In Tg(+) mice, physostigmine (Eserine; 0.03-0.3 mg/kg; subcutaneous injection; administered daily for 6 weeks) can ameliorate cued memory deficits and contextual memory impairments [2]. At doses ≥0.2 mg/kg, physostigmine (intravenous; 0.1, 0.2 mg/kg) postpones the awakening of male Sprague-Dawley rats from isoflurane anesthesia [4].

Animal/Disease Models: Heterozygous transgenic mice (Tg(+) mice) [2]
Doses: 0.03, 0.1 and 0.3 mg/kg
Route of Administration: SC; one time/day for 6 weeks
Experimental Results: Tg(+) Animal Situation Memory deficits normalized, causing them to become more similar to Tg(-) animals.

Absorption, Distribution and Excretion
PHYSOSTIGMINE IS READILY ABSORBED FROM GI TRACT, SC TISSUES, & MUCOUS MEMBRANES. ... RENAL EXCRETION PLAYS ONLY MINOR ROLE IN ITS DISPOSAL.
PHYSOSTIGMINE, A TERTIARY AMINE, CROSSES THE BLOOD-BRAIN BARRIER IN CONTRAST TO THE QUATERNARY ANTI-ACETYL CHOLINESTERASE DRUGS. /ACETYLCHOLINESTERASE/
Easily penetrates the blood-brain barrier.
Time to peak effect: iv within 5 min; duration of action: iv approximately 1 to 2 hr.
Very small amounts eliminated in urine; largely destroyed in body by hydrolysis.

---

Metabolism / Metabolites
Quickly hydrolyzed by cholinesterases
/PHYSOSTIGMINE/ IS LARGELY DESTROYED IN BODY, MAINLY BY HYDROLYTIC CLEAVAGE @ ESTER LINKAGE BY PLASMA ESTERASES. ... IN MAN, 1 MG DOSE ... INJECTED SC IS LARGELY DESTROYED IN 2 HR.
/PHYSOSTIGMINE/ COMBINES WITH THE ENZYME AT THE ESTERATIC SITE TO YIELD THE INACTIVE METHYLCARBAMOYL ENZYME.
Rapidly hydrolyzed by cholinesterases.

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of physostigmine during breastfeeding.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information in nursing mothers was not found as of the revision date. In animals, cholinergic drugs increase oxytocin release, and physostigmine increases serum prolactin in humans. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

---

Interactions
ACTIONS OF ANTICHOLINESTERASE AGENTS ON AUTONOMIC EFFECTOR CELLS & ON CORTICAL & SUBCORTICAL SITES IN CNS, WHERE RECEPTORS ARE LARGELY OF MUSCARINIC TYPE, ARE BLOCKED BY ATROPINE. /ANTI-CHOLINESTERASE AGENTS/
VARIOUS ACTIONS OF ANTI-CHOLINESTERASE AGENTS ON SKELETAL MUSCLE ARE AUGMENTED BY EPINEPHRINE OR EPHEDRINE ... & BLOCKED BY D-TUBOCURARINE. /ANTICHOLINESTERASEAGENTS/
SUFFICIENT CONCN OF ... PHYSOSTIGMINE ... PREVENTS ALKYLPHOSPHORYLATION OF ACETYLCHOLINESTERASE BY DIISOPROPYLFLUORO PHOSPHATE OCCUPATION OF ACTIVE SITES OF /CHOLINESTERASE/ ENZYME BY THE SHORTER ACTING DRUG PREVENTS ... ALKYLPHOSPHORYLATION BY ORGANOPHOSPHORUS CMPD ... IN VITRO & IN VIVO.
TOXOGONIN GIVEN 15 MIN PRIOR TO ADMIN OF PHYSOSTIGMINE CAUSED REDN IN TOXICITY TO MICE OF PHYSOSTIGMINE. PRALIDOXIME MESYLATE ALSO CAUSED SLIGHT REDN.
For more Interactions (Complete) data for PHYSOSTIGMINE (9 total), please visit the HSDB record page.

[1]. Pharmakotherapie--physostigmin post OP [Pharmacotherapy--physostigmine administered post-operatively]. Anasthesiol Intensivmed Notfallmed Schmerzther. 2007;42(3):188‐189.

[2]. Dong H, et al, Bertchume A, Vallera D, Csernansky JG. Acetylcholinesterase inhibitors ameliorate behavioral deficits in the Tg2576 mouse model of Alzheimer's disease. Psychopharmacology (Berl). 2005;181(1):145‐152.

[3]. Frascogna N. Physostigmine: is there a role for this antidote in pediatric poisonings? Curr Opin Pediatr. 2007;19(2):201‐205.

[4]. Physostigmine and Methylphenidate Induce Distinct Arousal States During Isoflurane General Anesthesia in Rats. Anesth Analg. 2016 Nov;123(5):1210-1219.

