The neurotransmitter acetylcholine is hydrolyzed at synapses in the nervous system and the neuromuscular junction by the enzyme acetylcholinesterase, which terminates cholinergic signalling. Neostigmine is a carbamate inhibitor of this enzyme.

Neostigmine Uses:

• US labeling:

  • Reversal of nondepolarizing muscle relaxants:

    • After surgery, it is useful in undoing the relaxing effects of nondepolarizing neuromuscular blocking drugs.

• Canadian labeling:

  • Myasthenia gravis:

    • It aids in the management of myasthenia gravis symptoms.
    • Use restrictions: For the symptomatic therapy or acute exacerbations, other medications may be preferable.

  • Postoperative bladder distention, Urinary retention:

    • After ruling out mechanical obstruction during surgery, it is advised for the prevention and treatment of bladder distention and urine retention.

  • Reversal of nondepolarizing muscle relaxants:

    • After surgery, nondepolarizing neuromuscular blocking drugs' effects are reversed.

• Off Label Use of Neostigmine in Adults:

  • Acute colonic pseudo-obstruction (Ogilvie’s syndrome)

Neostigmine dose in adults:

Neostigmine for the treatment of Myasthenia gravis:

Diagnosis:

Labeling in Canada: Note: Atropine pretreatment is suggested, and atropine should be administered in the event of a cholinergic reaction.

• A  single intramuscular dose of 0.022 mg/kg.
• Retesting with a single dose of 0.031 mg/kg on a subsequent day is possible if the initial test is inconclusive.

Treatment:

Canadian labeling:

• A first dosage of 15 mg taken orally three times per day.
• Typical dosage is 150 mg spread out over 24 hours in divided doses.
• At times of acute exhaustion, larger doses are given.
• Range of dosage: 15 to 375 mg per day, divided.
• Subcutaneous, Intramuscular or Intravenous dose of 0.5 to 2.5 mg may be administered depending on individual patient response.

Neostigmine dose for the treatment of Reversal of nondepolarizing neuromuscular blockade after surgery:

• US labeling:
  • Intravenous Bloxiverz:

Note: If the patient suffers bradycardia, an anticholinergic medication, such as atropine, should be administered before neostigmine. Peripheral nerve stimulation giving a train-of-four (TOF) stimulus demonstrating a twitch response to the first stimulus in the TOF of at least 10% of baseline should be used to assess the requirement for additional doses before beginning neostigmine therapy.

• Usual dose: Within 10 to 20 minutes of treatment, a train of four twitch ratio of 90% is often attained at doses of 0.03 to 0.07 mg/kg.
• maximum total dose: 0.07 mg/kg or 5 mg (whichever is less)

• Dose selection guide:

  • Rocuronium, which has a short half-life, requires a dose of 0.03 mg/kg, whereas pancuronium and vecuronium, which have longer half-lives, require a dose of 0.07 mg/kg.

• Canadian labeling:

  • If necessary, repeat intravenous doses of 0.5 to 2.5 mg. Only in extreme circumstances should the total dose be higher than 5 mg.
  • Note: Use atropine 0.6 to 1 mg as a premedic.

Neostigmine dose for the treatment of Postoperative bladder distention/ urinary retention:

• Prevention:

  • Immediately following surgery, administer 25 mg intramuscularly or subcutaneously; repeat every 4 to 6 hours for 2 to 3 days.

• Treatment:

  • If pee doesn't appear after 60 minutes after receiving 5 to 1 mg subcutaneously or intramuscularly, the patient needs to be catheterized.
  • The doses may be repeated every three hours for five doses after the patient has urinated or the bladder has empty.

Neostigmine dose for the treatment of acute colonic pseudo-obstruction (Ogilvie syndrome):

• intravenous infusion of 2 mg over 3–5 minutes,

Note: The dosing over an hour can lower the risk of bradycardia, but the efficacy may suffer.

Neostigmine dose in children:

Neostigmine Dose for the Treatment of Myasthenia gravis:

For the Diagnosis of Myasthenia Gravis:

Note: Pretreatment with atropine and intravenous fluids is necessary.

