Pyridostigmine (Mestinon, Amygra) is a reversible cholinesterase inhibitor that inhibits the breakdown of acetylcholine. It improves muscle strength in patients with myasthenia gravis and is used to reverse the effects of non-depolarizing muscle relaxants.

Pyridostigmine Uses:

• Myasthenia gravis:
  • Oral treatment is indicated for the treatment of myasthenia gravis.
• Reversal of nondepolarizing muscle relaxants:
  • The injectable formulation is indicated for the reversal of nondepolarizing muscle relaxants.
• Military use:
  • It is also used as pretreatment for Soman nerve gas exposure
• Off-Label Use of Pyridostigmine in Adults:
  • It is indicated for the alleviation or prevention of anticholinergic adverse effects induced by Disopyramide
  • Parenteral (IM, IV) formulation may also be used in Myasthenia gravis.

Pyridostigmine dose in Adults

Pyridostigmine Dose in the treatment of Myasthenia gravis:

• Oral: Highly individualized dosing ranges:
  • Immediate-release:
    • 60 - 1,500 mg per day, usually 600 mg per day given in 5 to 6 divided doses
  • Sustained-release:
    • 180 - 540 mg once or twice a day (at least duration of 6 hours between doses); Note: Use of immediate-release therapy may be necessary for combination with sustained-release therapy.
• IM, IV (off-label use):
  • To supplement during labor and postpartum.
  • In a Myasthenic crisis when oral therapy can not be given: ~1/30th of oral dose should be given;
  • Strict monitoring of the patient for cholinergic reactions. The intravenous route may cause significant complications e.g. cardiac arrest.
  • The intramuscular route is preferred. In a myasthenia crisis, continuous infusion may also be given.
• Continuous IV infusion: 
  • 1 - 2 mg per hour, gradually titrate with increments of 0.5 to 1 mg per hour,
  • The maximum rate: 4 mg per hour

Pyridostigmine Dose in the treatment of Reversal of nondepolarizing muscle relaxants:

• IV: 0.1 - 0.25 mg/kg/dose (onset to peak effect is dose-dependent; return of twitch height to 90% of control occurs within ~6 minutes; full recovery usually occurs within 15 to 30 minutes)

Note:

• Muscle twitch response to peripheral nerve stimulation should be monitored;
• Pyridostigmine to be administered after spontaneous recovery of neuromuscular function has begun.
• To minimize the side effects, Atropine sulfate or glycopyrrolate should be given before or simultaneously with pyridostigmine.
• There is a possibility of inadequate reversal; additional doses are not recommended. till adequate recovery, it should be managed by manual or mechanical ventilation.

Pyridostigmine dose in the pre-treatment of Soman nerve gas exposure (military use):

Note: It is used as premedication, pyridostigmine after Soman exposure should not be given; It is not effective and may be harmful if taken immediately before exposure or at the same time, as it can exacerbate the effects of sub-lethal exposure to Soman.

• Oral: 30 mg every 8 hours, should start taking several hours before exposure; at the first sign of Soman exposure discontinue it, then immediately start atropine and pralidoxime.

Pyridostigmine dose in the treatment of disopyramide-induced anticholinergic adverse effects (off-label):

• Oral: Sustained-release: 90 - 180 mg every 12 hours or as needed

Pyridostigmine dose in Childrens

Note: Every paediatric dosage guideline is based on the product formulations for immediate release.

Pyridostigmine dose in the treatment of congenital myasthenic syndromes:

• Infants, Children, and Adolescents:
  • Oral: 1 mg/kg/dose every four hours; typical range: 4–5 mg/kg/day in divided doses of four to six; maximum daily dose: 7 mg/kg/day in split doses of five to six

Pyridostigmine dose in the treatment of Juvenile Autoimmune myasthenia gravis:

• Infants, Children, and Adolescents:

Note: Larger doses should be administered prior to the time of greatest fatigue.