Physostigmine is a white, odorless, microcrystalline powder. Used as a cholinergic (anticholinesterase) agent and as a veterinary medication. (EPA, 1998)
Physostigmine is a carbamate ester and an indole alkaloid. It has a role as a miotic, an EC 3.1.1.8 (cholinesterase) inhibitor and an antidote to curare poisoning.
A cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity.
Physostigmine has been reported in Streptomyces, Physostigma venenosum, and other organisms with data available.
A cholinesterase inhibitor that is rapidly absorbed through membranes. It can be applied topically to the conjunctiva. It also can cross the blood-brain barrier and is used when central nervous system effects are desired, as in the treatment of severe anticholinergic toxicity.
See also: Physostigmine Salicylate (has salt form).

---

Drug Indication
For the treatment of glaucoma, and in the treatment of severe anticholinergic toxicity.

---

Mechanism of Action
Physostigmine inhibits acetylcholinesterase, the enzyme responsible for the breakdown of used acetylcholine. By interfering with the metabolism of acetylcholine, physostigmine indirectly stimulates both nicotinic and muscarinic receptors due to the consequential increase in available acetylcholine at the synapse.
CHARACTERISTIC PHARMACOLOGICAL EFFECTS OF ANTICHOLINESTERASE AGENTS ARE DUE PRIMARILY TO PREVENTION OF HYDROLYSIS OF ACETYLCHOLINE BY ACETYLCHOLINESTERASE @ SITES OF CHOLINERGIC TRANSMISSION. TRANSMITTER THUS ACCUMULATES, AND THE ACTION OF ACETYLCHOLINE THAT IS LIBERATED BY CHOLINERGIC IMPULSES OR THAT LEAKS FROM THE NERVE ENDING IS ENHANCED. /ACETYLCHOLINE/
... PHYSOSTIGMINE, A TERTIARY AMINE, EXERTS /MINIMAL/ EFFECTS NOT RELATED TO ACETYLCHOLINESTERASE INHIBITION. AT SUFFICIENTLY HIGH DOSAGE, HOWEVER, IT HAS DIRECT BLOCKING ACTION AT AUTONOMIC GANGLIA.
In chronic open-angle glaucoma, the exact mechanism by which miotics lower intraocular pressure is not precisely known; however, contraction of the ciliary muscle apparently opens the intratubular spaces and facilitates aqueous humor outflow.
Antagonizes action of anticholinergics, which block the post-synaptic receptor sites of acetylcholine, by inhibiting the destruction of acetylcholine by acetylcholinesterase, thereby increasing the concentration of acetylcholine at sites of cholinergic transmission.

---

Therapeutic Uses
Antidotes; Cholinesterase Inhibitors; Miotics; Parasympathomimetics
ANTICHOLINESTERASE AGENTS ARE OF GREAT VALUE IN MANAGEMENT OF PRIMARY /GLAUCOMA/AS WELL AS OF CERTAIN CATEGORIES OF SECONDARY /GLAUCOMA/ ... (EG APHAGIC GLAUCOMA, FOLLOWING CATARACT EXTRACTION); THE CONGENITAL TYPE RARELY RESPONDS TO OTHER THAN SURGICAL TREATMENT. PRIMARY GLAUCOMA IS SUBDIVIDED INTO NARROW-ANGLE (ACUTE CONGESTIVE) AND WIDE-ANGLE (CHRONIC SIMPLE) TYPES ... ANTICHOLINESTERASE AGENTS PRODUCE A FALL IN INTRAOCULAR PRESSURE IN BOTH TYPES ... BY LOWERING THE RESISTANCE TO OUTFLOW OF THE AQAEOUS HUMOR. ... /IN/ ACUTE CONGESTIVE GLAUCOMA ... MIOSIS IS ACHIEVED BY THE APPLICATION OF PILOCARPINE. ONE OR TWO DROPS OF 2% OR 4% PILOCARPINE NITRATE IS ADMINSTERED AT 10 TO 15 MIN INTERVALS FOR 1 HR; THEREAFTER, THE DRUG IS GIVEN EVERY 2 TO 3 HR. SOME OPHTHALMOLOGISTS ADMINISTER PHYSOSTIGMINE SALICYLATE IN ADDITION TO PILOCARPINE. ... CHRONIC WIDE-ANGLE & SECONDARY GLAUCOMA REQUIRE CAREFUL CONSIDERATION OF THE NEEDS OF THE INDIVIDUAL PATIENT IN SELECTING DRUG OR COMBINATION OF DRUGS ... CHOICES AVAIL INCLUDE ... ANTICHOLISNESTERASE AGENTS THAT ARE SHORT ACTING (EG PHYSOSTIGMINE SALICYLATE, 0.25% AND 0.5%) ... . /PHYSOSTIGMINE SALICYLATE/
IN CONTRAST /TO TREATMENT OF GLAUCOMA WITH POTENT, LONG ACTING ANTI-CHOLINESTERASE AGENTS/, TREATMENT WITH PILOCARPINE (4%), ALONE OR IN COMBINATION WITH PHYSOSTIGMINE (0.2%), 1-5 TIMES DAILY, WAS FOUND TO ENTAIL NO HIGHER INCIDENCE OF DEVELOPMENT OF LENTICULAR OPACITIES THAN APPEARED SPONTANEOUSLY IN UNTREATED PATIENTS IN COMPARABLE AGE GROUP.
MANY OF THE PERIPHERAL & CENTRAL EFFECTS OF ... ATROPINE & RELATED ANTIMUSCARINIC DRUGS CAN BE REVERSED BY IV ... PHYSOSTIGMINE. THE EFFECTIVENESS OF PHYSOSTIGMINE SALICYLATE MAY BE USEFUL IN REVERSING THE CENTRAL ANTICHOLINERGIC SYNDROME PRODUCED BY OVERDOSAGE OR AN UNUSUAL REACTION TO THESE DRUGS. INITIAL IV OR IM DOSE OF 2 MG IS INDICATED WITH ADDITIONAL INCREMENTS GIVEN AS NECESSARY.
For more Therapeutic Uses (Complete) data for PHYSOSTIGMINE (20 total), please visit the HSDB record page.

