EX1 Muscarinic agonists/antagonists

Muscarinic agonists

Bethanechol
Pilocarpine
Cevimeline

Cholinesterase inhibitors

Reversible inhibitors

Physostigmine

Neostigmine

Pyridostigmine

Donepezil

Cholinesterase inhibitors

Irreversible Inhibitors

Organophosphate insecticides

Malathion

Parathion

Cholinesterase inhibitors

Irreversible Inhibitors

Nerve agents

Sarin

VX

Cholinesterase reactivators

Pralidoxime

Agents that block acetylcholine release

Botulinum toxin

Muscarinic antagonists

Atropine

Scopolamine

Dicyclomine

Ipratropium

Tolterodine

Tropicamide

Direct acting muscarinic agonists physiological effects

 Increased GI motility and secretion

 Decreased heart rate

 Decreased blood pressure

 Decreased cardiac output

 Direct vasodilation

 Contraction of bladder and relaxation of urinary sphincters

 Miosis and decreased intraocular pressure

 Stimulation of secretions

bethanechol

muscarinic agonists

 Analog of acetylcholine that is resistant to rapid hydrolysis

 Direct muscarinic agonist with little effect at nicotinic receptors

 Used to stimulate GI motility and treat urinary retention

pilocarpine

muscarinic agonists

Used in the treatment of glaucoma and xerostomia due to poor salivary secretion

(not first line for glaucoma)

cevimeline

muscarinic agonists

Used in the treatment of xerostomia due to poor salivary secretion

ADR of muscarinic agonists

Mainly the result of unwanted or excessive muscarinic stimulation

 Hypotension

 Bradycardia

 Bronchoconstriction

 Diarrhea

 Cramping

 Urinary incontinence

 Excessive sweating

 Salivation

Contraindications of muscarinic agonists

Asthma, cardiovascular issues, peptic ulcer disease, weakened smooth muscle, urinary/intestinal obstruction

Acetylcholine receptor pharmacology graphs

Cholinesterase inhibitors physiological effects

same as muscarinic agonists

with exception of skeletal muscle (effective doses) /paralysis of skeletal muscle (toxically high doses)

Cholinesterase inhibitor adverse effects

SLUDGE (salivation, lacrimation, urination, defecation, GI distress, emesis)

Cholinesterase inhibitor contraindications

same as muscarinic agonists

Neostigmine and pyridostigmine

 Reversible cholinesterase inhibitors

 Quaternary ammonium compounds that don't enter the CNS

Uses:

 Treatment of myasthenia gravis (both are longer acting)

 Neostigmine is used to treat paralytic ileus and atony of the bladder

 Pyridostigmine is also used by the military to protect troops against nerve agents used in chemical warfare

Donepezil

 Reversible cholinesterase inhibitor

 Nonquaternary, so it can get into the CNS

 Used in the treatment of mild to moderate Alzheimer disease

Physostigmine

 Reversible cholinesterase inhibitor

 Nonquaternary, so it can get into the CNS

 Used in treating poisoning with atropine or other antimuscarinic agents

Organophosphate insecticides (parathion, malathion)

irreversible inhibitor

Parathion and malathion must be oxidized to active metabolites (paroxone and malaoxone)

 The conversion occurs more rapidly in insects than humans.

 In addition, most insects can not easily detoxify these metabolites

 Basis for selective toxicity as an insecticide

 However, they still can cause toxic effects in humans

 Some agents (especially parathion) can be absorbed through the skin

 Signs and symptoms of poisoning are typical of cholinesterase inhibitors

 Treat poisoning with atropine, pralidoxime, and other symptomatic support

Nerve Gases (sarin, VX)

 Very potent and toxic, irreversible cholinesterase inhibitors

 Just a few droplets of sarin can kill an adult

 Signs and symptoms are typical for cholinesterase inhibitors

 Treat poisoning with atropine and pralidoxime

Pralidoxime/2-PAM

Cholinesterase reactivator

 It chemically binds to the phosphate group that inhibits the enzyme and thereby regenerates the enzyme

 Antidote for organophosphate poisoning

 It must be used within 2 hours following exposure because the phosphorylated enzyme changes to a form that can not be regenerated

Muscarinic antagonists physiological effects

opposite of parasympathetic nervous system

thus drying secretions, decreasing motility of GI tract, relax bladder, bronchodilation, increased HR

Muscarinic antagonists therapeutic uses

Treatment of GI disorders

Urinary incontinence

Mydriatic agent (not in glaucoma patients)

Antidote for poisoning with choleinesterase inhibitors

cardiac stimulation

prevention of motion sickness

Muscarinic antagonists adr

dry mouth, skin, constipation, urine retention, blurred vision, sedation, confusion, amnesia

Muscarinic antagonists contraindications

glaucoma, prostatic hypertropy, cardiovascular instability, ulcerative colitis

muscarinic antagonists acute poisoning/treatment

anticholinergic syndrome

physostigmine or other cholinesterase inhibitors

Atropine

Muscarinic antagonists

 Prototypical antimuscarinic agent

Clinical uses:

 Bradycardia

 Inhibition of salivation and secretions (preanesthesia)

 Organophosphate or nerve agent poisoning

Scopolamine

Muscarinic antagonists

 Chemically similar to atropine

Clinical use:

 Transdermal patch (Transderm Scop) is used for the prevention of motion-sickness and vertigo

Dicyclomine

muscarinic antagonist

 Nonquaternary

 Widely used as an intestinal antispasmodic for the treatment of irritable bowel syndrome

Ipratropium

muscarinic antagonist

 Quaternary salt

 Administered by inhalation for the treatment of asthma and COPD

 Fewer systemic effects

Tolterodine

muscarinic antagonist

 Used to treat urinary incontinence

Tropicamide

muscarinic antagonist

 Widely used to dilate the pupil for ophthalmologic examination