PHA316 Cholinergic Transmission Cholinergic agonists and anticholinergics 2024 PDF

CHOLINERGIC TRANSMISSION - OBJECTIVES Describe synthesis and release of Ach as part of ANS Describe different types of cholinergic receptors and their function Explain underlying mechanisms for how drugs affect cholinergic transmission Categorize the different drugs affecting the cholinerg...

CHOLINERGIC TRANSMISSION - OBJECTIVES Describe synthesis and release of Ach as part of ANS Describe different types of cholinergic receptors and their function Explain underlying mechanisms for how drugs affect cholinergic transmission Categorize the different drugs affecting the cholinergic system into cholinergic or anticholinergic effects and predict their likely pharmacological effects, indications, dosing and adverse effects Describe pharmacodynamic differences between direct acting and indirect acting cholinergic agonists as well as differences within the classes Categorize the different drugs affecting the cholinergic system into cholinergic or anticholinergic effects and predict their likely pharmacological effects, indications, dosing and adverse effects Predict their likely pharmacological effects and adverse effects Describe the clinical uses of cholinomimetic agonists Overview Cholinergic Nervous System Mainly the “rest and digest” part of the PNS Primary neurotransmitter = Ach – Neurotransmitter is a substance present in neuron and is secreted by neurons to transmit signals to its postsynaptic targets Action of neurotransmitter mediated by different receptors depending on location  Overview Cholinergic System – Physiology of Ach transmission Ach synthesis (choline, choline acetylation by Cacetyltransferase) – Ach packaging facilitated by carrier mediated transporter Ach release via Ca2+ facilitated exocytosis Ach receptor interactions: – Ach at neuromuscular junction – Nicotinic receptor mediated to initiate action potential on muscle fiber – Ach at ganglia (fast cholinergic synapses) Ach at muscarinic receptors – Slower transmission – May also act as modulator Ach hydrolysis by acetylcholinesterase at fast cholinergic synapse Choline reuptake by transporter Presynaptic and postsynaptic modulation Figure 14.2 Events and sites of drug action at nicotinic cholinergic synapses Illustration cholinergic synthesis and release  Cholinergic System – Cholinergic Receptors and distribution along neuronal pathway Nicotinic actions of Ach. Receptor found in – All autonomic ganglia – Neuromuscular junction of voluntary muscles – Secretion of adrenaline from adrenal medulla Muscarinic actions of Ach – Found in the neuroeffector junction – Closely resemble parasympathetic activity – see table 13.1 Exceptions – Why ACh causes vasodilation even though most blood vessels do not have parasympathetic innervation - This is an indirect effect: ACh (like many other mediators) acts on vascular endothelial cells to release nitric oxide – Ach and secretion from sweat glands (sympathetic) Cholinergic System – Receptors and Nicotinic effect of Ach Nicotinic - types as follows – Stimulation at autonomic ganglion = stimulation of both sympathetic and parasympathetic – Stimulation of neuro muscular junction of somatic = contraction of skeletal muscles – CNS = Stimulatory in low doses but inhibitory in high doses Cholinergic System: Receptors and Muscarinic effect of Ach Types of Muscarinic receptors – Subtypes M1-M5 (see Gq and Gi coupling for the different subtypes) Contraction of all smooth muscles e.g bronchi, GIT, urinary bladder Relaxation of all sphincter e.g. urinary, rectal Increase in secretion e.g. sweat, salivary, lachrymal, gastric and intestinal Exceptions: Why ACh causes vasodilation even though most blood vessels do not have parasympathetic innervation - This is an indirect effect: ACh (like many other mediators) acts on vascular endothelial cells to release nitric oxide  Dale’s experiment showing that (ACh) produces two kinds of effect on the cat’s blood pressure - Exercise Explain why the BP decreased in A and B – Which Ach receptors mediate this response? After atropine, the same dose of ACh has no effect. Explain why Still under the influence of atropine, a much larger dose of ACh causes a rise in blood pressure – explain why. Which receptors mediate this response?  