Cholinergic Agonists and Antagonists Flashcards
Direct acting cholinergic agonists
Stimulate muscarinic or nicotinic receptors directly
Alkaloids and Choline esters
Indirect acting cholinergic agonists
Increase the amount of ACh available to act on mAChR and nAChR
Stimulate effector organs
Stimulate (followed by depression) muscle and ganglia
Stimulate (sometimes depress) receptors in the brain
(Reversible and irreversible)
Choline esters
Quaternary ammonium groups - not absorbed to CNS
Hydrolyzed by AChE: ACh > methacholine > carbachol > bethanechol (longest lasting)
MOA: direct cholinergic agonists
Alkaloids
Uncharged tertiary - well absorbed, can go to CNS
Basic (acidification of urine helps elimination)
MOA: direct cholinergic agonists
Muscarine (in mushrooms)
Quaternary amine
Highly toxic
Can enter CNS
M1
Nerves
M2
Heart, nerves, smooth muscle
M3
Glands, smooth muscle, endothelium
Predominates in most organs
M4
CNS (brain > SC)
M5
CNS (brain > SC)
Nm
Skeletal muscle and NMJ
Nn
Postganglionic cell body, dendrites, CNS (SC > brain)
IP3 and DAG cascade
M1, M3, M5
Inhibition of cAMP production
M2 and M4
Activation of K+ channels
M2
Na+ and K+ depolarizing ion channel
Nm and Nn
Skeletal muscle receptors
ONLY nAChR (nicotinic) Binding these receptors with agonist leads to depolarizing blockade
Depolarizing blockade
Binding AChR with greater affinity cause disorganized depolarization and doesn’t allow muscle cell to repolarize
Leads to flaccid paralysis/muscle relaxation
Ex. Succinylcholine
Prolonged presence of nAChR agonist
Abolishes effector response - postganglionic neuron stops firing
Skeletal muscle cells relax
General parasympathetic effects
Pupil constriction, accommodation, salivation, bronchiole constriction, lung secretions, gastric secretions, increase motility, diarrhea, urination
**INCREASE with agonist
PS and Eye
Constrict sphincter, increase aqueous humor flow
PS and Cardio
Only M2 mAChR
Reduce peripheral resistance
Atria > Ventricle - decrease rate and contractile strength
Release EDRF - relax SM around blood vessels
Small dose - slight BP decrease, increase HR reflex
Large dose - bradycardia and hypotension
PS and GI
Increase glandular secretions (salivary and gastric especially)
M3 - direct contraction
M2 - indirection contraction
Sphincter relaxation
PS and GU
Sphincter relaxation
Increase voiding
CNS - excitatory mAChRs
Increased cognitive function
CNS - inhibitory mAChRs
Tremors, hypothermia, and analgesia
CNS - nAChR activation
Dose dependent
Can have severe CNS consequences
PNS - nAChR activation
Simultaneously fire parasympathetics and sympathetics
Cardio - sympathetic dominates
GI/GU - parasympathetic dominates
Direct agonist use in Eye
Glaucoma - Increase flow via contraction (Replaced by beta blockers and prostaglandin derivatives)
Accommodative estropia - Cross eyed from accommodation error
Direct agonist for GI/GU
Bethanechol: Increase tone of stomach and intestines Increase tone of lower esophageal sphincter Fix urinary retention **Beware of bowel obstruction
Pilocarpine and Cevimeline:
Increase salivary secretions
Muscarinic direct agonist overdose
Treat with Atropine
N/V/D, urination, salivation, sweating, cutaneous vasodilation, bronchial constriction
Muscarinic direct agonist contraindications
**Asthma
Hyperthyroidism
Coronary insufficiency
Acid-peptic disease
Nicotinic direct agonist acute toxicity
Nicotine only common source CNS simulation Skeletal muscle depolarization blockade Respiratory paralysis HTN and cardiac arrhythmias Treat with atropine and diazepam (no muscle recovery)
Acetylcholine use
Intraocular during surgery
Rarely systemically given
Methacholine use
Treat airway hyperreactivity if no asthma
Rarely used due to risk of bronchospasm
Bethanechol use
Urinary retention and heartburn
**selective mAChR
Little cardiovascular effect
Carbachol
Glaucoma or miosis during surgery
Cevimeline
Treat xerostomia
*Metabolized with p450 pathway and eliminated in urine
Pilocarpine
Treat xerostomia
Glaucoma or miosis as well
**selective mAChR
Varenicline (Chantix)
Smoking cessation **selective nAChR alpha4beta2 in brain Reduce craving and withdrawal 90% eliminated unchanged in urine Potential psych side effects :(
Indirect agonists MOA
Inhibiting cholinesterase and allowing more ACh to interact with receptors therefore increase parasympathetic effects
Alcohol AChE Inhibitors
Positively charged quaternary
Reversible binding to AChE (electrostatic interactions and H bonding)
Ex. Endrophonium
Carbamic acid esters AChE inhibitors
Positive or neutral, quaternary or tertiary
Reversible binding to AChE (covalent bonds that are later hydrolyzed)
**Ex. Neostigmine, pyridostigmine, physostigmine
Organophosphate AChE inhibitors
Insecticides, nerve gases
Neutral and lipid soluble - CNS toxicity, readily absorbed everywhere including skin and lungs
Irreversible binding to AChE (very stable bond, aging increase phosphorus-enzyme bond)
Little excretion/metabolism
**Need to regenerate AChE as well as counteract ACh overload
Quaternary and charged AChE inhibitors
Poor absorption, insoluble in lipids (NO CNS) Parenteral preferred Act preferentially at NMJ Duration determined by complex stability **Neostigmine, pyridostigmine Edrophonium, echothiophate, ambenonium
