W13 Cholinergics (Mishra).pdf

Cholinergics (Parasympathomimetics) Pranaya Mishra PhD [email protected] Drug List Direct Acting Cholinergic Drugs Muscarinic Agonists Indirect Acting Cholinergic Drugs Nicotinic Agonists Choline Esters Natural Alkaloids Acetylcholine Carbachol Bethanechol Pilocarpine Muscarine Nicotine (Ac...

Cholinergics (Parasympathomimetics) Pranaya Mishra PhD [email protected] Drug List Direct Acting Cholinergic Drugs Muscarinic Agonists Indirect Acting Cholinergic Drugs Nicotinic Agonists Choline Esters Natural Alkaloids Acetylcholine Carbachol Bethanechol Pilocarpine Muscarine Nicotine (Acetylcholine) (Carbachol) Cholinesterase Inhibitors Reversible Irreversible Edrophonium Physostigmine Pyridostigmine Neostigmine Donepezil Organophosphates Parathion Malathion Cholinesterase Reactivator Pralidoxime “Dermatological Pharmacology 1” – Integument 1 Module 3 Learning Objectives • Explain the mechanism of action of choline esters and natural alkaloids. • Explain the main difference between the activation of muscarinic and the activation of nicotinic receptors. • Explain the mechanism of action of nicotine. • Explain the mechanism of action of cholinesterase inhibitors. • Explain the mechanism of action of cholinesterase reactivators. • Describe the pharmacologic effects of muscarinic agonists upon various organ systems. • Describe the pharmacologic effects of Nicotine. • Describe the pharmacological actions of cholinesterase inhibitors upon various organ systems. • Relate the effects of cholinergic drugs to the activation of specific receptors. • Describe the metabolism of choline esters and cholinesterase inhibitors. • Describe the main adverse effects of cholinergic drugs. • Describe the acute poisoning by cholinesterase inhibitors and outline the drugs used for treatment. • Describe the clinically important drug interactions of cholinergic drugs. • Outline the main contraindications of cholinergic drugs. • Outline the main therapeutic uses of cholinergic drugs. 4 Diseases Treated with Autonomic Drugs • Hypertension • Hypotension • Shock • Heart failure • Angina • Arrhythmias • Pheochromocytoma • Benign prostatic hyperplasia • Nasal congestion • Ophthalmic hyperemia (red eyes) • Myasthenia Gravis • Urinary retention • Urinary incontinence • Glaucoma • Asthma • COPD • Dry mouth • Sialorrhea 5 This list is not comprehensive; however, many of the most common uses are listed. Functions of the Parasympathetic Nervous System • • • PANS maintains essential body functions, such as digestive processes and elimination of wastes, and is essential for life usually acts to oppose or balance the actions of sympathetic system generally dominant over the sympathetic system in “rest and digest” situations 5 Dilatation Innervation by the ANS • Dual innervation o most organs in the body are supplied by both divisions (PANS and SANS) of the ANS, hence balancing the activities; however, dominance of one over another does exist (shown in table) • • • • for example, in the heart, the vagus nerve is predominant in controlling heart rate organs receiving only sympathetic innervation adrenal medulla, kidney, pilomotor muscles, and sweat glands control of BP mainly by sympathetic activity 8 Cholinergic (Parasympathetic) System • STEPS IN NEURO-HORMONAL TRANSMISSION: o transmitter Synthesis o transmitter release o transmitter action on the postjunctional membrane o termination of action Cholinergic (Parasympathetic) System DRUGS AFFECTING CHOLINERGIC TRANSMISSION • o o o ANTICHOLINESTERASES - Neostigmine INHIBITING CHOLINE CARRIER - Hemicholinium INHIBITION OF VESCICULAR STORAGE ▪ o INHIBITION OF RELEASE ▪ o Vesamicol Botulinum toxin INCREASE RELEASE ▪ Spider venom Cholinergic (Parasympathetic) System Acetylcholine is the major neurotransmitter at autonomic and somatic sites CLASSIFICATION OF CHOLINERGIC RECEPTORS: • • MUSCARINIC - G-protein coupled receptor NICOTINIC - Ion channel receptor MUSCARINIC RECEPTORS: Stimulated by muscarine and blocked by atropine • M1,M2, M3, M4, and M5 NICOTINIC RECEPTORS: Stimulated by nicotine and blocked by tubocurarine • NM and NN Location of Muscarinic and Nicotinic Receptors Location M1 M2 M3 CNS Heart (myocardium), smooth muscles Smooth muscles, bladder, exocrine glands, GIT (gastric parietal cells) Nicotinic-Muscle Nicotinic(NM) Nerve (NN) Location Neuromuscular Junction Ganglia, Adrenal medulla 14 Cholinergic receptor mechanisms :- Muscarinic Receptor Signaling 16 Nicotinic Receptor Signaling 17 Termination of the Action of ACh • Acetylcholine is hydrolyzed by the enzyme Cholinesterase o There are 2 types of cholinesterase ▪ ▪ Acetyl cholinesterase (true cholinesterase) – present at all cholinergic sites (NM junction) Butyryl Cholinesterase (Pseudocholinesterase) – present in plasma, liver, and intestine Cholinergic (Parasympathetic) System • Cholinergic/Cholinomimetic/ Parasympathetic Drugs o produce actions similar to acetylcholine DIRECT ACTING • • Choline Esters – Acetylcholine, Methacholine, Carbachol, Bethanechol Cholinomimetic alkaloids– Pilocarpine, Arecholine INDIRECT ACTING • Anticholinesterase o o Reversible: Neostigmine, Physostigmine, Pyridostigmine, Edrophonium, Donepezil Irreversible: Organophosphates, Carbamates The major groups of cholinoceptor-activating drugs, receptors, and target tissues. ACh, acetylcholine. Cholinergic (Parasympathetic) System • ACETYLCHOLINE o o acts on both muscarinic and nicotinic receptors no therapeutic implications Because: • Diffuse action o • more adverse effects Rapid hydrolysis o within seconds Cholinergic (Parasympathetic) System Pharmacological actions of ACh through muscarinic receptors: CVS: (Blood vessels (endothelium)- M3) (SA node, AV node- M2) • Decrease in BP: by causing vasodilation o • ACh activates M3 receptors (present on endothelial cells lining the smooth muscles of BV) and results in the production of NO/EDRF NO then diffuses to vascular smooth muscle cells leading to hyperpolarization and smooth muscle relaxation o o By activating guanylyl cyclase, increasing cGMP production in smooth muscle, resulting in relaxation BP lowering effect (vasodilation) is only achieved by direct administration of ACh as ACh is never released into the blood in any significant quantities (no innervation, hence no effects of indirect agonists) Vascular Effects of Acetylcholine  Ach-induced Nitric Oxide Mediated Vasodilation If given i.v. - acetylcholine will produce a dose-dependent reduction of blood pressure & associated changes in heart rate. Note: following administration of an i.v. bolus, acetylcholine will stimulate muscarinic receptors located on the vascular endothelium, resulting in the release of nitric oxide. Nitric oxide will relax arterial smooth muscle, resulting in a fall in arterial blood pressure. The fall in arterial pressure will in turn produce an associated baroreceptor mediated increase in heart rate. If the baroreceptor reflex is blocked by either a ganglionic blocker or a beta blocker, then acetylcholine's direct effect on the SA node to reduce heart rate can typically be observed. Effects of injection of acetylcholine on blood pressure – hypotension – potential reflex tachycardia Cholinergic (Parasympathetic) System Pharmacological actions of ACh through muscarinic receptors: CVS: • Decrease in heart rate and cardiac output o o decrease in the heart rate (negative chronotropy) decrease in the conduction (negative dromotropy) GIT: • • • increases the tone and peristalsis (M3) increases the secretions of the GIT glands (M3) causes intestinal contractions leading to diarrhea and involuntary defecation Cholinergic (Parasympathetic) System Pharmacological actions of ACh through muscarinic receptors: RESPIRATORY TRACT: • Constriction of bronchus (bronchospasm) (M3) • Increases the secretions of the respiratory glands (M3) Cholinergic (Parasympathetic) System Pharmacological actions of ACh through muscarinic receptors: EYE: • iris has parasympathetic innervation and ACh acts on muscarinic receptors (M3), resulting in o o o • contraction of Circular or Sphincter muscle, leads to pupillary constriction (miosis) (M3 receptors), increased outflow of aqueous humor, reduction in intraocular tension contraction of ciliary muscle (M3 receptors) – causes accommodation for near vision Acetylcholine causes spasm of accommodation by contraction of ciliary muscle, allowing the lens to become more convex o thus vision is fixed for near objects Cholinergic (Parasympathetic) Stimulation: Effects on Eye 27 Parasympathetic Control of Accommodation ons 1 & 2 Parasympathetic stimulation allows contraction of the ciliary muscle. 