Cholinergic Agonist and Antagonist Flashcards
What are the 4 primary direct effects ACh has on the cardiovascular system?
- Vasodilation (M3 effect)
- Decrease in cardiac rate (M2 effect)
- Decrease in rate of conduction in the SA and AV nodes (M2)
- Decrease in force of contraction (M2 effect)
What is the effect of IV infection of small dose of aceytlcholine?
- Vasodilation mediated by activation of endothelial M3 receptors
- Reflex tachycardia
What are the effects of a large dose of IV ACh?
- Vasodilation
- Bradycardia from enough ACh to overcome baroreceptor reflex by decrease conduction velocity through the AV node (M2 mediated)
What is the function of M3 receptors on endothelial cells?
- relaxation of vascular muscle via relase of NO from endothelial cells
- M3 muscarinic receptors on endothial cells are unninervated
What are the effects of Acetylcholine on vasculature (endothelial cells), eye iris, ciliary muscle, salivary/lacrimal glands, bronchi, heart, GI tract, urinary bladder, sweat glands, male reproductive tract, and uterus?
- Vasculature (endothelial cells): relase of NO and vasodilation (decrease in BP)
- Eye iris: contraction and miosis
- Ciliary muscle: contraction and accomodation of lens to near vision
- Salivary/lacrimal glands: watery secretions
- Bronchi: constrictions, increase secretions
- GI tract: increase tone, increase peristaltic activity, increase secretions, relaxation of sphincters
- Urinary bladder: contraction of detrusor muscle, relaxation of sphincter
- Sweat glands: diaphoresis
- Male reproductive tract: erection
- Uterus: variable
What are the two types of direct-acting cholinergic agonist chemical structure?
Esters of choline and naturally occuring alkaloids
What are the Choline Esters?
- Acetylcholine
- Methacholine
- Carbachol
- Bethanechol
Acetylcholine
M: muscarinic and nicotinic agoinst; rapidly hydrolysis by acetylcholinesterase and plasma butyrylcholinesterase
CA: to obtain rapid miosis during eye surgery
AE:
TCo: Half life too short, not used clinically
Bethanechol
M: strong muscarinic agonist, little/no nicotinic actions
CA: treatment of acute p/o and postpartum non obstructive (functional) unrinary retention, and for neurogenic atony of the urinary bladder with retention
AE: generalized cholinergic stimulation: sweating, salivation, flushing, low BP, nausea, abd pain, diarrhea, bronchospasm
TCo: almost completely selective for muscarinic receptors
Carbachol
M: muscarininc and nicotinic agonist
CA: obtaining miosis during surgery, reduce intraocular pressure after cataract surgery
AE:
TCo: poor hydrolysis by acetylcholinesterase
Methacholine
M: predominantly muscarinic agonist
CA: methacholine challenge test (diagnosis of bronchial airway hyperreactivity)
AE:
TCo: slower hydrolysis by acetylcholinesterase
What are the natural alkaloids?
Pilocarpine and Nicotine
Pilocarpine
M: partial muscarinic agonist (tertiary amine)
CA: management and second line agent for open angle glaucoma; treatment of symptoms of dry mouth and salivary mouth hypofunction caused by radiotherapy and Sjogren’s Syndrome
AE: can enter CNS and cause disturbances, stimulate sweating/salivation
TCo:
Nicotine
M: nicotinic agonist (tertiary amine)
CA: smoking cessation therapy
AE: increase HR/BP (catecholamine release); N/V/D, voiding of urine, salivary/bronchial secretions; Acute Nicotine Poisoning same symptoms except BP drops
TCO: low doses causes parasympathetic and sympathetic ganglionic depolarization resulting is discharge symptoms from both systems; In high doses caused ganlionic blockade (including neuromuscular) from prolonged depolarization
What is the MOA of indirect-cholinergic agonist (anticholinesterases)?
Inhibit acetylcholinesterase thereby increase the concentration of endogenous acetylcholine
What are the 3 chemical groups of indirect-acting cholinergic agonsist (anticolinesterases)?
- Edrophonium
- Carbamates
- Organophosphates
Edrophonium
M: reversibly binds active site of acetylcholinesterase (Quaternary ammonium)
CA: diagnosis of myasthenia gravis by increase ACh concentrations to reverse the non-depolarizing muscular blockers
AE: excessive muscarinic stimulation (salivation, lacrimation, miosis, diarrhea, bradycardia) excessive nicotinic stimulation (muscle weakness, paralysis)
TCo: short lived (2-10 minutes)
What are the 3 carbamates?
- Neostigmine
- Physostigmine
- Pyridostigmine
Physostigmine (carbamate)
M: covalent bond with acetylcholinesterase (tertiary amine)
CA: Tx of anticholinergic drug overdoses
AE: excessive muscarinic stimulation (salivation, lacrimation, miosis, diarrhea, bradycardia) excessive nicotinic stimulation (muscle weakness, paralysis)
TCo: can penetrate BBB so can effect CNS causing convulsions and bradycardia
Neostigmine
M: covalent bond with acetycholinesterase; Quaternary amine (does not enter CNS)
CA: reversal of non-depolarizing neuromuscular blockers after surgery, symptomatic treatment of myasthenia gravis, prevention/tx or p/o distention and urinary retention
AE: salivation, flushing, low BP, nausea, abd pain, diarrhea, bronchospasm
TCo:
Pyridostigmine
M: covalent bond with acetylcholinesterase (quaternary amine, does not enter CNS)
CA: treatment of myasthenia gravis (most common)
AE: excessive muscarinic stimulation (salivation, lacrimation, miosis, diarrhea, bradycardia) excessive nicotinic stimulation (muscle weakness, paralysis)
TCo:
What are the organophosphates drugs?