• Children less than 2 years of age:

  • If the desired reaction is not obtained after administering 0.04 mg/kg intramuscularly in a single dosage, the dose may be repeated once every four hours.
  • The usual dose ranges from 0.5 to 1.5 mg.

Neostigmine for the treatment of myasthenia gravis:

Note: Dosage requirements are variable.

• Children and Adolescents:

  • 0.3 to 2 mg/kg orally, split into two dosages each day.
  • 0.01 to 0.04 mg/kg intramuscularly, intravenously, or subcutaneously every two to six hours.

Neostigmine for the reversal of nondepolarizing neuromuscular blockade after surgery:

• Intravenous neostigmine:

  • Manufacturer labeling:

    • similar dosing as for adults.

  • Alternate dosing: Generic injectable products.

    • Infants and Children: 025 to 0.1 mg/kg/dose

Pregnancy Risk Factor C

• Studies on animal reproduction did not show any adverse outcomes.
• If given intravenously in the first trimester of pregnancy, anticholinesterases may cause uterine irritation and prematurity.
• Negative effects depending on the dose/can occur if Neostigmine is used alongside labor pain relief. Consider using other agents during pregnancy.

Use of neostigmine during lactation

• Breastfeeding women should exercise caution as the secretion of Neostigmine in breastmilk is not known.
• Transient myasthenia gravis can cause feeding difficulties in newborns.

Neostigmine Dose adjustment in renal disease:

• These adjustments were recommended by Aronoff 2007,

  • Creatine clearance >50mL/minute

    • There is no need to adjust the dosage

  • Creatinine clearance 10-50 mL/minute

    • Take half the normal dose.

  • Creatinine clearance: 10mL/minute

    • 25 percent of the usual dose should be taken.

  • Hemodialysis

    • There is no need to adjust the dosage

  • Peritoneal dialysis

    • There is no need to adjust the dosage

  • Continuous renal replacement therapy (CRRT),:

    • Half the normal dose should be taken

Dose adjustment in liver disease:

There are no dosage adjustments provided in manufacturer's labeling.

Side effects of neostigmine:

• Cardiovascular:

  • Atrioventricular Block
  • Cardiac Arrhythmia (Especially Bradycardia)
  • ECG Changes (Nonspecific)
  • Flushing
  • Hypotension
  • Nodal Arrhythmia
  • Syncope
  • Tachycardia
  • Thrombophlebitis

• Central Nervous System:

  • Dizziness
  • Drowsiness
  • Dysarthria
  • Headache
  • Loss Of Consciousness
  • Seizure
  • Voice Disorder

• Dermatologic:

  • Diaphoresis
  • Skin Rash
  • Urticaria

• Gastrointestinal:

  • Diarrhea
  • Dysphagia
  • Flatulence
  • Increased Peristalsis
  • Nausea
  • Salivation
  • Stomach Cramps
  • Vomiting

• Genitourinary:

  • Urinary Urgency

• Hypersensitivity:

  • Anaphylaxis
  • Hypersensitivity Reaction

• Neuromuscular & Skeletal:

  • Arthralgia
  • Fasciculations
  • Laryngospasm
  • Muscle Cramps
  • Muscle Spasm
  • Weakness

• Ophthalmic:

  • Lacrimation
  • Miosis

• Respiratory:

  • Bronchospasm
  • Dyspnea
  • Exacerbation Of Asthma
  • Increased Bronchial Secretions
  • Respiratory Depression
  • Respiratory Paralysis

Contraindication to Neostigmine:

These include:

• Hypersensitivity
• Peritonitis
• Mechanical obstruction of the urinary or intestinal tract
• Hypersensitivity to bromides (tablets only).
• Although cross-reactivity between cholinesterase inhibitors and allergens has been documented in a limited amount of cases, cross-sensitivity can still be suspected due to similar structures.

Warnings and precautions

• Cardiovascular effects

  • Bradycardia, hypotension, and dysrhythmia may be more common in patients with specific cardiovascular diseases, such as heart disease, cardiac arrhythmias, and recent acute coronary syndrome.

