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What are the most common Antimuscarinic drugs?

In order to understand Antimuscarinic drugs properly, it’s required to classify them according to their chemistry:

  1. Natural alkaloids/ Atropine, Hyoscine (Scopolamine).
  2. Semisynthetic derivatives/ Homatropine, Atropine methonitrate, Hyoscine butyl bromide, Ipratropium bromide, Tiotropium bromide.
  3. Synthetic compounds/
    • Mydriatics: Cyclopentolate, Tropicamide.
    • Antisecretory-antispasmodics:
      • Quaternary compounds: Propantheline, Oxyphenonium, Clidinium, Pipenzolate methyl bromide, Isopropamide, Glycopyrrolate.
      • Tertiary amines: Dicyclomine, Valethamate, Pirenzepine.
    • Vasicoselective: Oxybutynin, Flavoxate, Tolterodine, Darifenacin, fesoterodine, solifenacin, and trospium chloride.
    • Antiparkinsonian: Trihexyphenidyl (Benzhe- xol), Procyclidine, Biperiden.

Scopolamine (hyoscine)

Natural alkaloids can be found in plants belonging to the Solanaceae family. The dextroisomers are much less active than the levo-isomers. Atropine is a racemic substance, whereas scopolamine is (l-hyoscine). Scopolamine has a similar effect to atropine in the peripheral nervous system. Scopolamine, on the other hand, has a greater effect on the CNS (unlike atropine, CNS effects are observed at therapeutic doses) and a longer duration of action than atropine.

It has some unique features such as:

Scopolamine is one of the most effective anti-motion sickness medications in the market. It also has the unusual side effect of obstructing short-term memory. Scopolamine, like atropine, causes sedation, but at higher doses, it can cause excitement. Scopolamine can cause euphoria and is easily abused.

Therapeutic uses:

Scopolamine's therapeutic use is limited to motion sickness prevention by blocking muscarinic receptors in the vestibular system and the CNS, as well as postoperative nausea and vomiting. It is available as a topical patch for motion sickness, with effects lasting up to three days.

[Note: As with all drugs used to treat motion sickness, it is far more effective when used prophylactically than when used to treat motion sickness once it has occurred].

Pharmacokinetics and adverse effects:

These characteristics are comparable to those of atropine. Check Cholinergic Antagonists article to see atropine adverse effects ‼️

Atropine substitutes

Many semisynthetic derivatives of belladonna alkaloids, as well as a large number of synthetic compounds have been introduced in order to produce more selective action on specific functions. The majority of these are only marginally different from natural alkaloids but some newer ones appear promising.

Quaternary compounds

These have certain common features:

  • Incomplete oral absorption.
  • After parenteral/oral administration, there is poor penetration in the brain and eye, no central or ocular effects are observed.
  • In general, elimination takes longer. The majority of them have a longer duration of action than atropine.
  • Have a greater nicotinic blocking ability. At clinical doses, some ganglionic blockade may occur, postural hypotension and impotence are additional side effects.
  • A degree of neuromuscular blockade may also occur at high doses.

Drugs in this category are:

1) Ipratropium and tiotropium

Ipratropium and tiotropium are semisynthetic quaternary atropine derivatives. These medications are approved as bronchodilators for the long-term treatment of bronchospasm caused by chronic obstructive pulmonary disease (COPD). Ipratropium (a short-acting anticholinergic) is also used in the acute treatment of bronchospasm in asthma. Both agents are administered through inhalation. These drugs do not enter the systemic circulation or the CNS due to their positive charges, limiting their effects to the pulmonary system. Tiotropium (long-acting) is administered once daily, which is a significant advantage over ipratropium which requires dosing up to four times daily. Tiotropium binds very tightly to bronchial M1/M3 muscarinic receptors resulting in prolonged bronchodilation. Binding to M2 receptors is looser resulting in relative M1/M3 selectivity (less likely to enhance ACh release from vagal nerve endings in lungs due to M2 receptor blockade).

Ipratropium side effects

Transient local side effects such as dry mouth, tracheal scratching, cough, bad taste, and nervousness are reported in 20–30% of patients, but systemic effects are uncommon due to poor absorption from the lungs and GIT.

2) Propantheline

It was a popular anticholinergic drug used to treat peptic ulcers and gastritis, and it was taken orally in doses of 15–30 mg. It also has some ganglion blocking activity and is claimed to reduce gastric secretion at low doses with only minor side effects. Gastric emptying is delayed, and the effect lasts 6–8 hours. The availability of H2 blockers and proton pump inhibitors has resulted in a decrease in use.

3) Oxyphenonium

5–10 mg (children 3–5 mg) orally; used to treat peptic ulcers and gastrointestinal hypermotility, similar to propantheline.

4) Clidinium

2.5–5 mg orally; this antisecretory-antispasmodic has been used in conjunction with benzodiazepines to treat nervous dyspepsia, gastritis, irritable bowel syndrome, colic, peptic ulcers and other conditions.

5) Pipenzolate methyl bromide

5–10 mg (children 2–3 mg) orally; it has been promoted for flatulent dyspepsia, infantile colics and abdominal cramps in particular.

6) Isopropamide

5 mg orally; used to treat hyperacidity, nervous dyspepsia, irritable bowel syndrome and other gastrointestinal problems, particularly when combined with emotional/mental disorders.

7) Glycopyrrolate

Potent and rapidly acting antimuscarinic lacking central effects at 0.1–0.3 mg i.m. (5–10 g/kg). Almost exclusively used for preanaesthetic and anaesthetic medication.

