Editing File Indirect acting cholinergic drugs Objectives: ✓ Classification of indirect acting cholinomimetics ✓ Mechanism of action, kinetics, dynamics and uses of anticholinesterases ✓ Adverse effects & contraindications of anticholinesterases ✓ Symptoms and treatment of organophosphates toxicity. Important Notes Extra ❖ Also called Anticholinesterases Anticholinesterases prevent hydrolysis of Ach by inhibiting acetyl cholinesterase thus, increase Ach concentrations and actions at the cholinergic receptors (both nicotinic and muscarinic). Acetylcholine binds to acetylcholinesterase at M.O. two sites, anionic site and esteric site, then A the enzyme somehow breakdown the acetylcholine into acetic acid and choline. In order to inhibit this enzyme we need to create a substance that is similar to acetylcholine either in both sites or even one site. (Similar structure) Reversible anticholinesterases Irreversible anticholinesterases Durat Short Acting Intermediate Long Acting ion of actio acting n (Alcohols) (Carbamates (Phosphates esters) e.g. esters) e.g. e.g. insecticides, gas war e.g. Physostigmine, Drug edrophonium. Ecothiophate & Isoflurophate. s Neostigmine, Classi Using those drugs leads to death ficati Pyridostigmine. on Forms weak Binds to two sites used as insecticides(malathion) or hydrogen bond of cholinesterase nerve gases (sarin) . with enzyme. Form very stable covalent bond with All polar and cholinesterase . Feat acetylcholineste ures synthetic except All phosphates are lipid soluble except rase enzyme physostigmine. Ecothiophate which is polar • They act on both Muscarinic and nicotinic receptors. Phar • Some has CNS effect “only the lipid soluble drugs” macol CNS actions: ogical (excitation leads to convulsion leads to respiratory failure leads to coma). action e.g. physostigmine & phosphate ester s ✓ Revise the nicotinic and muscarinic actions from (Direct Acting) lecture, it is the same! Reversible indirect drugs: Drug Edrophonium Neostigmine Physostigmine MOA • Reversible anticholinesterase • Reversible • Reversible • Has muscarinic & anticholinesteras anticholinesterase and nicotinic actions e. forms weak hydrogen (prominent on GIT • Has muscarinic, bonds. & urinary tract) nicotinic action Special action P.K • NOT absorbed orally, given by • Good oral absorption. injection. Bc its polar • Tertiary ammonium • Alcohol (ionic bonds, not • Can be used orally compound. esters), so its polar • Quaternary • Non polar. Good lipid • Short duration of action (5-15 ammonium comp. solubility. • mins) • Cross BBB (has CNS • Esters prolong the effect of Polar compound No effects) the drug CNS effect Uses • Used only for the diagnosis of • Treatment of • Glaucoma. myasthenia gravis due to its myasthenia gravis. • Atropine toxicity limited duration of action. Longer duration (atropine is • Used to differentiate between • Paralytic ileus & Urinary anticholinergic drug) • used in atropine toxicity Cholinergic crisis and retention. because atropine has an Myasthenia Gravis because • Competitive effect on the CNS. Thus, we the drug will make the crisis neuromuscular blockers need a drug that can clean up atropine from all over by increasing worse. intoxication the body the level of Ach. Thus prevent • Not used with Myasthenia the action of NMBs Gravis because it was not (Neuromuscular Blocking used on MS patients before Agents) Mne • Eyelid drop moni • (E) Drop honium c • Myasthenia gravis - - Drugs Donepezil • Is a centrally acting reversible acetyl cholinesterase M.O.A inhibitor. M4, M5 P.K • Given orally • Used for treatment of dementia of Alzheimer's disease Uses Irreversible indirect drugs: Drug Ecothiophate (Organophosphorous compound) M.O. • Irreversible anticholinesterase A • Binds to cholinesterase by strong covalent bond P.K • Have very long duration of action • Aging make