Cholinergic agents Flashcards
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
Alkaloids
Muscarinic, nicotine, pilocarpine
uncharged, well absorbed (nicotine patch thru skin)
muscarine is neurotoxin (from mushrooms)
acidification of urine increases clearance
cholinergic agonists
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
Cholinergic functions in CNS
mostly M in Brain, N in the spinal cord
increased cognitive function (memory learning)
tremors hypothermia, seizures, analgesia
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
Contraindications of muscarinic agonists
asthma, hyperthyroidism, coronary insufficiency, acid-peptic disease
OD cause SLUDGE sx (tx= atropine)
ACh
Choline ester
rarely used systemically
intraocular drops during surgery –>miosis
Methacholine
Choline ester
inhalation for dx of bronchial airway hyperreactivity
Bethanechol
Choline ester selective mAChR agonist ex for urinary retention and heartburn little CV stimulation risk for UTI
carbachol
Choline ester
nonspecific cholinergic agonist
tx for glaucoma or miosis during surgery or examination
Pilocarpine
Alkaloid
pure mAChR agonist
xerostomia (PO), miosis during surgery (topical) glaucoma (topical)
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
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
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)
Neostigmine
quaternary carbamate AChE inhibitor
preferred for reversal of pharmacologic paralysis
has some direct action on N receptors on NMJ
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
