Cholinomimetics Study Notes PDF

Learning outcomes Explain the mechanism of action of anticholinesterases. Compare and contrast physostigmine and neostigmine. Apply the concepts of mechanism of action and pharmacological actions of reversible anticholinesterases provide the rationale for their uses (Alzheimer’s, myasthen...

Learning outcomes Explain the mechanism of action of anticholinesterases. Compare and contrast physostigmine and neostigmine. Apply the concepts of mechanism of action and pharmacological actions of reversible anticholinesterases provide the rationale for their uses (Alzheimer’s, myasthenia gravis, post-operative reversal of muscle relaxation, atropine poisoning). 1 Learning outcomes Describe the adverse effects of cholinomimetic drugs. Apply the concepts of mechanism of action and pharmacological actions of organophosphorus compound to provide rationale for the manifestations of its poisoning. List the measures for the management of organophosphorus poisoning. 2 Learning outcomes Apply the pharmacological actions of organophosphorus compounds and atropine to provide the rationale for using atropine in the management of organophosphorus poisoning. List the various groups of drugs with examples used in glaucoma. 3 Mechanism of anticholinesterases (AchE) Inhibit AchE Prevent the metabolism of ACh Prolongs the duration of action of ACh Reversible AchE are structurally similar to Ach and combine with both the sites of the enzyme & temporarily inhibit it Inhibitors of AchE indirectly provide a cholinergic action by prolonging the duration of action of acetylcholine at the cholinergic nerve endings → results in the accumulation of acetylcholine in the synaptic space. 4 Physostigmine vs neostigmine Pyridostigmine, Physostigmine Neostigmine Origin Natural alkaloid Synthetic derivative Structure Tertiary amine Quaternary amine Solubility Highly lipid soluble Not lipid soluble Do not cross blood Body compartments brain barriers and Tissue penetration including the CNS tissue penetration is comparatively less 5 Physostigmine vs neostigmine Pyridostigmine, Physostigmine Neostigmine Myasthenia gravis (both drugs) Management of Post-operative paralytic glaucoma Uses ileus Belladonna (atropine) Atony of the bladder poisoning Curare poisoning Cobra bite Less likely to cause Adverse Convulsions when high convulsions even at high effects doses are used doses 6 Therapeutic uses of reversible anticholinesterases Alzheimer’s disease – Galantamine Tacrine Donepezil Rivastigmine 7  Myasthenia gravis – Neostigmine Pyridostigmine Post-operative reversal of muscle relaxation – Neostigmine Atropine poisoning – Physostigmine 8 Uses of cholinomimetics Drug Characteristics Clinical uses Diagnosis of myasthenia → to Edrophonium Short acting differentiate myasthenia from cholinergic crisis Tertiary amine (enters CNS), Rx – glaucoma; antidote in Physostigmine intermediate acting atropine poisoning Rx – paralytic ileus, urinary Neostigmine Quaternary amines (no CNS retention, myasthenia, reversal Pyridostigmine entry), intermediate acting of non-depolarising neuromuscular blockers Donepezil Lipid soluble (CNS entry) Rx – Alzheimer disease Tacrine Note: used as insecticides Lipid soluble, long acting, Organophosphates (malathion, parathion) and as irreversible inhibitors nerve gas (sarin) 9 Adverse effects of cholinomimetics Salivation, lacrimation, urination, diaphoresis (increased sweating)/ defecation Gastrointestinal upset, emesis (“SLUDGE” syndrome) CNS stimulation Miosis and spam of accommodation Bronchoconstriction & tracheobronchial secretions AV block 10 Op poisoning & management Aging (within 1-2 hrs): The covalent bonding between AchE and organophosphates becomes more stable, irreversible and becomes resistant for reactivation. 11 Op poisoning & management Muscarinic: Diarrhea, urination, miosis, bronchospasm, bradycardia, lacrimation, emesis, salivation and sweating. (DUMBBLESS) Nicotinic: Muscle fatigue and weakness, twitching, fasciculation, tremors, muscle paralysis CNS: Ataxia, confusion, convulsions, depressed respiration and cardiovascular function. In severe acute exposure death could occur within few minutes due to cardiopulmonary failure 12 Op poisoning & management Initial treatment: Drugs: Rapid decontamination Atropine- Antimuscarinic agent - Block all actions of acetylcholine on Maintaining respiration. all Muscarinic receptors in central Suction of bronchial secretions. and at the periphery. Maintain intravenous line. Oximes- Pralidoxime, obidoxime Catheterize the urinary bladder. (cholinesterase reactivators) Control convulsions (diazepam) 13 Reactivation AchE by oximes Prevention aging and reactivation of AchE: Golden period is within 2 hrs of the exposure. 14 Drugs used in glaucoma Group Drugs Parasympathetic Agents Pilocarpine, physostigmine (Both topical) Dipivefrin, apraclonidine, brimonidine (all Adrenergic Agonists topical) Beta Blockers Timolol, levobunolol, carteolol (all topical) Carbonic Anhydrase Acetazolamide (oral), dorzolamide Inhibitors (topical) Prostaglandin Analogs Latanoprost, travoprost (topical) Osmotic agents Mannitol, glycerin 15 Simple book for better understanding 16