PNS pharma Flashcards
Bethanechol
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an irreversible muscarinic antagonist
benzylcholine mustard
anticholinesterase- reversible, short-acting/non-covalent
edrophonium
anticholinesterase- reversible, medium acting/covalent
(carbamates)
physostigmine, rivastigmine= non-charged, crosses BBB
neostigmine, pyridostigmine= charged, stays in periphery
note: the carbamates are transferred to Ser203 of triad on AchE and carbamylated AChE is more stable, takes minutes to hydrolyse
anticholinesterase- irreversible, long acting
organophosphgorus molecules, include:
- insecticides: parathion, malathion
- nerve gases: sarin, soman, tabun, novichoks
- previously used drugs (in glaucoma): echothiophate, Dyflos/DFP
note: all are uncharged and interact with catalytic triad ony (except echothiophate)
edrophonium facts
- too short acting to be therapeutically useful
- charged, can’t cross membrane– can’t reach CNS
- its earlier use was in diagnosis of MG (myasthenia gravis) –> the facial weakness and ptosis shows improvement within minutes of drug application
antidotes for organophosphorus poisoning
- atropine
- pralidoxime (2-PAM) = reactivates AChE; oxime is a strong nucleophile
antidotes for organophosphorus poisoning
- atropine:
- as it is lipid soluble it can counteract the effects systemically - pralidoxime (2-PAM):
- reactivates AChE; oxime is a strong nucleophile therefore captures the phosphate group and liberates Ser 203
- doesn’t cross BBB; therefore, can’t be used when CNS is affected
- used with atropine
current clinical uses of AChE inhibitors
- in treatment of myasthenia gravis: neostigmine, pyridostigmine (both don’t cross BBB)
- to reverse the actions of non-depolarising blockers at NMJ after surgery: neostigmine
- to treat mild to moderate dementia in Alzheimer’s: those that cross BBB
- (previously) as a test for MG- edrophonium (has been largely replaced by antibody testing and electrical conduction studies)
current clinical uses of AChE inhibitors
- in treatment of myasthenia gravis: neostigmine, pyridostigmine (both don’t cross BBB)
- to reverse the actions of non-depolarising blockers at NMJ after surgery: neostigmine
- to treat mild to moderate dementia in Alzheimer’s: those that cross BBB
- (previously) as a test for MG- edrophonium (has been largely replaced by antibody testing and electrical conduction studies)
what are the enzymes involved in the biosynthesis of catecholamines (e.g. adrenaline)
- TOH (tyrosine hydroxylase) = tyrosine->DOPA
- DDC (DOPA decarboxylase) = DOPA->dopamine
- DBH (dopamine beta-hydroxylase) = dopamine->Noradrenaline
- PNMT = Noradrenaline-> adrenaline
inhibitors of catecholamine synthesis:
1) TOH
2) DDC
3) DBH
1) alpha-methytyrosine
2) carbidopa
3) disulfiram
methyldopa
False neurotransmitter at noradrenergic synapses
- taken up into presynaptic termini;
- converted to alpha-methyl DA by DDC
- converted to alpha-methyl NA by DBH
inhibitors of catecholamine synthesis:
1) TOH
2) DDC
3) DBH
1) alpha-methytyrosine
- competitive inhibitor of TOH; blocks the rate limiting step and therefore is the only effective way to decrease NT production
2) carbidopa
3) disulfiram
methyldopa
used as an antihypertensive in cases which are difficult to treat
False neurotransmitter at noradrenergic synapses
-taken up into presynaptic termini;
-converted to alpha-methyl DA by DDC
-converted to alpha-methyl NA by DBH
-alpha-methyl NA is taken into vesicles and released with NA (and in place of some NA)
-alpha-methyl NA is more active on alpha-2 adrenoreceptors compared to alpha-1 receptors
-alpha-methylnoradrenaline results in a drop in blood pressure
inhibitors of catecholamine synthesis:
1) TOH
2) DDC
3) DBH
1) alpha-methyltyrosine (was used for pre-op treatment of phaeochromocytoma)
- competitive inhibitor of TOH; blocks the rate limiting step and therefore is the only effective way to decrease NT production
2) carbidopa with L-DOPA (parkinson’s treatment)
- exogenous L-DOPA is taken up by
3) disulfiram
methyldopa
used as an antihypertensive in cases which are difficult to treat
False neurotransmitter at noradrenergic synapses
-taken up into presynaptic termini;
-converted to alpha-methyl DA by DDC
-converted to alpha-methyl NA by DBH
-alpha-methyl NA is taken into vesicles and released with NA (and in place of some NA)
-alpha-methyl NA is more active on alpha-2 adrenoreceptors compared to alpha-1 receptors
