Lecture Note_Cholinergic Agonists PDF

Cholinergic Agonists Parasympathomimetic agents Learning outcomes Understand the major groups of cholinergic drugs, and their mechanism of action. Understand how do direct-acting and indirect-acting cholinergic agonists influence the activity of the parasympathetic nervous system. Under...

Cholinergic Agonists Parasympathomimetic agents Learning outcomes Understand the major groups of cholinergic drugs, and their mechanism of action. Understand how do direct-acting and indirect-acting cholinergic agonists influence the activity of the parasympathetic nervous system. Understand the therapeutic applications of cholinergic drugs, and the most significant risks associated with their use?  The major groups of cholinoceptor-activating drugs, receptors & target tissues Pendang-river Physostigmine Bmac-PiN Pyridostigmine Edrophonium Neostigmine Pilocarpine Donepezil muscarine Ambenonium Neostigmine Galantamine Rivastigmine Ach, Echothiophate methacholine, cevimeline, carbachol, Echo bethanechol Direct acting cholinomimetics Clinically used cholinergic agonists Choline esters: Bethanecol Carbachol Cevimeline Methacholine (diagnostic tool) Alkaloids ________________ Clinically used cholinergic agonists Choline esters: Ach (cannot be used clinically) Why? Bethanecol Carbachol Cevimeline Methacholine (diagnostic tool) Alkaloids Pilocarpine Clinically used cholinergic agonists Choline esters: Bethanecol Carbachol Cevimeline Methacholine (diagnostic tool) Alkaloids Pilocarpine Bethanechol Bethanecol Synthetic ______________ Selective of GIT, urinary bladder Longer duration of act than Ach and more resistant to cholinesterase Cannot cross BBB Clinical applications Treatment of paralytic ileus (following surgery) MOA: activates mAChR stimulates gastric motility, increases gastric tone restores impaired rhythmic peristalsis. Treatment of non-obstructive urinary retention MOA: stimulates muscarinic acetylcholine receptors increases the tone of the detrusor urinae muscle contraction sufficiently  micturition & empty the bladder. Bethanecol Synthetic ester Selective of GIT, urinary bladder Longer duration of act than Ach Cannot cross BBB Clinical applications Treatment of paralytic ileus MOA: activates mAChR stimulates gastric motility, increases gastric tone restores impaired rhythmic peristalsis. Treatment of non-obstructive urinary retention MOA: stimulates muscarinic acetylcholine receptors increases the tone of the detrusor urinae muscle contraction sufficiently  micturition & empty the bladder. Paralytic ileus Obstruction of intestine due to __________ of intestinal muscle Causes: Abdominal surgery Certain drugs Spinal injuries Inflammation within abdomen Disease of intestinal muscle Bethanecol Synthetic ester Selective of GIT, urinary bladder Longer duration of act than Ach Cannot cross BBB Clinical applications Treatment of paralytic ileus MOA: activates mAChR (M3) __________ gastric motility, ________ gastric tone restores impaired rhythmic peristalsis. Treatment of non-obstructive urinary retention MOA: stimulates muscarinic acetylcholine receptors increases the tone of the detrusor urinae muscle contraction sufficiently  micturition & empty the bladder. Bethanechol Synthetic ester Selective of GIT, urinary bladder Longer duration of act than Ach Cannot cross BBB Clinical applications Treatment of paralytic ileus (following surgery) MOA: activates mAChR stimulates gastric motility, increases gastric tone restores impaired rhythmic peristalsis. Treatment of non-obstructive urinary retention (oral tablet) MOA: stimulates muscarinic acetylcholine receptors increases the tone of the detrusor urinae muscle contraction sufficiently  micturition & empty the bladder. Urinary retention __________ to completely empty the bladder Common in Acute postoperative & postpartum non-obstructive urinary retention neurogenic atony of the urinary bladder Bethanechol Synthetic ester Selective of GIT, urinary bladder Longer duration of act than Ach Cannot cross BBB Clinical applications Treatment of paralytic ileus (following surgery) MOA: activates mAChR stimulates gastric motility, increases gastric tone restores impaired rhythmic peristalsis. Treatment of non-obstructive urinary retention MOA: _____________ muscarinic acetylcholine receptors _____________ the tone of the detrusor urinae muscle contract sufficiently  micturition & empty the bladder. Pilocarpine Pilocarpine Plant alkaloid Target: eye, exocrine glands (mainly M3) Can cross BBB Clinical applications ____________ (xerostomia) due to radiotherapy for cancer of head and neck OR due to Sjӧgrens syndrome (Oral use- tablet) Glaucoma (eyedrop) Pilocarpine Plant alkaloid Target: eye, exocrine glands (mainly M3) Can cross BBB Clinical applications _____________ (xerostomia) due to radiotherapy for cancer of head and neck OR due to Sjӧgrens syndrome (Oral use- tablet) Glaucoma (eyedrop) Sjӧgrens syndrome Autoimmune disorder Attacks lacrimal glands and salivary glands Primary features: Dry eyes Dry mouth Pilocarpine Plant alkaloid