• Cholinergic crisis

  • An overdose can cause cholinergic crises, which can be fatal and can result in extreme muscle weakness or respiratory paralysis.

• Hypersensitivity reactions

  • These include anaphylaxis and angioedema, fever, rash, anaphylaxis and urticaria. These conditions can be managed with epinephrine and atropine.

• Neuromuscular effects

  • Neostigmine given intravenously for the opposite of nondepolarizing neuromuscular blockers can result in neuromuscular dysfunction.

• Asthma

  • Patients with asthma should be cautious.

• Cardiovascular disease

  • Patients with bradycardia or cardiac arrhythmias, recent acute coronary syndrome, and coronary artery disease should be supervised.

• Hyperthyroidism

  • Patients with hyperthyroidism should be cautious.

• Megacolon/ GI dysfunction

  • Megacolon and decreased gastrointestinal motility should be avoided by taking oral doses (larger amounts).

• Myasthenia gravis

  • When testing for myasthenia Gravis and adjusting the dosage, it is important to have CPR.

• Peptic ulcer disease:

  • Patients with peptic ulcer disease should be cautious.

• Seizure disorder

  • Patients with epilepsy should be cautious.

• Vagotonia

  • Patients with vagotonia should be treated with caution.

Neostigmine: Drug Interaction

Monitoring parameters:

These include:

• Pulse
• BP
• ECG
• Acute colonic pseudoobstruction (off label use)
  • After administration, patient should remain supine and be continuously monitored for ECG. This will include regular clinical monitoring of the patient for 30 minutes.

How to administer Neostigmine?

Tablets (neostigmine bromide),: Prostigmin [Canadian Product]:

• Combining the medication with food or milk can reduce muscarinic effect. Extreme fatigue may require a higher dose.

Injectable (neostigmine-methylsulfate).

• Neostigmine Omega and Prostigmin [Canadian Products]:

  • You can give it subcutaneously, intramuscularly or intravenous.

• Bloxiverz

  • Give a slow IV injection for at least one minute.

• Acute colonic pseudoobstruction (off label use)

  • Give intravenous medication for 3 to 5 minutes.

Mechanism of action of Neostigmine:

• It inhibits acetylcholine degrading by acetylcholinesterase, which allows for impulse transmission across the myoneural junction. 
•  

The onset of action: Peristaltic activity:

• Oral: 2 to 4 hours
• Parenteral: 10 to 30 minutes

Duration:

• Intramuscular 2.5 to 4 hours

Absorption:

• Oral: Poor (1% to 2%)

Protein binding:

• 15% to 25% to albumin

Metabolism:

• Occurs in liver

Half-life elimination:

• Intramuscular:

  • Adults: 51 to 90 minutes

• Intravenous: Range: 24 to 113 minutes

  • Infants 2 to 10 months:
    • Mean: 39 ± 5 minutes
  • Children 1 to 6 years:
    • Mean: 48 ± 16 minutes
  • Adults 29 to 48 years:
    • 67 ± 8 minutes
  • Anephric patients:
    • 181 ± 54 minutes
  • Renal transplant patients:
    • 104.7 ± 64 minutes
  • Oral: Adults:
    • 42 to 60 minutes

Time to peak serum concentration:

• Oral: 1 to 2 hours.

Excretion:

• Urine (50% as unchanged drug; remainder as metabolites)

Neostigmine Brand Names (International):

• Bloxiverz
• Neostigmine Omega
• PMS-Neostigmine Methylsulfate
• Prostigmin
• Amostigmine
• Bloxiverz
• Episitgmin
• Epistigmin
• Fadastigmina
• Flextig
• Intrastigmina
• Metastigmin[inj.]
• Miostin
• Myostigmin
• Neostigmin
• Neotalis
• Normastigmin
• Polstigminum
• Prostig
• Prostigmin
• Prostigmin INJ
• Prostigmina
• Prostigmine
• Prostigmin[inj.]
• Setisin
• Stigmin
• Stigmosan
• Stignal
• Stigvita
• Syntostigmin
• Tilstigmin
• Vagostin
• Versia

Neostigmine Brand Names in Pakistan: