflux of potassium ions.
The influx of calcium ions contributes to myocardial contraction by triggering the release of calcium ions from intracellular stores (sarcoplasmic reticulum), leading to actin-myosin cross-bridge formation and muscle contraction.
The plateau phase helps to sustain myocardial contraction, allowing for efficient ejection of blood from the heart chambers.
Phase 3: Rapid Repolarization:
Phase 3 involves the rapid repolarization of the membrane potential back to its resting state.
I
t is initiated by the closure of voltage-gated calcium channels and the continued efflux of potassium ions through delayed rectifier potassium channels.
The closure of calcium channels reduces the influx of calcium ions, while the efflux of potassium ions accelerates repolarization, restoring the negative resting membrane potential.
As the membrane potential returns to its resting state, the cell is ready for the next cardiac cycle, and the action potential waveform returns to baseline.
Describe physiology of the pacemaker action potential.
Phase 4: Pacemaker Potential (Diastolic Depolarization):
The pacemaker action potential begins during phase 4, also known as the pacemaker potential or diastolic depolarization.
Unlike cardiac muscle cells, which have a stable resting membrane potential, pacemaker cells exhibit a gradual spontaneous depolarization during phase 4.
The gradual depolarization is primarily due to a mixed influx of sodium ions (Na+) through funny (If) channels and a slow efflux of potassium ions (K+).
The If channels are unique to pacemaker cells and open at negative membrane potentials, allowing a small influx of sodium ions that gradually depolarizes the cell.
Phase 0: Depolarization:
Once the membrane potential of the pacemaker cell reaches a threshold level (typically around -40 to -50 mV), voltage-gated calcium channels (L-type calcium channels) open.
The opening of these calcium channels leads to a rapid influx of calcium ions (Ca2+), triggering depolarization of the membrane potential.
This rapid depolarization constitutes phase 0 of the pacemaker action potential, similar to phase 0 of the cardiac action potential in myocardial cells.
Phase 3: Repolarization:
After reaching its peak, the influx of calcium ions decreases as L-type calcium channels close, and potassium channels open.
The opening of potassium channels allows potassium ions to move out of the cell, leading to repolarization of the membrane potential.
Repolarization in pacemaker cells is relatively gradual compared to myocardial cells, contributing to the slow rate of depolarization during phase 4.
Phase 4 Re-initiation:
Following repolarization, the membrane potential returns to its baseline level, and the pacemaker potential restarts the cycle of depolarization, initiating a new action potential.
The spontaneous depolarization during phase 4 ensures the continuous generation of rhythmic electrical impulses in the SA node, setting the pace for the heart’s contractions.
State the 4 main classes of anti-arrhythmic drugs according to VAUGHAN WILLIAMS CLASSIFICATION, their MOA and give examples.
- Class I: Sodium Channel Blockers:
Mechanism of Action (MOA): These drugs block sodium channels in cardiac cell membranes, thereby reducing the rate of depolarization and conduction velocity of action potentials. They primarily affect fast sodium channels (INa) during phase 0 of the cardiac action potential.
Examples:
Class IA: Procainamide, Quinidine, Disopyramide
Class IB: Lidocaine, Mexiletine
Class IC: Flecainide, Propafenone
- Class II: Beta-Adrenergic Receptor Blockers:
Mechanism of Action (MOA): These drugs antagonize beta-adrenergic receptors in the heart, leading to a reduction in sympathetic nervous system activity. By blocking beta-1 adrenergic receptors, they decrease the rate of sinoatrial (SA) node firing, slow atrioventricular (AV) conduction, and reduce myocardial contractility.
Examples:
Propranolol, Metoprolol, Atenolol, Bisoprolol
- Class III: Potassium Channel Blockers:
Mechanism of Action (MOA): These drugs prolong the duration of the action potential and the refractory period by blocking potassium channels (particularly the delayed rectifier potassium channels, IKr and IKs). By prolonging repolarization, they help stabilize the cardiac rhythm and prevent reentrant arrhythmias.
Examples:
Amiodarone, Sotalol, Dofetilide, Ibutilide
Class IV: Calcium Channel Blockers:
Mechanism of Action (MOA): These drugs inhibit calcium influx through voltage-gated L-type calcium channels in cardiac muscle cells. By reducing calcium entry during the plateau phase of the action potential (phase 2), they slow conduction through the AV node, decrease myocardial contractility, and prolong the refractory period.
Examples:
Verapamil, Diltiazem
Describe the 3 types of VOLTAGE GATED SODIUM CHANNELS.
- Resting: M channels open, h gates closed: No
*In the resting state, the VGSC is closed and is not conducting ions. This state occurs when the membrane potential is at or near its resting potential, typically around -70 millivolts (mV) in excitable cells.
- Activated: Both m and h gates open
*When the membrane potential depolarizes beyond a certain threshold (typically around -55 mV), the VGSC undergoes a conformational change, transitioning from the resting state to the activated state.
*In the activated state, the channel opens rapidly, allowing the influx of sodium ions (Na+) into the cell.
*This rapid influx of sodium ions contributes to the rapid upstroke of the action potential, leading to depolarization of the cell membrane.
- Inactivated: m gates open h gates closed
*Following activation, the VGSC quickly transitions to the inactivated state. Inactivation occurs within milliseconds of channel opening.
*In the inactivated state, the channel remains closed, and sodium conductance is blocked, preventing further influx of sodium ions.
*The inactivation gate of the channel is closed, blocking the pore and preventing ion flow, even if the membrane potential remains depolarized.
