Cholinergic Antagonists: Types, Mechanisms, and Effects

Cholinergic antagonists can be divided into three groups: antimuscarinic agents, ganglionic blockers, and neuromuscular blockers.

Antimuscarinic agents, also known as anticholinergic drugs, block primarily muscarinic receptors, causing inhibition of muscarinic functions.

Atropine is a well-known medication that belongs to the antimuscarinic group, with primary sites of action including the eye, GI tract, heart, salivary, sweat, and lacrimal glands.

Antimuscarinic activity of Atropine in the eye results in relaxation of the ciliary muscle, causing dilation of the pupil (mydriasis), inability to focus visually (cycloplegia), and unresponsiveness to light.

Ophthalmic preparations of Atropine are used before an eye exam or eye surgery, as well as to treat certain inflammatory conditions of the eye.

Atropine's effects can last for days, whereas other antimuscarinic agents like Cyclopentolate and Tropicamide can produce mydriasis that lasts for hours.

Atropine blocks M3 receptors in the GI tract, resulting in reduction of GI motility, prolonged gastric emptying, and lengthened intestinal transit time.

At higher doses, Atropine can also effectively block M2 receptors on the SA node and AV node, producing tachycardia, with a heart rate increase of up to 30-40 beats per minute.

Scopolamine is another well-known medication in the antimuscarinic group, with a greater effect on the CNS and a longer duration of action.

Scopolamine is one of the most effective medications used for prevention of motion sickness and post-operative nausea and vomiting.

Scopolamine is available in a patch formulation that provides effects lasting up to three days.

Ipratropium and Tiotropium are medications in the antimuscarinic group that block muscarinic acetylcholine receptors without specificity for subtypes.

This results in decreased contractility of smooth muscle in the lungs, leading to bronchodilation and reduction of mucus secretion.

Tiotropium and Ipratropium are administered by inhalation for maintenance treatment of bronchospasms in patients with COPD.

Ipratropium also comes in a nasal spray formulation, which is often used for treatment of rhinorrhea (runny nose).

The main difference between Ipratropium and Tiotropium is their duration of action, with Tiotropium being a long-acting agent dosed once daily and Ipratropium being a short-acting agent requiring up to four times daily dosing.

Other medications in the antimuscarinic group are used for treatment of overreactive bladder, including Tolterodine, Darifenacin, Solifenacin, Oxybutynin, Trospium, and Fesoterodine.

These agents have varying selectivity for the M3 receptor, which is the main receptor involved in bladder function.

Benztropine and Trihexyphenidyl are muscarinic blockers that suppress central cholinergic activity and are beneficial in treating Parkinson-like disorders.

The ABCDs of anticholinergic adverse effects are: agitation, blurred vision, constipation, confusion, dry mouth, stasis of urine, and sweating.

Ganglionic blockers are the second group of cholinergic antagonists, with Nicotine being the main agent in this group.

Nicotine is a cholinergic agonist that is also considered a functional antagonist due to its ability to stimulate and then block cholinergic function.

Nicotine acts on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia.

Effects of Nicotine result from increased release of neurotransmitters such as dopamine, serotonin, and norepinephrine.

Nicotine is a non-selective stimulant and depressant of autonomic ganglia, and its use can cause addiction due to CNS stimulation.

Neuromuscular blockers are the third group of cholinergic antagonists, which block the cholinergic transmission between motor nerve endings and nicotinic receptors on the skeletal muscle.

Neuromuscular blocking agents can be divided into two groups: non-depolarizing agents and depolarizing agents.

Non-depolarizing agents are competitive antagonists that bind to acetylcholine receptors but don't induce ion channel opening, preventing depolarization of the muscle cell membrane.

These agents are used to facilitate mechanical ventilation and tracheal intubation, as well as to increase muscle relaxation during surgery.

Non-depolarizing agents are not absorbed from the GI tract and must be injected, usually intravenously.

Time to onset of action is rapid, usually less than two minutes.

Once administered, these agents paralyze small, fast-contracting muscles first, followed by larger muscles.

The choice of an agent typically depends on the desired onset and duration of muscle relaxation.

Some of the most widely used non-depolarizing agents include Cisatracurium, Pancuronium, Rocuronium, Vecuronium, and Atracurium.

Atracurium causes histamine release, leading to a fall in blood pressure, flushing, and bronchoconstriction.

Atracurium also has a toxic metabolite called laudanosine, which can provoke seizures, especially in patients with impaired renal function.

Cisatracurium is often used in patients with multi-organ failure due to its metabolism being independent of hepatic or renal function.

Vecuronium and Rocuronium are metabolized by the liver, so their action may be prolonged in patients with hepatic dysfunction.

Pancuronium is excreted unchanged in urine and one of its main side effects is an increase in heart rate.

Depolarizing agents act as acetylcholine receptor agonists, mimicking the action of acetylcholine.

The only depolarizing agent still used in clinical practice is Succinylcholine.

Succinylcholine binds to the nicotinic receptor and causes the sodium channel to open, resulting in membrane depolarization.

Succinylcholine is resistant to acetylcholinesterase and causes prolonged depolarization, leading to a transient fasciculations and finally flaccid paralysis.

Succinylcholine has a rapid onset of action and is commonly used to facilitate rapid sequence endotracheal intubation in critically ill patients.

Succinylcholine is also sometimes used to provide adequate muscle relaxation during electroconvulsive therapy.

Following intravenous administration, Succinylcholine causes complete muscle relaxation within one minute, with effects typically lasting up to ten minutes.

Adverse effects of Succinylcholine include prolonged apnea in patients deficient in plasma pseudocholinesterase or those with genetic variations of this enzyme.

Prolonged depolarization caused by Succinylcholine can lead to continued flow of potassium into the extracellular fluid, resulting in hyperkalemia.

In patients with normal potassium levels, this is usually not a big issue, but in those with elevated potassium levels, Succinylcholine can cause serious EKG changes and even asystole.

In genetically susceptible patients, Succinylcholine can trigger rare and potentially fatal conditions like malignant hyperthermia.