Anticholinesterase

Physostigmine

It is a natural alkaloid obtained from Physostigma venenosum (Calabar bean).
It inhibit ChE, protect ACh from hydrolysis-produce cholinergic effects.
It is an ester of carbamic acid.
It is a tertiary amino compound-lipid soluble

Mechanisms of action

It bind to the anionic site (Glu) of cholinesterase enzyme, same way as acetylcholine. The carbamyl group is transferred to esteratic site (Ser). However the carbamylated enzyme is much slower to hydrolyze, thereby reducing the recovery of enzyme activity.

Pharmacological actions

More marked muscarinic and CNS effects
Stimulate ganglia but action on skeletal muscles is less prominent.

-Ganglia: stimulate ganglia primarily through muscarinic receptors present there. High doses cause persistent depolarization of the ganglionic nicotinic receptors and blockade of transmission.
-CVS: overall effects are often unpredictable.
Skeletal muscle: force of contraction increased. Repetitive firing, twitching and fasciculations are seen. Higher doses cause persistent depolarization of endplates resulting in blockade of neuromuscular transmission→ weakness and paralysis.
-CNS: it penetrates into brain produce a generalized alerting response→ improve cognitive function in Alzheimer’s disease. However higher doses produce excitement, mental confusion, disorientation, tremors, convulsions and coma.
Other effects:- these result from stimulation of smooth muscle and glands of the gastrointestinal, respiratory, urinary tracts and in the eye producing cholinergic effects

Pharmacokinetics

It is rapidly absorbed from g.i.t. and parenteral sites. Applied to eye it penetrate cornea freely.
It crosses blood-brain barrier and is disposed after hydrolysis by ChE.

Uses: As a miotic in glaucoma to supplement pilocarpine.
In belladonna poisoning it is given as 0.5-2 mg i.v. repeated as required.
Other drug overdosages- Tricyclic antidepressants, phenothiazines. Antihistaminics etc. have additional anticholinergic property. Overdose symptoms and coma produced by these drugs are partly antagonized by physostigmine.

Dose: 0.5-1 mg oral/parenteral
0.1-1.0% eye drops

Duration of action: Systemic 4-6 hrs
In eye 6-24 hrs

• Physiostigmine causes significant and often profound increase in pulse rate and blood pressure levels. It causes net increase in pulse up to 74 beaats/ min, systolic blood pressure increase up to 50 mm Hg and diastolic increase of up to 45 mm Hg. (1)
• Infant who developed respiratory distress after ocular instillation of cyclopentolate can be successfully treated with physiostigmine. (2)
• Physiostigmine can be used in the treatment of gamma-hydroxybutyrate toxicity. (3)
• Physiostigmine can be used for the treatment of severe CNS anticholinergic toxicity. (4)
• The most important measures in the treatment of physiostigmine poisoning are mechanical ventilation, with repeated bronchial aspiration and gastric lavage with potassium permanganate solution to oxidise any unabsorbed drug. (5)
• Scopolamine causes reduction of mean flow, frontal deficit and memory impairment in patients which is cholinergically mediated. This scopolamine induced hypofrontality is reversed by physiostigmine. (6)
• Physiostigmine can be used in the treatment of γ-Hydroxybutyric acid overdose. (7)
• Physiostigmine has been shown to reverse the effects of certain drugs with anticholinergic properties. Physostigmine administration can induce seizures in some patients. (8)
• A symptom free pretreatment with subchronic physiostigmine could protect man sufficiently against severe soman intoxication. (9)
• physiostigmine is more effective and safer than benzodiazepine for the treatment of anticholinergic agitation and delirium. (10)
• Physiostigmine is commonly used therapy for the anticholinergic manifestations of tricyclic antidepressant (TCA) overdose. Patients may develop asystole following the administration of physiostigmine to treat seizures. (11)
• Physiostigmine has channel blocking and agonist effects on the acetylcholine receptor ion channel complex. (12)
• A significant improvement is seen on a picture recognition test with intravenous administration of physiostigmine 0.375 mf and arecholine 4 mg in patients with alzheimer presenile dementia. (13)
• A single dose of physiostigmine intraoperativey has a sustained anti-inflammatory effect up to 120min after injection that is especially pronounced under the conditions of partial liver resection surgery. In addition to its protective peripheral action, physiostigmine exerts neuroprotective action by increasing levels of the neurotransmitter ACH. (14)
• There is an improvement in confrontation naming but not other measures of cognition or mood during open label physiostigmine treatment. It appears to improve naming in patients with anomia. (15)
• There is an interaction of physiostigmine and alfentanil on pain and hyperalgesia. (16)
• Physiostigmine may induce relatively blunted increases in serum epinephrine levels in patients with affective disorders. (17)
• Physiostigmine causes reduction of obstructive sleep apnea, thus may be a treatment option for obstructive sleep apnea syndrome. (18)
• A significant proportion of preschool children experiences severe emergence agitation after anaesthesia. The symptoms include disorientation, restlessness, inconsolable crying and thrashing which resemble acute psychosis. Physiostigmine is effective in the treatment of this emergence agitation. (19)
• Physiostigmine may slow the course of the disease or may acutely improve symptoms when combined with other agents in patients with primary degenerative dementia. (20)
• The mood and behavioural effects of physiostigmine on humans are accompanied by elevations in plasma beta-endorphin and cortisol. (21)

