08 Cholinergics Flashcards
Muscarinic receptors
M1 = CNS, salivary glands, stomach parietal cells M2 = heart, some smooth muscles, nerve M3 = smooth muscles, skin, exocrine glands secretion, vasodilation
M1/2/3 = IP3 and DAG M2/4 = inhibition of CAMP, activation of K channels (repolarization -> bradycardia, dec force of contraction and rate of AV conduction -> dec CO)
Nicotinic receptors
Nm = NMJ Nn = autonomic ganglia, CNS, adrenal medulla
Choline esters
Ach, methacholine, carbachol, bethanecol
Hydrophilic (poorly absorbed in CNS)
Ach, Carbachol = both receptors
Methacholine = more muscarinic
Bethanecol = only muscarinic
Alkaloids
Muscarine (toxic, less absorbed), pilocarpine = muscarinic (MuPasa)
Nicotine (easily absorbed), lobeline = nicotinic (NaLa)
Muscarinic receptor activator
M1/3/5 (Gq): IP3 and DAG; increase in Ca+ -> smooth muscle contractions except heart; increase in cGMP -> increase in K in cardiac cell
M2 (Gi), M4 (Gq): inhibit adenelyl cyclase -> decrease CAMP; activate K channel -> repolarization -> bradycardia
Nicotinic receptor activator
Opens Na and K channels -> depolarization of nerve/NMJ -> muscle contraction
Cholinomimetics
Direct acting = alkaloids (muscarine, nicotine, pilocarpine, lobeline) and choline esters (ach, methacholine, carbachol, bethanecol)
Indirect acting = simple alcohols (edrophonium), carbamates (neostigmine, pyridostigmine, physostigmine), organophosphates (ethothiophate, malathoin, parathion)
Simple alcohols
Quaternary ammonium group (edrophonium)
H-bond (weak), 5 minutes
Carbamic acid/carbamates
Quaternary/tertiary ammonium group, polar = poor absorption
Covalent bond, longer, reversible
Neostigmine
Pyridostigmine
Physostigmine: well absorbed, eye, exception = lipophilic = cross BBB, more toxic
Carbaryl: very lipid soluble
Organophosphates
Very lipid soluble = good absorption until BBB = toxic
Parathion and malathion: must be activated in body buy conversion to O2 analogs
Echothiophate: exception = hydrophilic, more stable
Group 1
Reversible cholinesterase inhibitor
Reversible bind electrostatically via H-bond
Short lived (2-10 min)
ex. Edrophonium
Group 2
Reversible cholinesterase inhibitor
Two-step hydrolysis sequence like Ach -> covalent bond is not hydrated
Long course (30 min- 6h)
ex. Carbamates
Group 3
Irreversible cholinesterase inhibitor
Covalent bond is stable
Binding-hydrolysis -> aging (breaking of O2-P groups of inhibitor) -> stronger P-enzyme bond
Pralidoxime: breaks P-enzyme bonds BEFORE AGING
Atropine: anti-cholinergic (reverse initial effects of organophosphates)
Clinical effects on the eye
Glaucoma: closed angle = increase intraocular pressure
Cholinomimetics: contraction of ciliary body + decreased secretion -> aqueous outflow -> dec intraocular pressure
Acute angle-closure glaucoma -> direct muscarinic agonist + another drug -> surgery
Esotropia in young children (cross eyed): cholinomimetics to help accommodation
Clinical effects on respi
Nonspecific bronchoprovocation test (asthma): methacholine
Clinical effects on GIT
Increases smooth muscle activity (post-operative ileus, congenital megacolon): bethanecol
Increase salivary secretion: pilocarpine,
Sjorgen syndrome: Cevimeline
Clinical effects on urinary tract
Cause contraction of the detrusor muscle: bethanecol (DOC), neostigmine
Clinical effects on NMJ
Myasthenia gravis (autoimmune disease that attacks NMJ = decreased contraction): Neostigmine (every 4h), pyridostigmine (every 6h); immunosuppressants; Ig and plasmapheresis Tensilon test: edrophonium = improved muscle strength
Respiratory arrest: intranasal neostigmine
Neuromuscular blockade: IV/IM neostigmine and edrophonium
Clinical effects on heart
Supraventricular tachyarrhythmias: edrophonium, adenosine, verapamil, diltiazem
Clinical effects on antimuscarinic drug intoxication
Atropine intoxication and TCA overdose: physostigmine (emergency), neostigmine, pyridostigmine
Clinical effects on CNS
Alzheimer’s (dec ach): Tacrine (direct and indirect), donepezil, galantamine, rivastigmin
Signs of muscarinic excess
Salivation Lacrimation Urination Defecation GI cramping Emesis
Signs of nicotinic excess
Muscle cramps Twitching Weakness Tachycardia and hypertension Fasciculations
Varenicline
Nicotinic partial agonist
Prevents stimulant effect of nicotine that causes dopamine release
Organophosphate poisoning symptoms
Diarrhea Urination Miosis Bronchospasms Bradycardia (dec HR) Excitation of skeletal m. and CNS Lacrimation Salivation Sweating vomiting --> Atropine and pralidoxime
