9- CNS pharmacology

Question 1

Describe mechanisms alter activity in ANS

Compare and contrast with selectivity of action/clinical uses

Answer 1

1) synthesis/storage/release =
no clinical utility;
lesser selectivity
altering affects potentially all synapses

2) metabolism of NTM
inhib NT degradation enzymes (AChE inhib and MAOI)
moderate utility in therapeutics
block reuptake –> prolong NT in synapse –> incr postsyn

3) postsyn receptor stim or block
GREATEST CLINICAL UTILITY b/c most selective (specific agonists and antagonists allow for selectivity)

Question 2

Which mechanism byw hich drugs alter activity in ANS has greatest clinical utility

Answer 2

postsyn receptor stim or block

Question 3

List the steps in synth, storage, release, and inactiv of ACh

Fwd rxn catalyzed
Backward rxnc atalyzed by

Answer 3

Acetyl-CoA + Choline ACh + CoA

Fwd catalyzed by CAT
Backward catalyzed by AChE

ACh then transport into vesicles by ACh transporter

After Ca2+ release, ACh vesicles fuse with presynap membrane and exocytose contents

Question 4

Botulinum toxin

1) mech
2) causes
3) uses

Answer 4

inhib ACh release at excitatory NMJ by cleaving synaptobrevin

flaccid paralysis

used in cholinergic hyperactivity

Question 5

Tetanus toxin

1) mech
2) causes

Answer 5

inhib ACh release at inhib NMJ by cleaving synaptobrevin

tetany

Question 6

Black Widow spider venom

mech

Answer 6

stim ACh release by incr excessive vesicle clumping and “explosive release”

Question 7

Achesterase inhib
mechansims

drug names

Answer 7

incr ACh activity in synapse and at receptor

physostigmine
donepezil
neostigmine
edrophonium
organophsophates

Question 8

Cholinergic receptors
Difference btwn nAChR and mAChR

Where found?

Answer 8

nicotinic = ANS ganglia (SNS and PNS preganglionic)
muscle type nAChR found in NMJ

muscarinic = postsyn terminal of postganglionic parasymp
also on sweat glands (SNS)

Question 9

Cholinergic receptors
Difference btwn nAChR and mAChr

signal transduction

Answer 9

nAChR = ligand gated ion channel or ionotropic

muscarinic = GPCRs or metabotropic

Question 10

Significance of presynaptic vs. postsynaptic cholinergic receptros

what type of receptors for each usu

Answer 10

presynap = pass messages sent by CNS to PNS (usu ionotropic for propagation)

postsynp = muscarinic receptors for affecting response from an end organ target (usu metabotropic)

Question 11

Muscarinic cholinergic drugs

Pharm actions of direct acting muscarinic agonists

Answer 11

effect simil to physiological stim of PNS
(incr salivation, miosis, accomodation, incr urinary and GI motility)

also vasodilation, decr periph resistance d/t NO and MRs on endothelial cells

incr sweating

DUMBBELSS

Question 12

Consequences of overdose on muscarinic agonists

Treatment

Answer 12

SLUDGE

tx = atropine

Question 13

Muscarinic cholinergic drugs
Acetylcholine
Pharm action

Answer 13

short half life –> not good

Question 14

Muscarinic cholinergic drugs
Behtanechol
mechanism

use

Answer 14

4’ amino acholine ester
can’t cross BBB
resistant to AChE

urinary retention (post op)
paralytic ileus (non-obstructive)

Question 15

Muscarinic cholinergic drugs Pilocarpine
Mechanism

Use

Answer 15

3’ amino alkyloid
crosses BBB

miosis for cataract surgery;
glaucoma
dx xerostomia (dry mouth)

Question 16

Charged 4’ compounds that can’t cross BBB

name drugs

Answer 16

Bethanechol

Acetylcholine

Question 17

lipid soluble 3’ alkyloid can cross BBB

name drugs

Answer 17

pilocarpine

Question 18

Muscarinic antagonists
Atropine
mech

use

Answer 18

3’ amine that crosses BBB

ER treatment of mushroom poison
AChE inhibitor toxicity
severe bradycardia
asthma attack unresponsive to beta agonists
Parkinson's disease
Extrapyramidal effects of antipsych

