An Overview On Direct-Acting Cholinergic Agonists

Introduction

Direct-acting cholinergic agonists mimic the effects of acetylcholine (Ach) by binding directly to cholinoceptors, which can be muscarinic or nicotinic. These classified into two categories: 1) choline esters, which consist of both endogenous Ach and synthetic esters such as carbachol and bethanechol; and 2) naturally occurring alkaloids as nicotine and pilocarpine. All these drugs have longer durations of action compared to Ach. Useful  drugs in context of therapeutic activity, such as pilocarpine and bethanechol, especially bind to muscarinic receptors and are sometimes called muscarinic agents. However, direct-acting agonists generally lack specificity, limiting their clinical utility.

Acetylcholine

Acetylcholine (Ach) which can not penetrate the membranes is a quaternary ammonium compound. Although it is the neurotransmitter for parasympathetic and somatic nerves as well as autonomic ganglia, it has little therapeutic use due to its broad range of actions and rapid inactivation by cholinesterases. Ach has both muscarinic and nicotinic activity, with effects including:

1. Decrease in Heart Rate and Cardiac Output: Ach mimics vagal stimulation of the heart, causing a brief decrease in heart rate (bradycardia) and cardiac output when injected intravenously, primarily by reducing the firing rate at the sinoatrial (SA) node.

• Decrease in Blood Pressure: Ach causes vasodilation and lowers blood pressure by an indirect mechanism, activating M3 receptors on endothelial cells of blood vessels. This leads to the production of nitric oxide, which then induces smooth muscle relaxation. Under normal conditions, vascular cholinergic receptors are not functional as ACh is not released into the blood in significant quantities. Atropine can block these receptors, preventing Ach-induced vasodilation.

• Other Actions: Ach increases salivary and gastric acid secretions, stimulates intestinal secretions and motility, enhances bronchiolar secretions, and causes bronchoconstriction. It also increases bladder muscle tone, inducing urination, and stimulates ciliary muscle contraction for near vision, and pupil constriction (miosis). Ach is used in eye surgery to induce miosis.

 Bethanechol

Bethanechol is a carbamoyl ester structurally related to Ach but is not hydrolyzed by acetylcholinesterase (AChE) and has strong muscarinic activity without nicotinic effects. Its main actions are on the smooth muscles of the bladder and gastrointestinal (GI) tract, with a duration of action of about one hour.

1. Actions: Bethanechol stimulates muscarinic receptors, increasing intestinal motility and bladder muscle tone, which promotes urination.

• Therapeutic Uses: Bethanechol is used to treat atonic bladder, particularly in cases of postpartum or postoperative nonobstructive urinary retention, and can also address neurogenic atony and megacolon.

• Adverse Effects: Potential adverse effects include generalized cholinergic stimulation, leading to symptoms like sweating, salivation, flushing, decreased blood pressure (with reflex tachycardia), nausea, abdominal pain, diarrhea, and bronchospasm. Severe reactions can be managed with atropine sulfate.

Carbachol (Carbamylcholine)

Carbachol has both muscarinic and nicotinic actions and is a poor substrate for AChE, making it more resistant to breakdown. It is used primarily in ophthalmology.

1. Therapeutic Uses: Due to its high potency and lack of selectivity, carbachol is mainly used in eye surgery to induce miosis and to lower intraocular pressure in glaucoma treatment.

• Adverse Effects: Systemic adverse effects are rare with ophthalmic use due to poor systemic absorption.

Pilocarpine

Pilocarpine is a tertiary amine stable to AChE hydrolysis, with muscarinic activity. It can penetrate the central nervous system (CNS) at therapeutic doses and is used mainly in ophthalmology.

1. Actions: Pilocarpine induces rapid miosis, ciliary muscle contraction, and spasm of accommodation when applied to the eye. It also strongly stimulates secretions like sweat, tears, and saliva, although its use for these effects is limited due to lack of selectivity.

• Therapeutic Uses: Pilocarpine is the drug of choice for emergency reduction of intraocular pressure in both open-angle and angle-closure glaucoma. It promotes aqueous humor drainage, reducing intraocular pressure rapidly. Additionally, it is used to treat xerostomia in patients undergoing radiation therapy and in Sjögren’s syndrome.

• Adverse Effects: Adverse effects include blurred vision, night blindness, and brow ache. Pilocarpine poisoning, characterized by exaggerated parasympathetic effects like profuse sweating and salivation, can be treated with atropine.

Conclusion

Direct-acting cholinergic agonists function by directly binding to cholinoceptors, mimicking the effects of acetylcholine (Ach). These agents fall into two categories: choline esters (such as carbachol and bethanechol) and naturally occurring alkaloids (such as nicotine and pilocarpine). Despite their therapeutic potential, their broad range of actions and lack of specificity often limit their clinical utility.

Acetylcholine (Ach), although crucial for neurotransmission in various systems, has limited therapeutic use due to its rapid degradation and broad range of effects, including decreasing heart rate and blood pressure, and increasing glandular secretions and bladder muscle tone.

Bethanechol is primarily used for its muscarinic effects on the bladder and gastrointestinal (GI) tract, particularly for treating urinary retention and neurogenic bladder atony. It has minimal nicotinic activity and a duration of action of about one hour.

Carbachol exhibits both muscarinic and nicotinic activity, making it highly potent but less selective. It is mainly used in ophthalmology for inducing miosis during eye surgery and reducing intraocular pressure in glaucoma.

Pilocarpine is favored in ophthalmology for its ability to rapidly induce miosis and reduce intraocular pressure, making it ideal for glaucoma treatment. It is also used to treat dry mouth in specific conditions like Sjögren’s syndrome. However, its lack of selectivity can lead to significant side effects.

Overall, while direct-acting cholinergic agonists are effective for certain medical conditions, their broad range of actions and potential for adverse effects necessitate careful therapeutic use.