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H F-XC A N GE H F-XC A N GE N y bu 4th stage 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. 1 ac .c tr om k lic C om k lic C .c re . . k e r- s o ft w a w w ac ww ww tr to to bu y N O W ! PD O W ! PD k e r- s o ft w a re H F-XC A N GE H F-XC A N GE N y bu 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 2 ac .c tr om k lic C om k lic C .c re . . k e r- s o ft w a w w ac ww ww tr to to bu y N O W ! PD O W ! PD k e r- s o ft w a re H F-XC A N GE H F-XC A N GE N y bu 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. 3 ac .c tr om k lic C om k lic C .c re . . k e r- s o ft w a w w ac ww ww tr to to bu y N O W ! PD O W ! PD k e r- s o ft w a re H F-XC A N GE H F-XC A N GE N y bu 4 ac .c tr om k lic C om k lic C .c re . . k e r- s o ft w a w w ac ww ww tr to to bu y N O W ! PD O W ! PD k e r- s o ft w a re H F-XC A N GE H F-XC A N GE N y bu k lic tr 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. 5 ac .c C om k lic C .c re . . k e r- s o ft w a w w ac ww ww tr om to to bu y N O W ! PD O W ! PD k e r- s o ft w a re