29 Muscarinic agonist Muscarinic antagonist Miosis and spasm of accommodation Mydriasis and paralysis of accommodation Cholinergic (Parasympathetic) System Pharmacological actions of ACh through muscarinic receptors: Urinary bladder: (M3) • • causes contraction of detrusor and relaxation of trigone/sphincter causes voiding of urine and urinary incontinence Glands: (M3) • causes increased secretion of sweat (thermoregulatory), saliva, and lacrimation Nicotinic Action of Acetylcholine • Autonomic ganglia (NN) o stimulation (at higher dose), both parasympathetic and sympathetic are stimulated ▪ • Adrenal medulla (NN) o o o • net effects depend on PANS/SANS innervation and dominance secretion of epinephrine and norepinephrine high dose of ACh after atropine causes tachycardia and rise in BP (i.e., nicotinic actions of ACh) only able to get the sympathetic effect because of blocking of Muscarinic receptors by atropine Skeletal muscle (NM): o stimulation leading to contraction of the skeletal muscle (twitch/hyperactivity) Cholinergic (Parasympathetic) Drugs Choline esters – Acetylcholine, Methacholine, Bethanechol, Carbachol • poorly absorbed from the stomach o charged, water soluble • poor lipid solubility • poor BBB penetration o fewer CNS effects Therapeutic Uses: Cholinergic (Parasympathetic) Drugs-Choline Esters • Bethanechol o o • stimulates atonic bladder, particularly in postpartum or postoperative, non-obstructive urinary retention also helpful in congenital megacolon and paralytic ileus (postoperative/neurogenic) Carbachol o o may be used in the eye, as a miotic agent to treat glaucoma by reducing IOT other uses limited because of its receptor nonselectivity Cholinergic (Parasympathetic) Drugs: Choline Esters Adverse effects: • Bethanechol o • causes the generalized effects of cholinergic stimulation, like sweating, salivation, flushing, decreased BP, nausea, abdominal pain, diarrhea, and bronchospasm Carbachol o at doses used for ophthalmological purposes, little or no side effects due to lack of systemic penetration (quaternary amine) Cholinergic (Parasympathetic) Drugs: Choline Esters • Methacholine o o o more muscarinic action than nicotinic hydrolysed by AChE - very short-lived, so not very useful therapeutically used in diagnosis of bronchial hyperactivity and asthmatic conditions (no effects in patients without asthma b/c no hyperactivity) Cholinergic (Parasympathetic) Drugs: Cholinomimetic Alkaloids • Pilocarpine o an alkaloid (a tertiary amine) ▪ ▪ ▪ ▪ obtained from the leaves of Pilocarpus microphyllus and other species, resistant to hydrolysis by AChE being uncharged, penetrates the CNS at therapeutic doses stimulates only muscarinic receptors Actions • applied topically to the cornea, produces rapid miosis and contraction of ciliary muscle (spasm of accommodation) Therapeutic uses - Pilocarpine • used as drug of choice in emergency lowering of IOT of both narrow-angle (also called closed-angle) and wide-angle (also called open-angle) glaucoma (used as eye drops) • beneficial in promoting salivation in patients with xerostomia resulting from irradiation of the head and neck and SjÖgren’s syndrome Adverse effects • profuse sweating (diaphoresis) and salivation can enter the brain and cause CNS disturbances (convulsion with high doses) ANTICHOLINESTERASE AGENTS (Indirect-acting Cholinergic Drugs) • • agents which inhibit the enzyme acetylcholine esterase (AChE) and hence protect ACh from hydrolysis Two types: Reversible and Irreversible o Reversible: ▪ ▪ ▪ Short acting: Edrophonium Intermediate acting: Neostigmine, Physostigmine Long acting: Pyridostigmine, Tacrine, Ambenonium ANTICHOLINESTERASE AGENTS (Indirect-acting Cholinergic Drugs) • Irreversible are insecticides and nerve gas poisons o o Organphosphorus compounds - Parathion, Malathion, Diazinon (TIK-20), Echothiophate; Soman, Sarin, Tabun (Nerve gas poisons) Carbamates - Carbaryl, Propoxur ANTICHOLINESTERASE AGENTS (Indirect-acting Cholinergic Drugs) Mechanism of action: • Acetyl cholinesterase (AChE) is an enzyme with anionic and esteratic site • Hydrolysis of ACh involves attraction of the positive charge N+ of ACh at anionic site and acetylation of serine leading to the acetylated enzyme • acetylated enzyme reacts with the water to produce acetic acid and free enzyme within milliseconds Reversible Anticholinesterases • Edrophonium, Neostigmine and Physostigmine • combine with the ChE and carbamylated (with carbamate group) enzyme is slow to hydrolyze and free the enzyme (in ~30 mins) 47 Reversible Anticholinesterases: Physostigmine • • naturally occurring alkaloid tertiary amine – o • uncharged, lipid-soluble, crosses BBB oral absorption is good Actions: • reversibly inhibits acetylcholinesterase • stimulates muscarinic and nicotinic sites of ANS by increasing the concentration of ACh Reversible Anticholinesterases: Physostigmine Therapeutic Uses: • used in glaucoma (as eye drop) to lower IOT as it produces miosis • also used in bladder and intestinal atony (as it increases intestinal and bladder motility) • as antidote in atropine overdose (poisoning) Reversible Anticholinesterases: Neostigmine • synthetic quaternary amine (charged); reversibly inhibits acetylcholinesterase in a manner