Target: eye, exocrine glands (mainly M3) Can cross BBB Clinical applications Dry mouth (xerostomia) due to radiotherapy for cancer of head and neck OR due to Sjӧgrens syndrome (Oral use- tablet) MOA: stimulate salivary secretions Glaucoma (eyedrop) Pilocarpine Plant alkaloid Target: eye, exocrine glands (mainly M3) Can cross BBB Clinical applications Dry mouth (xerostomia) due to radiotherapy for cancer of head and neck OR due to Sjӧgrens syndrome (Oral use- tablet) Glaucoma (given as eyedrop) In the healthy eye: Aq. Humour is secreted by the ciliary body. Normal intraocular pressure is maintained by removing aq humour continuously via drainage into the canal of schlemm In glaucoma: Drainage might be compromised due to blockade of canal of schlemm increased intraocular pressure glaucoma Pilocarpine Clinical applications Dry mouth (xerostomia) due to radiotherapy for cancer of head and neck OR due to Sjӧgrens syndrome (Oral use- tablet) Glaucoma (as eyedrop) MOA: acts on ____ receptor contraction of the iris sphincter muscle, producing a small pupil diameter (miosis) & contraction of the ciliary muscle (opens the trabecular network) facilitate outflow of aqueous humor through the canal of Schlemm. Cevimeline Cevimeline More selective muscarinic agonist predominantly affecting M3 receptors (exocrine glands) Clinical application treatment of symptoms of dry mouth in patients with Sjögren's Syndrome Carbachol Carbachol Clinical indications: Miotic agent Glaucoma Muscarinic Agonist: Adverse Effects Salivation Lacrimation Urination Diaphoresis GI effects Emesis Overdosage Miosis Bradycardia Arrhythmia Hypotension Broncoconstriction  DRUG Receptor Selectivity Clinical Use Pharmacokinetic Additional Target Properties Information Acetylcholine Muscarinic, None None Rapid metabolism Nicotinic Low absorption & distribution Alkaloid Pilocarpine Muscarinic Eye, Glaucoma Not metabolised Has CNS (M3) exocrine Xerostomia by cholinesterase effect gland Can cross BBB Bethanechol Muscarinic GIT, Urinary Paralytic Not metabolised Given Bladder ileus by cholinesterase orally/ SC Urinary Cannot cross BBB retention Carbachol Muscarinic, Eye, GIT, Glaucoma Not metabolised Given Choline Nicotinic Urinary by cholinesterase orally/ SC Esters Bladder Cevimeline Muscarinic Exocrine Dry mouth Not metabolised (M3) glands ass with by cholinesterase Sjogren’s Cannot cross BBB syndrome Indirect acting cholinomimetics (Anticholinesterases) X Reversible Anticholinesterase Pharmacological effects: All anticholinesterases have muscarinic and nicotinic actions Only _________ SOLUBLE drugs have CNS EFFECTS i.e. excitation, convulsion, respiratory failure, coma E.g. physostigmine & phosphate ester (EXCEPT echothiophate) Clinical Uses Myasthenia gravis Reversal of non-depolarising neuromuscular blockers Anticholinergic toxicity Urinary retention Glaucoma Alzheimer’s disease Myasthenia gravis Myasthenia gravis Reversal of non-depolaring neuromuscular blockers Anticholinergic toxicity Alzheimer’s disease  DRUG ADMINISTRATIO PHARMACOKINETIC CLINICAL USES N PROP Short action Edrophonium NOT 5- 15 mins Diagnosis of absorbed Polar Myasthenia orally (given gravis by injection) Neostigmine Can be used 0.5- 2 hrs Myasthenia orally but Polar gravis POOR Prominent action on GI Paralytic ileus absorption & urinary tract Urinary retention Competitive neuromuscula Intermediate r blocker acting intoxication Physostigmine Good oral 0.5 – 2 hrs Glaucoma absorption NON-POLAR, LIPID Atropine Can be used SOLUBLE toxicity topically in the eye Pyridostigmine 3-6 hrs Myasthenia Polar gravis Irreversible Anticholinesterase Irreversible Anticholinesterases Therapeutic: Echothiophate glaucoma Nerve Agents: Tabun, Sarin, Soman, VX Organophosphate insecticide All are highly lipid soluble EXCEPT echothiophate Well absorbed from skin, lung, gut & conjunctiva MOA Binds to ______________ by strong covalent bond hydrolysis by AChE very slow long duration of action “Aging” makes bond extremely stable Organophosphate: Clinical Use Glaucoma Organophosphate: Weapon of Mass Destruction Nerve Agents: Tabun, Sarin, Soman, VX Symptoms can appear within seconds after exposure to the vapor form of sarin, or within a few minutes to up to 18 hours after exposure to the liquid form Organophosphate: Weapon of Mass Destruction Nerve Agents: Tabun, Sarin, Soman, VX Symptoms can appear within seconds after exposure to the vapor form of sarin, or within a few minutes to up to 18 hours after exposure to the liquid form Symptoms of organophosphate toxicity Severe bradycardia, hypotension Bronchospasm Increased GI motility Cramps & diarrhea CNS Effects Convulsion, coma, respiratory failure Initial twitching of skeletal muscles progressing to muscle weakness & paralysis Treatment of organophosphate toxicity Atropine Cholinesterase reactivators MOA: MOA: Muscarinic antagonist Regeneration (reactivation) of recently inhibited cholinesterase Block muscarinic actions and enzyme, if given before ageing CNS effects  Organophosphate aging and the effect of pralidoxime to regenerate acetylcholinesterase