7/23/2019 Zees Pharmacology - Drugs Affecting CNS Transmitters

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Zees pharmacology - drugs afecting centralneurotransmission

Learning objectives

Be able to describe neurotransmission and potential sites for drug action

Know the key points of the roles and eects of dopaminergic noradrenergic, 5-!ergic,cholinergic, glutamatergic and "#B#ergic neurotransmission in the $%& 'and eects of somedrugs(

Neurotransmission via neurotransmitters Chemicals used to signal across neurons (bridging the gap for electrical activity)

2 types of receptors: EPSP and PSP either e!citatory or inhibitory

o "rugs #ill activate particular path#ays to e!cite or inhibit

$% Pre&synaptic neuron contains'stores the neurotransmitter and synthetic enymes N in storagevesicles

o *eleased on circumstances #hen +P invades a nerve terminal Stimulation Calcium

dependent movement and release of N into synaptic cleft2% Stimulation of neuron causes the release of N movement and release of transmitter,% ransmitter binds to receptors on post&synaptic neuron neuron is either e!cited or inhibited:

ransmission either continues or stops-% + system e!ists for the terminating the action of the transmitter at the receptor 2 methods

o Removal o transmitterby a transporter (re&upta.e for recycling) oro Catabolic enzymesto destroy the transmitter

mportant concept for neurotransmission/ #e must have

+ction potential in pre&synaptic neuron

Neurotransmitters ready to be stimulated and released

Post&synaptic receptors to receive these neurotransmitters

*emove the neurotransmitters

0a1or types of neurotransmitter substances in the CNS

Type I Type II Type IIIimple amino acids Catecholamines!amines

!purines

"europeptides

2&$-nmol'g3igh concentrations

%2&24nmol'g0edium concentrations

%2&%4nmol'g5o# concentrations

67 of synapses#astneurotransmission0a1or transmitters

0any synapses/ but notma1oritySlo#er neurotransmission

8e#er synapsesSlo#est neurotransmission moremodulatory compounds than full blo#ntransmission

"lutamate"lycine"#B#

$atecholamine '%#,dopamine, #dr(, amines'#$h, 5-!, #(, purines'#!), adenosine(

*ndogenous opiod peptides 'enkephalin()ituitary hormones 'o+ytocin(ormones release factors '$(Brain peptides 'substance )(

0ost synapses havereceptors for these N

0any but not ma1ority associated #ith particular

groups of nerves acting inparticular areas of thebrain%

9ery specic areas/ fe# synapses havereceptors/ more modulatory

*eceptors in the CNSIonotropic $ast% &etabotropic $slo'er%

;inding of N stimulates entry of ions via aligand-gated receptor ion channel

;inding of N stimulates the production o asecond messenger via a (-protein

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Secondmessengermust causephosphorylationon a cascade tocause a cellulare>ect muchslo#er%

rain Role "eurotransmitterCorte! +lertness'perception'cognition' initiation of

voluntary movement'moodN+/ +Ch/ "+/ 4&3

Straitum 8ine motor control "+ & )arkinsons . depletion of/# in striatum, 0ne motorcontrol aected

N%accumbe

ns

Emotion'mood

PsychosisA 0aniaA +ddictionA

"+ (4&3)

3ippocampus

5earning 4&3/ +Ch/ "+

+mygdala 8ear/ an!iety/ aggression 43/ "+/ N+halamus ntegration3ypothalamus

*egualtion of basic drives thirst/ hunger/temperature/ endocrine master control

"+/ releasing factors

Know the key points of the roles and eects of dopaminergic noradrenergic, 5-!ergic,

cholinergic, glutamatergic and "#B#ergic neurotransmission in the $%& 'and eects of somedrugs(

)art I, "oradrenaline. dopamine. /*T 0 The specialists

Noradrenaline/ dopamine/ 43 0onoamines ype neurotransmitters

*eceptors metabotrophic

ermination of action of N+/ "+ and 4&3 is via specic transporters reupta.e

o N+ &

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&omething e+tra1 Reserpine depletes NA/5-HT neurotransmitters, causing DEPRESSIN

+ntidepressants augment N+'43 transmission

o 0=+: *e&upta.e bloc.ers allo# N+'43 to reside in the synapse longer/ reduce

depressiono 0=+: Can also bloc. 0onoamine o!idase enyme inhibition to prevent loss