Tertiary and uncharged AChE inhibitors
Well absorbed - including CNS
More toxic
**Physostigmine
Donepezil, tacrine, rivastigmine, galantamine
Eye, GI, GU and Respiratory + AChE inhibitors
Same effect as direct cholinomimetics
Cardio and AChE inhibitors
Parasympathetic tone dominates
Modest bradycardia, fall in CO, little or no decrease in BP
NMJ and AChE inhibitors
Therapeutic levels can increase strength of contraction
Too much can cause blockade
Reversal of pharmacologic paralysis using AChE inhibitors
Reverse effects of nondepolarizing nerve blockers
**Neostigmine and edrophonium
Treat atony of GI and GI
AChE inhibitor and Glaucoma
Same effect as direct agonist but not commonly used
AChE inhibitor and dementia
Tacrine came first
Donepezil, rivastigmine, galantamine, and physostigmine preferred
Parkinsonian dementia also benefits
Compounds with anticholinergic properties
Atropine, antihistamines, tricyclic antidepressents, sleep aids, cold preparations
Antidote for anticholinergic compounds
AChE inhibitor
**Physostigmine (can cross BBB)
AChE inhibitor with nondepolarizing neuromuscular blocking agents
Blockade will diminish
Exception: mivacurium
AChE inhibitor with Succinylcholine
Enhance phase 1 block
Antagonize phase 2 block
AChE inhibitor with direct agonists
Enhance the effects
AChE inhibitor with beta blockers
May enhance bradycardic effects
AChE inhibitor with systemic corticosteroids
May enhance muscle weakness
AChE inhibitor acute intoxication
Increased parasympathetics
Ex. pesticides, veterinary vermifuges
Ingestion - GI first
Skin - sweating and muscle fasciculations
Lipid soluble agents have serious CNS involvement
TOD can be quick
AChE inhibitor antidote
Atropine
Cholinesterase regenerators needed for NMJ
Can add benzodiazepine (anticonvulsant) as well
Cholinesterase regenerator
Pralidoxime
Must be given before aging occurs
AChE inhibitor prophylaxis
Pyridostigmine in low doses
Antinicotinic drugs
Effect NMJ and ganglia
Not as clinically useful
mAChR blockers
Parasympatholytic - block the effects of parasympathetic discharge
**Think everything opposite of parasympathetics
Prototype - Atropine
Tertiary antimuscarinics
Used for eye or CNS
More readily absorbed and distributed
Atropine, tropicamide, benztropine
Quaternary antimuscarinics
Elicit effects in periphery
Ipratropium, glycopyrrolate
Metabolism/excretion of antimuscarinics
Effect usually declines rapidly
Excreted in the urine
Except - long lasting in the eye
MOA of atropine
Reversible antagonist of mAChRs
Most sensitive are salivary, bronchial, and sweat (gastric is the least sensitive)
**Does not distinguish between types of receptors
CNS and antimuscarinics
Low dose: minimal stimulant effect on CNS, mild sedative to brain
Reduce Parkinson tremor
Reduce motion sickness (scopolamine)
Eye and antimuscarinics
Dilate, can’t accommodate, reduce tears
Cardio and antimuscarinics
Mild tachycardia
Prevent CV effects of direct muscarinic agonists
Low dose - initial bradycardia (reflex)
High dose - tachycardia (vagal block)
Respiratory and antimuscarinics
Bronchodilation and reduced secretion
GI and antimuscarinics
Decreased saliva
Decreased gastric secretions to a lesser degree
Gastric emptying is prolonged and GI transit time prolonged
GI and antimuscarinics
Treat urinary incontinence - slow voiding, relax muscle
Sweat glands and antimuscarinics
Reduce thermocontrol/sweating even though they are only innervated by sympathetics
*Atropine fever
Antimuscarinics and Parkinsons
Reduce tremor
Benztropine, trihexyphenidyl, procyclidine
Antimuscarinics and Motion sickness
Antihistamines
*Scopolamine
Antimuscarinics in anesthesia
Atropine blocks vagal reflexes
Atropine paired with neostigmine when reversing skeletal muscle relaxation (block increase in parasympathetics)
Antimuscarinics in opthalmologic disorders
Mydriasis for long periods
Prevent synechia formation in uveitis and iritis
Antimuscarinics in respiratory disorders
Treat asthma and COPD
Ipratropium
**Tiotropium
Antimuscarinics in cardio disorders
Rarely used
Can alter vagal reflex
Antimuscarinics and GI disorders
Treat traveler’s diarrhea
Can be combined with opioid agent to discourage abuse (Lomotil)
Antimuscarinics and urinary urgency
Oxybutynin
Trospium
Darifenacin, solifenacin, and tolterodine - selective for M3, less xerostomia and constipation
Cholinergic poisoning
No effective treatment for muscarinic effects
Treat with antimuscarinic and AChE regenerator
Pralidoxime
Cholinesterase regenerator
Charged - only works at NMJ
Rapid onset cholinergic poisoning
Adequately treated with Atropine
Shows signs of DUMBBELLS
High concentration of atropine
Dry, blind, red, mad, hot
Atropine overdose
Treat with cholinesterase inhibitor
or treat symptomatically
Antimuscarinic contraindications
Glaucoma
History of prostatic hyperplasia (risk for acute urinary retention)
Acid peptic disease (slowed emptying increases discomfort)
Pirenzepine
M1 selective antimuscarinic used in other countries for peptic ulcer disease
Ganglion blocking drugs
Synthetic amines
*Mecamylamine - can cross BBB
Blocks both - Parasympathetic tone dominates
Use is infrequent