MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics- Anticholinesterases Dr. S. Parthasarathy MD., DA., DNB, MD (Acu), Dip. Diab. DCA, Dip. Software statistics- PhD ( physiology), IDRA

What are these ? These agents are used in clinical practice to inhibit the action of acetylcholinesterase at the neuromuscular junction, thus prolonging the half-life of acetylcholine So it antagonizes neuromuscular blockade

Cholinesterase means acetyl cholinesterase – true Edrophoni Phos Acetylate Neo Opc

Pouring acetyl choline in junctions Antagonizes neuro muscular blockers Initiate depolarization Start contraction Also presynaptic action If we don’t have blockers at the site , it may cause persistent depolarization to cause weakness

Its pouring acetyl choline !! The anticholinesterases produce effects equivalent to excessive stimulation of the cholinergic system, i.e. stimulation of muscarinic receptor responses at the autonomic effector organs, and stimulation of cholinergic receptors in the CNS.

Drugs – structure Neostigmine Pyridostigmine Edrophonium Physostigmine No NH4+ Crosses membranes Edrophonium Physostigmine

Organophosphorous compounds – lipid soluble – cross BBB

Systems

CVS Vagal influence of conducting tissue Bradycardia Decreased BP and output

Respiratory system cause bronchial smooth muscle contraction leading to bronchospasm and hypoxia, aggravated by an increase in secretions

GIT Oesophageal motility, gastric motility and production of gastric secretions are enhanced Rarely vomiting

Local application on eye Miosis Loss of accommodation

Tacrine is a short-acting anticholinesterase that can cross the blood–brain barrier producing central effects. used in the past to extend the duration of action of succinylcholine. Currently, it is used in the management of Alzheimer’s disease.

Edrophonium Dose 0.5 to 1 mg / kg Onset 1 minute Duration 10 minutes Need spontaneous recovery Atropine

Neostigmine 50 – 60 mic/ kg 1 minute 20 – 30 minute Glyco 15 mg neostigmine bromide PO is equivalent to 0.5 mg neostigmine methylsulfate parenteral Nausea Intestinal obstruction Phase 2 block ??

Pyridostigmine Derivative of neostigmine Onset - 16 minutes duration - 6 hours Not for reversal Myaesthenia

Physostigmine Physostigmine (also known as eserine from éséré, the West African name for the Calabar bean) is a parasympathomimetic alkaloid, Physostigmine is metabolized by plasma esterases; elimination does not depend on renal excretion, but others depend

Uses of physo Physostigmine is used to treat glaucoma, Alzheimer's disease, and delayed gastric emptying. It has been shown to improve long term memory. Recently, it has begun to be used in the treatment of orthostatic hypotension.

Physostigmine Because it is a tertiary amine, it can cross the blood–brain barrier, and physostigmine salicylate is used to treat the central nervous system effects of atropine, scopolamine, and other anticholinergic drug overdoses. Physostigmine is the antidote of choice for Datura stramonium poisoning. It is also an antidote for Atropa belladonna poisoning, the same as for atropine

Pharmacokinetics- neostigmine Metabolism Liver microsomal enzymes and hydrolysis by cholinesterase enzymes Elimination Half-Life: 47-60 min (IV); 51-90 min (IM); 42-60 min (PO) Excretion: 50% urine

Tensilon test Discontinue all anticholinesterase agents for >8 hr Give atropine 0.011 mg/kg IV (if IM give 30 minutes before) with neostigmine 0.022 mg/kg IM If cholinergic response, stop test and give 0.4-0.6 mg atropine IV If inconclusive, retest another day with neostigmine 0.031 mg/kg IM preceded by 0.016 mg/kg atropine

Edrophonium is used mainly to diagnose myasthenia gravis. A test dose of 2 mg followed 30 s later by 8 mg i.v. causes transient improvement in muscle power. Myesthenic crisis or cholinergic crisis

Myasthenia gravis Acute: 0.5-2.5 mg IV/IM/SC q Day Maintenance: 15-375 mg/day PO divided q6-8hr Use injectable with 0.6-1.2 mg atropine IV to counteract muscarinic effects

Nondepolarizing Neuromuscular Blockade, Reversal 30 – 70 mic./kg Dose varies with type of drug, time duration after NMBs Administer an IV anticholinergic (eg, atropine, glycopyrrolate) prior to, or concomitantly with neostigmine for NMB reversal; if bradycardia present, give anticholinergic before neostigmine

Alzheimer’s disease A deficiency of structurally intact cholinergic neurones leads to progressive dementia in patients with Alzheimer’s disease Donezipil Rivastigmine

Post op urinary retention Prevention: Neo -- 0.25mg IM after surgery. Repeat q4-6hr for 2-3 days Treatment: 0.5-1 mg IM and up to q3hr PRN (for 5 doses for retention) Colonic Pseudo-obstruction

Central anticholinergic syndrome . It can be reversed by intravenous physostigmine 2 mg followed by additional doses as required. Chemical warfare Oximes and atropine

Side effects Allergic: Allergic reactions and anaphylaxis Neurologic: Dizziness, convulsions, loss of consciousness, drowsiness, headache, dysarthria, miosis and visual changes Cardiovascular: Cardiac arrhythmias (including bradycardia, A-V block and nodal rhythm) and nonspecific EKG changes have been reported,

Side effects Respiratory: Increased oral, pharyngeal and bronchial secretions, and dyspnea; respiratory depression, respiratory arrest and bronchospasm have been reported following the use of the injectable form

Frequency of side effects not studied Dermatologic: Rash and urticaria Gastrointestinal: Nausea, emesis, flatulence, and increased peristalsis and salivation Genitourinary: Urinary frequency Musculoskeletal: Muscle cramps and spasms, arthralgia Miscellaneous: Diaphoresis, flushing and weakness

Possible intraarticular neostigmine – used for analgesia

Summary Ach – cholinesterase – anticholinesterase – pour Ach every where Types Anionic – esteritic sites – Uses Side effects