*The inactivation of sodium channels helps ensure that the action potential is brief and prevents continuous depolarization of the cell membrane.
*The inactivated state is typically transient, and the channels eventually transition back to the resting state, either spontaneously or through a process known as recovery from inactivation.
Describe the MOA of Class IA drugs and their examples.
*Act on the active sodium channels
*Decreased the slope of phase 0.
*Prolong repolarization by also acting on K voltage gated channels.
Sodium Channel Blockade:
*Class IA drugs bind to sodium channels in cardiac cell membranes, particularly during depolarization (phase 0) of the action potential.
*By binding to these channels, they inhibit the influx of sodium ions, thereby reducing the rate of depolarization and slowing conduction velocity.
*This sodium channel blockade helps to suppress abnormal automaticity and reentrant pathways responsible for certain types of arrhythmias.
- Potassium Channel Blockade:
*In addition to sodium channel blockade, Class IA drugs also block potassium channels, particularly the delayed rectifier potassium channels (IKr and IKs), during repolarization (phase 3) of the action potential.
*By inhibiting potassium efflux, these drugs prolong the duration of the action potential and the refractory period, delaying repolarization and reducing the likelihood of premature depolarizations and reentrant arrhythmias.
EXAMPLES: Quinidine AND Procainamide
Describe the MOA, indications and adverse effects of quinidine.
Has mild alpha blocking and anticholinergic effects.
Used in the treatment of a wide variety of arrhythmias.
Can increase AV nodal conduction velocity (Combined with digoxin, calcium channel blocker or beta blocker)
Adverse effects include nausea, vomiting, diarrhea, granulomatous hepatitis, thrombocytopenia.
Cinchonism (Headache, tinnitus, vertigo)
Discuss Cinchonism.
What drug cause Cinchonism?
Cinchonism is a condition characterized by a range of symptoms that can occur as a result of quinine toxicity or sensitivity. Quinine is an alkaloid derived from the bark of the cinchona tree and is commonly used to treat malaria and certain types of cardiac arrhythmias. However, in some individuals, particularly at higher doses or with prolonged use, quinine can lead to adverse effects known collectively as cinchonism. The symptoms of cinchonism typically include:
Headache: Headache is a common symptom of cinchonism and may vary in severity. It can range from mild discomfort to intense pain and may be accompanied by other symptoms such as dizziness or nausea.
Tinnitus: Tinnitus refers to the perception of noise or ringing in the ears in the absence of external sound stimuli. It is a characteristic symptom of cinchonism and may be experienced unilaterally or bilaterally.
Vertigo: Vertigo is a sensation of spinning or dizziness, often described as feeling off-balance or lightheaded. It is another common symptom of cinchonism and may be associated with feelings of nausea or vomiting.
Discuss the MOA, indications and adverse effects of PROCAINAMIDE.
Have similar effects to those of quinidine
Less anticholinergic effects
No alpha blocking effects
N-Acetylprocainamide (NAPA) is an active metabolite that behaves like a class III drug.
A lupus-like syndrome can be induced, especially in patients who have a slow acetylator phenotype.
Describe the MOA CLASS IB DRUGS and give examples.
-Block inactivated sodium channels
-Shortened Effective Refractory Period (ERP): Class IB drugs typically shorten the effective refractory period, which is the period during which cardiac cells are unable to respond to a new stimulus. This can be beneficial in certain arrhythmias by preventing reentry of excitation waves.
-Block late sodium current (common in hypoxic tissues)
*Reduce aberrant electrical activity, and suppress arrhythmias, particularly those arising from ischemic or hypoxic conditions.
This dual mechanism of action contributes to their efficacy in managing certain types of ventricular arrhythmias, especially those associated with acute myocardial infarction or ischemia.
Lidocaine
Mexiletine
Describe the MOA, INDICATIONS AND ADVERSE EFFECTS OF LIDOCAINE.
Lidocaine is commonly used to treat ventricular arrhythmias in emergency situations
Low oral bioavailability (Parenteral drug)
Lidocaine is one of the least cardiotoxic of the currently used sodium channel blockers.
Lidocaine’s most common adverse effects—like those of other local anesthetics—are neurologic: paresthesia’s, tremor, nausea of central origin, lightheadedness, hearing disturbances, slurred speech, and convulsions.
Describe the MOA of CLASS IC drugs and give examples.
Induce considerable phase 0 depression by strongly binding to the sodium channels (all states)
They have little or no effect on action potential duration
However, these drugs have marked depressive effects on cardiac function and, thus, must be used with discretion.
Several studies have cast serious doubts on the safety of the class IC drugs, particularly in patients with structural heart disease.
Flecainide
Propafenone
Describe the MOA of CLASS II: β BLOCKERS.
Blockade of Beta-adrenergic Receptors: Beta blockers competitively block beta-adrenergic receptors, specifically beta-1 and beta-2 receptors.
Beta-1 receptors are predominantly found in cardiac tissue, particularly in the sinoatrial (SA) node, atrioventricular (AV) node, and myocardium.
By blocking these receptors, beta blockers reduce the effects of endogenous catecholamines, such as epinephrine and norepinephrine, on the heart.
Reduction of Sympathetic Activity:
Beta blockers decrease sympathetic nervous system activity by inhibiting the actions of norepinephrine and epinephrine.
This leads to reduced heart rate (negative chronotropic effect), decreased myocardial contractility (negative inotropic effect), and diminished conduction velocity through the AV node (negative dromotropic effect). These effects collectively result in a decrease in cardiac workload and oxygen demand.
INCREASE IN SYMPATHETIC TONE DECREASES ERP.
