Medical Pharmacology Topics
The key electrophysiologic properties of cardiac tissue are automaticity, excitability, refractoriness and conduction. Antiarrhythmic drugs may act by altrering any of these properties.
Automaticity is the ability to generate action potentials sontaneously. Cardiac cells that are normally automatic include the sinuatrial (SA) node cells (80-120 beats/min), atrioventricular (AV) node cells (40-60 beats/min), and Purkinje fibers (20-40 beats/min). In a normal heart, SA node cells beat faster than other automatic cells, therefore they will initiate the action potential that propagates throughout the myocardium with each beat. When the SA node cells are damage and can no longer achive the initial action potential, the AV node can initiate the action potential.
Excitability is the ability to respond to stimulus by generating an action potential. Each cell has a threshold potential, and stmuli below the threshold will be insufficient to trigger the action potential.
Refractoriness refers to a period following initiation of the action potential during which the cell is unable to generate another action potential in response to a threshold stimulus. Refractoriness is due to the temporary inactivation of voltage-gated channels.
Conduction is the spread
of cardiac impulses from cell to cell. Speed and efficiency of conduction is
directly related to the initial phase of the action potential (phase 0). The
faster the rate of increase (Vmax), the more rapidly the
cell will reach threshold. Conversely, depresion of the rate of increase will
lead to slower conduction, and in extreme cases conduction block. Since Vmax
is a function of the available fast Na
channels, a Na
channel locker will slow conduction.
Arhythmias are abnormalities in the rate, regularity or site of origin of the cardiac impulse, or in the conduction of thet impulse such that the nermal sequence of activation of the atria and ventricles is altered. They are caused by conditions like acute myocardial ischemia, infarction, cardiomyopathy, congenital or vascular heart isease, electrolyte imbalance, hypoxia, trauma, septicemia or drugs.
The physiological mechanisms that lead to arhythmias can be categorized as either abnormalities of impulse formation or abnormalities of impulse conduction.
Resting Potential
The resting membrane potential
of cardiac cells is a consequence of the distribution an selective permeability
of the three main ions: K,
Na
and Ca
.
:
Whe the cell is at rest, the Na/K
ATPase maintains a higher K
concentration inside the cells than outside. The resting membrane potential
of most cardiac cells approximate the equilibrium potential of K
because the permeability of cardiac cells to K
is much higher than to other ions.:
The Na/K
ATPase maintains a lower Na
concenration inside the cell than outside when the cell is at rest. This exclusion
of Na
from the cytoplasm, as well as exclusion of other positive ions gives the
cell a relative negative charge compared with the more positive extracellular
fluid. Permeability to Na
changes dramatically during the action potential due to voltage-gated fast
Na
channels.:
At rest, cytoplasmic Ca
is maintained at very low concentrations by (1) sequestration into the sarcoplasmic
reticulum (SR) by a Ca
pump, and (2) extrusion to the extracellular fluid through a Na/Ca
exchanger. Permeability to Ca
changes dramatically during the action potential due to voltage-gated Ca
channels in the sarcolema and SR. The equilibrium potential
for an ion represents the membrane potential at which no net movement ofthe
ion occurs, i.e. the diffusional forces pushing the ion in one direction are
offset by the electrical potential. SInce we already know the resting membrane
potential is mostly determined by the K
equilibrium potential, we can use the Nerst equation to determine the resting
potential of most cardiac cells, which have a cytoplasmic K
concentration of 140 mM and 4 mM outside:
EK+
= RT ln [K]o
= -61.5 log 140 = -95 mV
zF [K]i
4
It is important to note
that, since [K]
is the determinant factor in the membrane potential of cardiac cells, changes
in extracellular [K]
( [K]o)
can profoundly influence cardiac function. An increase in [K]o
will hyperpolarize the cell, while a decrease in [K]o
will depolarize the cell.
Different types of cardiac
cells will exhibit either fast response action potentials or slow response action
potentials. Fast action potentials more closely resemble the conditions just
described above regarding the contributions of K,
Na
and Ca
to the resting membrane potential, while conditions in cells with slow response
action potentials are somewhat different.
Fast Action Potentials and Contractility
Fast response action potentials are normal in atrial muscle, ventricular muscle and Purkinje fibers. All of these have a resting membrane potential around -90 mV. Purkinje fibers are responsible for conducting the action potential from the rigth atrium down to the ventricles.
The fast response
action potential occurs in 5 phases (pass mouse over the different colors in
figure to see labels):
channels. The influx of Na
produces a rapid depolarization.
channels close and there is a small initial repolarization.
channels in sarcolema and sarcoplasmic reticulum open, increasing the cytosolic
[Ca].
At the same time, K
channels close. For about 250 msec, the influx of Ca
is balanced by a small outflow of K,
keeping the cell almost depolarized in a "neutral plateau".
channels open while the slow Ca
channels close. As more K
leave and fewer Ca
enter the negative restingmembranen potential is restored.]
and [Ca]
and high intracellular [K]
are maintained by the Na/K
ATPase, the Na/Ca
exchanger and the Ca
pump in the sarcoplasmic reticulum.During phases 1-2 no stimulus will evoke an action potential. This is known as the absolute refractory period. During phase 3, a stimulus can evoke an action potential, although a stronger stimulus is required than at the resting membrane potential, and the action potential is abnormal. This is known as the relative refractory period.
