References - PowerPoint Presentation

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References

Human Physiology D.U. Silverthorn

Pharmacology H.P.Rang, M.M.DalePharmacology G.M.BrennerClinical Pharmacology D.R.LaurenceGoodman and Gilman’s The Pharmacology Basis of TherapeuticsBritish National Formulary(BNF)

M.MosaddeghSlide3

Off all the things I have lost, I miss my mind the most.Slide4

Central Nervous System(CNS)

Chemical Transmission and drug acting in the CNS

Chemical signalling in the CNS

Introduction to Central Nervous System PharmacologySlide5

Targets of drug actionsSlide6

Chemical transmission in CNS

Neurotransmitters:Released by presynaptic terminals, rapid excitatory or inhibitory responses in postsynaptic neuronsNeuromodulators:By neurons, slower pre or postsynaptic responses, mediated by G-protein coupled receptors

Neurotrophic factors:

mainly by non-neuronal cells, act on tyrosine-kinase-linked, 1)regulate gene expression 2) control neuronal growth and phenotypic characteristicsSlide7

NeurotransmittersSlide8

Classification of psychotropic drugs

Anxiolytics and sedatives:

sedative, hypnotics, minor tranquillisers;Barbiturates, BNDsAntipsychotics:

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, piracetamSlide9
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Amino acid transmittersSlide11
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Ionotropic R. (ligand-gated ion channel)

NMDA= N-methyl-D-aspartate, AMPA= a-amino-3hydroxy-5-methyl isoxasole,

kainate isolated from seaweedSlide13

NMDA receptors

NMDA receptors are highly permeable to ca

2+They are blocked by Mg

2+

, if the cell is depolarised.

Anaesthetic and psychomimetic agents e.g. ketamine, phencyclidine and dizocilpine are selective blocking agents for NMDA-operated channels. Slide14
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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.Slide16

The potential therapeutic interest in

glutamine antagonists

Reduction of brain damage following head injury and strokesTreatment of epilepsySchizophreniaSlide17

NMDA and metabotropic rec. participate in

various adaptive & pathophysiological events

Three such roles are now generally accepted are:Synaptic plasticityExcitotoxicityPathogenesis of epilepsySlide18

Gamma-aminobutyric acid (GABA)

GABA is main inhibitory NT in the brain

In the spinal cord and brainstem, glycine is also importantIn brain, nigrostriatal system 10mol/g tissue, grey matter 2-5mol/g

Glutamine Glutamate

GABA

Glutamic acid decarboxylase (GAD) found only in GABA-synthesising neurons in the brain.

GAD

glutaminaseSlide19

GABA

GABA

Succinic semialdehyde

glutamate

a-ketoglutarate

GABA-T

Inhibited by Vigabatrine

Treatment of epilepsySlide20

GABA receptors

GABA

ALigand-gated channelLocated postsynapticMediate fast postsynaptic inhibition

The associate channel is selectively permeable to Cl ions

GABA

B

G-protein-coupled receptors

Located pre- and post-synaptic

Resemble metabotropic glutamate receptorsSlide21
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Channel modulators eg ethanol &

anaesthetic agents

ClSlide24

Drugs acting on GABA

A

receptorsMuscimol: 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 GABA

A

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 GABA

A

receptorSlide25

Selective agonist of GABA

B

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”.Slide26

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: Slide27

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)Slide28

Dopamine (inhibitory NT)

Tyrosine Dopa Dopamin NADopamine dihydroxy phenylacetic acid (DOPAC)Dopamine Homovanillic acid (HVA)

DOPAC and HVA in urine are an index of dopamine release in human subjects.

Tyrosine hydroxylase

Dopa decarboxylase

dopamine b-hydroxylase

MAO

MAO

COMTSlide29

D

1

and D5: G-protein linked receptors, activate adenyl cyclase and so increase CAMP levelsD2, D3 and D

4

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.Slide30

Dopamine from hypothalamus has an inhibitory effect on prolactin release. So antipsychotic drugs by D

2

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?!!!!!!! Slide31
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Serotonin

(5-hydroxy tryptamine) 5-HT

Tryptophan 5-hydroxytryptopha 5-HT 5-hydroxyindoleacetic

acid (5-HIAA) in urine

Urinary excretion of 5-HIAA provides a measure of 5-HT turnover.

hydroxylase

decarboxylase

MAO & aldehyde dehyrogenaseSlide33

5-HT

1

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.Slide34

acetylcholine

Arousal, learning and motor controlSlide35
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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. Slide37

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,……. Slide38

NT synthesis

L-dopa

Converted to Dop.,

Dop. Syn

Parkinson

NT storage

reserpine

Block NA storage

hypertension

NT release

amantadine

Dop. release

Parkinson

NT release

Amphet.

NA release

narcolepsy

NT reuptake

fluoxetine

Block ser. reuptake

Depression,

OCD

NT degreation.

donepezil,

Tacrine

Inh. Cholineetrase, ACH catabolism

Alzheimer

selegiline

Inh. MAO & Dop. catabolism

ParkinsonSlide39

Rec. activation

Bromocrip

Buspirone

diazepam

Dop. Rec.

Ser. Rec.

BND Rec.

Parkinson

Anxiety, dep.

anxiety

Rec. blockage

Benztropine

Clozapine

ondansetron

Ach Rec.

Dop. &Ser.

Ser. Rec.

Parkinson

Schizophrenia

Nausea,vomit.

Neuronal conduction

Carbamazepin

phenytoin

Lidocaine

procaine

Block Na

+

channels

Epilepsy

Epilepsy

L.Anaesthesia

L.Anaesthesia

Neuronal membrane function

Halothane

Nitrous oxide

Alters physicochem properties of membrane

General Ana.

General Ana.Slide40

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