Download 10th Lecture

Pharmacology PHL 101
Abdelkader Ashour, Ph.D.
10th Lecture
Membrane Potential
 An electrical potential difference, or membrane potential,
can be recorded across the plasma membrane of living
cells
 The potential of unstimulated muscle and nerve cells, or
resting potential, amounts to – 50 to – 100mV (cell interior
is negative)
 A resting potential is caused by a slightly unbalanced
distribution of ions between the intracellular fluid and
extracellular fluid
 All living cells have a (resting) membrane potential, but
only excitable cells such as nerve and muscle cells are
able to greatly change the ion conductance of their
membrane in response to a stimulus, as in an action
potential
Action Potential
 Definition: an action potential (also known as a nerve impulse) is a pulse-like wave of
voltage that passes on through an axon or along a muscle fiber that influences other
neurons or induces muscle contraction
 During depolarization:
Opening of sodium channels and influx of sodium
ions is usually associated with cell stimulation
 During repolarization:
Inactivation of sodium channels and repolarizing
efflux of potassium ions is usually associated
with cell inhibition
 The normal ratio of ion concentrations across
the membrane is maintained by the continual
action of the sodium–potassium pump, which
transports three sodium ions out of the cell and
two potassium ions in
 The action potential stops at the end of the
neuron, but usually causes the secretion of
neurotransmitters at the synapses that are
found there
 These neurotransmitters bind to receptors on
adjacent cells
Cardiac Action Potential
 The cardiac action potential differs from the neuronal action potential by having an
extended plateau, in which the membrane is held at a high voltage for a few
hundred milliseconds prior to being repolarized by the potassium current as usual
 This plateau is due to the action of slower
Ca2+ channels opening even after the Na2+
channels have inactivated
 The cardiac action potential plays an
important role in coordinating the
contraction of the heart
 The cardiac cells of the sinoatrial node
provide the pacemaker potential that
synchronizes the heart
 The action potentials of those cells
propagate to and through the
atrioventricular node (AV node), then from
the AV node travel through the bundle of His
and thence to the Purkinje fibers.
 Phases of a cardiac action potential
 The sharp rise in voltage ("0")
corresponds to the influx of sodium
ions, whereas the two decays ("1"
and "3", respectively) correspond to
the sodium-channel inactivation and
the repolarizing efflux of potassium
ions
 The characteristic plateau ("2")
results from the opening of voltagesensitive calcium channels
Cardiac Action Potential
 The cardiac action potential differs from the neuronal action potential by having an
extended plateau, in which the membrane is held at a high voltage for a few
hundred milliseconds prior to being repolarized by the potassium current as usual
 This plateau is due to the action of slower
Ca2+ channels opening even after the Na2+
channels have inactivated
 The cardiac action potential plays an
important role in coordinating the
contraction of the heart
 The cardiac cells of the sinoatrial node
provide the pacemaker potential that
synchronizes the heart
 The action potentials of those cells
propagate to and through the
atrioventricular node (AV node), then from
the AV node travel through the bundle of
His and thence to the Purkinje fibers
Antihypertensive drugs, Classes, the most important ones
1. Diuretics
2. Angiotensin Converting Enzyme Inhibitors (ACE inhibitors)
3. Angiotensin Receptor blockers
4. Renin Inhibitors
5. Calcium Channel Blockers
6. Potassium Channel openers
7. a1-adrenoceptor antagonists (a1-blockers)
8. Beta Blockers
9. a2-adrenoceptor agonists
10. Peripheral Vasodilators
Antihypertensive drugs, Classes, the most important ones
5. Calcium Channel Blockers (CCBs):
 Mechanism of action.
 These drugs bind to calcium channels located on the vascular smooth muscle,
cardiac myocytes, and cardiac nodal tissue (sinoatrial and atrioventricular
nodes).
 These channels are responsible for regulating the influx of calcium into muscle
cells, which in turn stimulates smooth muscle contraction and cardiac myocyte
contraction.
 In cardiac nodal tissue, calcium channels play an important role in pacemaker
currents and in phase 0 of the action potentials. Therefore, by blocking calcium
entry into the cell, CCBs cause vascular smooth muscle relaxation
(vasodilation), decreased myocardial force generation, decreased heart rate,
and decreased conduction velocity within the heart, particularly at the
atrioventricular node.
 Examples: nifedipine, verapamil
Antihypertensive drugs, Classes, the most important ones
6. Potassium Channel openers:
 Mechanism of action.
 These are drugs that activate (open) ATP-sensitive K+-channels in vascular smooth
muscle. Opening these channels hyperpolarizes the smooth muscle, which closes
voltage-gated calcium channels and decreases intracellular calcium, leadings to
muscle relaxation and vasodilation, decreasing systemic vascular resistance and
lowering blood pressure.
 Examples: Nicorandil, minoxidil sulphate
7. a1-adrenoceptor antagonists (a1-blockers)
 Mechanism of action.
 These drugs block the effect of sympathetic nerves on blood vessels by binding to aadrenoceptors located on the vascular smooth muscle. Most of these drugs acts as
competitive antagonists to the binding of norepinephrine to the smooth muscle
receptors
 a--blockers dilate both arteries and veins because both vessel types are innervated
by sympathetic adrenergic nerves; however, the vasodilator effect is more
pronounced in the arterial resistance vessels. Thus they decrease systemic vascular
resistance and lower blood pressure.
 Examples: prazosin, doxazosin
Antihypertensive drugs, Classes, the most important ones
8. b-blockers :
 Mechanism of action.
 Beta-blockers are drugs that bind to b-adrenoceptors and thereby block the binding
of norepinephrine and epinephrine to these receptors. This inhibits normal
sympathetic effects that act through these receptors. Thus, drugs decrease heart
rate, conduction velocity and force of contraction
 The first generation of b-blockers were non-selective, meaning that they blocked
both b1 and b2 adrenoceptors. Second generation b-blockers (b1-blockers) are more
cardioselective in that they are relatively selective for b1 adrenoceptors.
 Examples:
 For non-selective b blockers: propranolol
 For selective b1 blockers: atenolol
9. a2-adrenoceptor agonists (centrally acting sympatholytics)
 Mechanism of action.
 Centrally acting sympatholytics block sympathetic activity by binding to and activating
a2-adrenoceptors  inhibition of NE release. This reduces sympathetic outflow to the
heart thereby decreasing cardiac output by decreasing heart rate and contractility
 Reduced sympathetic output to the blood vessels decreases sympathetic vascular
tone, which causes vasodilation and reduced systemic vascular resistance, which
decreases arterial pressure
 Examples: clonidine