Cholinergic agents Flashcards by Charles Simpkin

Choline Esters

ACh, carbachol, bethanechol
quartenary ammonium groups= poor abs and distribution to CNS
hydrolyzed in GI= less active when given PO
ACh>Methacholine>carbachol=bethanechol (speed of hydrolyzation by AChE)

cholinergic agonists

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Alkaloids

Muscarinic, nicotine, pilocarpine
uncharged, well absorbed (nicotine patch thru skin)
muscarine is neurotoxin (from mushrooms)

acidification of urine increases clearance

cholinergic agonists

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Nicotinic stimulant toxicity

CNS: alerting in low doses, tremor, emesis, stimulation or resp. center, convulsion, coma at high dose

peripherally activates both PSNS and SNS
CNS= SNS ( HTN with alternating tachy and brady)
GI/GU= PSNS: N/V/D/urination

tx=atropine for exs PSNS activity and anticonvulsants (diazepam)
Neuromuscular blockade is not responsive to treatment

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Cholinergic functions in CNS

mostly M in Brain, N in the spinal cord
increased cognitive function (memory learning)

tremors hypothermia, seizures, analgesia

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Clinical uses of direct acting cholinergic agonists

1) Glaucoma (contracts ciliary mm.) opens angle
2) accomodiative esotropia (congenital far-sighted induced strabismus)
3) Post-op Ileus, Congenital megacolon, urinary retention, GERD (contracts LES)
4) Salivary secretion in Sjogrens

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Contraindications of muscarinic agonists

asthma, hyperthyroidism, coronary insufficiency, acid-peptic disease

OD cause SLUDGE sx (tx= atropine)

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ACh

Choline ester
rarely used systemically
intraocular drops during surgery –>miosis

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Methacholine

Choline ester

inhalation for dx of bronchial airway hyperreactivity

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Bethanechol

Choline ester 
selective mAChR agonist 
ex for urinary retention and heartburn 
little CV stimulation 
risk for UTI

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carbachol

Choline ester
nonspecific cholinergic agonist
tx for glaucoma or miosis during surgery or examination

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Pilocarpine

Alkaloid
pure mAChR agonist
xerostomia (PO), miosis during surgery (topical) glaucoma (topical)

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Varenicline

(chantix)
smoking cessation
PARTIAL nAChR agonist (just at lower levels than nicotine)
stimulates DA from mesolimbic system to decrease craving and withdrawal

s/e: Nausea, changes in behavior, depression, suicidal ideation

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uses of indirect-acting cholinergics

1) Glaucoma
2) dementia and alzheimer (corrects cholinergic neuron deficit)
3) antidote to anticholinergic poisoning (from antihistamines, atropine OD etc)
4) reversal of neuromuscular paralysis ( post-surgical)
5) myasthenia gravis

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Duration of AChE

alcohols (edrophonium) are short lived
Carbamic acids 30min-6h
Organophosphates are very long lived d/t stable enzyme interaction (if enzyme aging occurs thru breaking of oxygen phos bonds, then complex is even more stable)

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Neostigmine

quaternary carbamate AChE inhibitor
preferred for reversal of pharmacologic paralysis
has some direct action on N receptors on NMJ

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Physostigmine

Tertiary carbamic acid AChE inhibitor
preferred antidote for anti-cholinergic poisoning (from atropine, antihistamines, sleep-aids etc)

Uncharged molecule, therefore it can cross into the CNS and correct neurological sx

AChE inhibitors interactions

1) neuromuscular blocking agents ( decreased blockage)
2) succinycholine
3) AChR agonists (enhanced effects)
4) Beta blockers (enhanced bradycardia)
5) Corticosteroids (enhanced mm. weakness in ME pt)

AChE toxicity

Acute: SLUDGE (salivation lacrimation, urination, diarrhea, miosis)
GI sx occur earliest after ingestion
percutaneous–>seating, mm ataxia, fasciculations

death d/t respiratory failure

Pralidoxime

Cholinesterase reactivators
removes phosphorus group from AChE-organophosphate complex
restores AChE, and restores normal response at NMJ within minutes
must be given before aging has occurred
charged, so it can only correct the NMJ
given with Atropine after AChE poisoning

Atropine-chemistry and metabolism

tertiary amine alkaloid
readily absorbed and distributed
half life of 2h, 60% is excreted unchanged
physiological effects in the eyes last longest

Atropine MOA

reversible antagonist of mAChR (non-selective)
most selective for salivary, bronchial, and sweat glands
gastric glands least sensitive

decreased salivation and micturition are seen first

Cholinergic antagonists -CNS

sedative effect at higher doses
reduced Parkinson tremor
scopolamine- drowsiness, altered mental status
and reduced vestibular disturbances

Cholinergic antagonists- eye

mydriasis
cycloplegia (inability to accommodate d/t weakened ciliary mm)
reduced lacrimation

Cholinergic antagonists- CV

little effect on BP or HR in normals
prevents CV effect of muscarinic agonists
low doses cause bradycardia
high doses cause tachycardia

Cholinergic antagonists-Respiratory system

bronchodilation and reduced secretion useful for surgical procedures also to treat COPD and asthma

Cholinergic antagonists-GI

decreased salivation (xerostomia) decreased gastric secretion at HIGH DOSE NO effect on pancreatic secretions increased intestinal transit time and slowed gastric emptying

Cholinergic antagonists-GU

relax smooth mm of ureters and bladder wall, slows voiding

Cholinergic antagonists-sweat glands

anhidrosis can cause atropine fever in children and adults (high dose)

drugs that reduce movement disorders

``` mAChR antagonists reduce PD tremors benztropine orphenadrine procyclidine trihexyphenidyl ```

Scopolamine

mAChR antagonist used to treat sea sickness (reduces vestibular disturbances) Injection, PO, or Transdermal (post-auricular)

ipratropium

mAChR antagonist first-line inhalation therapy for asthma and COPD (d/t bronchodilation) short t1/2 q.i.d. charged molecule, so not absorbed systemically (good)

Tiotropium

mAChR antagonists longer bronchodilator action compared to ipratropium d/t longer t1/2 can be taken QD

oxybutynin

selective M3 antagonist , prototypical drug used to reduce urinary frequency s/e: xerostomia, dizziness, constipation, blurred vision

trospium

selective M3 antagonist, similar to oxybutynin for urinary frequency

darifenacin solifenacin tolterodine

selective M3 antagonist , prototypical drug used to reduce urinary frequency better d/t reduced xerostomia and constipation longer t1/2

contraindications of AChR antagonists

glaucoma prostatic hyperplasia (risk for acute urinary retention) acid-peptic disease (d/t slowed gastric emptying time, which would increase discomfort)

Mecamylamine MOA

ganglion-blocker: competitively blocks ACh on nAChR at PSNS and SNS ganglia (BLOCK ALL autonomic output) Charged, can enter CNS **bc PSNS usually predominates, results in enhanced SNS activity (except in vasculature

Mecamylamine organ effects

CNS- sedation, tremor, chorea eye- cycloplegia, moderate dilation CV-decreased vascular tone, decreased BP, decreased contractility, moderate tachycardia GI-reduced secretion and motility GU: urinary hesitancy or retention in men with BPH inhibited erection and ejaculation

clinical use of mecamylamine

HTN and smoking cessation