Question 19

Muscarinic antagonists
Scopolamine

mech

use

Answer 19

3’ amine that crosses BBB

MORE CNS depression and vestib suppression than atropine
preanesthetic
motion sickness

Question 20

Muscarinic antagonists

mech

use

Answer 20

3’ amine that crosses BBB

causes mydriasis and cycloplegia (paralysis of accommodation)
6 hrs

Question 21

AChE inhibitors

pharmacologic actions

why do they affect both muscarinic and nicotinic cholinergic transmission

Answer 21

inhib of AChE hydrolysis of ACh –> prolong ACh action

because ACh active at both muscarinic and nicotinic AChR

Question 22

Reversible AChE (useful or not?)
Name of drugs

Answer 22

Useful

Physostigmine
Donepezil
Neostimine
Edrophonium

Question 23

Irreversible AChE (useful or not)
Name of drugs

Answer 23

toxic

organophosphates

Question 24

Adrenergic neurotransmission

Synthesis from Tyrosine to epinephrine

Answer 24

Tyr –> L dopa via Tyr Hydroxylase

L dopa –> DA via DA decarboxylase

DA –> NE via DA beta hydroxylase

NE –> E via PNMT

Question 25

Adrenergic neurotransmission Drugs and their targets

Answer 25

Alpha methyl tyrosine Alpha methyldopa both inhib Tyr hydroxylase

Question 26

Adrenergic neurotransmission Storage of dopamine? Drug targets

Answer 26

VMAT transports DA into vesicles (then convert to NE) Reserpine inhib VMAT, decr DA, decr NE

Question 27

Adrenergic neurotransmission Mech of release of NE?

Answer 27

after Ca2+ release, NE fuse with presynap and exocytose into cleft

Question 28

Adrenergic neurotransmission inactivation

Answer 28

terminated by reuptake into neuron using (DA = DAT; NE = NET) degrade after uptake into neuron or by liver (catecholamines escape circulation) via MAO A or MAOB or COMT

Question 29

NT that are degraded by MAO A MAO B

Answer 29

NE; serotonin, tyramine DA

Question 30

Drug targets of MAO A nad B

Answer 30

Phenelzine = irrev inhib of MAO A and MAO B Selegiline = irrev inhib of MAO B

Question 31

Interaction btwn adrenergic with receptor

Answer 31

NE bind adrenergic R on postsyn membrane

Question 32

Distinguish btwn direct acting indirect acting adrenergic agonists

Answer 32

direct = bind directly to target receptors and elicits same effect as NT (most therapeutics) indirect = drug effect on processing of NT --> incr NT (usu incr storage and release) (displace endogenous NE into cytoplasm after uptake by VMAT) or inhib of NT reuptake from synapse

Question 33

Oral effectiveness of adrenergic agonist incr with

Answer 33

1) non-catechols = no 3,4-hydroxy group on rings) since not substrate for COMT in liver 2) has methyl group on alpha carbon of phenylethylamine to protect from MAO in liver ex = ephedrine, amphetamine

Question 34

Distribution of adrenergic agonist | ability to enter CNS incr with ___

Answer 34

drugs with no hydroxyl group on phenyl ring so more lipophilic (ephedrine, amphetamine)

Question 35

Duration of action of adrenergic agonist half life is incr by ___

Answer 35

same factors that protect drug from COMT or MAO metab

Question 36

Adrenergic antagonists | mode of action for sympatholytic vs receptor blocker

Answer 36

sympatholytic = interfere with adrenergic presynaptically (decr specificity) receptor blocker = block SNS stim by combine with adrenergic receptor at postganglionic symp (better utility than sympatholytic)

Question 37

describe how an agonist of α2 adrenergic receptors can have antagonistic effects on the SNS.

Answer 37

CNS = stim of alpha2 (postsyn) in brain stem vasomotor center --> decr peripheral SNS activity SNS = stim peripheral alpha2 (presynap)--> decr NE release from symp neurons