---

Drug Warnings
PHYSOSTIGMINE OFTEN CAUSES HYPEREMIA OF CONJUNCTIVA. ... RARELY TOLERATED FOR PROLONGED PERIODS BECAUSE CONJUNCTIVITIS & ALLERGIC REACTIONS OCCUR FREQUENTLY. LONG TERM ADMIN CAN PRODUCE FOLLICLES IN THE CONJUNCTIVA. IN PROLONGED TREATMENT WITH PHYSOSTIGMINE OINTMENT MAY CAUSE PIGMENTATION OF LID MARGINS.
THE CONJUNCTIVAL INSTILLATION OF SOLN ... MAY RESULT IN SYSTEMIC EFFECTS IF MEASURES (EG PRESSURE ON INNER CANTHUS) ARE NOT TAKEN TO PREVENT ABSORPTION FROM NASAL MUCOSA.
... CONTRAINDICATED IN ASTHMATIC PATIENT. IT SHOULD NOT BE EMPLOYED ALONG WITH CHOLINE ESTERS EXCEPT FOR OPHTHALMOLOGIC USE. /NEOSTIGMINE/
VET: ITS CATHARTIC ACTION IN CATTLE IS OFTEN PAINFUL. ... CONTRAINDICATED IN ... IMMOVABLE INTESTINAL OBSTRUCTION, CARDIAC OR PULMONARY DISEASES, & IN AGED ... ANIMALS.
For more Drug Warnings (Complete) data for PHYSOSTIGMINE (12 total), please visit the HSDB record page.

---

Pharmacodynamics
Physostigmine is a parasympathomimetic, specifically, a reversible cholinesterase inhibitor which effectively increases the concentration of acetylcholine at the sites of cholinergic transmission. Physostigmine is used to treat glaucoma. Because it crosses the blood-brain barrier, it is also used to treat the central nervous system effects of atropine overdose and other anticholinergic drug overdoses. Physostigmine can reverse both central and peripheral anticholinergia.

C15H21N3O2

275.34614

275.163

57-47-6

Physostigmine salicylate;57-64-7;Physostigmine hemisulfate;64-47-1;Physostigmine-d3;1217704-11-4

5983

Brown to black solid powder

1.2±0.1 g/cm3

422.3±55.0 °C at 760 mmHg

102-104 °C(lit.)

209.2±31.5 °C

0.0±1.1 mmHg at 25°C

1.616

1.89

1

4

2

20

403

2

C[C@@]12CCN([C@@H]1N(C3=C2C=C(C=C3)OC(=O)NC)C)C

PIJVFDBKTWXHHD-HIFRSBDPSA-N

InChI=1S/C15H21N3O2/c1-15-7-8-17(3)13(15)18(4)12-6-5-10(9-11(12)15)20-14(19)16-2/h5-6,9,13H,7-8H2,1-4H3,(H,16,19)/t13-,15+/m1/s1

(3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-yl methylcarbamate

Physostigmine Eserine Antilirium Physostol Esromiotin Ezerin

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~50 mg/mL (~181.59 mM)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.08 mM) (saturation unknown) in 10% DMSO + 40% PEG300 +5% Tween-80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 + to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

---

 (Please use freshly prepared in vivo formulations for optimal results.)