Pyridostigmine☆

Pyridostigmine☆ Tim Anderson and Carey N Pope, Oklahoma State University, Stillwater, OK, United States ã 2017 Elsevier Inc. All rights reserved.

Introduction Basic Chemistry Human Pharmacokinetics Pharmacokinetic Properties Targets-Pharmacodynamics Target Name(s) Therapeutics Indications Contraindications Adverse Effects Agent–Agent Interactions Pre-Clinical Research Pharmacokinetics Potency References

1 2 2 2 2 2 3 3 3 3 3 3 3 4 4

Name of the Clinical Form Pyridostigmine bromide Related Names Source: EMTREE, PubChem Kalymin 60 N; mestinon-SR; Regonol; Pyridinium, 3-(((dimethylamino)carbonyl)oxy)-1-methyl-Pyridostigmine; 3 hydroxy 1 methylpyridinium bromide dimethyl carbamate; pyridostigmine bromide Chemical Names (1-methylpyridin-1-ium-3-yl) N,N-dimethylcarbamate CAS Number 155-97-5

Introduction Pyridostigmine is a carbamate inhibitor of acetylcholinesterase with a quaternary ammonium structure. It is mainly used to treat myasthenia gravis, by indirectly increasing the concentration of acetylcholine at the neuromuscular junction and promoting increased cholinergic nicotinic receptor activation. Myasthenia gravis is an autoimmune disorder that leads to muscle weakness by reducing the density of neuromuscular nicotinic receptors. Thus, pyridostigmine increases acetylcholine levels in the neuromuscular junctions, with a consequent increase in motor tone. Pyridostigmine has also been used to protect against exposure to anticholinesterase nerve agents (e.g., sarin). Because pyridostigmine has a much shorter duration of inhibition and does not “age” (as possible with many organophosphorus anticholinesterases), the relatively short-term inhibition of some proportion of acetylcholinesterase molecules by pyridostigmine can protect those enzymes from the much longer inhibition elicited by subsequent exposure to an organophosphorus agent. Through this prophylactic action, pre-treatment with pyridostigmine can enhance survival and reduce long-term damage from nerve agent intoxication (Lee, 1997). On the other hand, some studies suggest that pyridostigmine could have contributed to some Gulf War illnesses (Kerr, 2015). Pyridostigmine’s quaternary ammonium structure prevents it from readily crossing the blood brain barrier, relegating its effects on acetylcholinesterase to outside the central nervous system. Pyridostigmine can also be used to reverse the effects of muscular blockade by nondepolarizing muscle relaxants, for example, atracurium.

☆ Change History: January 2017. T Anderson and CN Pope added keywords, abstract, and PubChem references; included IUPAC names; revised text; modified citations and included references.

Reference Module in Biomedical Sciences

https://doi.org/10.1016/B978-0-12-801238-3.97627-X

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Pyridostigmine

Basic Chemistry

Chemical Structure Structure

Comments Chemical Formula Properties Physical Properties Molecular Weight Solubility Ionization Constant

Has an agreeable characteristic odor and bitter taste. C9 H13 N2 O2 (Bromide, C9 H13 Br N2 O2) White or almost white, hygroscopic crystals from absolute ethanol; melting point 152–154 C. 181.2 Very soluble in water and alcohol. Insoluble in ether, acetone, and benzene. Value Strongly basic

pka

Salt

Conditions

Reference Plumb (2011)

Comments

Human Pharmacokinetics As a result of its quaternary structure, pyridostigmine is poorly and variably absorbed from the gastrointestinal tract, and a large proportion is excreted by the kidneys as the unmodified drug. Following oral dosing, however the effects of pyridostigmine can become evident within 30 min. Improvement in muscular function in patients with myasthenia gravis lasts for 3–4 h and is maintained with repeated dosing.

Pharmacokinetic Properties

Absorption Bioavailability

Distribution Volume of Distribution Plasma Protein Binding Metabolism Plasma Half-Life Bio Half-Life Clearance

Routes of Elimination

Value

Units

5.2–10

%

1.35–1.93

l kg

Prep. and route of admin.

1

Reference

Comments

Aliquilonius et al. (1980)

Oral bioavailability is not decreased by concurrent consumption of food; however, food prolongs time to maximum plasma concentration by up to 3 h.

Aliquilonius et al. (1980)

Binds to Abu-Quare (2002) Pyridostigmine readily binds to human serum albumin in vitro, albumin though this effect may be negligible in vivo. The main metabolite is the hydrolysis product 3-hydroxy-N-methylpyridinium, which is promptly glucuronidated. 1.54–2.02 h Aliquilonius et al. (1980) 0.65

lh

1

Aliquilonius et al. (1980)

Both glomerular filtration and tubular secretion contribute to urinary clearance. Up to 20% of an oral dose is excreted unchanged in the urine. Clearance rates are reduced in older patients.

Primarily eliminated by the kidneys.

Targets-Pharmacodynamics Pyridostigmine intensifies both the nicotinic and muscarinic effects of endogenous acetylcholine by inhibiting acetylcholinesterase. It has also been shown to have direct allosteric actions on some nicotinic acetylcholine receptors (Akaike et al., 1984).

Target Name(s):

•

Acetylcholinesterase

Pyridostigmine

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Therapeutics Pyridostigmine enhances neuromuscular transmission in voluntary and involuntary muscle contractions in patients with myasthenia gravis. Although slower acting than neostigmine (another carbamate acetlycholinesterase inhibitor), it has a longer duration of action and may be preferred because of the need for less frequent dosing. Pre-administration protects against intoxication by some nerve agents. Pyridostigmine can also be used for the postoperative reversal of nondepolarizing (competitive) blockade of neuromuscular nicotinic receptors, generally given together with atropine to block excessive muscarinic receptor activation.

Indications

Value

Prep. and route of admin.

Units

Myasthenia gravis (adult) Dosage 540–720 mg/day Myasthenia gravis (dog) Dosage 1–3 mg kg

1

Reference

Comments

p.o.

Hardman and Limbird (2001)

This is the total daily dose, made up of 180 mg doses at 6–8 h intervals throughout the day.

p.o.

Plumb (2011)

Doses should be given every 8–12 h.

Contraindications Intestinal or urinary obstruction.

Adverse Effects Nausea, vomiting, increased salivation, diarrhea, and abdominal cramps may occur. Muscarinic side effects of anticholinesterases include increased sweating, salivary, and gastric secretions, as well as increased gastrointestinal, bladder and uterine motility, and bradycardia. Nicotinic receptor-mediated effects can include muscle fasciculations, muscle pain, and autonomic alterations through increased activation of ganglionic nicotinic receptors.

Agent–Agent Interactions

Agent Name Antimuscarinics Aminoglycosides Polymyxins Chloroquine Hydroxychloroquine Clindamycin Lithium Muscle relaxants, nondepolarizing Procainamide Propafenone Propanolol Quinidine Suxamethonium

Mode of Interaction Antagonism of effect. Antagonism of effect of pyridostigmine. Antagonism of effect of pyridostigmine. Chloroquine has the potential to increase symptoms of myasthenia gravis and thus diminish effect of pyridostigmine. Hydroxychloroquine has the potential to increase symptoms of myasthenia gravis and thus diminish effect of pyridostigmine. Antagonism of effects of pyridostigmine. Antagonism of effects of pyridostigmine. Pyridostigmine antagonizes effect of nondepolarizing muscle relaxants. Antagonism of effect of pyridostigmine. Possibly antagonism of effect of pyridostigmine. Antagonism of effect of pyridostigmine. Antagonism of effect of pyridostigmine. Effect of suxamethonium enhanced.

Pre-Clinical Research Pharmacokinetics The volume of distribution and clearance rates in humans were 1.43 L kg 1980)

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and 0.65 L kg

1

h 1, respectively (Aliquilonius et al.,

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Pyridostigmine

Potency

Organ/ tissue

Prep. and route of admin.

Value

Units

Rat LD50

2.7

mg kg

1

i.p.

LD50 LD50

3.1 2.8

mg kg mg kg

1

s.c. i.m.

1

Cell line/ Type

Effects

Exp. End Point

Reference

Comments

Wolthuis and Vanwersch (1984) Ashani et al. (1983) Harris et al. (1984)

References Akaike A, Ikeda SR, Brookes N, Pascuzzo GJ, Rickett DL, and Alburquerque EX (1984) The nature of interactions of pyridostigmine with the nicotinic acetylcholine receptor-ionic channel complex II Patch clamp studies. Molecular Pharmacology 25: 102–112. Aliquilonius SM, Eckerna¨s SA, Hartvig P, Lindstro¨m B, and Osterman PO (1980) Pharmacokinetics and oral availability of pyridostigmine in man. European Journal of Clinical Pharmacology 18: 423–428. Ashani Y, Leader H, Raveh L, Bruckstein R, and Spiegelstein M (1983) In vitro and in vivo protection of acetylcholinesterase against organophosphate poisoning by pretreatment with a novel derivative of 1,3,2-dioxaphosphorinane 2-oxide. Journal of Medicinal Chemistry 26: 145–152. Hardman JG and Limbird LE (2001) Goodman and Gilman’s: The pharmacological basis of therapeutics, 10th edn. New York: McGraw-Hill Medical Publishing Division. 188. Harris LW, Lennox WJ, Talbot BG, Anderson DR, and Swanson DR (1984) Toxicity of anticholinesterase: Interactions of pyridostigmine and physostigmine with soman. Drugs and Chemical Toxicology 7: 507–526. Kerr KJ (2015) Gulf War illness: An overview of events, most prevalent health outcomes, exposures, and clues as to pathogenesis. Reviews on Environmental Health 30: 273–286. Lee EJ (1997) Pharmacology and toxicology of chemical warfare agents. Annals of the Academy of Medicine, Singapore 26: 104–107. Plumb DC (2011) Plumb’s veterinary drug handbook, 7th edn. Ames, IA: Wiley-Blackwell. pp 1185–6. Wolthuis OL and Vanwersch RA (1984) Behavioral changes in the rat after low doses of cholinesterase inhibitors. Fundamental and Applied Toxicology 4(Pt 2): 195–208.