In this article, we will study the important pharmacological aspects of anticholinergic drugs such as classification, pharmacokinetics, mechanism of action, important actions on various organ systems, clinical uses, drug interactions, adverse effects and toxicity.

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Atropine 3D sticks

Image: “Stick model of the (R)-atropine molecule, the pharmacologically inactive enantiomer in atropine. Sometimes referred to as D-hyoscyamine.” by Ben Mills – Own work. License: Public Domain


Definition of Anticholinergic Drugs

Anticholinergic drugs or cholinergic antagonists are the drugs that bind to cholinergic receptors (muscarinic and nicotinic) to prevent the effect of acetylcholine and other cholinergic agonists. These drugs are also called parasympatholytics. Anticholinergic drugs are classified into three groups: antimuscarinic drugs, antinicotinic drugs (neuromuscular blockers and gnaglionic blockers) and cholinesterase regenerators.

Antimuscarinic Drugs

  • Atropine
  • Benztropine

    Chemical structure of benztropine

    Image: “Chemical structure of a benztropine analog” by Ed (Edgar181) – Own work. License: Public Domain

  • Cyclopentolate
  • Darifenacin
  • Fesoterodine
  • Ipratropium
  • Oxybutynin
  • Scopolamine
  • Solifenacin
  • Tiotropium
  • Tolterodine
  • Trihexyphenidyl
  • Tropicamide
  • Trospium chloride

These are further classified into:

M1 selective blockers: Pirenzepine and telenzepine

Non-selective blockers: Atropine

Pharmacokinetics of antimuscarinic drugs

  • Atropine is a tertiary amine belladonna alkaloid. It is relatively lipid soluble and readily crosses membrane barriers. Atropine has high affinity for muscarinic receptors.
  • Eliminated partially by metabolism in the liver and partially unchanged in urine.
  • Half life is 2-4 hours, and duration of action is 4-8 hours. However, ocular retention is more than 72 hours.

Mechanism of action of antimuscarinic drugs

Muscarinic blocking agents bind competitively and prevent acetylcholine from binding to the sites. However, their antagonistic actions can be reduced by increasing the concentration of the muscarinic agonists.

Always remember: Their action on organ systems will always be opposite to the cholinergic agonists.

Effect of antimuscarinic drugs on organ systems

Central nervous system (CNS): Antimuscarinic agents produce sedation, amnesia, delirium, anti-motion sickness and antiparkinson effects.

Scopolamine has a greater and longer duration of action on the CNS compared to atropine. It is the most effective anti-motion sickness drug available. It also has unusual effect of blocking short term memory. It produces sedation at low dose and excitement at high dose. It produces euphoria and is susceptible to abuse.

For motion sickness, it is available as topical patch that is effective for 3 days and can be used as prophylactic medication. It is also used for postoperative nausea and vomiting.

Benztropine, biperiden, and trihexyphenidyl are used in parkinsonism as adjuncts when patients become unresponsive to levodopa.

Eye: Mechanism of action is by blockage of M3 receptors.

Mydriasis

Image: “Mydriasis ” by Bin im Garten – Own work (own picture). License: CC BY-SA 3.0

Antimuscarinic drugs administered topically cause mydriasis, cycloplegia and paralyze accommodation. The drugs are absorbed from the conjunctival sac into the eye.

The duration of action varies for each drug: atropine (>72 hours), homatropine (24 hours), cyclopentolate (2-12 hours) and tropicamide (0.5-4 hours).

Important: Among the muscarinic receptor blockers, tropicamide has shorter duration of action.

Bronchi: Mechanism of action is by blockage of M3 receptors.

Atopine is used parenterally to decrease secretions during general anaesthesia.

Ipratropium is used by inhalation to promote bronchodilation in asthma and COPD. As it is poorly absorbed and rapidly metabolized, the antimuscarinic effects outside the lung, like tachycardia and arrhythmias, are less likely. It is administered 4 times daily.

Tiotropium is a newer drug, which is administered once daily.

Gut: Mechanism of action is by blockage of M1 and M3 receptors.

Atropine and scopolamine act as most potent antispasmodic agents by decreasing gastric motility. The dose of atropine used for antispasmodic action also decreases saliva secretion, ocular accommodation and urination. Because of these effects, compliance with atropine is decreased.

Antimuscarinic drugs like atropine, methscopolamine and propantheline can be used in peptic ulcer because of their antisecretory action; however, they are not used nowadays as they are inferior to H2 blockers and proton pump inhibitors.

Bladder: oxybutynin and tolterodine are used to reduce urgency in mild cystitis and to reduce bladder spasms after urologic surgery.

Tolterodine, darifenacin, solifenacin and fesoterodine are used for the treatment of stress incontinence.

Oxybutynin 3d balls

Image: “Chemical structure of oxybutynin 3D” by Simek – Own work. License: Public Domain

Oxybutynin is available as transdermal patch, which is better tolerated due to the fewer side effects.

Cardiovascular: Low dose of atropine blocks M1 receptors on presynaptic neurons and decreases the heart rate. High dose of atropine blocks M2 receptors at SA node and increases the heart rate.

Secretions: Atropine blocks muscarinic receptors in the salivary glands producing dryness of the mouth (xerostomia). Sweat glands and lacrimal glands are similarly affected, resulting in decrease in secretions.

Therapeutic uses of antimuscarinic drugs

Atropine is used as an antispasmodic agent to treat bradycardia; as antisecretory agent to block secretions in the upper and lower respiratory secretions prior to surgery; for treatment of organophosphorous poisoning and overdose of anticholinesterases such as physostigmine.

Scopolamine is used for motion sickness.

Adverse effects of antimuscarinic drugs

Antimuscarinic agents can be described with the mnemonics Dry As Bone, Red As Beet, Mad As Hatter.

Atropine causes inhibition of secretion of the sweat glands causing hyperthermia in children and elderly, which is called atropine fever. Because of inhibition of sweating, salivation and lacrimation, it is termed as dry bone.

Large doses of atropine cause tachycardia and arrhythmias; also, block in the intraventricular conduction, which is difficult to treat.

In elderly patients, atropine causes angle closure glaucoma; and urinary retention in men with prostatic hyperplasia.

Constipation and blurred vision are common adverse effects in all age groups.

CNS toxicity from antimuscarinic agents includes sedation, amnesia, delirium, hallucination (MAD AS HATTER) and convulsions.

Dilatation of cutaneous vessels of the arms, head, neck and trunk are seen in overdoses of atropine, which is called atropine flush (RED AS BEET).

Atropine at a dose of 0.5 mg causes bradycardia, dryness of the mouth and inhibition of sweating. At 5.0 mg it causes tachycardia, palpitations, marked dryness of the mouth, mydrasis and blurring of vision. At >10.0 mg dose, it causes hallucinations, delirium and coma.

Treatment of toxicity

Treatment of toxicity is usually symptomatic.

Important: Severe tachycardia requires cutaneous administration of small doses of physostigmine.

Hyperthermia is managed with cooling blankets or evaporative cooling.

Contraindications of antimuscarinic drugs

The antimuscarinic agents should be used cautiously in infants because of danger of hyperthermia.

Acute angle closure glaucoma

Image: “Photograph showing acute angle-closure glaucoma, which is a sudden elevation in intraocular pressure that occurs when the iris blocks the eye’s drainage channel—the trabecular meshwork.” by Jonathan Trobe, M.D. – The Eyes Have It. License: CC BY 3.0

Antimuscarinic drugs are contraindicated in persons with closed angle glaucoma and in men with prostatic hyperplasia.

Antinicotinic Drugs

Antinicotinic drugs are classified into two types:

  1. Neuromuscular blocking agents
  2. Ganglionic blockers

Neuromuscular blocking agents

These are further classified into two classes:

  1. Non-depolarizing Blockers: Pancuronium, cisatracurium, rocuronium, vecuronium
  2. Depolarizing Blockers: Succinylcholine

These classes of drugs act as antagonists (non-depolarizing type) and agonists (depolarizing type) at the receptors of the end plate of neuromuscular junction.

At lower doses, they produce complete muscle relaxation facilitating their use in tracheal intubation during surgery. They also allow fast recovery from anaesthesia and decrease post-operative respiratory depression.

Mechanism of action of non-depolarazing blockers

These are also called competitive blockers. At low doses, these drugs compete with ACh at the receptor without stimulating it, thus preventing depolarization of muscle cell membrane and inhibit muscular contraction.

This effect can be reversed by administration of cholinesterase inhibitors like neostigmine and edrophonium, which increase the concentration of ACh at neuromuscular junctions, and also by direct electrical stimulation.

At high doses, these drugs block the ion channel at the motor end plate reducing the neuromuscular transmission. This effect cannot be reversed by cholinesterase inhibitors and electrical stimulation.

Susceptibility to the drugs follows in this order: small contracting muscles of the face and eyes are paralyzed first, followed by finger, limbs, neck and trunk muscles and, lastly, the diaphragm. Recovery occurs in the inverse order.

Rocuronium has the most rapid onset of action of 60-120 sec.

Pharmacokinetics of non-depolarizing blockers

These drugs are administered via i.v or i.m routes. These are not effective orally.

Because of the presence of quartery amine in the structure, they are not absorbed through the gut. Also, they do not cross membranes, cells and blood brain barriers.

These drugs are not metabolized and are redistributed. Pancuronium, metocurine, pipecuronium and tubocuranium are excreted unchanged in urine and have a duration of action of less than 30 min.

Vecuromnium and rocuronium are excreted unchanged in bile and have a duration of action of 10 to 20 min.

In addition to hepatic metabolism, atracurim is eliminated via another method called Hoffman elimination, which is rapid spontaneous breakdown resulting in formation of laudanosine. Laudanosine in high concentration causes seizures.

Cisatracurium (stereoisomer of atracurium) is degraded in the plasma by ester hydrolysis, and its dose needs not be altered in renal failure as its elimination is not dependent on hepatic or renal function. It is one of the most commonly used muscle relaxants in clinical practice.

Drug interactions of non-depolarizing blockers

Cholinesterase inhibitors like edrophonium, neostigmine, pyridostigmine and physostigmine interact with neuromuscular blocking agents and overcome their action.

Halogenated hydrocarbon anaesthetics like desflurane sensitise the neuromuscular junction to these drugs and increase the blocking effect.

Myasthenia

Image: “Eyes of a patient with myasthenia gravis” by Cumulus at Dutch Wikipedia. License: CC BY-SA 3.0

Amino glycoside antibiotics like gentamicin and tobramycin compete with calcium ions and inhibit ACh release, and thus the effect of blockade is synergised with pancuronium.

Calcium channel blockers also increase the neuromuscular blockade effect.

Elderly patients and patients with myasthenia gravis are sensitive to non-depolarizing drugs, and the dose should be decreased in them.

Mechanism of action of depolarizing agents

These drugs act by depolarizing the plasma membrane of the muscle membrane. But their action is not reversed by anticholinesterases and thus the depolarization of muscle fiber persistently increases. Succinylcholine is the depolarizing muscle relaxant available. The process of depolarization occurs in two phases.

Phase 1 starts with opening of sodium channels attached with the nicotinic receptors resulting in depolarization of the receptor. This causes transient twitching of the muscle.

Phase 2 includes continuous binding of the depolarizing agent to the receptor, which makes it incapable of transmitting impulses. When this continues, gradual repolarization of the sodium channel takes place, thus blocking it and resulting in resistance to depolarization and flaccid paralysis.

Administration of a non-depolarizing neuromuscular blocker prior to sucuccinylcholine reduces the muscle soreness caused by succinylcholine. The duration of action is short because of hydrolysis by pseudocholinesterse.

Therapeutic uses of depolarizing agents

During induction of anaesthesia in endotracheal intubation to prevent aspiration of gastric contents, succinylcholine is used because of its rapid onset of action.

It is also used during electroconvulsive shock treatment.

Pharmacokinetics of depolarizing agents

Injection of succinylcholine i.v. results in redistribution of the drug and hydrolysis by pseudocholinesterase in the liver and plasmas, resulting in short duration of action. Continuous infusion will produce longer duration of action.

Adverse effects of depolarizing agents

On interaction with inhaled anaesthetics, succinylcholine causes malignant hyperthermia. Contraction of jaw muscles is the first sign noticed in this condition.

Muscle pain is the most common post-operative complaint when succinylcholine is administered.

In patients with deficiency of pseudocholinesterase, there will be prolonged apnoea due to paralysis of the diaphragm. In patients with electrolyte imbalance, succinylcholine causes release of potassium resulting in prolonged apnoea.

Succinylcholine causes potassium outflow from the cells, which can be a dangerous effect in patients with burns and in patients with massive tissue damage, spinal cord injury, peripheral nerve dysfunction and muscular dystrophy.

Ganglionic blocking agents

Ganglionic blockers act specifically on the nicotinic receptors present on the sympathetic and parasympathetic systems. As these drugs show no selectivity towards sympathetic and parasympathetic systems, they are used in experimental pharmacology.

Effects of ganglionic blocking drugs

On CNS, antinicotinic action includes reduction of nicotine craving and amelioration of tourette’s syndrome.

Actions on various organ systems

Eye: Ganglionic blockers cause mydriasis and cycloplegia.

GIT: There is reduction of motility and severe constipation.

Genitourinary tract: There is impairment of ejaculation and reduced contractility of the bladder.

Heart: There is moderate tachycardia and reduction in cardiac output at rest.

Glands: There is reduction in salivation, lacrimation, sweating and gastric secretion.

Blood vessels: There is reduction in arterial and venous tone, causing dose dependent reduction in blood pressure. Orthostatic hypotension is usually marked.

Hexamethonium and mecamylamine were used in the past for the treatment of hypertension but were banned later for the adverse effects.

Varenicline ball-and-stick model

Image: “Ball-and-stick model of varenicline (brand names Champix and Chantix)—a nicotinic agonist used to treat nicotine addiction. Created using Accelrys DS Visualizer 4.1 and Adobe Photoshop CC 2015.” by Vaccinationist – PubChem. License: CC BY-SA 4.0

Trimethaphan is another ganglionic blocker used intravenously to treat accelerated hypertension and to produce controlled hypertension, but later, due to its poor lipid solubility, short half life and orally inactive nature, it was banned.

Varenicline, mecamylamine and nicotine in the form of patches are the ganglionic blockers that enter CNS and are used in smoking cessation.

Adverse effects of ganglionic blockers include postural hypotension, dry mouth, blurred vision, constipation and severe sexual dysfunction.

Cholisterase Regenerators

Pralidoxime is the cholinesterase regenerator. It is used to treat organophosphate poisoning (parathion and malathion).

Important: It is only effective before aging of the complex of ACh and the organophosphate compound.

Review Questions

The correct answers can be found below the references.

1.A patient was administered a neuromuscular blocker (NMB) prior to surgical procedure to produce skeletal muscle paralysis. This NMB drug caused initial skeletal muscle fasciculation before the onset of paralysis. The effect of this drug could not be reversed with neostigmine. Which of the following neuromuscular blockers was most likely administered to this patient?

  1. Cisatacurium
  2. Succinylcholine
  3. Diazepam
  4. Tubocurarine

2. Which of the following drugs would be the most effective drug for a person planning to go on a cruise?

  1. Atropine
  2. Tropicamide
  3. Scopolamine
  4. Tiotropium

3. Which of the following is the most dangerous effect of belladonna alkaloids in infants and toddlers?

  1. Dehydration
  2. Hallucination
  3. Hypertension
  4. Hyperthermia
  5. Intraventricular heart block

 

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