Cholinergic Agonists and Antagonists Flashcards
Muscarinic Receptors
G protein linked,
5 identified but only M1,M2,M3 have known function
located on SM, cardiac muscel, exocrine glands, sweat glands, BVs of major vascular beds, coritical & subcortical sites of CNS
M1
increases IP3, DAG, and Ca
activates myenteric plexus
M2
Opens K+ channels: Decreases HR and contraction, decreased CO
Decreased cAMP and Ca- inhibits NE release from sympathetic nerve temrinals
M3
Increases IP3, DAG, Ca: cilliary muscle contraction (pupillary constriction, near vision acomidation), contract bronchilar muscle, GI SM, uterine muscle, bladder detrusor muscle.
Relaxes vascularm uscle via NO
Stimulates secretions of the GI tract, eccrine sweat glands, tear glands, salivary glands, tear glands, pancreas digestive fluids, and liver bile.
Nicotinic receptors
Ligand gated ion channels. pentameric transmembrane receptors.
permeable to Na and K. loacted in plasma membranes of parasympathetic and sympathetic post-ganglionic cells in autonomic ganglia, cortical and sub cortical areas of the brain (Nn) and membranes of SKm (NM).
Nicotine
selective for NN receptor in the CNS.
Used to minimize wihdrawal symptoms durign smoking cessation
Side effects: irritation at site of administration, dyspepsia
Succinyl Choline
blocks the NM receptor at the neuromuscular junction. causes depolarization block and inhibits muscle contraction (during electroshock therapy). used as a muscle relaxant during intubation.
Metabolized by butyrlcholinesterase
contraindication: ptatients with familial hyperthermia and SKM myopathies, and not to be taken several days after a widespread muscle injury.
Acetylcholine
Prototype compound.
binds toboth nicotinic and muscarinic receptors of autonomic nervous system, CNS, NMJ.
Rapidly hydrolyzed by AchE
no therapeutic use
methacholine
quaternary nitrogen analog, Charged so won’t cross BBB.
Hydrolyzed by CE but slowed so longer duration of action than Ach.
mostly acts an muscarinic receptors- SM, glands, heart
Therapeutic: Used to diagnose bronchial hyperactivity in patients suspected of having asthma.
Toxicity: bronchiolar constriction
Contraindiaction: pts taking B-blockers (its the antidote to methacholine overdose)
Carbachol
Quaternary nitrogen analog, charged won’t cross BBB
Acts at both muscarinic and nicoinic receptors
Metabolized by AchE but slowly because it is resistant.
therapeutic: topical miotic agent for ocular surgery and glaucoma. reduces pressure.
Toxicity: excessive muscarinic activation → bronchoconstriction and reduced cardiac conduction.
Bethanachol
Quaternary Nitrogen analog, charged so won’t cross BBB
Selective for muscarinic receptors of the bladder and GI (cholinergic activation)
Resistant to hydrolysis
Has less M2 effects so less cardiovascular effects
Therapeutic: used postoperatively to treat non-obstructuve urinary retention, post partum urinary retention, and neurogenic atony of the bladder.
Toxcicity: bradycardia, bronchoconstriction
Contraindications: asthma, peptic ulcer, bradycardia.
Muscarine
Prototype
quaternary amine
muscarinic activity, resistant to hydrolysis
Toxicity: mushroom poisonin causes excessive muscarinic activation.
Treat with atropine
Pilocarpine
non-selective muscarinic receptor agonist
alkaloid of south american shrub pilocarpus jaborandi
tertiary amine- Crosses BBB
Therapeutic uses: dry mouth and neck from radio therapy or Sjogren’s syndrom. open angle glaucoma. acute and chronic angle-closure glaucoma.
Toxicity: Excess muscarinic activation (slowed AV consuction, can cause heart block) hypotension, excess salivation, bronchoconstriciton.
Acetylcholinesterase
Butrylcholinesterase
AchE- found in NMJ, cholinergic synapse, and RBC (makes discrete muscular movements possible)
butrylcholinesterase- plasma, glial cells, liver.
inhibition cause rise of Ach in all synpases resulint in:
muscarinic actions at autonomic effector targets, nicotninc actions at autonomic ganglia, nicotinic actions at the motor end plate, muscarinic and nicotinic actions in CNS.
*act indirectly as cholinergic agonists*
Neostigmine
Reversible cholinesterase inhibitor
quaternary nitrogen so can’t cross BBB
Direct stimulation of NM receptors. Direct stimulatory effects at muscle endplate. Used to reverse neuromuscular bloackade.
Therapeutic: mysthenia gravis, reversal of non-depolarizing neuromuscular blockade.
Toxicity: muscarinic and nicotinic excess stim. muscle weakness.
Contraindication: GI obstruction
Edrophonium
Reversible cholinesterase inhibitor
Activates NM receptors directly at the NMJ.
Rapid onset, short duration of action
Rx: diagnosis of mysthenia gravis. differential diagnosis between myasthenia gravis and a cholinergic chrisis (excess Ach) due to cholinesterase toxicity. Excess cholinesterase inhibition can cause muscle weakness and present like myesthenia gravis. (symptoms get better if it is myesthenia gravis, worse if it is cholinergic crisis).
Side effects: bradycardia, cardiac standstill.
Contraindication: intestinal bloackade, urinary blockade (increases motility and can cause damage)
Phyostigmine
Reversible cholinesterase inhibitor
Increases Ach at nicotinic and muscarinic receptors
Crosses BBB
lasts for 2 hours
Rx: antidote for muscarinic antagonist poisoning. counteracts delirium with excess anticholinergic activity. glaucoma
Toxicity: convulsions, respiratory and CV depression.
Contraindications: Asthma, CV disease, GI obstruction.
Donepezil
Reversible cholinesterase inhibitor in the CNS
Rx: Alzheimer’s disease (cholinergic nerves involved in memory function)
long half life
Organophosphates
Irreversible inhibitors of cholinesterase. Phosphrylate the esteratic site so it becomes a stable compound.
Recovery depends on synthesis of new AchE molecules.
Sweating, lacrimation, miosis, blurred vision, accomidative spasm. Increased urinary freuncy, incontinence. Increased bronchial secreations, bronchoconstriction, paralysis of of respiratory muscles. Salivation, gastric distress, bradycardia, tremor.
Echothiophate
Irreversivle AchE inhibitor
Organophosphate used clinically to produce long term miosis in open angle glaucoma.
causes miosis and accomidative spasm, may caused blurred vision.
Muscarinic antagonists
Block muscarinic receptors. Block parasympathetic function and sympathetic cholinergic activity. can also block nicotinic cholinergic receptors at autonomic ganglia at high doses
is reversible but can persist for hours or days.
Atropine
Muscarinic antagonist, crosses BBB
Rx: organophosphate poisoning, increased secretions during surgery. Induction of mydriasis and cycloplegia (paralysis of cilliary muscle in optho); reduce urgency and frequency of peeing; relieve hyper molbility of the colon and; hypertonicity of the small intestines; reverse; bradycardia of vagal origin; decrease airway secretions.
Toxicity: increased body temp (due to decreased sweating) rapid pulse, dry mouth, dry flushed skin, cycloplegia, constipation, disorientaiton, can cause acute angle glaucoma in the elderlym urinary retention in men with BPH.
hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter, the bowels lose their tone, and the heart runs alone. treated with physostigmine
*Jimson weed*
Scolpolamine
Muscarinic antagonist
Rx: nausea and vomiting associated with motion sickeness or chemo. antisalivary during surgery
Toxicity: increased body temp (due to decreased sweating) rapid pulse, dry mouth, dry flushed skin, cycloplegia, constipation, disorientaiton, can cause acute angle glaucoma in the elderlym urinary retention in men with BPH.
hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter, the bowels lose their tone and the heart runs alone.
Glycopyrrolate
Quaternary nitrogen muscarinic antagonist, can’t cross BBB
Rx: used to protect against excessive muscarinic effects of cholinesterase inhibitors during reversal or neuromuscular bloackade. Prevents overstimulation of gut. antisalilagogue
Toxicity: can cause heat stroke due to no sweating.
Pralidoxamine (2PAM)
Peripheral AchE reactivator
Rx: respiratory muscel weakness in organophosphate poisoning
