Cholinergic Agonists and Antagonists

Question 1

Muscarinic Receptors

Answer 1

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

Question 2

M1

Answer 2

increases IP3, DAG, and Ca

activates myenteric plexus

Question 3

M2

Answer 3

Opens K+ channels: Decreases HR and contraction, decreased CO

Decreased cAMP and Ca- inhibits NE release from sympathetic nerve temrinals

Question 4

M3

Answer 4

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.

Question 5

Nicotinic receptors

Answer 5

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 (N_n) and membranes of SKm (N_M).

Question 6

Nicotine

Answer 6

selective for N_N receptor in the CNS.

Used to minimize wihdrawal symptoms durign smoking cessation

Side effects: irritation at site of administration, dyspepsia

Question 7

Succinyl Choline

Answer 7

blocks the N_M 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.

Question 8

Acetylcholine

Answer 8

Prototype compound.

binds toboth nicotinic and muscarinic receptors of autonomic nervous system, CNS, NMJ.

Rapidly hydrolyzed by AchE

no therapeutic use

Question 9

methacholine

Answer 9

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)

Question 10

Carbachol

Answer 10

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.

Question 11

Bethanachol

Answer 11

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.

Question 12

Muscarine

Answer 12

Prototype

quaternary amine

muscarinic activity, resistant to hydrolysis

Toxicity: mushroom poisonin causes excessive muscarinic activation.

Treat with atropine

Question 13

Pilocarpine

Answer 13

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.

Question 14

Acetylcholinesterase

Butrylcholinesterase

Answer 14

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*

Question 15

Neostigmine

Answer 15

Reversible cholinesterase inhibitor

quaternary nitrogen so can’t cross BBB

Direct stimulation of N_M 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

Question 16

Edrophonium

Answer 16

Reversible cholinesterase inhibitor

Activates N_M 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)

Question 17

Phyostigmine

Answer 17

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.

Question 18

Donepezil

Answer 18

Reversible cholinesterase inhibitor in the CNS

Rx: Alzheimer’s disease (cholinergic nerves involved in memory function)

long half life

Question 19

Organophosphates

Answer 19

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.

Question 20

Echothiophate

Answer 20

Irreversivle AchE inhibitor

Organophosphate used clinically to produce long term miosis in open angle glaucoma.

causes miosis and accomidative spasm, may caused blurred vision.

Question 21

Muscarinic antagonists

Answer 21

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.

Question 22

Atropine

Answer 22

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*

Question 23

Scolpolamine

Answer 23

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.

Question 24

Glycopyrrolate

Answer 24

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.

Question 25

Pralidoxamine (2PAM)

Answer 25

Peripheral AchE reactivator

Rx: respiratory muscel weakness in organophosphate poisoning