Neostigmine

Breast Feeding; Lactation; Milk, Human; Cholinesterase Inhibitors; Parasympathomimetics

Muscle relaxants (peripherally-acting) and cholinesterase inhibitors

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-CHE AGENTS/

VARIOUS ACTIONS OF ANTI-CHE AGENTS ON SKELETAL MUSCLE ARE AUGMENTED BY EPINEPHRINE OR EPHEDRINE...& BLOCKED BY D-TUBOCURARINE. /ANTICHOLINESTERASE AGENTS/

QUINIDINE MAY ANTAGONIZE THE EFFECTS OF NEOSTIGMINE (PROSTIGMINE)...IN THE TREATMENT OF MYASTHENIA GRAVIS. ...THE ANTICHOLINERGIC EFFECT OF QUINIDINE MAY ANTAGONIZE THE VAGAL-STIMULATING EFFECT OF CHOLINERGIC DRUGS. QUINIDINE SHOULD BE USED WITH CAUTION IN PATIENTS WITH MYASTHENIA GRAVIS WHO ARE BEING TREATED WITH CHOLINERGIC DRUGS.

Neostigmine failed to modify the development of neuromuscular block in the presence of a high local concn of tubocurarine.

For more Interactions (Complete) data for NEOSTIGMINE (13 total), please visit the HSDB record page.

Several adverse effects of neostigmine can affect multiple organ systems, most of which are related to the cholinergic adverse effects of the drug. Cardiac muscarinic effects include bradyarrhythmias like junctional escape rhythms, complete heart block, and asystole. One potentially life-threatening adverse effect of neostigmine is bronchoconstriction. Neostigmine and other anticholinesterase inhibitors can stimulate the muscarinic receptors in the airway smooth muscle, potentially leading to bronchospasm. Other adverse effects include increased secretions, miosis, nausea, and increased peristalsis.

Signs and Symptoms of OverdoseNeostigmine overdose may cause muscarinic symptoms such as nausea, vomiting, diarrhea, sweating, increased bronchial and salivary secretions, and bradycardia. A severe overdose can also cause a cholinergic crisis, which can cause muscle weakness and may result in death due to the involvement of respiratory muscles. Distinguishing between cholinergic and myasthenic crises is crucial, as their management differs.

EFFECTS...ON CNS ARE...CHARACTERIZED BY STIMULATION OR FACILITATION @ VARIOUS SITES, SUCCEEDED BY INHIBITION OR PARALYSIS @ HIGHER CONCN. ... RESPIRATORY & OTHER SUBCORTICAL CENTERS LIKEWISE SHOW STIMULATION AFTER LOW DOSES & DEPRESSION WITH HIGHER OR TOXIC DOSES. /ANTI-CHOLINESTERASE AGENTS/

MISCELLANEOUS OCULAR SIDE EFFECTS THAT MAY OCCUR FOLLOWING LOCAL INSTILLATION OF ANTI-CHE AGENTS ARE HEADACHE, BROW PAIN, BLURRED VISION, PHACODINESIS, PERICORNEAL INJECTION, CONGESTIVE IRITIS, VARIOUS ALLERGIC REACTIONS, AND RARELY, RETINAL DETACHMENT. WHEN ANTI-CHE DRUGS ARE INSTILLED INTRACONJUNCTIVALLY AT FREQUENT INTERVALS, SUFFICIENT ABSORPTION MAY OCCUR TO PRODUCE VARIOUS SYSTEMIC EFFECTS, WHICH RESULT FROM INHIBITION OF TISSUE ACHE... /ANTI-CHOLINESTERASE AGENTS/

GASTROINTESTINAL SYMPTOMS OCCUR EARLIEST AFTER INGESTION, & INCL ANOREXIA, NAUSEA & VOMITING, ABDOMINAL CRAMPS, & DIARRHEA. WITH PERCUTANEOUS ABSORPTION OF LIQ, LOCALIZED SWEATING & MUSCULAR FASCICULATION IN IMMEDIATE VICINITY ARE GENERALLY EARLIEST MANIFESTATIONS. NICOTINIC ACTIONS AT NEUROMUSCULAR JUNCTIONS OF SKELETAL MUSCLE...FATIGABILITY AND GENERALIZED WEAKNESS, INVOLUNTARY TWITCHINGS...SEVERE WEAKNESS & PARALYSIS...THE MOST SERIOUS CONSEQUENCE...IS PARALYSIS OF RESPIRATORY MUSCLES. /ANTI-CHOLINESTERASE AGENTS/

