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PHRM 825 Exam 1 > Muscarinic agonists > Flashcards

Muscarinic agonists Flashcards

1
Q

M1 receptor

A

tissue: postganglionic
response: depolarization
mechanism: Gq increase in PLC, IP3, DAG, Ca2+

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2
Q

M2 receptor

A

tissue: heart
response: inhibition
mechanism: Gi inhibition of adenylyl cyclase, activation of K+ channels

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3
Q

M3 receptor

A

tissue: smooth muscles, exocrine glands, endothelium
response: contraction, secretion, relaxation
mechanism: Gq increase in PLC, IP3, DAG, Ca2+

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4
Q

mnemonic for M receptor mechanisms

A

qiq
-Gq - M1
-Gi - M2
-Gq - M3

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5
Q

Which type of receptor does ACh have higher affinity towards?

A

muscarinic

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6
Q

Muscarinic agonist effects: heart

A

M2 activation: decreased HR, conduction, and force (bradycardia)

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7
Q

Muscarinic agonist effects: smooth muscles

A

M3 activation: increase contraction (M2 inhibit relaxation)

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7
Q

Muscarinic agonist effects: exocrine glands

A

M3 activation: increase secretion (lachrymal, tracheobronchial, salivary, digestive, sweat glands)

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8
Q

Muscarinic agonist effects: sphincters

A

M3 relaxation

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9
Q

Muscarinic agonist effects: CNS

A

mainly mediated by M1 ONLY IF a drug has access to the CNS
-tremor, hypothermia, increased locomotor activity, improved cognition

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10
Q

Parasympathetic cholinergic molecules

A

endogenous: acetylcholine (+ charged neurotransmitter)
exogenous: muscarine and nicotine
-muscarine has a choline group in it

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11
Q

Cholinergic agents

A

involving acetylcholine receptors for parasympathetic effect
-ACh: neurotransmitter

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12
Q

Parasympathomimetic actions (agonists) of cholinergic agents

A

direct agonists: activates cholinoceptors (bind directly and activate)
indirect agonists: stimulate ACh release (elongate life), inhibit AChE (prevent ACh degradation, stays active longer)

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13
Q

Parasympatholytic actions (antagonists) of cholinergic agents

A

direct or indirect
-many drugs have anticholinergic side effects

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14
Q

ACh biosynthesis and neurotransmission process

A
  1. choline is transported into presynaptic nerve terminal by a sodium depended choline transporter (CHT) (inhibit with hemicholinium)
  2. ACH synthesized from choline and acetyl-CoA by choline acetyltransferase (ChAT)
  3. ACH transported into storage vesicle by vesicle-associated transporter (VAT) (inhibit with vesamicol)
  4. release of transmitter occurs when action potential opens voltage-gated Ca2+ channels and increases intracellular Ca2+, fusion of vesicles with surface membrane results in release of ACh (block wiht botulinum toxin/botox)
  5. ACh binds to cholinoceptors on postsynaptic cells
  6. ACh is metabolized by AChE
  7. autoreceptors and receptors on presynaptic nerve end modulate transmitter release
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15
Q

Direct acting cholinergic agonists

A

choline esters: ACh, methacholine, carbachol, bethanechol
alkaloids: muscarine, pilocarpine

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16
Q

Indirect acting cholinergic agonists (AChE inhibitors)

A

reversible: edrophonium, physostigmine, neostigmine
irreversible: organophosphates

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17
Q

symptoms of fast mushroom poisoning

A

PSNS: bradychardia, N/V, cramps, diarrhea, bronchoconstriction, salivation, visual disturbances
SNS: sweating, hypotension
muscarine: isolated in 1868, charged muscarine doesn’t cross the BBB well

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18
Q

esters SAR

A

ACh and carbachol: active at both N and M
modification of acetyl group to carbamate - resistant to AChE
b substitutions: more selective for M, reduce AChE
a substitutions: retain N, reduce M

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19
Q

pilocarpine

A

promote sweating, urination, and salivation
-1876: used to treat glaucoma
hypofunction of salivary glands
-xerostomia (dry mouth): M3 receptor
-Sjogern’s syndrome: secretions of salivary glands are reduced, use to increase secretions

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20
Q

Glaucoma: antimuscarinic drugs contraindicated in glaucoma

A

ciliary muscle: M3 agonist pilocarpine, contraction facilitates outflow of aqueous humor, decrease intraocular pressure
ciliary body: a2 agonist brimonidine, inhibit production and increase outflow of aqueous humor, decrease intraocular pressure
ciliary epithelium: NE-b, secretion of aqueous humor
-b antagonist timolol: decrease intraocular pressure

