Introduction
Cholinergic antagonists are drugs that bind to muscarinic or nicotinic receptors, inhibiting the effects of acetylcholine and other cholinergic agonists. The most clinically relevant are those that target muscarinic receptors, often referred to as antimuscarinic agents or parasympatholytics. They interrupt parasympathetic innervation, leaving sympathetic actions unopposed. Ganglionic blockers preferentially target nicotinic receptors in sympathetic and parasympathetic ganglia, while neuromuscular blocking agents interfere with efferent impulses to skeletal muscles, mainly used in surgical settings.
Nature
Atropine, a tertiary amine derived from belladonna alkaloids, competes with acetylcholine for muscarinic receptors, exerting both central and peripheral effects. Its duration of action is approximately 4 hours, but topical administration in the eye can have prolonged effects. Atropine’s inhibitory effects are most pronounced in bronchial tissue, salivary and sweat glands, and the heart.
Mode of action
In the eye, atropine induces mydriasis, unresponsiveness to light, and cycloplegia, with potential risks in angle-closure glaucoma. In the gastrointestinal tract, it acts as an antispasmodic. Cardiovascular effects vary with dose, causing either a slight decrease or progressive increase in heart rate. Atropine also reduces secretions from salivary, sweat, and lacrimal glands, leading to dry mouth and potential hyperthermia, especially in vulnerable populations like children and the elderly.
Therapeutic effect
Therapeutically, atropine is used topically in ophthalmology for mydriasis and cycloplegia and systemically as an antispasmodic, to treat bradycardia, and as an antisecretory agent in respiratory tract surgeries. Additionally, it serves as an antidote for cholinergic agonist poisoning, including organophosphates and certain mushrooms. Atropine’s pharmacokinetics involve absorption, partial liver metabolism, and primarily renal elimination, with a half-life of about 4 hours.
Adverse effects
Adverse effects of atropine include dry mouth, blurred vision, tachycardia, urinary retention, constipation, and central nervous system symptoms ranging from restlessness to delirium and potential collapse of circulatory and respiratory systems, necessitating caution, especially in children due to their heightened sensitivity.
Scopolamine (scopolamine)
Scopolamine:
Actions: Scopolamine, a tertiary amine alkaloid similar to atropine, has stronger central nervous system (CNS) effects and longer duration of action. It effectively prevents motion sickness and can cause short-term memory loss. Unlike atropine, scopolamine causes sedation and can induce excitement at higher doses. It may also produce euphoria and has potential for abuse.
Therapeutic Uses: Used to prevent motion sickness and postoperative nausea and vomiting, scopolamine is more effective when used prophylactically. A topical patch can provide up to three days of relief.
Pharmacokinetics and Adverse Effects: Scopolamine shares similar pharmacokinetics and adverse effects with atropine but has a longer half-life.
Aclidinium, Glycopyrrolate, Ipratropium, and Tiotropium:
Overview: These are quaternary derivatives of atropine used as bronchodilators for COPD. Ipratropium is short-acting, while glycopyrrolate, tiotropium, and aclidinium are long-acting muscarinic antagonists. They are delivered via inhalation and do not affect the systemic circulation or CNS due to their positive charge.
Uses: Approved for maintenance treatment of bronchospasm in COPD. Ipratropium is also used in acute asthma management, while tiotropium is for chronic asthma management.
Tropicamide and Cyclopentolate:
- Uses: These are used in ophthalmic solutions to induce mydriasis and cycloplegia with shorter durations than atropine. Tropicamide lasts for 6 hours, and cyclopentolate for 24 hours.
Benztropine and Trihexyphenidyl:
- Uses: These are adjunctive treatments for Parkinson’s disease and other parkinsonian syndromes, including those induced by antipsychotics.
Oxybutynin and Other Antimuscarinic Agents for Overactive Bladder:
Actions: These drugs lower bladder pressure, increase bladder capacity, and reduce bladder contractions by blocking muscarinic receptors. Adverse effects may occur due to their action on receptors in the GI tract, salivary glands, CNS, and eye. Darifenacin and solifenacin are more selective for M3 receptors.
Therapeutic Uses: Used to manage overactive bladder and urinary incontinence, oxybutynin is also used for neurogenic bladder.
Pharmacokinetics: Available in oral forms, these agents typically have a long half-life for once-daily dosing. Oxybutynin is also available as a transdermal patch and topical gel. They are primarily metabolized by CYP3A4 and CYP2D6, except for trospium, which undergoes ester hydrolysis.
Adverse Effects: Common side effects include dry mouth, constipation, and blurred vision. Extended-release formulations and transdermal patches may have fewer adverse effects. Trospium, which minimally crosses the blood-brain barrier, is preferred for treating overactive bladder in patients with dementia.
Conclusion
In conclusion, cholinergic antagonists play a crucial role in clinical practice, primarily targeting muscarinic receptors to counteract the effects of acetylcholine. Atropine, one of the most notable agents in this class, exhibits diverse actions across various organ systems, making it valuable in ophthalmology, cardiology, gastroenterology, and emergency medicine. However, its use requires careful consideration due to its potential for adverse effects, especially in vulnerable populations. Despite these challenges, atropine remains a vital tool in the management of conditions such as bradycardia, glaucoma, and cholinergic poisoning. Further research and refinement of its therapeutic applications are necessary to optimize its efficacy and minimize risks in clinical settings.
