Download PharmacologyLec 1 Central nervous system pharmacology

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PharmacologyLec 1
‫اﺳﺎﻣﺔ اﯾوب‬.‫د‬
Central nervous system pharmacology
There are two reasons why understanding the action of drugs act on the central
nervous system, the first is that centrally acting drugs are of therapeutic
importance,the second reason is that the CNS is functionally far more complex
than any other system in the body, and this makes the understanding of drug
effects very much more difficult.The communication between neurons in the CNS
occurs through chemical synapses in the vast majority of cases.
An action potential in the presynaptic fiber propagates into the synaptic terminal
and activates voltage-sensitive calcium channels in the membrane of the
terminalCalcium flows into the terminal, and the increase in intraterminal calcium
concentration promotes the fusion of synaptic vesicles with the presynaptic
membrane.The transmitter contained in the vesicles is released into the synaptic
cleft and diffuses to the receptors on the postsynaptic membrane. Binding of the
transmitter to its receptor causes a brief change in membrane conductance
(permeability to ions) of the postsynaptic cell.
NEUROTRANSMISSION IN THE CNS
In many ways, the basic functioning of neurons in the CNS is similar to thatof the
autonomic nervous system, for example,transmission of information in the CNS
and in the periphery both involvethe release of neurotransmitters that diffuse
across the synaptic space tobind to specific receptors on the postsynaptic
neuron.However, severalmajor differences exist between neurons in the
peripheral autonomic nervoussystem and those in the CNS. The circuitry of the
CNS is much morecomplex than that of the autonomic nervous system, and the
number ofsynapses in the CNS is far greater. The CNS, unlike the peripheral
autonomicnervous system, contains powerful networks of inhibitory neuronsthat
are constantly active in modulating the rate of neuronal transmission.In addition,
the CNS communicates through the use of more than10 (and perhaps as many as
50) different neurotransmitters. In contrast,the autonomic nervous system uses
only two primary neurotransmitters,acetylcholine and norepinephrine.
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SYNAPTIC POTENTIALS
In the CNS, receptors at most synapses are coupled to ion channels. Thatis,
binding of the neurotransmitter to the postsynaptic membrane receptorsresults
in a rapid but transient opening of ion channels. Open channelsallow specific ions
inside and outside the cell membrane to flow downtheir concentration gradients.
The resulting change in the ionic compositionacross the membrane of the neuron
alters the postsynaptic potential,producing either depolarization or
hyperpolarization of the postsynapticmembrane, depending on the specific ions
that move and the direction oftheir movement.
A. Excitatory pathways
Stimulation ofexcitatory neurons causes a movement of ions those results in a
depolarizationof
the
postsynaptic
membrane.
These
excitatory
postsynapticpotentials (EPSP) are generated by the following:
1) Stimulation ofan excitatory neuron causes the release of neurotransmitter
molecules,such as glutamate or acetylcholine, which bind to receptors on the
postsynapticcell membrane. This causes a transient increase in the permeability
of sodium (Na+) ions.
2) The influx of Na+ causes a weak depolarization,or EPSP, that moves the
postsynaptic potential toward its firingthreshold.
3) If the number of stimulated excitatory neurons increases,more excitatory
neurotransmitter is released. This ultimately causes theEPSP depolarization of the
postsynaptic cell to pass a threshold, therebygenerating an all-or-none action
potential.
B. Inhibitory pathways
Stimulation of inhibitory neurons causes movement of ions that resultsin a
hyperpolarization of the postsynaptic membrane. These inhibitorypostsynaptic
potentials (IPSP) are generated by the following:
1) Stimulation of inhibitory neurons releases neurotransmitter molecules,such as
γ-aminobutyric acid (GABA) or glycine, which bind toreceptors on the
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postsynaptic cell membrane. This causes a transientincrease in the permeability
of specifi c ions, such as potassium (K+) andchloride (Cl–) ions.
2) The influx of Cl– and efflux of K+ cause a weak hyperpolarization,or IPSP, that
moves the postsynaptic potential away from its firing threshold. This diminishes
the generation of action potentials.
C. Combined effects of the EPSP and IPSP
Most neurons in the CNS receive both EPSP and IPSP input. Thus, severaldifferent
types of neurotransmitters may act on the same neuron,but each binds to its own
specific receptor. The overall resultant actionis due to the summation of the
individual actions of the various neurotransmitterson the neuron.
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SITES OF DRUG ACTION
Drugs acting on the synthesis, storage, metabolism, and release of
neurotransmitters fall into the presynaptic category. For example, reserpine
depletes monoamine synapses of transmitter by interfering with intracellular
storage, The stimulant amphetamine induces the release of catecholamines from
adrenergic synapsesand tetanus toxin blocks the release of transmitters.After a
transmitter has been released into the synaptic cleft, its action is terminated
either by uptake or by degradation. For most neurotransmitters, there are uptake
mechanisms into the synaptic terminal and also into surrounding neuroglia.
Cocaine, for example, blocks the uptake of catecholamines at adrenergic
synapses and thus potentiates the action of these amines.Anticholinesterases
block the degradation of acetylcholine and thereby prolong its action.
In the postsynaptic region, the transmitter receptor provides the primary site of
drug action. Drugs can act either as neurotransmitter agonists, such as the
opioids, which mimic the action of enkephalin, or they can block receptor
function. Receptor antagonism is a common mechanism of action for CNS drugs.
An example is strychnine's blockade of the receptor for the inhibitory transmitter
glycine. This block, which underlies strychnine's convulsant action. Drugs can also
act directly on the ion channel of ionotropic receptors. For example, barbiturates
can enter and block the channel of many excitatory ionotropic receptors.
Methylxanthines, which can modify neurotransmitter responses mediated
through the second-messenger cAMP. At high concentrations, the
methylxanthines elevate the level of cAMP by blocking its metabolism and
thereby prolong its action.
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