Pharmacology PHL 101 Abdelkader Ashour, Ph.D. 10 th 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)  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  A resting potential is caused by a slightly unbalanced distribution of ions between the intracellular fluid and extracellular fluid

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 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 Depolarization Repolarization  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

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 Ca 2+ channels opening even after the Na 2+ 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 voltage- sensitive 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 Ca 2+ channels opening even after the Na 2+ 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   -adrenoceptor antagonists (   -blockers) 8.Beta Blockers   -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:  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:  Examples: Nicorandil, minoxidil sulphate  1 -adrenoceptor antagonists (  1 -blockers)  Mechanism of action.  These drugs block the effect of sympathetic nerves on blood vessels by binding to  - adrenoceptors located on the vascular smooth muscle. Most of these drugs acts as competitive antagonists to the binding of norepinephrine to the smooth muscle receptors   --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:  Examples: prazosin, doxazosin

Antihypertensive drugs, Classes, the most important ones :  -blockers :  Mechanism of action.  Beta-blockers are drugs that bind to  -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  -blockers were non-selective, meaning that they blocked both   and   adrenoceptors. Second generation  -blockers (   -blockers) are more cardioselective in that they are relatively selective for   adrenoceptors.  Examples:  For non-selective  blockers: propranolol  For selective   blockers: atenolol       adrenoceptor agonists (centrally acting sympatholytics)  Mechanism of action.  Centrally acting sympatholytics block sympathetic activity by binding to and activating  -adrenoceptors  inhibition of NE release. This reduces sympathetic outflow to the heart thereby decreasing cardiac output by decreasing heart rate and contractility  Centrally acting sympatholytics block sympathetic activity by binding to and activating   -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:  Examples: clonidine