The fast response action
potential is responsible for muscle contraction. The electrial activity leads
to the mechanical response after a short lag time. As [Ca]
increases, Ca
binds troponin, allowing actin and myosin filaments to slide pass one another
and develp tension (contraction).
Slow Action Potentials and Automaticity
Slow action potentials are normal in he sinoatrial (SA) node and the atrioventricular (V) node. Normally, cardiac excitation beguins automatically in the SA node, located in the right atrial wall. Each action potential propagates from the SA node through both atria via gap junctions, including the AV node. After reaching the AV node, the action potential is propagated to the ventricles through Purkinje fibers. SA node and AV node cells have normal resting potentials around -65 mV.
The slow response action potential occurs in three phases (analogous to some
of the phases of the fast action potential):
channels. The influx of Ca
depolarizes the cell.
channels open while Ca
channels close. As more K
leaves and fewer Ca
enters, the negative resting potential is restored.
efflux and increases in Na
and Ca
influx are maintained until the cell reaches threshold depolarization automatically.
In addition to nodal cells,
Purkinje fibers also exhibit spontaneous depolarization during phase 4, also
known as diastolic depolarization. Therefore there are two different mechanisms
for diastolic depolarization. In nodal "slow response" tissue, diastolic
depolariation is due to decreased K
conductance (eflux) at the same time there is an increase in
Na
and Ca
conductance (influx). In "fast response" Purkinje cells, diastolic
depoolarization is due to a decrease in K
conductance at the same time there is an increase in Na
conductance.
Abnormalities of Impulse Formation
Abnormalities of impulse formation may be due to alteration of automaticity (enhanced or depressed), development of abnormal automaticity (ectopic pacemakers), or triggere activity (early or delayed after-depolarizations). Automaticity can be modulated by changing one of three factors:
Abnormal automaticity develops
when damage or ischemic myocardioal cells, which are not usually automaticv,
become depolarized and develop automaticity. Since more of the fast Na
channels are inactivated as the resting potential becomes more depolarized,
the appearance and character of the resulting action potential becomes like
that of a slow action potential.
Early after-depolarizations (EAD) are interruptions of phase 3 repolarization (relative refractory period) that may appear when the cardiac action potential is markedly prolonged (?). The EAD may then trigger one or more bizarre action potentials whose exact origin is not clear. This type of triggered activity is most commenly seen under conditions of very slow heart rate, low extracellular K+ and treatment with drugs (often anti-arhythmics) that prolong the duration of the action potential.
EADs are throught to be responsible for Torsade de Pointe, an arhythmia caused by many antiarythmic drugs. Torsade de Pointe is usually self-limiting, resulting in brief runs of ventricular tachycardia (and syncope) that spontaneously revert to sinus rhythm. However, in some cases may progress to ventricular fibrilation.
Delayed after-depolarizations
(DAD) ae oscillations in ionic conductance and membrane potential that occur
shortly after return to resting membrane potential following a cardiac action
potential. They may be sufficient to bring the cell to threshold and trigger
an action potential, or a succession of action potentials. DADs are sometims
seen under conditions of intracellular Ca
overload in sick or damaged cardiac tisue, or in normal myocardium exposed to
drugs like digitalis, or under high sympathetic tone, particularly when heart
rate is very high.
Abnormalities of Impulse conduction
Abnormalities of impulse conduction may be due to conduction delay or block, or to reentry. The same factors that provide for physiological slowing of the cardiac impulse in the AV node makes it a common site for pathological delay or complete block of the cardiac impulse. Slowed down conduction - and in extreme cases unidirectional or bidirectional block - is commonly seen in sick or damaged myocardium.
Reentry refers to a case where a single cardiac impulse reenters a portion of the myocardium that the impulse has already passed through and exited at least once. This is thought to require unidirectional block and slowed conduction through a portion of the normal conduction path for the cardiac impulse. Under normal conditions, an impulse that spreads in two or more directions will eventually encounter itself or another impulse traveling towards it. Then the two impulses will cancel each other and allow a refractory period for the tissue to repolarize and start over. If there is a block impeading the passage of the initial impulse in one direction but not the others, the impulse will propagate only in one direction and eventually travel back to the place it was initiated, without being cancelled by another impulse branch. This condition is known as reentry because the tissue where the impulse already passed had time to repolarize and as the impulse reenters the same tissue it will continue uninpeeded.
Continue
to "Cardiac Arrythmias" or take a quiz:
[Q1].
Extra: The Electrocardiogram
Back to Basics: Resting
Membrane Potential (Physiology)
Action Potential
(Physiology)
Advance Topics: Cell Excitability (Intro Pharm & Tox)
Need more practice? Answer the review questions below.
Questions coming soon