9- CNS pharmacology Flashcards
Describe mechanisms alter activity in ANS
Compare and contrast with selectivity of action/clinical uses
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)
Which mechanism byw hich drugs alter activity in ANS has greatest clinical utility
postsyn receptor stim or block
List the steps in synth, storage, release, and inactiv of ACh
Fwd rxn catalyzed
Backward rxnc atalyzed by
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
Botulinum toxin
1) mech
2) causes
3) uses
inhib ACh release at excitatory NMJ by cleaving synaptobrevin
flaccid paralysis
used in cholinergic hyperactivity
Tetanus toxin
1) mech
2) causes
inhib ACh release at inhib NMJ by cleaving synaptobrevin
tetany
Black Widow spider venom
mech
stim ACh release by incr excessive vesicle clumping and “explosive release”
Achesterase inhib
mechansims
drug names
incr ACh activity in synapse and at receptor
physostigmine donepezil neostigmine edrophonium organophsophates
Cholinergic receptors
Difference btwn nAChR and mAChR
Where found?
nicotinic = ANS ganglia (SNS and PNS preganglionic)
muscle type nAChR found in NMJ
muscarinic = postsyn terminal of postganglionic parasymp
also on sweat glands (SNS)
Cholinergic receptors
Difference btwn nAChR and mAChr
signal transduction
nAChR = ligand gated ion channel or ionotropic
muscarinic = GPCRs or metabotropic
Significance of presynaptic vs. postsynaptic cholinergic receptros
what type of receptors for each usu
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)
Muscarinic cholinergic drugs
Pharm actions of direct acting muscarinic agonists
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
Consequences of overdose on muscarinic agonists
Treatment
SLUDGE
tx = atropine
Muscarinic cholinergic drugs
Acetylcholine
Pharm action
short half life –> not good
Muscarinic cholinergic drugs
Behtanechol
mechanism
use
4’ amino acholine ester
can’t cross BBB
resistant to AChE
urinary retention (post op) paralytic ileus (non-obstructive)
Muscarinic cholinergic drugs Pilocarpine
Mechanism
Use
3’ amino alkyloid
crosses BBB
miosis for cataract surgery;
glaucoma
dx xerostomia (dry mouth)
Charged 4’ compounds that can’t cross BBB
name drugs
Bethanechol
Acetylcholine
lipid soluble 3’ alkyloid can cross BBB
name drugs
pilocarpine
Muscarinic antagonists
Atropine
mech
use
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
Muscarinic antagonists
Scopolamine
mech
use
3’ amine that crosses BBB
MORE CNS depression and vestib suppression than atropine
preanesthetic
motion sickness
Muscarinic antagonists
mech
use
3’ amine that crosses BBB
causes mydriasis and cycloplegia (paralysis of accommodation)
6 hrs
AChE inhibitors
pharmacologic actions
why do they affect both muscarinic and nicotinic cholinergic transmission
inhib of AChE hydrolysis of ACh –> prolong ACh action
because ACh active at both muscarinic and nicotinic AChR
Reversible AChE (useful or not?) Name of drugs
Useful
Physostigmine
Donepezil
Neostimine
Edrophonium
Irreversible AChE (useful or not) Name of drugs
toxic
organophosphates
Adrenergic neurotransmission
Synthesis from Tyrosine to epinephrine
Tyr –> L dopa via Tyr Hydroxylase
L dopa –> DA via DA decarboxylase
DA –> NE via DA beta hydroxylase
NE –> E via PNMT
Adrenergic neurotransmission
Drugs and their targets
Alpha methyl tyrosine
Alpha methyldopa
both inhib Tyr hydroxylase
Adrenergic neurotransmission
Storage of dopamine?
Drug targets
VMAT transports DA into vesicles (then convert to NE)
Reserpine inhib VMAT, decr DA, decr NE
Adrenergic neurotransmission
Mech of release of NE?
after Ca2+ release, NE fuse with presynap and exocytose into cleft
Adrenergic neurotransmission
inactivation
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
NT that are degraded by
MAO A
MAO B
NE; serotonin, tyramine
DA
Drug targets of MAO A nad B
Phenelzine = irrev inhib of MAO A and MAO B
Selegiline = irrev inhib of MAO B
Interaction btwn adrenergic with receptor
NE bind adrenergic R on postsyn membrane
Distinguish btwn
direct acting
indirect acting
adrenergic agonists
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
Oral effectiveness of adrenergic agonist incr with
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
Distribution of adrenergic agonist
ability to enter CNS incr with ___
drugs with no hydroxyl group on phenyl ring so more lipophilic (ephedrine, amphetamine)
Duration of action of adrenergic agonist
half life is incr by ___
same factors that protect drug from COMT or MAO metab
Adrenergic antagonists
mode of action for sympatholytic vs receptor blocker
sympatholytic = interfere with adrenergic presynaptically (decr specificity)
receptor blocker = block SNS stim by combine with adrenergic receptor at postganglionic symp
(better utility than sympatholytic)
describe how an agonist of α2 adrenergic receptors can have antagonistic effects on the SNS.
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
