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References • • • • • Human Physiology D.U. Silverthorn Pharmacology H.P.Rang, M.M.Dale Pharmacology G.M.Brenner Clinical Pharmacology D.R.Laurence Goodman and Gilman’s The Pharmacology Basis of Therapeutics • British National Formulary(BNF) M.Mosaddegh Off all the things I have lost, I miss my mind the most. Central Nervous System(CNS) Introduction to Central Nervous System Pharmacology • Chemical Transmission and drug acting in the CNS • Chemical signalling in the CNS Targets of drug actions Targets of drug action Tranport proteins Receptors Channel-linked G-protein coupled Kinase-linked Gene-transcription-linked Ion channels Enzymes Chemical transmission in CNS • Neurotransmitters:Released by presynaptic terminals, rapid excitatory or inhibitory responses in postsynaptic neurons • Neuromodulators:By neurons, slower pre or postsynaptic responses, mediated by G-protein coupled receptors • Neurotrophic factors:mainly by nonneuronal cells, act on tyrosine-kinase-linked, 1)regulate gene expression 2) control neuronal growth and phenotypic characteristics Neurotransmitters Neurotransmitters(NT) Fast NT Slow NT and neuromodulators Glutamate, GABA operate through ligand-gated ion channel dopamine, neuropeptides mainly through G-protein-coupled receptors Classification of psychotropic drugs • Anxiolytics and sedatives:sedative, hypnotics, minor tranquillisers;Barbiturates, BNDs • Antipsychotics: Neuroleptic, antischizophernic, major tranquillisers • Antidepressants:Thymoleptics; MAOi, TCAs • Psychomotor stimulants:Psychostimulants; caffeine, cocaine, amphetamine • Psychomimetics:Hallucinations, Psychodisleptics; LSD, mescaline, phencyclidine • Cognition enhancers:nootropics; tacrine, donepezil, piracetam Amino acid transmitters Amino acid transmitters Excitatory transmitters Inhibitory transmitters L-glutamate, Aspartamate, probably homocycteate (controversial) GABA, Glycine Glutamate Uniformly distributed in CNS interconnection with GABA and glycine synthesis Conc.in CNS much >other tissues termination by reuptake into nerve terminals under pathological conditions (brain ischaemia) reuptake is reverse synthesis occurs all cells glutamate receptors NMDA AMPA Kainate Metabotropic G-protein linked R. Ionotropic R. (ligand-gated ion channel) NMDA= N-methyl-D-aspartate, AMPA= a-amino-3hydroxy-5-methyl isoxasole, kainate isolated from seaweed NMDA receptors • NMDA receptors are highly permeable to ca2+ • They are blocked by Mg2+, if the cell is depolarised. • Anaesthetic and psychomimetic agents e.g. ketamine, phencyclidine and dizocilpine are selective blocking agents for NMDA-operated channels. • Kynurenic acid: endogenous, glycine antagonist, produced by glia and other cells, indirectly inhibits glutamate action. Endogenous polyamines, spermine and spermidine, facilitate channel opening on a different site. The experimental drugs, ifenprodil & eliprodil, block their action. • Cyclothiazide, aniracetam, ampakines facilitate agonist action at AMPA receptors and are cognition enhancers but in animal models. The potential therapeutic interest in glutamine antagonists • Reduction of brain damage following head injury and strokes • Treatment of epilepsy • Schizophrenia NMDA and metabotropic rec. participate in various adaptive & pathophysiological events • Three such roles are now generally accepted are: • Synaptic plasticity • Excitotoxicity • Pathogenesis of epilepsy Gamma-aminobutyric acid (GABA) • GABA is main inhibitory NT in the brain • In the spinal cord and brainstem, glycine is also important • In brain, nigrostriatal system 10mol/g tissue, grey matter 2-5mol/g • Glutamine Glutamate GAD GABA glutaminase • Glutamic acid decarboxylase (GAD) found only in GABA-synthesising neurons in the brain. Succinic semialdehyde GABA GABA GABA-T a-ketoglutarate glutamate Inhibited by Vigabatrine Treatment of epilepsy GABA receptors • • • • GABAA Ligand-gated channel Located postsynaptic Mediate fast postsynaptic inhibition • The associate channel is selectively permeable to Cl ions • GABAB • G-protein-coupled receptors • Located pre- and postsynaptic • Resemble metabotropic glutamate receptors Cl Channel modulators eg ethanol & Drugs acting on GABAA receptors • Muscimol: a powerful GABAA receptor agonist • Bicuculline: a specific antagonist, a naturally occuring convulsant compound. They are useful experimental tools. • BNDs selectively potentiate effects of GABA on GABAA receptors by binding to the BNDreceptor • BNDs are PABA agonists and convulsant analogues such as flumazenil are PABA antagonists • DBI (diazepam binding inhibitor) is an endogenous modulator of GABA-mediated transmission which occurs in the brain and elsewhere. • Picrotoxin,a convulsant substance acts by blocking the chloride channel associated with the GABAA receptor • Selective agonist of GABAB is