Cholinergic agonists

[SH4:p263-264]

• ACh has no therapeutic application because of its rapid hydrolysis and non-specific site of action
• Synthetic cholinergic agonist drugs
  * Primarily activate muscarinic receptors which are innervated by postganglionic parasympathetic nerves
  * Also act on autonomic ganglia and on cells with cholinergic (nicotinic) receptors
  * Blocked by atropine

Synethetic cholinergic agonists

Synthetic ACh-derivatives with clinical applications are:

• Methacholine
• Carbachol
• Bethanechol

Side effects

Can exacerbate

• Asthma (Bronchoconstriction)
• Coronary artery disease (Vasodilation causing decrease in diastolic BP)
• Peptic ulcer disease (Increased gastric acid secretion)

Methacholine

• Slower hydrolysis by AChE
  --> Longer duration of action than ACh
• Almost totally resistant to plasma cholinesterase
• Greater receptor selectivity than ACh
  * Predominant muscarinic action
  * Lack of significant nicotinic action
• Rarely used clinically due to unpredictable muscarinic effect (especially CVS effects)

Carbachol and bethanechol

• Toally resistant to hydrolysis by AChE or plasma cholinesterase
• Bethanechol more selective (muscarinic)
• Carbachol has more significant nicotinic activity
  * Especially on autonomic ganglia

Side effects

• Both carbachol and bethanechol
  * CVS effects not very prominent
  * More prominent effects on GIT and urinary tract
• GIT effects include:
  * Increased lower oesophageal sphincter tone
  * Increased peristalsis
  * Enhanced secretion
  * N&V
  * Spontaneous defaecation
• Urinary effects include:
  * Stimulation of urethral peristalsis
  * Contraction of detrusor muscle
  * Trigone and external sphincter relaxation

Clinical use

• Bethanechol is used as stimulant of smooth muscles of GIT and urinary bladder (e.g. neurogenic bladder)
• Carbachol is not used for its action on GIT or urinary bladder
  * Due to relatively greater effects at autonomic ganglia
• Carbachol is used as a topical drug on eyes
  * Chronic treatment of narrow-angle glaucoma
  * Produce miosis during intraocular surgery

Cholinomimetic alkaloids

Cholinomimetic alkaloids derived from plants include:

• Pilocarpine
• Muscarine
• Arecoline

Pilocarine

• Dominant muscarinic effects
• Sweat glands are particularly sensitive to pilocarine
• Clinically used
  * As a topic agent (on eyes) --> For treatment of glaucoma
  * As oral agent --> Treatment of xerostomia (associated with Sjogren syndrome or radiation therapy)
• Pilocarine, used as a topical agent on eyes, causes:
  * Miosys (persists for several hours)
  * Paralysis of ciliary muscles, with loss of accommodation (cycloplegia) (usually recovers within 2 hours)
  * Sustained decrease in intraocular pressure

NB:

• Xerostomia = Dry mouth

Muscarine

• Almost only act exclusively at muscarinic cholinergic receptors