21
Q

clinical use of muscarinic receptor agonists

A

pilocarpine: open angle glaucoma, dry mouth due to hypofunction of salivary glands
bethanechol: GI stimulation, treatment of urinary retention
methacholine: provocative test for hyperreactive airways
carbachol: ocular (surgery, glaucoma)

22
Q

side effects of muscarinic receptor agonists

A

PNS effects (DUMBBELS): diarrhea, urination, miosis, bradycardia, bronchoconstriction, emesis, lacrimation, salivation and sweating (SNS)
-use with caution in patients with asthma, coronary insufficiency, or peptic ulcer

23
Q

acetylcholinesterase

A

located in synapses
substrate selectivity: ACh (highly selective)

24
Q

plasma cholinesterase

A

located in plasma (non-neuronal)
substrate selectivity: ACh, succinylcholine, local anesthetics (procaine) (not as selective for the last two)

25
Q

Cholinesterases and hydrolysis of ACh

A

AChE has the highest turnover rate of any known mammalian enzyme
hydrolyzes ACh molecules with a turnover time of 150 microseconds (~7000x/sec)
reaction requires water, cleaves at the esteric site (between the O on the rest of ACh and the C on the amino acid)

26
Q

hydrolysis of ACh

A

ACh -> cleaved to choline and acetylated enzyme (inactive) -> nucleophilic attack by H2O -> reactivated enzyme

27
Q

cholinesterase inhibitors: indirectly acting cholinergic

A

reversible
-alcohol: edrophonium
-carbamates: physostigmine, neostigmine, pyridostigmine
-others: donepezil
irreversible
-organophosphates: echothiopate, sarin, malathion

28
Q

AChE inhibitors: edrophonium

A

quaternary ammonium alcohol
simplest structures
bid to anionic site and block ACh binding
reversible
non-covalent

29
Q

AChE inhibitors: neostigmine, pyridostigmine, physostigmine

A

carbamates
quaternary or tertiary ammonium groups
reversible
covalent modification to AChE
more slowly hydrolyzed than ACh
-most basic nitrogen: protonated at physiological pH for physostigmine

30
Q

therapeutic AChE inhibitors: edrophonium, neostigmine, pyridostigmine

A

action: inhibition of AChE
-edrophonium via noncovalent, reversible
-“stigmines” as substrates that are more slowly hydrolyzed than ACh
-DOES NOT readily cross the BBB

clinical use
-edrophonium: short acting (min), diagnosis of MG (skeletal muscle weakness due to loss of skeletal muscle N receptors)
-pyridostigmine: Tx of MG, reveral of nondepolarizing neuromuscular blockage, pretreatment for potential nerve gas exposure (occupy AChE so nerve gas has nowhere to go)
-neostigmine: Mg, reversal of nondepolarizing neuromuscular blockade, post-op urinary retention

problems: excessive cholinergic receptor activation

31
Q

physostigmine

A

action: inhibition of AChE, stigmines as substrates that are more slowly hydrolyzed than ACh

clinical use: can cross BBB, antidote to antimuscarinic poisoning

problems: excessive cholinergic receptor activation

32
Q

AChE inhibitors: isofluorophate, echothiophate

A

organophosphates
irreversible
covalent modification to AChE (so stable it’s hard to detach)
longer acting
used in Tx of glaucoma
most organophosphates are toxic

33
Q

inhibition of AChE: drug and hydrolysis times

A

ACh: 150 micro sec
edrophonium (alcohol): minutes
neostigmine: hour
echothiophate: several hours

34
Q

echothiopate therapeutic use

A

action: inhibition of AChE, long acting (essentially irreversible)

clinical use: originally for glaucoma (increase ACh and enhance M activation and subsequent outflow of aqueous humor), not used currently (better drugs available)

problems: excessive cholinergic receptor activation (miosis)

35
Q

AChE inhibitors: sarin, soman

A

organophosphates
nerve gases
irreversible
covalent modification of AChE (much stronger bonding)

36
Q

AChE inhibitors: malathion, diazinon

A

organophosphates
insecticides
irreversible
covalent modification to AChE
rapidly activated in mammals

37
Q

biotransformation of insecticides

A

malathion -cyt p450-> malaoxon
–insects
malathion -carboxyesterase-> inactive
–mammals, birds

38
Q

antidote for AChE “poisoning”

