Parasympatholytics

Parasympatholytics or also muscarinic receptor antagonists are substances that competitively inhibit the effect of acetylcholine at its receptors (see below acetylcholine).

You can distinguish between:

• natural substances and
• Synthetic substances

The natural substances scopolamine and atropine are found as alkaloids in nightshade plants such as deadly nightshade, henbane and thorn-apple.

Examples of synthetic substances are pirenzepine, tropicamide, cyclopentate, oxybutynin and others.

Clinically important is the division into:

• Substances with quaternary nitrogen
  • N-butylscopolamine
  • Trospium chloride
  • Ipratropium bromide
  • Tiotropium bromide
• Substances with tertiary nitrogen
  • Atropine
  • Scopolamine
  • Biperides
  • Oxybutinin

Substances with quaternary nitrogen, such as N-butylscopolamine, remain limited in their effect on the periphery.

Substances with tertiary nitrogen such as atropine or biperides act both in the periphery and in the central nervous system. Of the muscarinic receptor antagonists, pirenzepine is the only substance which relatively selectively antagonizes M1-receptors (see below acetylcholine receptors).

Since M-receptors are almost always tonic activated (except M3-receptor of the vascular endothelium), M-receptor antagonists may show effects in healthy humans. All M-receptor antagonists are competitive antagonists. Their effects are different and depend on which type of receptor they antagonise.

• Heart: tachycardia, atropine reduces the heart rate in low doses (effects on presynaptic M-receptors whose antagonism leads to the release of acetylcholine; the antagonism of postsynaptic receptors appears to be significantly weaker.
• Gastrointestinal tract: reduction of glandular activity (dryness of the oral mucosa); reduction of smooth muscle activity (atropine poisoning leads to a suspension of intestinal peristalsis)
• Skin: Inhibition of sweat gland secretion; this leads to dry and reddened skin in atropine poisoning. The body temperature rises.
• CNS: In high doses, atropine has a central excitation effect (psychotic excitation). Scopolamine is easily CNS-compatible and has a central attenuating effect even at low doses. In higher doses it has a central excitatory effect like atropine.

Some muscarinic receptor antagonists are metabolized renally others metabolically via CYP3A4 others via CYP2D6.

Indications are:

• pupil dilation (mydriatic): tropicamide, cyclopentolate
• Bradycardic cardiac arrhythmias (also with AV block) are treated with atropine (0.5 mg i.v.), for example in the early phase of an infarction.
• In cases of poisoning with alkyl phosphates, which cause life-threatening activation of the M-receptors, atropine is applied i.v. (2-5mg every 10-15 min).
• Parkinson's syndrome: biperides and trihexylphenidyl are used.
• Irritable bladder (detrusor hyperactivity): this disorder occurs mainly in older people (urge to urinate, increased micturition frequency, urge incontinence). For this indication: Trospium chloride, oxybutynin, tolterodine and Darefenacin are used.
• Kidney and biliary colic: Because of its spasmolytic component, N-butylscopolamine (20-40mg i.v.) is usually combined with an analgesic.
• Bronchial asthma and COPD: Itratropium bromide or tiotropium bromide (longer duration of action) can be administered by inhaler to reduce bronchoconstriction. However, these drugs lose their importance in the treatment of bronchial asthma.

The undesirable effects of this group of drugs are due to the antagonization of muscarinic receptors dryness of skin and mucous membranes, constipation, tachycardia, mydriasis, accommodation disorders, micturition disorders, urinary retention. In elderly patients also states of confusion and disorders of cognitive functions.

Substances which are substrates for CYP3A4 and CYP2D6.

Narrow-angle glaucoma, obstructive urinary tract diseases, tachyarrhythmia, tachycardia in hyperthyroidism, paralytic ileus, megacolon, myasthenia gravis.

1. Estler CJ (1995) (Eds): Pharmacology and toxicology. 4th ed. Schattauer, Stuttgart and New York pp. 41-46.
2. Graefe KH et al (2016) Sympathetic Nervous System. In: Graefe KH et al. (Eds) Pharmacology and Toxicology Georg Thieme Verlag Stuttgart S. 114