Pyridostigmine

Pyridostigmine belongs to the group of indirect parasympathomimetics, which increase the effect of the body's own acetylcholine by inhibiting acetylcholinesterase. Acetylcholine is an important neurotransmitter that plays an important and major role in the nervous system. These include mediating muscle contractions as well as signal transmissions. Pyridostigmine plays a role in the therapy of myasthenia gravis and also influences blood pressure, heart rate and digestion.

Use & Indications

Pyridostigmine is primarily used for the treatment of myasthenia gravis, an autoimmune disease in which antibodies are directed against the acetylcholine receptor (AchR). This dysfunction consequently leads to muscle weakness and extreme fatigue. Pyridostigmine causes an increased release of acetylcholine, which counteracts this pathological muscle weakness. Furthermore, pyridostigmine counteracts bladder/bowel paralysis, as its mechanism of action stimulates muscle activity.

The active ingredient is commercially available in the form of coated tablets for oral administration (^Mestinon®) in various strengths. Other available dosage forms include sustained-release tablets, coated tablets and injectable solutions. The dosage is adjusted individually and differs depending on the severity of the disease. However, there are guideline values that can be used as a guide. Thus, adults can take one to three coated tablets of 60mg two to four times a day, for children initially rather lower doses are suitable.

The bromine salt of pyridostigmine (pyridostigmine bromide) is used therapeutically.

History

During the second Gulf War, which took place in 1990/91 between Iraq and the United States, pyridostigmine was given prophylactically to members of the armed forces to protect against possible attacks with nerve agents used as chemical weapons in war situations. Such nerve agents, in fact, inhibit acetylcholinesterase, which leads to an accumulation of acetylcholine and thus to excessive stimulation of the muscles, which can be life-threatening.

Pharmacodynamics/mechanism of action

Pyridostigmine is similar to neostigmine in its effect, but differs from it in that it has a faster onset of action and a longer duration of action. In Germany, for example, pyridostigmine is now more commonly used as a cholinesterase inhibitor because, unlike neostigmine, it can be administered orally. As quaternary nitrogen compounds, they both belong to the group of reversible inhibitors.

They act primarily in the central nervous system by acting as indirect parasympathomimetics to block cholinesterase (the enzyme responsible for breaking down acetylcholine into acetate and choline) in the synaptic cleft, thereby increasing the amount of acetylcholine and thus enhancing stimulus transmission across synapses. In this way, they promote the activity of the parasympathetic nervous system, the involuntary nervous system, under whose influence relaxation occurs by, for example, lowering the heart rate or slowing down the conduction of excitation. They bind reversibly, i.e. they block the enzyme and dissociate again.

Pharmacokinetics

Because of the quaternary ammonium structure of pyridostigmine, it hardly enters the central nervous system. Gastrointestinal absorption is also poor, but differs individually and depends on some concomitant factors, such as gastric filling status. When food is ingested, absorption is delayed. Thus, when the drug is taken on an empty stomach, efficacy occurs after 30-60 minutes, whereas values are delayed by up to 90 minutes with concomitant food intake.

Bioavailability with oral administration is rather low and varies between 11% and 19%. Taking the drug on an empty stomach increases not only absorption but also bioavailability.

Pyridostigmine is excreted mainly by the kidney when taken orally.

Drug Interactions

• The excipient methylcellulose prevents absorption of the drug when administered concomitantly. Therefore, preparations containing this excipient should be avoided.
• Anticholinergics such as atropine and scopolamine inhibit the action of pyridostigmine bromide, the active ingredient. These substances further impair intestinal motility (movement of the bowel) and thus the absorption of pyridostigmine bromide.
• Muscle relaxants (drugs that cause temporary relaxation of skeletal muscles) such as suxamethonium act longer in the presence of pyridostigmine bromide.
• Furthermore, aminoglycoside-type antibiotics (e.g., neomycin, kanamycin), local anesthetics, and drugs for cardiac arrhythmias may also affect the action of pyridostigmine bromide.
• Insect repellents containing the active ingredient DEET, such as Anti Brumm forte or Nobite skin spray, should not be applied to the skin when taking pyridostigmine, as they enhance the effect of the drug.

Contraindications & precautions

The drug must not be taken in case of:

• hypersensitivity (allergy) to the active substance or any other component of the formulation.
• In case of mechanical obstruction of the digestive or urinary tract.

In case of respiratory diseases such as asthma or COPD, the drug should be handled only with caution and prior consultation with the doctor, since in the case of intake in the cases of bronchial constriction or restriction of lung function may occur!

There is also an increased risk of taking the drug in heart disease.

The dosage of the drug must be precisely adjusted to the patient, because in case of overdose there is an excess of acetylcholine, which leads to a cholinergic crisis and can end in life-threatening conditions (such as respiratory depression). In that case, atropine can be used as an antidote (antidote).

Side effects

The occurrence of side effects depends on the dose. They may manifest as follows:

• Eyes: constriction of the pupils, increased tear secretion, adaptation disorders of the eye (e.g., blurred vision).
• Cardiovascular system: accelerated pulse, slowed heartbeat, cardiac arrhythmias (e.g., palpitations).
• Vascular disorders: Feeling of heat, low blood pressure
• respiratory system: narrowing of the airways, increased bronchial secretion
• digestive tract: nausea, vomiting, diarrhea, abdominal discomfort
• skin: excessive sweating, urticaria (hives)
• Muscular system: increased muscle weakness, muscle tremors, muscle cramps, involuntary muscle twitching

Pregnancy and lactation

In case of existing pregnancy as well as during breastfeeding, it is recommended to talk to a doctor or pharmacist before taking a drug containing the active substance pyridostigmine bromide, as the active substance may cross the placental barrier and pass minimally into breast milk.

In addition, intravenous administration of the active ingredient may induce premature labor, especially towards the end of pregnancy.