Targets or depressionTarget )reerred substrate Inhibitor 5se

0+=a N+/ 4&3 Paragyline "epression

N (upta.e $) N+ "esipramineSE* 4&3 8luo!etine (proac)

e)*+R&

1opamine

+ctivation of dopaminergic neurons is associated

#ith 2 main e>ects:o ;ehaviour: Psychosis'schiophrenia/

addiction 0esocortical'mesolimbic path#ay

o 8ine motor control: Par.insons disease

Nigrostraiatal path#ay

"+ and role in brain: Schiophreniao ;loc. e>ects of dopamine

o 0ain stain is potent "2 antagonist

o Patient #ould be cataleptic/ no movement

1iagnosis o schizophrenia

Symptomology is divided into positive/ negative and cognitive symptoms

Some symptoms are treatable #hile others are not

Some symptoms relate to particular transmitters

)ositive symptoms "egative symptoms Cognitive symptoms"elusions/ auditoryhallucinations

(things that are added tothem)

Social #ithdra#al/ lac. of drive/blunting of emotions (things that

are ta.en away)

5ac. of attention/ decits inmemory and problems #ith

e!ecutive functioning

argeting dopamine depends on if patients has schiophrenia or par.insons disease "omapine ("2) antagonist used as antipsychotics

"rug used: *aloperidol e)*+R&

o Side e>ect: Poor'no movement

"2 agonist used in par.insons disease

"rug used: romocriptine e)*+R&

o Side e>ect: Psychotic (5=5)

)art II, +cetylcholine

+s above in the table*emoval $via enzyme%

o Choline acetyltranserase ma6es +Ch rom

choline!+cetylco+o +cetylcholinesterase (+ChE) brea.s do#n +Ch into acetate and choline/ terminating the

actiono +ctivation of cholinergic nerves: Enriched #ithin hippocampus and parts of corte!%

Strongly associated #ith cognition/ memory and learningF deciency ? +lheimersdisease (selective destruction of cholinergic nerves)

0ost common condition resulting in dementia is +lheimers disease

Neuropathology of +lheimers disease

o Shrin.ing of temporal corte! and frontal lobe as much as 27

o Presence of di>use plaGueso Presence of neurobrillary tangles

o H7 loss in choline acetyltransferase (Ch+)

o "ecreased +Ch release

reatment

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o +ChE inhibitors (e%g% tacrine) in +lheimers disease

Senile dementia alheimers type

mpairment in memory/ impaired concentration

"isorientation

+lterations in personality/ mood/ #andering

+pahasia (loss of language)/ apra!ia (loss of purposeful movements)/ agnosia (loss of

recognition of ob1ects)

)art III, +mino acid transmitters 0 Type I

herapeutics relevant in epilepsy e!tra e!citation of neuronal ring too much e!citability

o "enition: Episodic high freGuency discharges by a group of neurons (occurs because

they are damaged'congenital defect)o 0ay spread to other areas of the brain

o Symptoms depend on primary site of discharge and degree of spread

o Partial seiures'generalised seiures

nvolvement of corte! is associated #ith convulsions

o Epilepsy can arise from acilitated e7citatory transmissionor reduced inhibitory

transmission2 .ey transmitters

Ilutamate (ionotropic) N0"+ receptors

o +l#ays e!citatoryo +llo#s inJu! of Na and Ca

I+;+ (y&aminobutyric acid) & ionotropic

o +l#ays inhibition

o +llo#s inJu! of Cl&

Epilepsy either too much glutamine or not enough I+;+

;loc.ing glutamate receptors can aid in epilepsy

(ltuamate

0a1or e!citatory transmitter in the CNS

"istributed di>usely throughout the brain type / found every#here

Precise role diKcult to pin do#n clues from group of drugs that inhibit glutamatergic

mechanismso Conciousness (anaesthetic .etamine is a glutamate antagonist)

o +ctivation of neuronal e!citability (ne#er anti&convulsants that limit epileptic seiures

inhibit glutamate activation)

N0"+ receptors

Ilutamate activates N0"+ receptors

+ctivation allo#s for entry of Na and Ca

his generates EPSPs in the neuron #ith the receptor

Stimulates'enhances further activation of the neuron

+ssociated #ith N0"+ receptors are several allosteric

sites

"&1+ receptor does not only recognise glutamate.but interacts 'ith other items such as glycine.polyamine. &g28 etc

Letamine and PCP (N0"+ channel site)

nhibitors of N0"+ activation via binding #ithin N0"+

channel site

PCP ($64s) used as anaesthetic

o Side e>ects included alterations in short&term memory/ hallucinations/ nightmares/

psychosis/ delirium

PCP also .no#n as Dangel dust

Letamine still sued as a veterinary anaesthetic