A

pralidoxime chloride (protopam, 2-pyridine aldoxime methyl chloride, 2-PAM)
antidote for pesticide or nerve gas poisoning
most effective if given within a few hours after exposure

39
Q

pralidoxime (2-PAM): AChE inhibitor antidote

A

action: strong nucleophile, will hydrolyze organophosphate if treated BEFORE AGING OCCURS, regenerates AChE
-DOES NOT CROSS BBB, combine with M receptor antagonist atropine

clinical use: Tx of organophosphate toxicity

40
Q

antidotal therapy for acute organophosphate intoxication: pralidoxime

A

strong nucleophile, can’t cross BBB
nicotinic receptors - depolarizing blockade
-target: neuromuscular junction
–muscle weakness - respiratory failure - death

muscarinic receptors - hyperactivity
-target: peripheral parasympathetic NS
–bradycardia - arrhythmias/arrest - death
–excessive airway secretion/constriction - asphyxiation - death

41
Q

antidotal therapy for acute organophoasphate intoxication: atropine

A

blocks access to M receptor (antagonist) but NOT N receptors
muscarinic receptors - hyperactivity
-target 1: peripheral parasympathetic NS
–bradycardia - arrhythmias/arrest - death
–excessive airway secretion/constriction - asphyxiation - death
-target 2: CNS
–decreased respiratory drive - respiratory failure - death
–generalized seizures - convulsions - death

42
Q

Alzheimer’s disease

A

most common cause of dementia after age 50
atrophy of brain
widening of sulci and thinning of gyri
improper processing of b-amyloid precursor protein (b-APP) leads to toxic form (b-A42) that promotes apoptosis
pathological exam: senile plaques (b-amyloid), neurofibrillary tangles
loss of cholinergic neurons in brain

43
Q

drugs for Alzheimer’s

A

donepezil
rivarstigmine
galantamine
memantine (donepezil and memantine)

44
Q

Tx of Alzheimer’s: donepezil

A

bind to anionic site and block ACh binding
reversible
non-covalent
enhances cognitive ability
doesn’t slow progression of disease
approved for all stages of Alzheimer’s

45
Q

Tx of Alzheimer’s: rivastigmine

A

reversible carbamate AChE inhibitor
enhances cognitive ability by increasing cholinergic function
loses effectiveness as disease progresses
SE: N?V, anorexia, weight loss
newer long-acting carbamate: eptastigmine

46
Q

Tx of Alzheimer’s: galantamine

A

reversible competitive AChE inhibitor
extract from daffodil (Narcissus pseudonarcissus) bulbs (natural product)
loses effectiveness as disease progresses
may be nicotinic receptor agonist
inhibitors of P450 enzymes (3A4, 2D6) will increase galantamine bioavailability

47
Q

Tx of Alzheimer’s: memantine

A

N-methyl-D-aspartate (NMDA) receptor antagonist
NMDA receptors are activated by glutamate in CNS in areas association with cognition and memory
neuronal loss in Alzheimer’s may be related to increased activity of glutamate
glutamate regulators to improve memory, attention, reason, language, and ability to perform simple tasks
may slow progression, approved for moderate to severe
favorable adverse effect profile

48
Q

clinical pharmacology: drug, type of inhibition, route of admin, clinical use

A

edrophonium: rev, IM or IV, diagnostic for MG
neostigmine: rev, IM, IV, or oral, MG, post operative ileus and bladder distention, surgical adjunct
physostigmine: rev, IM, IV, or oral, glaucoma, Alzheimer’s, antidote to anticholinergic overdose
donepezil: rev, oral, Alzheimer’s
rivastigmine: reversible carbamate, Alzheimer’s
galantamine: reversible competitive AChE inhibitor, Alzheimer’s
ecothiophate: irrev, local, glaucoma

49
Q

cholinergic agent side effects and toxicity

A

DUMBBELS: diarrhea, urination, miosis, bradycardia, bronchoconstriction, emesis, lacrimation, salivation and sweating
SLUD: salivation, lacrimation, urination, defecation
increased sweating, decreased HR, pupils constricted, CNS activation
Tx: cholinergic receptor antagonist (atropine)

50
Q

cholinergic drug use with caution

A

asthma and COPD: increase bronchoconstriction
coronary deficiency: further lowers HR
peptic ulcer: increase acid secretion
obstruction of urinary/GI tract: if increased contraction doesn’t remove obstruction
epilepsy: M1Rs, CNS penetrable drugs (ex. pilocarpine, physostigmine)

PHRM 825 Exam 1 (4 decks)

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