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References
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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 10mol/g tissue, grey
matter 2-5mol/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
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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: 5mol/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
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