Pharmacology PHL 101

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Pharmacology PHL 101
Abdelkader Ashour, Ph.D. 10th Lecture
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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

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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 sodiumpotassium 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

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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 voltage-sensitive calcium channels

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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

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Antihypertensive drugs, Classes, the most
important ones

• Diuretics
• Angiotensin Converting Enzyme Inhibitors (ACE
  inhibitors)
• Angiotensin Receptor blockers
• Renin Inhibitors
• Calcium Channel Blockers
• Potassium Channel openers
• a1-adrenoceptor antagonists (a1-blockers)
• Beta Blockers
• a2-adrenoceptor agonists
• Peripheral Vasodilators

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Antihypertensive drugs, Classes, the most
important ones

• 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

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Antihypertensive drugs, Classes, the most
important ones

• 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

• a1-adrenoceptor antagonists (a1-blockers)
• Mechanism of action.
• These drugs block the effect of sympathetic
  nerves on blood vessels by binding to
  a-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
• 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

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Antihypertensive drugs, Classes, the most
important ones

• 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

• 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