baclofen, useful for spasticity and related motor disorders. • Glycine: 5mol/g in grey matter of spinal cord, its receptor functionally resembles the GABAA receptors • Strychnine, a convulsant poison, is a competitive glycine antagonist • Tetanus toxin, acts mainly by interfering with glycine release, cause violent muscle spasm, which knows as “Lackjaw”. Noradrenaline (NA) • Mechanisms of synthesis, storage, release and reuptake of in the CNS are the same as periphery • NA cell bodies occur in specific clusters mainly in the pons and medulla. One important cell group is locus ceruleus (LC). • Its action in CNS is inhibitory (b-receptors) but some are excitatory (a or b-receptors). • NA transmission is important on: • 1) arousal system 2) controlling wakefulness and alertness 3) blood pressure regulation • 4) control of mood (lack of NA activity on the brain causes depression. 5) function of reward system • Pychotropic drugs act in NA transmission in CNS include: ADS, amphetamine, cocaine, some antihypertensive drugs (clonidine, methyldopa) Dopamine (inhibitory NT) dopamine b-hydroxylase • Tyrosine Dopa Dopamin Tyrosine hydroxylase Dopa decarboxylase • Dopamine dihydroxy phenylacetic acid (DOPAC) MAO COMT • Dopamine MAO Homovanillic acid (HVA) • DOPAC and HVA in urine are an index of dopamine release in human subjects. NA • D1 and D5: G-protein linked receptors, activate adenyl cyclase and so increase CAMP levels • D2, D3 and D4 are important in the CNS and in contrast inhibit adenyl cyclase and so decrease CAMP levels. • Dopamine has an important role on emesis, prolactin release, mood, motor coordination and olfaction. • Dopaminergic neurons have a rule in the production of nausea and vomiting so dopamine rec. agonists (eg bromocriptine) and drugs increase dopamine release in brain (L-dopa) can cause nausea as side effect. • Dopamine antagonists,eg phenothiazines, metoclopramide, have antiemetic activity. • Dopamine from hypothalamus has an inhibitory effect on prolactin release. So antipsychotic drugs by D2 receptor blockage can increase prolactin secretion and cause breast development and lactation even in males. • In contrast, dopamin receptor agonist, bromocriptine, used clinically to supress prolactin secretion by tumours of pituitary glands. • What is relationship between growth hormone, dopamine and acromegally?!!!!!!! Serotonin (5-hydroxy tryptamine) 5-HT • Tryptophan 5-hydroxytryptopha decarboxylase hydroxylase • 5-HT 5-hydroxyindoleacetic MAO & aldehyde dehyrogenase • acid (5-HIAA) in urine • Urinary excretion of 5-HIAA provides a measure of 5-HT turnover. • 5-HT1 rec. are the main target of drugs used to treat anxiety and depression such as buspirone, a 5-HT1A receptor agonist. • 5-HT2 rec. are the target of hallucinogenic drugs. Their antagonists are used for the migrane. • Ondansetron is a 5-HT3 rec. antagonist used as an anti-emetic drug. • The functions of 5-Ht are: control of food uptake, regulation of body temperature, blood pressure, control of mood and emotion, sexual functions, control of sensory pathway including nociception and control of sleep/wakefulness. acetylcholine Arousal, learning and motor control Melatonin • Melatonin exclusively synthesised in pineal from seotonin by o-methylation and acetylation. It is high at night and low by day. • This rhythm controlled by input from retina via noradrenergic retinohypothalamic tract that terminates in the suprachiasmatic nucleus (SCN), which called biological clock,in hypothalamus. • Biological clock generates cicardian rhythms. • Melatonin is a means of controlling jet-lag and improving the performance of night-shift workers. Nitric oxide (NO) • Produced by neuronal form of nitric oxide synthase (nNOS), which is resent in many CNS neurons. • In large amounts, NO forms peroxynitrite, which contribute in neurotoxicity. • Inhibition of nNOS reduces LTP and LTD. Inhibition of nNOS also protects against ischaemic brain damage in animal models. • May be involved in Parkinson, senile dementia,……. NT synthesis L-dopa Converted to Dop., Dop. Syn Parkinson NT storage reserpine Block NA storage NT release amantadine Dop. release hypertensio n Parkinson NT release Amphet. NA release narcolepsy NT reuptake fluoxetine Block ser. reuptake Depression, OCD NT degreation. Inh. Cholineetrase, ACH catabolism Alzheimer Inh. MAO & Dop. catabolism Parkinson donepezil, Tacrine selegiline Rec. activation Bromocrip Buspirone diazepam Rec. blockage Benztropine Clozapine ondansetron Neuronal Carbamazepin conduction phenytoin Lidocaine procaine Neuronal Halothane membrane Nitrous oxide function Dop. Rec. Ser. Rec. BND Rec. Ach Rec. Dop. &Ser. Ser. Rec. Block Na+ channels Parkinson Anxiety, dep. anxiety Parkinson Schizophrenia Nausea,vomit. Epilepsy Epilepsy L.Anaesthesia L.Anaesthesia Alters General Ana. physicochem General Ana. properties of membrane THANK YOU!