Tertiary amines

1) Dicyclomine

20 mg oral/i.m., 5–10 mg for children; has direct smooth muscle relaxant action as well as a weak anticholinergic effect. It has antispasmodic properties at doses that cause few atropinic side effects. However, infants have developed atropinic toxicity symptoms, and it is not recommended for children under the age of six months. It is also antiemetic and has been used to treat morning sickness and motion sickness. Other symptoms include dysmenorrhoea and irritable bowel syndrome.

2) Valethamate

The primary indication for this anticholinergic-smooth muscle relaxant is to hasten cervix dilatation when it is delayed during labor, as well as a visceral antispasmodic for urinary, biliary and intestinal colic.

3) Pirenzepine

It is taken orally in doses of 100–150 mg per day and selectively blocks M1 muscarinic receptors, inhibiting gastric secretion without the typical atropinic side effects (these are due to blockade of M2 and M3 receptors). Pirenzepine's likely site of action in the stomach is intramural plexuses and ganglionic cells rather than parietal cells themselves. Although it is nearly as effective as cimetidine in relieving peptic ulcer pain and promoting ulcer healing, it has been overshadowed by H2 blockers and proton pump inhibitors.

Vasicoselective drugs

These atropine-like synthetic drugs are used to treat overactive bladder. Intravesical pressure is reduced, bladder capacity is increased, and the frequency of bladder contractions is reduced by blocking muscarinic receptors in the bladder. Side effects such as dry mouth, constipation, and blurred vision limit the tolerability of these agents when used on a regular basis.

1) Oxybutynin

This more recent antimuscarinic has a high affinity for receptors in the urinary bladder and salivary glands, as well as smooth muscle relaxant and local anaesthetic properties. It is more selective for M1/M3 subtypes and has less effect on M2 subtypes. It is used to treat detrusor instability, which causes urinary frequency and urge incontinence, due to its vasicoselective action. Beneficial effects in post-prostatectomy vasical spasm, neurogenic bladder, spina bifida, and nocturnal enuresis have been demonstrated. Oral dosing causes anticholinergic side effects, but intravasical instillation increases bladder capacity with few side effects. Oxybutynin is metabolized by CYP3A4, so its dose should be reduced in patients taking CYP3A4 inhibitors. Oxybutynin is available as a transdermal system (topical patch), which is better tolerated than oral formulations because it causes less dry mouth.

2) Tolterodine

This M3 selective muscarinic antagonist acts preferentially on the urinary bladder and is less likely to cause dry mouth and other anticholinergic side effects. It is used to treat overactive bladder symptoms such as frequency and urgency of urination. Because it is metabolized by CYP3A4, the dose should be cut in half in patients taking CYP3A4 inhibitors (erythromycin, ketoconazole, etc.)

3) Flavoxate

Has oxybutynin-like properties and is used to treat urinary frequency, urgency and dysuria caused by a lower urinary tract infection.

Darifenacin and Solifenacin are two other M3 subtype selective antimuscarinics that can assist with bladder problems.

Mydriatics

Atropine is an effective mydriatic, but its slow and long-lasting action makes it unsuitable for refractive testing. Despite the fact that the pupil dilates in 30–40 minutes, cycloplegia takes 1–3 hours and the subject is visually impaired for about a week. These difficulties are attempted to be overcome by the substitutes.

1) Homatropine

It has a tenfold lower potency than atropine. When injected into the eye, it takes 45–60 minutes to take effect, mydriasis lasts 1–3 days, and accommodation recovers in 1–2 days. It frequently results in unsatisfactory cycloplegia in children with high ciliary muscle tone.

2) Cyclopentolate

It is powerful and fast acting; mydriasis and cycloplegia occur in 30–60 minutes and last for about a day. Although it is preferred for cycloplegic refraction, children may experience transient behavioral abnormalities due to drug absorption after passage through the nasolacrimal duct. It's also used to treat iritis and uveitis.

3) Tropicamide

It has the quickest (20–40 minute) and shortest (3–6 hour) action, but it is an unreliable cycloplegic. However, it is adequate for adult refraction testing and as a short-acting mydriatic for fundoscopy. By combining with phenylephrine, the mydriatic action can be enhanced.

Antiparkinsonian drugs

Benztropine and trihexyphenidyl

In the treatment of Parkinson's disease and other types of parkinsonian syndromes, including antipsychotic-induced extrapyramidal symptoms, benztropine and trihexyphenidyl are useful as adjuncts with other antiparkinsonian agents.

These are most of the selective blockers of muscarinic receptors read the ganglionic and neuromuscular-blocking agents to complete Cholinergic Antagonists agents.

muscarinic and ganglionic blockers and their therapeutic uses common side effects observed with muscarinic agonists
References

1. Whalen, K., Finkel, R. and Panavelil, T.A. (2015). Pharmacology. Philadelphia: Wolters Kluwer.

2. Tripathi, K.D. (2015). Essentials of medical pharmacology. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd.

3. Katzung, B.G. (2018). Basic & clinical pharmacology. 14th ed. New York I 11 Pozostałych: Mcgraw-Hill Education, Copyright.

4. Rosenfeld, G.C. and Loose, D.S. (2014). Pharmacology. Baltimore, Md: Lippincott Williams & Wilkins.

5. Trevor, A.J., Katzung, B.G. and Marieke Kruidering-Hall (2015). Pharmacology examination & board review. New York: Mcgraw-Hill.

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