References:

DS Janowsky, SC Risch, LY Huey. Central cardiovascular effects of physiostigmine in humans. Hypertension. 1985;7:140-145.
Oksan Derinoz, Hamdi C Emeksiz. Use of physiostigmine for cyclopentolate overdose in an infant. Pediatrics. Sept 2012;130(3):e703-e705.
Traub SJ, Nelson LS, Hoffman RS. Physiostigmine as a treatment for gamma-hydroxybutyrate toxicity: a review. J Toxicol Clin Toxicol. 2002;40(6):781-7.
R Teoh, AV Page, R Hardern. Physiostigmine as treatment for severe CNS anticholinergic toxicity. Emerg Med J. 2001;18:412.
G Cumming, LK Harding, K Prowse. The Lancet. July 1968;292(7560):147-149.
I Prohovnik, SE Arnold, G Smith, LR Lucas. Physiostigmine reversal of scopolamine induced hypofrontality. Journal of cerebral blood flow & metabolism. 1997;17:220-228.
Scott Yates. Physiostigmine treatment of γ-Hydroxybutyric acid overdose: Appropriate or inappropriate use of a reversal agent?: In response. Mayo Clinic Proceedings. AUg 2000;75(8):872-873.
William E Walker, Richard C Levy, Irwin B Hanenson. Physiostigmine- its use and abuse. Journal of the American College of Emergecy Physicians. JUne 1976;5(6):436-439.
IHCHM Philippens, RAP Vanwersch, B Groen, B Olivier, PLB Bruijnzel, BPC Melchers. SUbchronic physiostigmine pretreatment in Marmosets: absence of side effects and effectiveness against soman poisoning with negligible postintoxication incapacitaton. Toxicol Sci. 2000;53(1):84-91.
Burns MJ, Linden CH, Graudins A, Brown RM, Fletcher KE. A comparison of physiostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med. April 2000;35:374-381.
Paul Pentel, CHarkes D Peterson. Asystole complicating physiostigmine treatment of tricyclic antidepressant overdose. Annals of emergency medicine. Nov 1980;9(11):588-590.
KP Shaw, Y Aracava, A Akaike et al. The reversible cholinesterase inhibtior phsiostigmine has channel blocking and agonist effects on the acetylcholine receptor ion channel complex. Molecular Pharmacology. Dec 1985;28(6):527-538.
JE Christie, A Shering, J Ferguson, AI Glen. Physiostigmine and arecoline: effects of intravenous infusions in Alzheimer presenile dementia. Psychiatry. 1981;138:46-50.
Konstanze Plaschke, Ann Katrin Muller, Jurgen Kopitz. Surgery induced changes in rat IL 1β and acetylcholine metabolism: role of physiostigmine. May 2014. DOI: 10.1111/1440-1681.12267.
Daniel H Jacobs, Jeffrey Shuren, Michael Gold, John C Adair et al. Physiostigmine pharmacotherapy for anomia. Neurocase: The neural basis of cognition. 1996;2(2):83-91.
Wehrfritz A, Schmidt S, Mueller C, Ihmsen H, Koppert W. Interaction of physiostigmine and alfentanil in a human pain model: 14AP12-1. European journal of anaesthesiology. May/June 2008;25:221.
Physiostigmine induced epinephrine release in patients with affective disorder. Am J Psychiatry. 1986;143:919-921.
Jan Hedner, Holger Kraiczi, Yuksel Peker, Paul Murphy. Reduction of sleep disordered breathing after physiostigmine. American journal of respiratory and critical care medicine. 2003;168(10):1246-1251.
W Funk, H Hollnberger, J Geroldinger. Physiostigmine an danaesthesia emergence delirium in preschool children: a randomized blinded trial. European journal of anaesthesiology. Jan 2008;25(1):37-42.
Michael A Jenike, Marilyn Albert, Lee Baer, Jeanette Gunther. Oral physiostigmine as treatment for primary degenrative dementia: A double blind placebo controlled inpatient trial. J Geriatr Psychiatry Neurol. Jan 1990;3(1):13-16.
Mood and behavioral effects of physiostigmine on humans are accompanied by elevations in plasma beta-endorphin and cortisol. Scoence. Sept 1980;209(4464):1545-1546.