Indirect Cholinergic Drugs PDF, 12/4/2024

Dr. Asmaa Fady Ph D., JMHPE, MSc., MBBCh, College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 1 No. ...

Dr. Asmaa Fady Ph D., JMHPE, MSc., MBBCh, College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 1 No.  At the end of this lecture the student should: College of Medicine – ‫كلية الطب‬  Classify indirect acting cholinomimetics.  Describe mechanism of action, kinetics, dynamics and uses of anticholinesterases.  Know the major adverse effects & contraindications of anticholinesterases.  Describe the major symptoms and treatment of organophosphates toxicity.  Know the major side effects for the different classes of direct cholinomimetics. – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 2 No.  College of Medicine – ‫كلية الطب‬ OPC ecothiophate 3  (also called anticholinesterases) Anticholinesterases are similar in structure to Ach so combine with cholinesterase instead of Ach. College of Medicine – ‫كلية الطب‬ Mechanism of action: Anticholinesterases prevent hydrolysis of Ach by antagonizing cholinesterase thus increase Ach concentrations and actions at the cholinergic receptors:  Muscarinic  Nicotinic receptors  Neuro Muscular Junction  CNS – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 4 No. College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 5 No.  Indirect Cholinomimetics (Anticholinesterases) Nicotinic receptors College of Medicine – ‫كلية الطب‬ Ach anticholinesterases Effects & Muscarinic cholinesterase receptors Choline + Acetate  1- Reversible 2- Irreversible 1- Binding to Loose weak hydrogen Firm stable covalent enzymes bond bond College of Medicine – ‫كلية الطب‬ 2- Activity of Enzymes can regain Enzymes can not enzymes activity regain their activity 3- Duration of action Short or Long till re-synthesis Intermediate of new enzymes 4- Examples - Edrophonium Organophosphorus - Physostigmine compounds: - Neostigmine Ecothiophate & Isoflurophate 7  Short acting, reversible  Alcohol  Forms weak hydrogen bond with cholinesterase College of Medicine – ‫كلية الطب‬ Edrophonium Intermediate acting, reversible  Carbamates esters  Binds to two sites of cholinesterase enzyme  All polar except physostigmine Physostigmine Neostigmine Pyridostigmine – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 8 No.  Very long acting, Phosphate esters e.g. Ecothiophate – Isoflurophate College of Medicine – ‫كلية الطب‬  Very long duration of action  Forms very stable covalent bond with cholinesterase  All phosphates are lipid soluble except ecothiophate which is polar. – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 9 No.  ❑ ALL Anticholinesterases College of Medicine – ‫كلية الطب‬ have muscarinic and nicotinic actions (N & M actions) and some have CNS effects (only lipid soluble drugs). Course Name and – ‫اسم ورقم المقرر‬ 12/4/2024 10 No.  Pharmacological effects of anticholinesterases ❑ Muscarinic actions ❑ Nicotinic actions College of Medicine – ‫كلية الطب‬ ❑ CNS actions: Excitation, convulsion, respiratory failure, coma only for lipid soluble anticholinesterases: Physostigmine & Phosphate ester except Ecothiophate.  Organs Cholinergic actions Eye Contraction of circular muscle of iris (miosis)(M3) Contraction of ciliary muscles for near vision (M3) Decrease in intraocular pressure College of Medicine – ‫كلية الطب‬ Heart bradycardia ( heart rate ) (M2) endothelium Release of NO (Vasodilatation) Lung Constriction of bronchial smooth muscles Increase bronchial secretion M3 GIT Increased motility (peristalsis) Increased secretion Relaxation of sphincter M3 Urinary Contraction of muscles bladder Relaxation of sphincter M3 Exocrine Increase of sweat, saliva, lacrimal, bronchial, intestinal glands secretions M3  Neuromuscular junction College of Medicine – ‫كلية الطب‬ Therapeutic dose: muscle contraction Toxic dose: Contraction followed by relaxation or paralysis. Ganglia: stimulation of sympathetic and parasympathetic ganglia Adrenal medulla release of catecholamines (A & NA).   It is a short-acting Ach E inhibitor of 10 to 20 minutes. College of Medicine – ‫كلية الطب‬  It is a quaternary amine, and its actions are limited to the periphery.  Polar so given as injection.  Its use became limited.  Uses: Diagnosis of myasthenia gravis Course Name and – ‫اسم ورقم المقرر‬ 12/4/2024 14 No.   It is an intermediate acting Ach E inhibitor of 30 minutes to 2 hours. College of Medicine – ‫كلية الطب‬  Tertiary ammonium compound so, it can penetrate the CNS.  Nonpolar  Good lipid solubility  Good oral absorption  It stimulates muscarinic, nicotinic sites of the ANS and the CNS.  Uses: 1. Glaucoma 2. Treatment of the central manifestations associated with toxicity with anticholinergic drugs, such as atropine. Course Name and – ‫اسم ورقم المقرر‬ 12/4/2024 15 No.   Intermediate duration of action of 30 minutes to 2 hours.  Quaternary ammonium comp. (No CNS effect) College of Medicine – ‫كلية الطب‬  Polar compound  Poor oral absorption  Stimulate M & N receptors of ANS, and N receptors of NMJ Unlike the Physostigmine:  It does not enter the CNS (does not overcome toxicity of central-acting antimuscarinic agents such as atropine)  Greater effect than physostigmine on skeletal muscle Course Name and – ‫اسم ورقم المقرر‬ 12/4/2024 16 No.  Uses: 1. Prevents postoperative abdominal distention and urinary retention College of Medicine – ‫كلية الطب‬ 2. Treatment of myasthenia gravis 3. An antidote for competitive neuromuscular blockers toxicity Adverse effects: Parasympathetic excess (generalized cholinergic stimulation)  Sweating, salivation, flushing, diaphoresis  Nausea, abdominal pain, diarrhea  Urinary urgency  Decreased blood pressure, bradycardia  Bronchospasm – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 17 No.  Carbamate esters Drug Actions Kinetics Uses Physostigmine Nicotinic 0.5-2hr Glaucoma muscarinic Lipid Central manifestations of College of Medicine – ‫كلية الطب‬ CNS soluble atropine toxicity Neostigmine Nicotinic & 0.5-2hr Myasthenia gravis treatment muscarinic polar Paralytic ileus Urinary retention Curare toxicity Pyridostigmine Nicotinic & 3-6 Myasthenia gravis muscarinic polar treatment Ambenonium Nicotinic & 4-8 Myasthenia gravis treatment muscarinic polar   Action is mainly in the CNS College of Medicine – ‫كلية الطب‬  Patients with Alzheimer’s disease have a deficiency of cholinergic neurons in the CNS  Used as first-line treatments for Alzheimer's disease  GI distress is their primary adverse effect Course Name and – ‫اسم ورقم المقرر‬ 12/4/2024 19 No. College of Medicine – ‫كلية الطب‬  These drugs are extremely toxic: 1. Nerve gases 2. Insecticides, such as parathion and malathion Isoflurophate Ecothiopate 20  Mechanism of action: “Irreversible – non-competitive block to choline esterase enzyme” College of Medicine – ‫كلية الطب‬ 1- They phosphorylate the esteratic site of enzyme. 2- At first loose & reversible then non-competitive irreversible block (aged enzyme). 3-All are highly lipid soluble except ecothiophate 4- Accumulation of endogenous Ach leads to muscarinic & nicotinic action. 5- Their action ends when the body resynthesizes new enzymes. 21  1- Muscarinic effects:  Increased bronchial secretions, excessive sweating, salivation, lacrimation, miosis, bronchospasm, College of Medicine – ‫كلية الطب‬  GIT: abdominal cramps, vomiting, involuntary passage of stool and urine.  Cardiac: bradycardia, hypotension, arrhythmias. 2- Nicotinic effects:  Twitching, fasciculation then muscle weakness and flaccid paralysis. 3- CNS manifestations:  Headache, dizziness, tremor, restlessness, anxiety, confusion, convulsion and coma. – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 22 No.  II. Irreversible Anticholinesterase agents Organophosphorus Compounds College of Medicine – ‫كلية الطب‬ 12/4/2024 23  I) Support respiration and give supportive therapy: 1. Diazepam is also administered to reduce the persistent convulsion College of Medicine – ‫كلية الطب‬ caused by these agents. 2. General supportive measures (oxygen supply & artificial respiration) II) Atropine (to block muscarinic & central actions of acetylcholine) III) Cholinesterase reactivators –Oximes- Course Name and – ‫اسم ورقم المقرر‬ 12/4/2024 24 No.   Atropine is administered to prevent muscarinic side & central effects of these agents, such as increased bronchial and salivary College of Medicine – ‫كلية الطب‬ secretion, bronchoconstriction, and bradycardia.  Pralidoxime (2-PAM) can reactivate inhibited Ach E.  If given before aging , it can reverse both muscarinic and nicotinic peripheral effects of organophosphates, but not the CNS effects  Can’t reverse the aging of the enzyme complex – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 25 No.  Indirect Cholinomimetic Edrophonium Very Short Diagnosis of Myasthenia gravis M, N 5-15 min, Polar Neostigmine Intermediate 0.5-2hr Myasthenia gravis treatment M, N polar Paralytic ileus College of Medicine – ‫كلية الطب‬ Urinary retention curare toxicity Physostigmine Intermediate 0.5-2hr Glaucoma M,N, CNS Lipid soluble atropine toxicity Ambenonium Intermediate Myasthenia gravis treatment Pyridostigmine 4-8 and 3-6 M, N polar Ecothiophate Long 100hr, polar Toxin. No therapeutic use M, N Donepezil dementia of Alzheimer’s M, N disease  Eye : treatment of glaucoma Pilocarpine (direct muscarinic agonist) Physostigmine (indirect cholinomimetics) College of Medicine – ‫كلية الطب‬ Urinary retention and paralytic ileus Bethanechol (direct) Neostigmine (indirect) Myasthenia gravis (only indirect cholinomimetics) Pyridostigmine, Neostigmine, Ambenonium Xerostomia Pilocarpine –Cevimeline (Sjogren’s syndrome) Alzheimer’s disease: Donepezil College of Medicine – ‫كلية الطب‬ – Course Name and ‫اسم ورقم المقرر‬ 12/4/2024 28 No.