• • Oral:
    • 1 mg/kg/dose every 4 - 6 hours;
    • The maximum daily dose: 7 mg/kg/day in 5-6 divided doses;
    • The usual daily dose: 600 mg/day; doses as high as 1500 mg/day have been used
  • IM, IV:
    • 0.05-0.15 mg/kg/dose;
    • The maximum dose: 10 mg

Pyridostigmine Dose in the treatment of Reversal of nondepolarizing neuromuscular blocker: 

• Infants, Children, and Adolescents:
  • IM, IV: 0.1- 0.25 mg/kg/dose.
  • Note: To reduce side effects, atropine or glycopyrrolate should be administered right away.

Pyridostigmine Dose in the treatment of Vincristine-induced neurotoxicity:

• Children ≥2 years and Adolescents:
  • Oral: 3 mg/kg/day in 2 divided doses, with pyridoxine for 3 weeks.

Pregnancy Risk Factor B/C (manufacturer dependent)

• Studies on animal reproduction have not shown any adverse effects.
• It can also cross the placenta, which can cause transient neonatal myasthenia graveis in 10-15% of neonates.
• This is because maternal antibodies can cross over the placenta.
• Myasthenia gravis can be treated with pyridostigmine during pregnancy. It should also be used during labor.
• The mother's health and prognosis should be considered.
• If there is clear indication that the mother needs antidotes, it should be administered without fear of teratogenicity.

Use of pyridostigmine during breastfeeding

• Breastfeeding women should be aware that Pyridostigmine can be found in breast milk.
• Breastfeeding can lead to myasthenia gravis exacerbations if the mother is not well controlled.
• Myasthenia gravis infants may experience transient myasthenia graveis as a newborn.
• They may also have difficulty eating and should be closely monitored for fatigue.
• According to current guidelines, breastfeeding is safe for women who are taking pyridostigmine for myasthenia Gravis.
• Two mothers who used pyridostigmine to treat myasthenia gravis during pregnancy and after giving birth are available.
• They were given 180 mg to 300 mg/day and samples were taken from 5 - 102 days after delivery. 
• The plasma concentrations of infants were much lower than the limit of quantification.
• Also, the average milk concentration quantified was =0.1% of weight-adjusted maternal dose.

Dose in Kidney disease:

No dosage adjustments on labeling. However.

There is prolong elimination in renal impairment, lower initial dose may be required.   

Dose in Liver disease:

No dosage adjustments listed in the manufacturer's labelling.   

Side Effects of Pyridostigmine:

• Central Nervous System:
  • Twitching
  • Hyperesthesia
• Dermatologic:
  • Xeroderma
• Gastrointestinal:
  • Abdominal Pain
  • Diarrhea
• Genitourinary:
  • Dysmenorrhea
  • Urinary Frequency
• Neuromuscular & Skeletal:
  • Myalgia
  • Neck Pain
• Ophthalmic:
  • Amblyopia
• Respiratory:
  • Epistaxis

Uncommon Side effects of Pyridostigmine:

• Cardiovascular:
  • Bradycardia (Transient)
  • Chest Tightness
  • Decreased Heart Rate
  • Increased Blood Pressure
• Central Nervous System:
  • Confusion
  • Depressed Mood
  • Disturbed Sleep
  • Drowsiness
  • Headache
  • Hypertonia
  • Lack Of Concentration
  • Lethargy
  • Localized Warm Feeling
  • Numbness Of Tongue
  • Tingling Of Extremities
  • Vertigo
• Dermatologic:
  • Alopecia
  • Diaphoresis
  • Skin Rash
• Gastrointestinal:
  • Abdominal Cramps
  • Bloating
  • Borborygmi
  • Flatulence
  • Increased Peristalsis
  • Nausea
  • Salivation
  • Vomiting
• Hypersensitivity:
  • Hypersensitivity Reaction
• Neuromuscular & Skeletal:
  • Fasciculations
  • Muscle Cramps
  • Weakness
• Ophthalmic:
  • Eye Pain
  • Lacrimation
  • Miosis
  • Visual Disturbance
• Respiratory:
  • Acute Bronchitis (Exacerbation)
  • Exacerbation Of Asthma
  • Increased Bronchial Secretions

Contraindications to Pyridostigmine:

• Hypersensitivity to any anticholinesterase agent or component of pyridostigmine
• Occlusions of the urinary tract or stomach by mechanical means
• It is not known if anticholinergic stimulants cause allergic reactions. 
• Cross-sensitivity is possible because of the similar chemical structure and pharmacological effects.