-alpha-methylnoradrenaline results in a drop in blood pressure
inhibitors of catecholamine synthesis:
1) TOH
2) DDC
3) DBH
1) alpha-methyltyrosine (was used for pre-op treatment of phaeochromocytoma)
- competitive inhibitor of TOH; blocks the rate limiting step and therefore is the only effective way to decrease NT production
2) carbidopa with L-DOPA (parkinson’s treatment)
- exogenous L-DOPA used to boost DA synthesis; L-DOPA is taken up by cell and converted to DA
- normally, L-DOPA is degraded outside the cell by peripheral decarboxylase
- carbidopa can’t cross BBB; it inhibits peripheral decarboxylase so that the L-DOPA isn’t broken down
3) disulfiram
- used in treatment of alcohol addiction; inhibits alcohol dehydrogenase enzyme
- experimentally used to inhibit DBH
methyldopa
used as an antihypertensive in cases which are difficult to treat
False neurotransmitter at noradrenergic synapses
-taken up into presynaptic termini;
-converted to alpha-methyl DA by DDC
-converted to alpha-methyl NA by DBH
-alpha-methyl NA is taken into vesicles and released with NA (and in place of some NA)
-alpha-methyl NA is more active on alpha-2 adrenoreceptors compared to alpha-1 receptors
-alpha-methylnoradrenaline results in a drop in blood pressure
NA vesicular storage
-typically clear-cored vesicles
-stored with ATP in ratio 4:1
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catecholamine vesicular storage
- NA with ATP in clear-cored vesicles
- NA stored with ATP in ratio 4:1
- NA, ATP and NPY- dense-cored vesicles
- NA and DA loaded by VMAT-2
Reserpine
- high affinity, irreversible blocker of VMAT-2
- binds to amine substrate site of VMAT-2 and blocks uptake of monoamines (DA, NA,5-HT)
- leads to depletion of stored NA
- acts in periphery and the brain; used as antihypertensive previously but was discontinued as it causes severe depression
- recovery from reserpine blockade requires synthesis of new vesicles
FDA approved VMAT-2 inhibitors
- tetrabenazine and valbenazine
- reversibly bind to VMAT-2 and block uptake of catecholamines (mainly DA)
- used to manage abnormal involuntary movements associated with Huntington’s disease, tardive dyskinesia etc.
FDA approved VMAT-2 inhibitors
- tetrabenazine and valbenazine
- reversibly bind to VMAT-2 and block uptake of catecholamines (mainly DA)
- used to manage abnormal involuntary movements associated with Huntington’s disease, tardive dyskinesia etc.
agent causing direct blockade of adrenergic neurons
Guanethidine:
- uptake into presynaptic adrenergic nerve terminal via NET
- loaded into vesicles by VMAT-2 ; causes gradual and long lasting depletion of NA
- in very high doses it can irreversibly damage the nerve
- was previously used to treat hypertension
indirectly acting sympathomimetic
dexamphetamine and tyramine
-they are not adrenoreceptor agonists but make good substrates for monoamine transporter; therefore they don’t act on postsynaptic receptor but are taken up y the transporter at presynaptic terminal
- transported into terminal by NET (& DAT)
- loaded into vesicles by VMAT-2, therefore displaces NA
- the displaced NA collects in the presynaptic terminal and some is metabolized by MAO but mostly escapes to the synapse by reverse transport via NET(&DAT) and acts on postsynaptic receptors
MAO
enzyme that breaks down NA at presynaptic terminal
indirectly acting sympathomimetic
dexamphetamine and tyramine
- CNS stimulants: used in narcolepsy; paradoxically in ADHD
- they are not adrenoreceptor agonists but make good substrates for monoamine transporter; therefore they don’t act on postsynaptic receptor but are taken up y the transporter at presynaptic terminal
- transported into terminal by NET (& DAT)
- loaded into vesicles by VMAT-2, therefore displaces NA
- the displaced NA collects in the presynaptic terminal and some is metabolized by MAO but mostly escapes to the synapse by reverse transport via NET(&DAT) and acts on postsynaptic receptors
MDMA
- more profound impact on 5-HT release
- is a hallucinogenic (called ecstacy)
MAO
enzyme that breaks down NA at presynaptic terminal
mixed acting sympathomimetics
ephedrine
-can indirectly release NA like the indirectly acting BUT can also directly act on adrenoreceptors
uses:
- a nasal decongestant; causes NA-mediated vasoconstriction in the nose
- airway relaxation by acting on bronchial beta-2- adrenoreceptors
explain ‘cheese effect’– what class of drugs does it have to do with?
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