...EFFECTS ON CNS INCL CONFUSION, ATAXIA, SLURRED SPEECH, LOSS OF REFLEXES, CHEYNE-STOKES RESPIRATION, GENERALIZED CONVULSIONS, COMA, & CENTRAL RESPIRATORY PARALYSIS. ... TIME OF DEATH AFTER SINGLE ACUTE EXPOSURE MAY RANGE FROM LESS THAN 5 MINUTES TO NEARLY 24 HR, DEPENDING UPON DOSE, ROUTE, AGENT... CAUSE OF DEATH IS PRIMARILY RESPIRATORY FAILURE, USUALLY ACCOMPANIED BY A SECONDARY CARDIOVASCULAR COMPONENT. /ANTI-CHOLINESTERASE AGENTS/

Neostigmine induced (0.1-1 mM) positive inotropic effects on driven guinea pig isolated atria. Neostigmine also incr cardiac frequency of spontaneously beating atria. The positive inotropic effect of neostigmine was not caused by a nicotine-like action of the drug.

Morphological techniques were used to determine the acute and chronic effects of neostigmine on rat muscles. Transient calcium deposits were independent of fiber type and found at sites corresponding to neostigmine-induced focal lesions. Characteristic intermediate findings consisted of rod bodies and ribosomal clusters. Such clusters were frequently mingled and clumped sarcoplasmic reticulums, T-systems, or mitochondria. The focal myopathic changes were reversible with the exception of those in the synaptic region of the end plates.

1) ESTABLISH CLEAR AIRWAY & TISSUE OXYGENATION BY ASPIRATION OF SECRETIONS & IF NECESSARY, BY ASSISTED PULMONARY VENTILATION WITH OXYGEN. IMPROVE TISSUE OXYGENATION AS MUCH AS POSSIBLE BEFORE ADMINISTERING ATROPINE TO MINIMIZE THE RISK OF VENTRICULAR FIBRILLATION. /CARBAMATES, CHOLINESTERASE INHIBITORS/

2) ADMIN ATROPINE SULFATE IV, OR IM IF IV INJECTION IS NOT POSSIBLE... IN MODERATELY SEVERE POISONING: ADULT DOSAGE, INCLUDING CHILDREN OVER 12 YR: 0.4-2.0 MG REPEATED EVERY 15 MIN UNTIL ATROPINIZATION IS ACHIEVED (TACHYCARDIA, FLUSHING, DRY MOUTH, MYDRIASIS). MAINTAIN ATROPINIZATION BY REPEATED DOSES FOR 2-12 HR, OR LONGER, DEPENDING ON SEVERITY OF POISONING... DOSAGE FOR CHILDREN UNDER 12 YEARS: 0.05 MG/KG BODY WT REPEATED EVERY 15 MIN UNTIL ATROPINIZATION IS ACHIEVED. MAINTAIN ATROPINIZATION WITH REPEATED DOSAGE OF 0.02-0.05 MG/KG. SEVERELY POISONED INDIVIDUALS MAY EXHIBIT REMARKABLE TOLERANCE TO ATROPINE; TWICE THE DOSES SUGGESTED ABOVE MAY BE NEEDED... /CARBAMATES, CHOLINESTERASE INHIBITORS/

3. PRALIDOXIME (PROTOPAM-AYERST, 2-PAM) IS OF DOUBTFUL VALUE IN POISONINGS BY CARBAMATE INHIBITORS OF CHOLINESTERASE. ATROPINE ALONE IS ALMOST ALWAYS AN ADEQUATE ANTIDOTE. PRALIDOXIME IS PROBABLY CONTRAINDICATED IN POISONINGS BY CARBARYL, SPECIFICALLY. IF VICTIM OF CARBAMATE POISONING EXHIBITS SEVERE MUSCLE WEAKNESS &/OR RESPIRATORY DEPRESSION, OR IF POISONING INVOLVES A COMBINATION OF CARBAMATE & ORGANOPHOSPHATE, A DILUTE SOLUTION OF PRALIDOXIME (TOTAL DOSE IN 250 ML 5% GLUCOSE SOLN) MAY BE GIVEN CAUTIOUSLY IV. THE INFUSION SHOULD BE TERMINATED IF PATIENT'S CONDITION WORSENS. PRALIDOXIME DOSAGE: ADULTS, 1.0 G; FOR CHILDREN UNDER 12 YR, 20-50 MG/KG. 4. OBSERVE TREATED PATIENTS CLOSELY AT LEAST 24 HR TO INSURE THAT SYMPTOMS (POSSIBLY PULMONARY EDEMA) DO NOT RECUR AS ATROPINIZATION WEARS OFF. IN VERY SEVERE POISONINGS, METABOLIC DISPOSITION OF TOXICANT MAY REQUIRE SEVERAL HR OR DAYS DURING WHICH ATROPINIZATION MUST BE MAINTAINED. /CARBAMATES, CHOLINESTERASE INHIBITORS/