similar to Physostigmine • poor oral absorption • CNS action absent as it does not enter the CNS o o hence no CNS side effects and not used to overcome toxicity of central-acting antimuscarinic agents such as atropine Reversible anticholinesterases: Reversible anticholinesterases: Neostigmine Pyridostigmine and Ambenonium • • • • • prominent action on skeletal muscles (more than physostigmine) also stimulates the bladder and GIT used in paralytic ileus, urinary retention, and symptomatic treatment of myasthenia gravis also used as an antidote for tubocurarine and other competitive neuromuscular blocking agents D/A- 0.5-2 hrs • • • cholinesterase inhibitors used in the chronic management of MG D/A- 3-6 hrs (Pyridostigmine) 4-8 hrs (Ambenonium) 51 Reversible Anticholinesterases: Edrophonium • • short-acting anticholinesterase drug (10-20 mins) actions similar to those of neostigmine o used for the diagnosis of myasthenia gravis (Tensilon test) and also used to differentiate myasthenia from cholinergic crisis ▪ https://www.youtube.com/watch?v=k7YX9kuWrxA Reversible Anticholinesterases: Demecarium • • • a quaternary amine, structurally related to neostigmine M/A and side effects are similar to neostigmine used to treat chronic open-angle and closed-angle glaucoma Reversible anticholinesterases: Tacrine, Donepezil, Rivastigmine, and Galantamine • anti-ChE drugs are used in Alzheimer’s disease Irreversible Anticholinesterases: Echothiophate • an organophosphate binds covalently via its phosphate group to the serine-OH group at the active site of acetylcholinesterase-leading to the permanent inactivation of the enzyme acetylcholinesterase • restoration of AChE activity requires the synthesis of new enzyme molecule 54 Irreversible Anticholinesterases: Echothiophate • following covalent modification of AChE, the phosphorylated enzyme slowly releases one of its ethyl group: this phenomenon is called aging • aging makes it impossible for enzyme reactivator (such as pralidoxime), to break the bond between the remaining drug and the enzyme Irreversible Anticholinesterases: Echothiophate Actions: • • generalized cholinergic stimulation, paralysis of motor function (causing breathing difficulties), and convulsions produces intense miosis (basis of therapeutic application) Therapeutic uses: • • chronic treatment of open-angle glaucoma potential risk of cataracts limits the use of Echothiophate (not a first-line agent in the treatment of glaucoma) Common Adverse Effects of AChE Inhibitors • generalized cholinergic stimulation, such as salivation, flushing, decreased BP, nausea, abdominal pain, diarrhea, and bronchospasm • CNS effects: convulsions (high dose), especially with Physostigmine Organophosphorus compoundsParathion, Malathion (insecticides) • Organophosphorus compounds react with esteratic site which is hydrolyzed extremely slowly with water or not at all • phosphorylated enzyme undergoes aging by the loss of one of the alkyl groups and becomes totally resistant to hydrolysis 59 Cholinesterase Reactivators Pralidoxime • • phosphorylated ChE reacts very slowly or not at all with the water Oximes like Pralidoxime (PAM) bind with anionic site of ChE and undergo reaction to cause hydrolysis of phosphoserine bond, resulting in free enzyme o • should be administered as early as possible followed by OP poisoning (not later than 24 hours maximum, as aging occurs) PAM is ineffective in case of Physostigmine or Neostigmine (Carbamates) poisoning as anionic site is not free. Toxicity of AChE inhibitors: Organophosphorus poisoning Acute toxicity: • • Excessive muscarinic and nicotinic stimulations Muscarinic effects: remember DUMBBELSS o o o o o o o o o Diarrhea Urination Miosis Bradycardia Bronchoconstriction Excitation (CNS and muscle) Lacrimation Salivation and Sweating Toxicity of AChE inhibitors: Organophosphorus poisoning Acute toxicity: • Nicotinic effects: o o Skeletal muscle excitation followed by paralysis CNS stimulation Management: • • • to counteract muscarinic effects: give atropine for regeneration of AChE: Pralidoxime (2-PAM) PAM should be given as soon as possible to avoid aging USES OF CHOLINOMIMETIC DRUGS: Summary • Open/Wide angle glaucoma o • Myasthenia Gravis o • Atropine, TCA, Phenothiazines (Physostigmine) Alzheimer's Disease o • (Neostigmine, Pyridostigmine) Drug poisoning o • (Neostigmine, Pyridostigmine) Parlytic ileus/Congenital megacolon: o • (Neostigmine, Pyridostigmine) Urinary retention o • (Pilocarpine, Physostigmine) Donepezil, Galantamine, Rivastigmine, Tacrine (cerebroselective anti-ChE) SjÖgren’s Syndrome o (Pilocarpine) Questions Thanks! 65