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PHRM 825 > 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
plasma cholinesterase
located in plasma (non-neuronal) substrate selectivity: ACh, succinylcholine, local anesthetics (procaine) (not as selective for the last two)
25
Cholinesterases and hydrolysis of ACh
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
hydrolysis of ACh
ACh -> cleaved to choline and acetylated enzyme (inactive) -> nucleophilic attack by H2O -> reactivated enzyme
27
cholinesterase inhibitors: indirectly acting cholinergic
reversible -alcohol: edrophonium -carbamates: physostigmine, neostigmine, pyridostigmine -others: donepezil irreversible -organophosphates: echothiopate, sarin, malathion
28
AChE inhibitors: edrophonium
quaternary ammonium alcohol simplest structures bid to anionic site and block ACh binding reversible non-covalent
29
AChE inhibitors: neostigmine, pyridostigmine, physostigmine
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
therapeutic AChE inhibitors: edrophonium, neostigmine, pyridostigmine
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
physostigmine
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
AChE inhibitors: isofluorophate, echothiophate
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
inhibition of AChE: drug and hydrolysis times
ACh: 150 micro sec edrophonium (alcohol): minutes neostigmine: hour echothiophate: several hours
34
echothiopate therapeutic use
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
AChE inhibitors: sarin, soman
organophosphates nerve gases irreversible covalent modification of AChE (much stronger bonding)
36
AChE inhibitors: malathion, diazinon
organophosphates insecticides irreversible covalent modification to AChE rapidly activated in mammals
37
biotransformation of insecticides
malathion -cyt p450-> malaoxon --insects malathion -carboxyesterase-> inactive --mammals, birds
38
antidote for AChE "poisoning"
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
pralidoxime (2-PAM): AChE inhibitor antidote
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
antidotal therapy for acute organophosphate intoxication: pralidoxime
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
antidotal therapy for acute organophoasphate intoxication: atropine
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
Alzheimer's disease
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
drugs for Alzheimer's
donepezil rivarstigmine galantamine memantine (donepezil and memantine)
44
Tx of Alzheimer's: donepezil
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
Tx of Alzheimer's: rivastigmine
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
Tx of Alzheimer's: galantamine
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
Tx of Alzheimer's: memantine
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
clinical pharmacology: drug, type of inhibition, route of admin, clinical use
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
cholinergic agent side effects and toxicity
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
cholinergic drug use with caution
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 (5 decks)

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