Exercise Use Table 14.2: Muscarinic receptor subtypes What muscarinic receptor subtypes are found in each of the following locations? the effect of cholinergic activation on each of the following – Smooth muscle of the GIT? – Smooth muscles of the eye? – Smooth muscles of the bladder? – Smooth muscles of the airways? – Blood vessels endothelium? – Salivary glands? – Cardiac muscle? What is the effect of cholinergic stimulation of each of the following – Heart rate? – Blood vessels? – GIT motility? – Gastric secretions? – Micturition? – eye  Effects Of Drugs On Cholinergic Transmission Drugs can influence cholinergic transmission either: by acting on postsynaptic ACh receptors as agonists or antagonists or by affecting the release or destruction of endogenous ACh. EFFECTS OF DRUGS ON CHOLINERGIC TRANSMISSION – ILLUSTRATION- Drug classes Direct Acting Indirect Acting Cholinergic Reversible Agonist Agonists Indirect Acting Irreversible Cholinergic Agonists Drugs Muscarinic Antagonists Cholinergic Ganglionic Antagonist Blockers Neuromuscular blockers  Cholinergic agonists Direct acting e.g. Bethanechol, Pilocarpine – Acts directly on the cholinergic receptors Indirect acting – Acetyl cholinesterase inhibitors (AChE inhibitors): Bind to AChE → ↑↑ Ach in synaptic cleft and nerve endings → ↑↑ Ach Activity. Enhanced cholinergic transmission at autonomic synapses and at the neuromuscular junction – Reversible e.g - neostigmine, pyridostigmine, physostigmine) – Irreversible AChE inhibitors e.g. organophosphate pesticides,  Therapeutic use Cholinergic agonists – Direct acting parasympathomimetics Pilocarpine for glaucoma – Clinical Use – Open angle glaucoma. primary close angle glaucoma pending surgery. Q4-8 hrs. Not first choice. – Mechanism of action – produces contraction of the ciliary muscles thereby improving drainage of aqueous humour. This reduces intra-ocular pressure – Dosage forms – eye drops, ophthalmic gel – Why local activity? – ADR/Caution/limitations –Headache, Induced Myopia in under 50, Reduced visual acuity in pts with cataract↑ Risk of retinal detachment in pts with retinal damage and, absorbed by melanin so pts with brown iris need higher conc.  Therapeutic use Cholinergic agonists – Direct acting parasympathomimetics Bethanechol for genito urinary disorders – M of A – parasympathetic activity on M3 receptors in the bladder. Receptor specificity for muscarinic – List from table – Clinical Use – Limited, Post operative, post partum functional urinary retention, neurogenic atony of the bladder, to stimulate bladder emptying, – Dosage form – Oral for systemic effect – ADR/Interactions: ADR/Interactions: Abdominal cramps, Diarrhea, Urinary urgency, Sweating (Explain the underlying mechanisms for the listed ADRs). – Contraindications – Asthma, PUD. why would bethanecol be contraindicated in asthmatic patients?  Therapeutic use Cholinergic agonists – Direct acting parasympathomimetics: exercise Bethanechol for genito urinary disorders – What effects do you think bethanechol is likely to have on the GIT? Explain your answer  Therapeutic use Cholinergic agonists – Indirect acting parasympathomimetics Myasthenia Gravis e.g. Pyridostigmine, neostigmine. – Clinical Use: Symptomatic Tx for Myasthenia Gravis (autoimmune disorder due to reduced nicotinic receptors for Ach at neuromuscular junction). Abnormal fatigue of skeletal muscles – ADR: ADR mainly those associated with ↑↑parasympathetic stimulation. Also bladder and GIT stimulation(predict possible ADRs). Reversal of non-depolarising neuromuscular blockade (antidote) e.g. neostigmine – IV neostigmine to reverse effect of neuromuscular blockers (Muscle relaxants) in anaesthesia Dimentia e.g. donepezil, galantamine: for symptomatic treatment of mild to moderate dementia of Alzheimers disease Severe anticholinergic toxicity: e.g. Physostigmine for atropine OD. Poisoning due to Atropa belladonna, commonly known as belladonna or deadly nightshade, is a toxic perennial herbaceous plant - Physostigmine  Exercise Look up the mentioned cholinergic agents in the BEML (Botswana Essential Medicines List) and check for – Their classification according to the BEML – The listed formulations Cholinergic agonists: Adverse effects Bradycardia and cardiac arrest – due to cardiac depressant of Ach on muscarinic receptors Sweating and salivation – Diarrhoea, hyper motility Caution in patients with bronchial asthma: bronchospasm can result from contraction of smooth muscles due to effect of Ach on muscarinic receptors. Explain the underlying mechanism for each of the above ADR/SE  Cholinergic agonists: Poisoning associated with parasympathomimetics Muscarinic poisoning – muscarine a poison found in certain mushrooms is not degraded by acetylcholinesterase. Causes excessive stimulation of cholinergic system. Symptoms include abdominal cramps, diarrhea, increased secretions, bronchospasms, bradycardia, miosis. Suitable antidote is atropine. Organophosphate poisoning: e.g. malathion, parathion. They are irreversible cholinesterase inhibitors. Poisoning managed with resp support and atropine (competitive muscarinic antagonist)  Summary Cholinergic Agonists – Muscarinic Agonists Muscarinic agonists General (Ach) – Underlying mechanism – Direct acting – Effects on CV - ↓CO, ↓HR, ↓Force of contraction, vasodilation?