Pharmacology of Cholinergic Agonists

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Pharmacology of Cholinergic Agonists
Dr. Thomas Abraham PHAR 417 Fall 2005
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Cholinergic Agonists

• Parasympathomimetic, cholinoceptor agonists.
• Have predominant actions on
• autonomic effector organs innervated by
  postganglionic parasympathetic nerves.
• cells containing cholinergic receptors.
• Cholinergic agonists primarily divided into
• acetylcholine and synthetic choline esters
• cholinomimetic natural alkaloids and analogs
• Cholinergic agonists also activate Nicotinic
  receptors found in the ganglia, neuromuscular
  junction and CNS

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Cholinergic Agonists
ACETYLCHOLINE AND CHOLINE ESTERS

• Ø      ACETYLCHOLINE
• endogenous neurotransmitter no selectivity for
  muscarinic vs. nicotinic receptors
•  
• rapid metabolism by acetylcholinesterase,
  butyrylcholinesterase short half-life
•  
• limited therapeutic or diagnostic value
•  

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Cholinergic Agonists

•  
• Ø      DERIVATIVES OF CHOLINE ESTERS
• resistant to AChE metabolism.

Susceptibility to cholinesterase
metabolism Acetylcholine gtgtgt Methacholine gtgt
Carbachol gt Bethanechol

• mainly muscarinic receptor agonists but
  Carbachol has significant nicotinic receptor
  activity.

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Cholinergic Agonists

• Ø      Activation of specific muscarinic
  receptors in various organs elicits physiological
  response
• Decreased heart rate (negative chronotropy),
  decreased conduction velocity, decreased atrial
  contractility (negative inotropy).
• Vasodilation of arteries and arterioles
  indirectly by the release of
• nitric oxide from endothelial cells.
• 3. Gastrointestinal increased intestinal
  smooth muscle contraction,
• motility relaxation of sphincters, nausea,
  flatulence, defecation.
• 4. Urinary tract increased detrusor muscle
  contraction, decreased
• trigone, sphincter muscle tone, decreased
  bladder volume.
•  
• 5.     Increased bronchial constriction,
  increased salivation, lacrimation,
• miosis, increased accommodation for near
  vision.

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Cholinergic Agonists
Vasodilation of arteries by Muscarinic Agonists
Endothelium
Vascular Sm. Muscle

• These experiments show that endothelial cells
  on arteries and veins contain muscarinic
  receptors which when activated would lead to
  relaxation of vascular smooth muscle and
  vasodilation.

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Cholinergic Agonists
Vasodilation of arteries by Muscarinic Agonists
Notice that Acetylcholine injection into this
experimental animal results in decreased BP
(blue) and heart rate (HR) but these effects
dont last long.
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Cholinergic Agonists

• Multiple muscarinic receptors regulate the
  various physiological effects of endogenous
  acetylcholine or synthetic analogs

M1 receptor M2 receptor M3 receptor M4 receptor
G-protein coupling Gq/11 Gi/o Gq/11 Gi/o
Second Messenger System Activation of PLC Ca2, PKC Inhibition of adenylate cyclase, K current activation Activation of PLC Ca2, PKC Inhibition of adenylate cyclase, K current activation
Receptor location Brain, sypm. ganglia, Glands, Smooth Muscle Heart, Brain, Autonomic Nerve endings Brain, sypm. ganglia, Glands, Smooth Muscle Brain
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Cholinergic Agonists

• Signal transduction systems of Muscarinic
  receptors
• Coupling of muscarinic receptors to
  phosphoinositide hydrolysis
• results in initiating various
  calcium-dependent processes e.g. smooth muscle
  contraction, secretion of saliva, mucous, release
  of digestive enzymes, etc

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Cholinergic Agonists
II. Coupling of muscarinic receptors to
effectors via Go/i
M2 receptor activation results in decreased heart
rate and decreased neurotransmitter release from
cholinergic nerves.
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Cholinergic Agonists

• Therapeutic Uses of Choline esters
• To produce miosis during ocular surgery and
  decrease intraocular pressure acetylcholine
  (Miochol), carbachol (Isopto Carbachol).
•   
• Airway hyperactivity test methacholine
  (Provocholine).
•   
• Urinary incontinence and increase GI motility
  bethanechol (Urecholine).
• Cautions and contraindications
•  
• Use with caution in patients with asthma,
  hyperthyroidism, coronary insufficiency, peptic
  ulcer disease.
•  
•   
• Toxicity evidenced by hypotension, bradycardia,
  GI cramps, belching, lack of visual
  accommodation, headaches, salivation.

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Cholinergic Agonists
CHOLINOMIMETIC NATURAL ALKALOIDS

•  Ø      More selective for muscarinic vs.
  nicotinic receptors.
•  
• Muscarine from amanita, inocybe, clitocybe
  sp. of mushrooms pilocarpine from
  pilocarpus plant arecholine from betel nut.

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Cholinergic Agonists
Mushrooms of Amanita species contain muscarine,
which if ingested can cause intoxication
There are many old mushroom pickers and many
bold mushroom pickers but there are no old, bold
mushroom pickers
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Cholinergic Agonists

• Ø      Systemic administration produces less
  selective muscarinic effects than
• local application
• Cardiovascular system small doses of muscarine
  (i.v.) decrease heart rate and blood pressure
  while pilocarpine can have direct muscarinic
  effects and indirect (ganglionic) effects.
• Smooth muscle effects pupillary constriction by
  pilocarpine (miosis), initial increase followed
  by decreased intraocular pressure, decreased
  accommodation of lens (for far vision) muscarine
  increases bronchial and GI muscle contraction
  while muscarine and pilocarpine promote
  urination.
• Exocrine glands muscarine and pilocarpine
  result in sweating,
• nausea, vomiting, salivation, lacrimation.
• Ø      Therapeutic uses of pilocarpine for the
  reduction of intraocular pressure
• in open-angle glaucoma supplied as ophthalmic
  solution and sustained release delivery system
  (Occusert Pilo-20).

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Cholinergic Agonists
Drainage of Aqueous Humor through the Eye
Closed angle
Aqueous humor is produced by the ciliary body to
maintain shape of the eyeball. Poor drainage
through the canal of Schlemm results in elevated
intraocular pressure.
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Cholinergic Agonists
Drainage of Aqueous Humor through the Eye
Closed angle
Muscarinic agonists cause contraction of the
ciliary muscles to relax the trabecular network
to allow more fluid movement through the
canal. Increasing the thickness of the lens also
allows for more movement of aqueous fluid to the
anterior chamber. Constriction of the sphincter
muscles of the iris also allows proper fluid
drainage by pulling away the iris from the
closed angle.