bond extremely stable and make treatment difficult from toxicity • All are highly lipid soluble except Ecothiophate Uses • Used for glaucoma Org Symptoms of organophosphate toxicity ano Heart : Lung : ph Severe bradycardia and bronchospasm osp hypotension. hat GIT : CNS : e Increase motility which lead to CNS effects convulsion , coma cramps and diarrhea and respiratory failure tox icit Skeletal muscles : initial twitching of skeletal muscles causing y muscle weakness and paralysis. Treatment of organophosphate toxicity • Support respiration • Cholinesterase reactivators ( Oximes ) • Atropine ( to block muscarinic action and CNS effect ) • Immediate treatment because delaying makes the bonds more stable Cholinesterase Reactivators (Oximes) Pralidoxime Drug (PAM) • Cholinesterase reactivator M.O.A • Acts by regeneration of cholinesterase enzyme • Reactivates recently inhibited enzymes before aging ✓ I.V over 15-30 min for organophosphate intoxication. Uses Side effects of Cholinergic drugs: Those ADRs are of both INDIRECT and DIRECT acting drugs: ❖ Bradycardia ❖ Sweating & Salivation ❖ Bronchoconstriction ❖ Diarrhea Uses of some Cholinergic drugs: Eye: Treatment of glaucoma Pilocarpine (direct muscarinic agonist) Physostigmine Ecothiophate (indirect cholinomimetics) 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. (Dementia of Alzheimar’s disese) Chemical Administratio Drugs Actions Kinetics Uses structure n •Myasthenia gravis Quaternary Nicotinic treatment Neosti Can be used ammonium muscarinic -0.5-2hr •Paralytic ileus orally gmine compound M, N -polar •Urinary retention •Curare toxicity Good oral Physos Nicotinic Tertiary ammonium absorption, can muscarinic -0.5-2hr •Glaucoma tigmin compound be used topically M, N, CNS -nonpolar •Atropine toxicity e in the eye (lipid soluble ) Pyridos Nicotinic • Myasthenia muscarinic - -3-6hr tigmin Quaternary gravis treatment e M, N -polar Amben Nicotinic - onium muscarinic -4-8hr •Myasthenia gravis Quaternary M, N -polar treatment Quaternary Edroph (Attach mainly to Nicotinic •Diagnosis of acetyl cholinesterase muscarinic injection Myasthenia gravis, onium by weak hydrogen M, N -5-15 min not for the bond.) -Polar treatment. MCQs: 1- which one of the following is lipid soluble A)Neostigmine. B)Physostigmine. C)Donepezil. D)Ecothiophate. 2-which one of the following has the shortest duration of action A)Ambenonium. B)Ecothiophate. C)Edrophonium. D)Neostigmine. 3-Which of the following is an anticholinesterase drug that has an effect on the CNS? A)Pyridostigmine. B)Isoflurophate. C)Physostigmine. D)Ambenonium. 4-Which of the following drugs is used in the diagnosis of Myasthenia gravis? A)Edrophonium. B)Ambenonium. C)Neostigmine. D)pyridostigmine. 5-All anticholinesterases have : A)Nicotinic action. B)Muscarinic action. C)Both nicotinic and muscarinic action. D)α1 & α2 action. C B C C A - - - - - Answers: 5 1 2 3 4 SAQ: 1)What's the function of indirect cholinergic drugs? prevent hydrolysis of Ach by inhibiting acetyl cholinesterase thus increase Ach concentrations and actions at the cholinergic receptors (both nicotinic and muscarinic). 2)What is the Drug used in treatment of dementia of Alzheimer's disease? Donepezil. 3)How the endrophonium inhibit the acetyl cholinesterase? By attach to acetyl cholinesterase by weak hydrogen bond. “It is not hard, you just made it to the end!” Team Leaders: Yazeed Alharbi & Aseel Badukhon Thanks for those who worked on this lecture: Abdullah abdurahman al-asseri Abdulhakim Alonaiq Bader Altamimi Fayez Ghiyath Aldarsouni Maan Abdulrahman Shukr Mohammed alnajeim Omar Alsuhaibani Sultan Omar Almalki Yazeed abdullah alkhayyal Ahmed Lateef Alanzy Adel Alorainy References: Special thanks to: Rahaf Al-Thnayan ✓ Team436 Alfahdah Al-Saleem ✓ Doctors’ notes and slides Layla Al-Sabbagh @Pharma4370 [email protected].