(NO), ↓BP Smooth muscles – Contraction – GIT - Contraction, Increased motility – Bladder – increased muscle tone, sphincter relaxation – Bronchial - bronchoconstriction Sweating, lacrimation, salivation – ↑secretion Eye – pupil constriction – Receptor specificity(selectivity)- Importance thereof  Summary: General Pharmacy Consideration: All Parasympathomimetics All Parasympathomimetics – Be aware of adverse effects such as abdominal cramping, muscle cramping, excessive salivation – Advise patients to report N/V, diarrhea and any other adverse effects Direct acting – Blurred vision and advise accordingly – Orthostatic hypotension and advise accordingly Indirect acting – Advise Schedule meds around mealtime for optimal therapeutic effect – Advise pt on monitoring for muscle weakness (cholinergic crisis (overdose) or myesthenic crisis (underdose)  Exercise 1 – ACH Receptor Activity S Dale’s experiment Figure 14.1 Take home Explain the underlying receptor mechanism for the following observations ❖Bronchoconstriction observed after Ach administration ❖Vasodilation observed after 2mcg Ach administration and fall in Blood Pressure- ❖Bradycardia after 50mcg of Ach administration ❖No effect where 2mg of atropine is followed by 50mcg of Ach ❖Increased Blood Pressure where 2mg of Atropine is followed by 5mg of Ach – Tachycardia and not bradycardia following the above –  Cholinergic Transmission Continued: Anticholinergics Objectives a previously stated including Describe the effects of atropine on major organs (eye, heart, vessels, bronchi, GIT. Genitourinary, exocrine glands and skeletal muscle) List the signs, symptoms and treatment of atropine poisoning List the major clinical indications and contraindications for the use of muscarinic antagonists – List common antimuscarinic/anticholinergic agents used for mydriasis, cycloplegia, parkinsonism, PUD, asthma, Describe the autonomic effects of antiniconic agents Describe the use of cholinesterase regenerators Anticholinergics: Main 4 mechanisms of pharmacological block of Ach Inhibition of choline uptake Inhibition of choline release Block of post synaptic receptors or ion channels Persistent post synaptic depolarisation Categories of Anticholinergic Drugs and General Mechanism of Action (Muscarine and Nicotinic) Anticholinergics: Antimuscarinics –Examples (atropine, scopalomine, trihexyphenidyl) Anticholinergics: Antimuscarinics Reflection Where do they act? What is the difference between selective and non-selective anti-muscarinic agents? Focus here is on general principles detailed discussion/comparisons under system/condition specific pharmacology  Antimuscarinic Drugs – Effects - Exercise What do you expect to be the effect of atropine on – Secretions Salivary Sweat – GIT GIT spasms? Motility Secretion– – Smooth Muscles Bronchial – Urinary tract and associated symptoms? – CNS Excitatory and effect on extrapyrimidal effects for later CNS toxicity due to atropine can be reversed with physostigmine (antidote for atropine)  Antimuscarinic Drugs – Effects - Exercise What then do you expect to be the effect of atropine/anticholinergic agents in a: – Patient with Diarrhea? – Patient with constipation? Clinical indications for atropine see table Contraindications for atropine – See table  Anticholinergics Action by Organ/Tissue adapted from AMBOSS Muscarinic Receptors Organ/Tissue Action M1, M4, M5 Central nervous system Influences neurologic function (e.g., cognitive impairment) ↑ Heart rate M2 Heart Increases AV-node conduction → arrhythmias Gastrointestinal tract ↓ Intestinal peristalsis , ↓ Salivary and gastric secretions Urinary tract ↓ Bladder contraction (decreases detrusor muscle tone, increases the internal urethral sphincter tone) Airway Bronchodilation ↓ Bronchial secretions Eye (Dilation) Mydriasis → narrowing of the iridocorneal angle Impaired accommodation Smooth muscle Blood vessels: minimal effect on vascular tone and blood pressure M3 Exocrine glands ↓ Secretions (sweat  Clinical use of Muscarinic Antagonists Common Anticholinergic Drug Examples Adapted from AMBOSS Chemical characteristics Drug example Effect Indication First drug of choice in unstable ↑ Heart rate (symptomatic) sinus bradycardia (IV) Premedication: prior to intubation to decrease salivary, respiratory, and gastric secretions. Atropine ↓ Secretions of exocrine glands Note in lomotil. (prototype) ↓ Tone and motility of smooth muscles Ophthalmology: uveitis Tertiary Amines: Lipophilic (good oral bioavailability and CNS p Antidote enetration + absorption from ↓ Cholinergic overactivity in CNS for anticholinesterase poisoning conjunctival sac into the eye) Mydriasis and cycloplegia Scorpion