6. IF...INGESTED IN QUANTITY SUFFICIENT TO CAUSE POISONING, EMPTY THE STOMACH & INTESTINE. A. IF VICTIM IS ALERT & RESPIRATION IS NOT DEPRESSED, GIVE SYRUP OF IPECAC, FOLLOWED BY 1-2 GLASSES OF WATER TO INDUCE VOMITING; ADULTS (INCLUDING CHILDREN OVER 12), 30 ML; CHILDREN (UNDER 12 YR), 15 ML. CAUTION: OBSERVE VICTIM CLOSELY AFTER ADMIN IPECAC, IF CONSCIOUSNESS LEVEL DECLINES, OR IF VOMITING HAS NOT OCCURRED IN 15 MIN, PROCEED IMMEDIATELY TO INTUBATE THE STOMACH. FOLLOWING EMESIS, HAVE VICTIM DRINK A SUSPENSION OF /PRC: 30 G ACTIVATED CHARCOAL IN 3-4 OZ OF WATER (CHILDREN), 100 G IN 8-10 OZ OF WATER (ADULTS)/...TO BIND TOXICANT REMAINING IN THE GI TRACT. /CARBAMATES, CHOLINESTERASE INHIBITORS/

For more Antidote and Emergency Treatment (Complete) data for NEOSTIGMINE (6 total), please visit the HSDB record page.

N07AA01

S - Sensory organs

N - Nervous system

QS - Sensory organs

QN - Nervous system

QA - Alimentary tract and metabolism

Neostigmine is a cholinesterase inhibitor used in the treatment of myasthenia gravis and to reverse the effects of muscle relaxants such as gallamine and tubocurarine. Neostigmine, unlike physostigmine, does not cross the blood-brain barrier. By inhibiting acetylcholinesterase, more acetylcholine is available in the synapse, therefore, more of it can bind to the fewer receptors present in myasthenia gravis and can better trigger muscular contraction.

Neostigmine is a parasympathomimetic, specifically, a reversible cholinesterase inhibitor. The drug inhibits acetylcholinesterase which is responsible for the degredation of acetylcholine. So, with acetylcholinesterase inhibited, more acetylcholine is present By interfering with the breakdown of acetylcholine, neostigmine indirectly stimulates both nicotinic and muscarinic receptors which are involved in muscle contraction.. It does not cross the blood-brain barrier.

...PHARMACOLOGICAL EFFECTS OF ANTICHOLINESTERASE AGENTS ARE DUE PRIMARILY TO PREVENTION OF HYDROLYSIS OF ACH /ACETYLCHOLINE/ BY ACHE /ACETYLCHOLINESTERASE/ AT SITES OF CHOLINERGIC TRANSMISSION. TRANSMITTER THUS ACCUMULATES, AND THE ACTION OF ACH /ACETYLCHOLINESTERASE/ THAT IS LIBERATED BY CHOLINERGIC IMPULSES OR THAT LEAKS FROM THE NERVE ENDING IS ENHANCED.

Neostigmine increased both miniature end-plate potential and end-plate potential amplitudes but did not affect quantal content in isolated frog sciatic nerve-Sartorius muscle prepn. This suggests that cholinesterase inhibition was the only effect.

Long term (24-96 hr) treatment of a mouse-derived myogenic cell line (G8) with neostigmine markedly reduced binding of alpha-bungarotoxin (alpha-BuTx) to these cells. Protein synthesis in these cultures was markedly reduced and cell morphology degenerated. Myotubes maintained slightly hyperpolarized resting membrane potentials, and were able to respond to iontophoretic acetylcholine (Ach) application with overshooting action potentials. Degenerative changes at the neuromuscular junction associated with chronic neostigmine treatment in vivo are probably due to a direct action of the anticholinesterase on the muscle, rather than to altered intracleft ACh levels or to presynaptic effects of the anticholinesterase.

The intraluminal probe mounted with 2 electrode-strain gauge pairs, 4 cm apart, was used to study the effect of a neutral interview, a stressful interview, a meal (478.7 cal) and neostigmine (0.5 mg, im) on the contractile electrical complex, continuous electrical response activity and their associated contractions in 17 normal subjects. Neostigmine resulted in an incr in contractile electric complex & continuous electric response activity indexes 5-10 and 25-30 min after the injection, respectively. Both the meal and neostigmine incr the percentage of propagated contractile electric complexes during all of the recording periods.

The half-life ranged from 42 to 60 minutes with a mean half-life of 52 minutes.

The pharmacokinetics of neostigmine was evaluated in man after iv and oral admin. The mean plasma T/2 for neostigmine after iv admin was 0.89 hr. Following oral admin peak concn occurred 1-2 hr after intake, but biol availability was only 1-2% of the admin dose. In patients with myasthenia gravis, the decrement of the evoked electric muscle response of repetitive nerve stimulation correlated well with plasma concn of neostigmine.

Neostigmine undergoes hydrolysis by cholinesterase and is also metabolized by microsomal enzymes in the liver.

NEOSTIGMINE IS DESTROYED BY PLASMA ESTERASES, AND THE QUATERNARY ALCOHOL AND PARENT COMPOUND ARE EXCRETED IN THE URINE.

NEOSTIGMINE YIELDS 3-HYDROXYPHENYL TRIMETHYLAMMONIUM IN THE RAT. ROBERTS, JB ET AL; BIOCHEM PHARMAC 17: 9 (1968). /FROM TABLE/

3982TWQ96G

NEOSTIGMINE

Established Pharmacologic Class [EPC] - Cholinesterase Inhibitor

Mechanisms of Action [MoA] - Cholinesterase Inhibitors

Neostigmine is a Cholinesterase Inhibitor. The mechanism of action of neostigmine is as a Cholinesterase Inhibitor.

NEOSTIGMINE

Drugs that inhibit cholinesterases. The neurotransmitter ACETYLCHOLINE is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system.

Drugs that mimic the effects of parasympathetic nervous system activity. Included here are drugs that directly stimulate muscarinic receptors and drugs that potentiate cholinergic activity, usually by slowing the breakdown of acetylcholine (CHOLINESTERASE INHIBITORS). Drugs that stimulate both sympathetic and parasympathetic postganglionic neurons (GANGLIONIC STIMULANTS) are not included here.

Neostigmine bromide is poorly absorbed from the gastrointestinal tract following oral administration

NEOSTIGMINE...IS ABSORBED POORLY AFTER ORAL ADMINISTRATION, SUCH THAT MUCH LARGER DOSES ARE NEEDED THAN BY THE PARENTERAL ROUTE. ...THE EFFECTIVE PARENTERAL DOSE OF NEOSTIGMINE IN MAN IS 0.5 TO 2.0 MG, THE EQUIVALENT ORAL DOSE MAY BE 30 MG OR MORE. LARGE ORAL DOSES MAY PROVE TOXIC IF INTESTINAL ABSORPTION IS ENHANCED FOR ANY REASON.

...THE EXCRETION OF NEOSTIGMINE IS RETARDED IN PATIENTS WITH SEVERE KIDNEY DISEASE, MAKING THIS ANTICHOLINESTERASE DRUG AN ACCEPTABLE CHOICE IN PATIENTS WITH RENAL FAILURE.

The pharmacokinetics of neostigmine in patients with normal renal function were determined and compared with those of patients undergoing renal transplantation or bilateral nephrectomy. Ten to 15 min prior to the end of operation and anesthesia, d-tubocurarine infusion was terminated and neostigmine, 0.07 mg/kg and atropine 0.03 mg/kg were given by infusion over a 2-min period. In anephric patients the elimination half-life was prolonged. Total serum clearance was decr from 16.7 ml/kg/min in patients with normal renal function to 7.8 ml/kg/min in anephric patients. Neostigmine pharmacokinetics following renal transplantation were not different from those in patients with normal renal function. Renal excretion accounts for 50% of neostigmine clearance.

MEDICATION (VET)

MEDICATION

NEOSTIGMINE BROMIDE, USP (PROSTIGMIN), IS AVAILABLE FOR ORAL USE IN 15-MG TABLETS. NEOSTIGMINE METHYLSULFATE, USP (PROSTIGMIN METHYLSULFATE), IS MARKETED FOR PARENTERAL INJECTION IN STERILE SOLUTION IN AMPULS AND VIALS CONTAINING 0.25, 0.5, OR 1.0 MG/ML.