Indirect Acting Cholinergic Inhibitors (BSN 2024) PDF

INDIRECT ACTING CHOLINOMIMETICS (CHOLINESTERASE INHIBITORS). Introduction  Acetylcholine action is terminated via hydrolysis by acetylcholinesterase within cholinergic synapses  Indirect acting cholinomimetics inhibit this enzyme Chemistry  There are 3 chemical groups of...

INDIRECT ACTING CHOLINOMIMETICS (CHOLINESTERASE INHIBITORS). Introduction  Acetylcholine action is terminated via hydrolysis by acetylcholinesterase within cholinergic synapses  Indirect acting cholinomimetics inhibit this enzyme Chemistry  There are 3 chemical groups of cholinesterase inhibitors: i. simple alcohols eg edrophonium ii. carbamic acid esters of alcohols (carbamates, eg, neostigmine, physostigmine, pyridostigmine) iii. organic derivatives of phosphoric acid (organophosphates, eg, echothiophate, malathion, parathion, soman). Pharmacokinetics  Quartenary carbamates eg. neostigmine are poorly absorbed from the skin, eye, lung as they are poorly lipid soluble.  Tertiary amines eg. physostigmine are well absorbed and can be used topically in the eye.  Physostigmine crosses the BBB and is more toxic than the quartenary carbamates. Pharmacokinetics (2)  The organophosphate cholinesterase inhibitors (except for echothiophate) are well absorbed from the skin, lung, gut and conjunctiva.  Penetrate into the CNS (except echothiophate)  Are dangerous to humans and highly effective as insecticides. Mechanism of action 1. Edrophonium (simple alcohol) - Reversibly binds electrostatically and by hydrogen bonds to the active site of cholinesterase enzyme, preventing access of Ach. - The enzyme-inhibitor complex does not involve a covalent bond thus is short-lived (2–10 minutes) 2. Carbamate esters  Bind to the active site of cholinesterase enzyme and undergo hydrolysis (step 1)  Then forms a covalent bond with the enzyme, inhibiting the enzyme activity for 30 min to 6hrs. 3. Organophosphates  Undergo initial binding and hydrolysis by cholinesterase, resulting in a phosphorylated active site.  The covalent phosphorus-enzyme bond is extremely stable and hydrolyzes at a very slow rate (hundreds of hours).  The complex may in addition undergo a process called aging, which further strengthens the phosphorus-enzyme bond.  Pralidoxime is able to break the phosphorus-enzyme bond if given before aging has occurred. Organ system effects 1. CNS- high doses of lipid soluble agents cause convulsions, coma & respiratory arrest. 2. Eye, GIT, Respiratory tract & urinary tract- similar to direct acting cholinomimetics 3. CVS- bradycardia & reduced cardiac output. Organ system effects (2) 4. Neuromuscular junction  Low concentrations increase the strength of contraction of muscles weakened by myasthenia gravis.  High (toxic) concentrations result in fasciculation of muscle fibres and neuromuscular blockade. CLINICAL USES OF INDIRECT ACTING CHOLINOMIMETICS. Clinical Uses 1. Eye - Useful in glaucoma (↑d intraocular pressure) - MOA: ↓ intraocular pressure by causing contraction of the ciliary body so as to facilitate outflow of aqueous humor - Physostigmine commonly used Aqueous humor flow . 2. GIT & urinary tract  Neostigmine can be used to increase smooth muscle activity in:  Paralytic ileus  Congenital megacolon  Reflux oesophagitis  Urinary retention 2° to surgery/ postpartum/ spinal cord dysfunction 3. Neuromuscular junction  Cholinesterase inhibitors eg. pyridostigmine are useful for management of myasthenia gravis  Edrophonium may also be used to diagnose myasthenia gravis (improved muscle strength is observed).  Also useful to reverse neuromuscular blockade post surgical anaesthesia. Myasthenia gravis Toxicity- muscarinic stimulants  Overdose eg in organophosphate poisoning results in:  Nausea & Vomitting  Diarrhea  Urinary urgency  Salivation  Sweating  Bronchoconstriction  These effects are blocked by atropine. ANTICHOLINERGICS. Anticholinergics  Also known as antimuscarinic or parasympatholytic agents  Divided into muscarinic & nicotinic subgroups  Atropine (hyoscyamine) is the prototype drug- found in the plant Atropa belladona  Other examples- Scopolamine, homatropine Pharmacokinetics- Atropine  Well absorbed from the gut & conjunctiva  Widely distributed in the body, including into the CNS  50% of the dose is excreted unchanged in urine Mechanism of action  Atropine causes reversible (surmountable) blockade of cholinomimetic actions at muscarinic receptors. Organ system effects 1. CNS - Scopolamine causes drowsiness - Toxic doses cause hallucinations, agitation & coma - Reduce tremor of Parkinson’s disease - Useful in treatment of motion sickness 2. Eye  Block pupillary constrictor muscles leading to mydriasis (pupil dilatation)  Weaken contraction of the ciliary muscles (cycloplegia)  Reduce lacrimal secretion 3. CVS  Cause tachycardia 4. Respiratory system  Cause bronchodilation & reduce secretions  Used before administration of inhalant anesthetics to reduce the accumulation of secretions in the trachea and the possibility of laryngospasm. 5. GIT  Reduce salivary secretions 6. GUT  Relaxes smooth muscle of the ureters and bladder wall and slows voiding.  Can precipitate urinary retention in men who have prostatic hyperplasia Clinical uses 1. CNS disorders- Parkinson’s disease, motion sickness. 2. Eye- useful if both mydriasis & cycloplegia are required 3. Respiratory disorders- Ipratropium, a synthetic analog of atropine, is used in asthma. - Tiotropium is used in COPD. 4. Cholinergic excess- eg. organophosphate poisoning Toxicity  Atropine excess manifests clinically as dry mouth, mydriasis, tachycardia, hot and flushed skin, agitation, and delirium THE END.