- Echothiophate
- Parathion
- Malathion
- Tabun
- Sarin
- Soman
Echothiophate
M: phosphorylate the active site of the acetylcholinesterase
CA: rarely used for open-angle glaucoma
AE: excessive muscarinic stimulation (salivation, lacrimation, miosis, diarrhea, bradycardia) excessive nicotinic stimulation (muscle weakness, paralysis)
TCo: only organophosphate that is not liposoluble
Thiophosphate Insecticides
Malathion and Parathion
M: phosphorylate acetylcholinesterase
CA:
AE: malathion is for public use; parathion is not for general public
TCo: activated in body to conversion to oxygen anologs
Nerve Agents
Tabun, Sarin, Soman
M: phosphorylate acteylcholinesterase
CA:
AE: CNS toxicity
TCo: among most potent synthetic toxic agents
Acetylcholinesterase Inhibitors used in Alzheimer disease
Donepezil, Rivastigmine, Galantamine
M: orally active centrally acting inhibitors of acetylcholinesterase
CA: treatment of Alzheimer’s disease
AE:
TCo:
Pralidoxime
M: split the phosphate-enzyme bond to reactivate inhibited acetylcholinesterase
CA: cholinesterase regenerator for organophosphate insecticide poisoning (ineffective in CNS)
AE:
TCo:
What are the Belladonna Alkaloids?
Atropine and Scopolamine
Atropine
M: muscarinic receptor competitive antagonist (tertiary amine)
CA: antisialogogue prior to surgery (decrease respiratory secretions), increase HR or decrease AV-block, overdose of cholinergic drugs, to alleviated muscarinic side effects of anticholinesterase drugs
AE: dry mouth, blurred vision, sandy eyes, tachycardia, constipation; CNS (restlessness, confusions, hallucinations, delirum, depression, and collapse of circulatory/respiratory system and death)
TCo: both central and peripheral muscarinic blocker
Scopolamine
M: muscarinic receptor antagonist
CA: anti-motion sickness drugs, mydriasis/cycloplegia for diagnostic procedures, block short term memory
AE:
TCo: CNS and PNS
What are the two types of synthetic/semisynthetic drugs and what specific drugs belong to them?
- Quaternary Ammonium Muscarinic Antagonist
- Ipratropium and Tiotropium
- Tertiary Amine Muscarinic Antagonist
- Homatropine and Tropicamide
- Benztropine and Trihexyphenidyl
Ipratropium and Tiotropium
M: muscarinic antagonists (quaternary ammonium)
CA: inhalation drugs for COPD and asthma
AE:
TCo: contraindicated towards angle-closure gluacoma, prostatic hypertrophy, and the elderly
Homatropine and Tropicamide
M: muscarinic antagonist (tertiary amine)
CA: mydriatic for fundoscopy, mydriasis with cycloplegia (better than atropine because shorter action)
AE:
TCo: contraindicated in pts with angle-closure glaucoma, prostatic hypertrophy, and in the elderly
Benztropine and Trihexyphenidyl
M: muscarinic antagonist (tertiary amine)
CA: treats Parkinson’s disease and the extrapyramidal effects of antipsychotic drugs
AE:
TCo: contraindicated in pts with angle-closure glaucoma, prostatic hypertrophy, and in elderly
Glycopyrrolate
M: antimuscarinic (quaternary ammonium)
CA: orally to inhibit GI motility, parenterally to prevent bradycardia during surgical procedures
AE:
TCo:
Tolterodine
M: antimuscarinic
CA: overactive bladder
AE:
TCo:
What are the 2 mechanisms of a ganglion blockade?
- Prolonged depolarization
- By antagonisms of nicotinic receptors (Hexamethonium and Mecamulamine)
What are the 2 types of neuromuscular blockers?
- Competitive antagonists (nondepolarizing blockers)
- Agonsists (depolarizing blockers)
Tubocurarine
M: competitive antagonist of nicotinic receptors (nondepolarizing blockers)
CA: adjuvant drugs in anaesthesia during surgery to relax skeletal muscle
AE:
TCo:
Succinylcholine
M: binds to nicotinic receptor and depolarized the junction, persists in the synaptic cleft stimulating the receptor: receptor desensitizes which leads to flaccid paralysis
CA: rapid endotracheal intubation, ECT
AE: malignant hyperthermia (excessive calcium relase from SR), most incidents due to combination of succinycholine and halogenated anesthetic which can be treated by Dantrolene (blocks Ca2+ relase from SR)
TCo:
What are the drugs that act presynaptically?
- Hemicholinium-3
- Vesamicol
- Botulinum Toxin
Hemicholinium-3
M: block the CHT (Na+ dependent choline transporter)
CA:
AE:
TCo:
Vesamicol
M: blocks ACh-H+ antiporter whcih transports ACh into vesicles
Botulinum Toxin
M: inhibits acetylcholine relase
CA: treatment of disease involving muscle spasms, cosmetic treatment