stings, Scopolamine (hyos ↓ Vestibular disturbances cine) (antiemetic) Motion sickness Dicyclomine, propantheline GIT, GU Irritable bowel syndrome + Other? GU (↓urgency, incontinence, spasms). Note other Oxybutynin anticholinergics Overactive bladder, urinary urgency Trihexyphenidyl (benzhexol) CNS Effects Parkinson's disease  Clinical use of Muscarinic Antagonists Common Anticholinergic Drug Examples Adapted from AMBOSS Chemical characteristics Drug Effect Indication Site/M of A Antimuscarinics cause bronchodilation Ipratropium but also inhibit bromide mucociliary clearance therefore Quartenary accummulating Hydrophilic (poor mucus except oral bioavailabilit ipratropim y and CNS penetr Tiotropium bromide Longer bromide which ation) duration of does not have action that as side effect. Why minimal systemic COPD and bronchial anticholinergic  Antimuscarinic Drugs – Effects and Therapeutic Use - Summary Therapeutic use based on action in the different organs and tissues as well as action of different Muscarinic receptor subtypes (M1, M2, M3, M4, M5) – Emergency reversal of cholinergic toxicity/overdose e.g atropine – GIT disorders e.g. irritable bowel syndrome e.g dicyclomine, PUD GIT spasms Motility Secretion – Bronchial Smooth Muscles - asthma e.g. ipratropium bromide – Cardiac rhythm abnormalities – Ophthalmic disorders – to elicit dilation of pupil or cycloplegia e.g. cyclopentolate, homatropine, atropine, tropicamide – Pre-anesthesia to reduce excessive respiratory secretions – CNS Sedation Motion sickness e.g. scopolamine Muscle tremors associated with parkinson’s disease  Other Drugs with Anticholinergic properties Tricyclic antidepressants (predominantly amitriptyline, imipramine, and trimipramine) Antipsychotics (e.g.clozapine, quetiapine) First-generation antihistamines (e.g. promethazine, diphenhydramine)  Clinical features of anticholinergic overdose Clinical features of anticholinergic overdose Dry mouth, warm, flushed skin, thirst, tachycardia, arrhythmias, mydriasis, confusion, and agitation Possibly anticholinergic delirium: Excessive use of tricyclic antidepressants (or other medications with significant anticholinergic effects) can cause life-threatening delirium, hallucinations, and psychomotor symptoms.  Contraindications anticholinergic (antimuscarinic) use Caution Infants and risk of hyperthermia Elderly – BPH and urinary retention – Glaucoma – Myasthenia gravis  Anticholinergics (Antinicotinic) agents Historical clinical use and available rarely used. Varying mechanisms of action Effects on Physiological Function – See Paton’s description of a “hexamithonium man” See following 2 diagrams for examples Anticholinergics (Antinicotinic) agents Ganglionic Hexamethonium blockers Antinicotinic Botulinum toxin agent Neuromuscular Pancuronium blockers Suxamethonium  Botulism toxin Botulism toxin is a neurotoxin produced by the bacterium Clostridium botulinum. – Foodborne botulism ingested through improperly processed food in which the bacteria or the spores survive, then grow and produce the toxins. It is a rare but potentially fatal disease if not diagnosed rapidly and treated with antitoxin and intensive respiratory care. Early symptoms include marked fatigue, weakness and vertigo, usually followed by blurred vision, dry mouth and difficulty in swallowing and speaking. (Explain the symptoms based on your understanding of cholinergic pharmacology) The cosmetic form of botulinum toxin, sometimes referred to as "Botox" by patients, is an injectable to – manage and treat therapeutic and cosmetic purposes ILLUSTRATION Pharmacological agents affecting CHOLINERGIC TRANSMISSION  Cholinesterase regenerators Example: Pralidoxime When is it indicated? What is the underlying mechanism of action – It is a chemical antagonist – It has an oxime group that has high affinity for the phosphorus atom in the organophosphate insecticide – Displaces the enzyme and leading to regeneration of the active enzyme Clinical use: Adjunct to atropine in poisoning due to organophosphate insecticides or nerve agent Available through specialised poisoning centres – Requires loading dose – Explain why? Contraindications: poisoning with organophosphorus compounds without AchE activity  Pharmacy Consideration: Anticholinergics Take history as – other drugs may also have anticholinergic activity e.g antihistamines therefore possible drug interactions or candidates for therapeutic substitution – Not recommended in patients with acute angel closure glaucoma – Why not??? – Increased chance of anticholinergic toxicity in special populations (hyperthermia – potentially lethal in infants, acute angle glaucoma, urinary retention in elderly – General anticholinergic SE in general populations Antidote for anticholinergic overdose/toxicity