Antimuscarinic Agents: Cholinergic Antagonists

• Cholinergic antagonists bind to cholinoceptors (muscarinic or nicotinic) and prevent the effects of acetylcholine (ACh) and other cholinergic agonists.
• Clinically useful cholinergic antagonists selectively block muscarinic receptors.
• Anticholinergic agents is a common but imprecise term, as they only antagonize muscarinic receptors.
• Antimuscarinic agents is a more accurate term for drugs that antagonize muscarinic receptors.
• Parasympatholytics is another term for antimuscarinic agents.
• Ganglionic blockers preferentially target nicotinic receptors in sympathetic and parasympathetic ganglia, and are clinically less significant.
• Neuromuscular-blocking agents (mostly nicotinic antagonists) disrupt efferent impulse transmission to skeletal muscles.
• These are used as skeletal muscle relaxants during surgical anesthesia and to facilitate intubation.

Antimuscarinic Agents

• Antimuscarinic drugs like atropine and scopolamine block muscarinic receptors, inhibiting muscarinic functions.
• These drugs also block the few sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands.
• Antimuscarinic drugs have little action at skeletal neuromuscular junctions (NMJs) or autonomic ganglia because they do not block nicotinic receptors.
• Antimuscarinic drugs are used in a variety of clinical situations.

Atropine

• Atropine is a tertiary amine belladonna alkaloid with high affinity for muscarinic receptors.
• It competitively binds and prevents ACh from binding to muscarinic receptor sites.
• Atropine acts both centrally and peripherally.
• Its general actions last about 4 hours, except in the eye where effects can last for days.
• Bronchial tissue, sweat and saliva secretion, and the heart are most sensitive to atropine's inhibitory effects.

Actions

• Eye: Atropine causes mydriasis (pupil dilation), unresponsiveness to light, and cycloplegia (inability to focus for near vision).
• Intraocular pressure may rise dangerously in patients with angle-closure glaucoma.
• Gastrointestinal (GI): Atropine reduces GI tract activity and acts as an antispasmodic.
• Atropine and scopolamine are the most potent antispasmodic drugs available.
• Gastric motility is reduced, but hydrochloric acid production is not significantly affected, making atropine ineffective for treating peptic ulcers.
• Cardiovascular: Low doses cause a slight decrease in heart rate by blocking M1 receptors on inhibitory prejunctional neurons, increasing ACh release.
• Higher doses cause a progressive increase in heart rate by blocking M2 receptors on the sinoatrial node.
• Secretions: Atropine causes dry mouth (xerostomia) by blocking muscarinic receptors in salivary glands and affects sweat and lacrimal glands similarly.

Therapeutic Uses

• Ophthalmic: Used topically for mydriatic and cycloplegic effects, allowing measurement of refractive errors without interference from accommodation.
• Shorter-acting antimuscarinics like cyclopentolate and tropicamide have replaced atropine due to atropine's prolonged mydriasis (7 to 14 days vs. 6 to 24 hours with other agents).
• Antispasmodic: Used to relax the GI tract.
• Cardiovascular: Used to treat bradycardia of varying etiologies.
• Antisecretory: Used to block secretions in the upper and lower respiratory tracts prior to surgery.
• Antidote for cholinergic agonists: Used to treat organophosphate poisoning (insecticides, nerve gases), overdose of anticholinesterases like physostigmine, and some types of mushroom poisoning.
• Large doses may be required to counteract poisons, with atropine's ability to enter the CNS being important for treating central toxic effects of anticholinesterases.

Pharmacokinetics

• Atropine is readily absorbed, partially metabolized by the liver, and primarily eliminated in urine with a half-life of about 4 hours.
• Adverse effects include dry mouth, blurred vision, "sandy eyes," tachycardia, urinary retention, and constipation.
• CNS effects include restlessness, confusion, hallucinations, and delirium, potentially progressing to circulatory and respiratory system collapse, and death.
• Low doses of cholinesterase inhibitors like physostigmine may be used to overcome atropine toxicity.
• Atropine can induce urinary retention and is dangerous in children due to their sensitivity to its effects, particularly rapid increases in body temperature.

Scopolamine

• Scopolamine is another tertiary amine plant alkaloid that produces similar peripheral effects to atropine, but has greater CNS action and a longer duration of action.

Actions

• Scopolamine is effective against motion sickness and blocks short-term memory.
• It produces sedation, but at higher doses can cause excitement
• Scopolamine may produce euphoria and is susceptible to abuse.

Therapeutic Uses

• Limited to prevention of motion sickness and postoperative nausea and vomiting.
• Available as a topical patch that provides effects for up to 3 days for motion sickness.

Pharmacokinetics and Adverse Effects

• Similar to atropine, except with a longer half-life.

Aclidinium, Glycopyrrolate, Ipratropium, and Tiotropium

• Ipratropium and tiotropium are quaternary derivatives of atropine, while glycopyrrolate and aclidinium are synthetic quaternary compounds.
• Ipratropium is a short-acting muscarinic antagonist (SAMA), while glycopyrrolate, tiotropium, and aclidinium are long-acting muscarinic antagonists (LAMAs).
• These agents are bronchodilators approved for maintenance treatment of bronchospasm associated with chronic obstructive pulmonary disease (COPD).
• Ipratropium and tiotropium are also used in the acute and chronic management of bronchospasm in asthma, respectively.
• All of these agents are delivered via inhalation.
• Due to their positive charge, they do not enter the systemic circulation or the CNS, restricting effects to the pulmonary system.

Tropicamide and Cyclopentolate

• Used as ophthalmic solutions for mydriasis and cycloplegia.
• Their duration of action is shorter than that of atropine.
• Tropicamide produces mydriasis for 6 hours, and cyclopentolate for 24 hours.

Benztropine and Trihexyphenidyl

• Used as adjuncts with other antiparkinsonian agents to treat Parkinson’s disease and antipsychotic-induced extrapyramidal symptoms.

Oxybutynin and Other Antimuscarinic Agents for Overactive Bladder

• Oxybutynin, darifenacin, fesoterodine, solifenacin, tolterodine, and trospium are synthetic atropine-like drugs with antimuscarinic actions.

Actions

• These lower intravesical pressure, increase bladder capacity, and reduce the frequency of bladder contractions by competitively blocking muscarinic (M3) receptors in the bladder.
• Antimuscarinic actions at M3 receptors in the GI tract, salivary glands, CNS, and eye may cause adverse effects.
• Darifenacin and solifenacin are relatively more selective M3 muscarinic receptor antagonists; other drugs are mainly nonselective muscarinic antagonists.

Therapeutic Uses

• Used for management of overactive bladder and urinary incontinence.
• Oxybutynin is also used in patients with neurogenic bladder.

Pharmacokinetics

• All agents are available in oral dosage forms.
• Most have a long half-life, allowing once-daily administration (immediate-release oxybutynin and tolterodine must be dosed two or more times daily, while extended-release formulations allow for once-daily dosing).
• Oxybutynin is also available in a transdermal patch and topical gel formulation.
• These drugs are hepatically metabolized by the cytochrome P450 system (primarily CYP 3A4 and 2D6), except for trospium, which is thought to undergo ester hydrolysis.

Adverse Effects

• Side effects include dry mouth, constipation, and blurred vision which limit tolerability.
• Extended-release formulations and the transdermal patch have a lower incidence of adverse effects and may be better tolerated.
• Trospium minimally crosses the blood–brain barrier and has fewer CNS effects, making it a preferred choice in treating overactive bladder in patients with dementia.

Ganglionic Blockers

• Ganglionic blockers act on the nicotinic receptors of both parasympathetic and sympathetic autonomic ganglia, and some block the ion channels of the autonomic ganglia.
• These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists.
• These drugs block the entire output of the autonomic nervous system at the nicotinic receptor.
• These responses are complex and unpredictable, so ganglionic blockade is rarely used therapeutically, but often serves as a tool in experimental pharmacology.

Nicotine

• Nicotine, a component of cigarette smoke, is a poison with many undesirable actions, without therapeutic benefit.
• Depending on the dose, nicotine depolarizes autonomic ganglia, resulting first in stimulation and then paralysis of all ganglia.
• The stimulatory effects result from increased release of neurotransmitters, due to effects on both sympathetic and parasympathetic ganglia.
• Overall response involves increased blood pressure and cardiac rate and increased peristalsis and secretions.
• At higher doses, blood pressure falls due to ganglionic blockade, and activity in both the GI tract and bladder musculature ceases.

Neuromuscular-Blocking Agents

• These drugs block cholinergic transmission between motor nerve endings and nicotinic receptors on skeletal muscle.
• They act either as antagonists (nondepolarizing) or as agonists (depolarizing) at the receptors on the endplate of the NMJ.
• Neuromuscular blockers (NMBs) facilitate rapid intubation when needed due to respiratory failure.
• During surgery, they facilitate endotracheal intubation and provide complete muscle relaxation at lower anesthetic doses.
• This increases the safety of anesthesia by allowing patients to recover quickly and completely, but NMBs should not substitute for inadequate anesthesia.
• NMBs are used in the intensive care unit (ICU) to facilitate intubation and mechanical ventilation in critically ill patients.

Nondepolarizing (Competitive) Blockers

• Curare was the first known NMB.
• Tubocurarine has been replaced by agents with fewer adverse effects, such as cisatracurium, mivacurium, pancuronium, rocuronium, and vecuronium.

Mechanism of Action

• At low doses, nondepolarizing agents competitively block ACh at nicotinic receptors, preventing depolarization of the muscle cell membrane and inhibiting muscular contraction.
• Their competitive action can be overcome by administration of cholinesterase inhibitors like neostigmine and edrophonium which increase ACh concentration in the neuromuscular junction.
• Anesthesiologists employ this strategy to shorten the duration of the neuromuscular blockade, muscle will respond to direct electrical stimulation from a peripheral nerve stimulator allowing for monitoring of the extent of neuromuscular blockade.
• At high doses, nondepolarizing agents can block the ion channels of the motor endplate, weakening neuromuscular transmission and reducing the ability of cholinesterase inhibitors to reverse their actions and , does not respond to direct electrical stimulation.

Actions

• Muscles have differing sensitivity to blockade by competitive agents.
• Small, rapidly contracting muscles of the face and eye are most susceptible and are paralyzed first, followed by the fingers, limbs, neck, and trunk muscles.
• The intercostal muscles are affected next, and lastly, the diaphragm.
• The muscles recover in the reverse manner.
• Sugammadex is a selective relaxant binding agent that terminates the action of both rocuronium and vecuronium for speedy recovery.

Pharmacokinetics

• All NMBs are injected intravenously or occasionally intramuscularly.
• These agents possess two or more quaternary amines in their bulky ring structure that prevent absorption from the gut.
• They penetrate membranes very poorly and do not enter cells or cross the blood-brain barrier.
• Pancuronium is excreted unchanged in urine.
• Cisatracurium undergoes organ-independent metabolism (via Hofmann elimination) to laudanosine, which is further metabolized and renally excreted.
• Vecuronium and rocuronium are deacetylated in the liver and excreted unchanged in bile.
• Mivacurium is eliminated by plasma cholinesterase.
• The choice of agent depends on the desired onset and duration of muscle relaxation and the route of elimination.

Drug Interactions

• Cholinesterase inhibitors: Drugs such as neostigmine, physostigmine, pyridostigmine, and edrophonium can overcome the action of nondepolarizing neuromuscular blockers.
• With increased dosage, cholinesterase inhibitors can cause a depolarizing block as a result of elevated ACh concentrations at the endplate membrane.
• If the neuromuscular blocker has entered the ion channel, cholinesterase inhibitors are not as effective in overcoming blockade.
• Halogenated hydrocarbon anesthetics: Drugs such as desflurane enhance neuromuscular blockade by exerting a stabilizing action at the NMJ and sensitizing the NMJ to the effects of neuromuscular blockers.
• Aminoglycoside antibiotics: Drugs such as gentamicin and tobramycin inhibit ACh release from cholinergic nerves by competing with calcium ions, synergizing with pancuronium and other competitive blockers.
• Calcium channel blockers: These agents may increase the neuromuscular blockade of competitive blockers.

Depolarizing Agents

• Depolarizing blocking agents depolarize the plasma membrane of the muscle fiber, similar to ACh.
• These agents are more resistant to degradation by acetylcholinesterase (AChE) and thus more persistently depolarize the muscle fibers.
• Succinylcholine is the only depolarizing muscle relaxant in use today.

Mechanism of Action

• Succinylcholine attaches to the nicotinic receptor and acts like ACh to depolarize the junction.
• The depolarizing agent first causes the opening of the sodium channel associated with the nicotinic receptors, which results in depolarization of the receptor (Phase I).
• This leads to a transient twitching of the muscle (fasciculations).
• Continued binding of the depolarizing agent renders the receptor incapable of transmitting further impulses.
• With time, continuous depolarization gives way to gradual repolarization as the sodium channel closes or is blocked, leading to resistance to depolarization (Phase II) and flaccid paralysis.

Actions

• As with the competitive blockers, the respiratory muscles are paralyzed last.
• Succinylcholine initially produces brief muscle fasciculations that cause muscle soreness.
• This may be prevented by administering a small dose of nondepolarizing neuromuscular blocker prior to succinylcholine.
• Normally, the duration of action of succinylcholine is extremely short, due to rapid hydrolysis by plasma pseudocholinesterase.
• Succinylcholine that gets to the NMJ is not metabolized by AChE, allowing the agent to bind to nicotinic receptors, and redistribution to plasma is necessary for metabolism (therapeutic benefits last only for a few minutes).

Therapeutic Uses

• Because of its rapid onset of action, succinylcholine is useful when rapid endotracheal intubation is required during the induction of anesthesia and during electroconvulsive shock treatment.

Pharmacokinetics

• Succinylcholine is injected intravenously.
• Its brief duration of action results redistribution and rapid hydrolysis by plasma pseudocholinesterase.
• Therefore, it is sometimes given by continuous infusion to maintain a longer duration of effect drug effects rapidly disappear upon discontinuation.

Adverse Effects

• Hyperthermia: Succinylcholine can potentially induce malignant hyperthermia in susceptible patients.
• Apnea: Administration of succinylcholine to a patient who is deficient in plasma cholinesterase or who has an atypical form of the enzyme can lead to prolonged apnea due to paralysis of the diaphragm.
• The rapid release of potassium may also contribute to prolonged apnea in patients with electrolyte imbalances who receive this drug.
• In patients with electrolyte imbalances who are also receiving digoxin or diuretics (such as heart failure patients) succinylcholine should be used cautiously or not at all.
• Hyperkalemia: Succinylcholine increases potassium release from intracellular stores, dangerous in burn patients and patients with massive tissue damage in which potassium has been rapidly lost.