Warnings and precautions

• Cholinergic effects
  • You may experience excessive cholinergic activity symptoms, such as: There may be excessive cholinergic activity symptoms such as salivation, sweating and urinary incontinence.
  • Overdose can cause a cholinergic crises (e.g. In the event of an overdose, such as muscle weakness, discontinue use immediately. Cholinergic crisis should be distinguished from myasthenic crises.
• Hypersensitivity reactions
  • Hypersensitivity reactions are possible. Keep atropine or epinephrine on hand to treat such reactions.
• Cardiovascular disease
  • The dangers of having a Bradycardia or any other cardiac arrhythmias are real. Use caution when treating cardiac patients with Bradycardia or other cardiac arrhythmias
• Glaucoma
  • It may be combined with antiglaucoma medications to cause or exacerbate night-vision problems.
• Renal impairment
  • Patients with impaired renal function should be cautious. A lower initial dose should be used first, then increase the dosage.
• Respiratory disease
  • Patients with chronic pulmonary diseases such as asthma, bronchospastic or chronic obstructive lung disease (COPD) should be cautious.

Pyridostigmine: Drug Interaction

Note: Drug Interaction Categories:

• Risk Factor C: Monitor When Using Combination
• Risk Factor D: Consider Treatment Modification
• Risk Factor X: Avoid Concomitant Use

Monitoring parameters:

• ECG
• Blood pressure and heart rate especially with IV
• Cholinergic reactions (eg, nausea, vomiting, diarrhea, increased salivation), especially with IV use

How to administer Pyridostigmine (Mestinon, Amygra)?

Oral:

• Swallow whole, do not crush the extended-release tablet.

IV:

• For reversal of nondepolarising Muscle relaxants.
• Myasthenic crisis (off-label use) administer Intramuscular, slow intravenously, or as a continuous infusion.
• Patients who may need larger doses should be treated with atropine before pyridostigmine treatment.

Mechanism of action of Pyridostigmine (Mestinon, Amygra):

• Acetylcholinesterase, an enzyme that is responsible for the metabolism acetylcholine and facilitates impulse transmission across the neuromuscular junction, is also known as Acetylcholinesterase.
• Pyridostigmine prevents the destruction by acetylcholinesterase of acetylcholine and facilitates impulses across neuromuscular junction

The onset of action:

• Recovery from vincristine neurotoxicity: Onset of action: 1 to 2 weeks
• Myasthenia gravis:
  • Oral: Within 30 minutes
  • IM: 15 - 30 minutes
  • IV: 2 - 5 minutes

Duration:

• Oral: 3 - 4 hours in the daytime
• IM, IV: 2 - 3 hours

Absorption: Oral:

• Very poor

Protein Binding:

• None

Metabolism:

• Cholinesterase enzymes break it down in the liver and tissue locations.

Bioavailability:

• 10% to 20%

Half-life elimination:

• Oral: 1 - 2 hours; renal failure: ~6 hours
• IV: ~1.5 hours

Time to peak plasma concentration after oral administration:

• 1 - 2 hours

Excretion:

• Through Urine (80% to 90% as unchanged drug)

International Brand Names of Pyridostigmine:

• Mestinon
• Regonol
• Mestinon SR
• Amygra
• Antilon
• Astinon
• Brostagin
• Delostigar
• Distinon
• Dosmin
• Dostimid
• Kalymin
• Meshanon
• Mestinon
• Mestinon Retard
• Mestinon Timespan
• Pyrido
• Pyrimine
• Pyrinol
• Pyrinon
• Pystinon
• Stigmide

Pyridostigmine Brand Names in Pakistan: