Toxicology of cholinomimetics, especially nicotine and cholinesterase inhibitors, is important for clinical implications. In this article, clinical features of adverse effects, resulting from acute and chronic exposures to cholinomimetics, are described. Management of poisoning, including the role of atropine and cholinesterase reactivators, is also discussed.
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Nicotine 3D


Overview of Toxicity of Cholinomimetic Activators

Cholinomimetics, especially some organophosphates, are used as insecticides in agriculture and accidental poisoning with them is not uncommon. They are also used for purposes of homicide, suicide, warfare or chemical terrorism. Hence, it is important to understand their toxicology, to learn to suspect, diagnose and manage the poisoning with these agents.

Here is a quick review of Cholinergic Agents: (See also Cholinomimetic Agents – ANS Pharmacology)

Direct-acting cholinomimetics directly stimulate the receptors, while indirect-acting cholinomimetics block the action of cholinesterase thus allowing persistence of acetylcholine on the receptor.

Direct-acting nicotinic or muscarinic stimulants

These act by stimulating the nicotinic or muscarinic receptors.

  • Choline esters
    • Acetylcholine (all acetylcholine receptors)
    • Bethanechol (M3 receptors)
    • Carbachol (all muscarinic receptors and some nicotinic receptors)
    • Methacholine (all muscarinic receptors)
  • Plant alkaloids
    • Arecoline
    • Nicotine
    • Muscarine
    • Pilocarpine (M3 receptors)

A mnemonic for signs and symptoms of acute organophosphate poisoning:

DUMBBELSS: Diarrhea, Urination, Miosis, Bronchospasm, Bradycardia, Excitation of skeletal muscles and CNS, Lacrimation, Salivation, Sweating

If that’s too long, another commonly used mnemonic is SLUDGE (or SLUDGEM, where M stands for miosis) for salivation, lacrimation, urination, defecation, gastrointestinal distress, emesis. These mnemonics help remember that:

  • Poisoning with organophosphates presents with signs of muscarinic excess such as nausea, vomiting, excessive salivation, excessive perspiration, diarrhea, urinary urgency, bronchospasm, flushing, etc.
  • Miosis (or even pin-point pupils) is a very important clinical sign to suspect poisoning with cholinomimetics.
  • Severe poisoning can lead to convulsions, coma and even death.
  • Similar signs can also be seen in poisoning due to certain mushrooms (e.g., genus Inocybe) containing muscarinic alkaloids. Signs of mushroom poisoning usually appear within 15-30 minutes of their consumption.
  • Atropine is the antidote of choice.
  • Topical pilocarpine can cause adverse effects like blurred vision, night blindness and brow ache.

Nicotine toxicity

  • Acute nicotine toxicity can occur due to ingestion of nicotine insecticides or tobacco. Most of the nicotine in a cigarette is destroyed by burning or escapes via smoke, reducing chances of nicotine poisoning among cigarette smokers.
  • Symptoms of acute toxicity include nausea, vomiting, hypertension, cardiac arrhythmias, central nervous system stimulation (convulsions, coma, death due to respiratory arrest), skeletal muscle end-plate depolarization blockade (skeletal and respiratory muscle paralysis) and symptoms of muscarinic excess (due to parasympathetic ganglion stimulation). In acute poisoning, fatal dose of nicotine is ~40 mg or 1 drop of pure liquid.
  • Treatment of acute nicotine toxicity is mainly symptomatic, i.e., atropine for symptoms of muscarinic excess, diazepam for central nervous system stimulation, mechanical ventilation for neuromuscular paralysis, etc.
  • Chronic nicotine toxicity in smokers is known to be associated with increased risk of vascular disease, coronary artery disease, sudden coronary death, peptic ulcer, certain pulmonary diseases, etc.
  • Smoking cessation is the most important step, which requires counseling and motivation.
  • For motivated patients, nicotine in forms with low abuse potential (gum, transdermal patch, nasal spray, inhaler, etc.) is used as replacement therapy. Slowly absorbed nicotine from these forms occupies the α4β2 receptors in central nervous system and reduces craving.
  • Varenicline, a partial agonist at the α4β2 receptors, is also effective for smoking cessation.

Varenicline

Important side effects of varenicline are nausea, insomnia, exacerbation of anxiety and depression and, possibly, suicidal ideation.

Muscarine Intoxication

The symptoms of intoxication with mushrooms rich in muscarine, especially Inocybe, are very typical: The symptoms start early, after one-quarter to two hours, with headache, nausea, vomiting, and constriction of the pharynx. Then salivation, lacrimation, and diffuse perspiration set in, combined with miosis, disturbed accommodation, and reduced vision. Gastric and small bowel colic leads to diarrhea, and there is a painful urge for urination. Bronchoconstriction leads to asthmatic attacks and severe dyspnea, and bradycardia combined with marked hypotension and vasodilation results in circulatory shock. Death after 8 to 9 hours has been reported in about 5% of the cases, but can be avoided completely by prompt diagnosis and treatment with atropine.

Pilocarpine

Pilocarpine is a medication used to treat increased pressure inside the eye. As eye drops it is used for angle closure glaucoma until surgery can be performed, ocular hypertension, open angle glaucoma, and to bring about constriction of the pupil following their dilation. By mouth it is used for dry mouth as a result of Sjogren’s syndrome or radiation therapy. The M3 receptor is found on the iris sphincter muscle, where pilocarpine causes the muscle to contract (miosis). Pilocarpine also acts on the ciliary muscle and causes it to contract. When the ciliary muscle contracts, it opens the trabecular meshwork. This action facilitates drainage of aqueous humor to decrease intraocular pressure.

Another important use of Pilocarpine is the diagnosis of cystic fibrosis by stimulation of the sweat glands in the sweat test to measure the concentration of chloride and sodium that is excreted in sweat.

Indirect-acting

Indirect acting parasympathomimetic drugs may be either reversible cholinesterase inhibitors, irreversible cholinesterase inhibitors or drugs that promote ACh release or anti-adrenergics. The latter inhibits the antagonistic system, the sympathetic nervous system.

  • Reversible cholinesterase inhibitors
    • Donepezil
    • Edrophonium
    • Neostigmine
    • Physostigmine
    • Pyridostigmine
    • Rivastigmine
    • Tacrine
    • Caffeine (non-competitive)
    • Huperzine A
  • Irreversible cholinesterase inhibitors
    • Echothiophate
    • Isoflurophate
    • Malathion
  • ACh release promoters
    • Cisapride
    • Domperidone
    • Metoclopramide
    • Risperidone
    • Paliperidone
    • Trazodone – via blockade of the α adrenergic receptors
  • Anti-adrenergics

Toxicity of Cholinesterase Inhibitors

Cholinesterase inhibitors (organophosphates and carbamates) are widely available as pesticides and veterinary vermifuges, which can cause poisoning by acute or chronic exposure.

Acute intoxication presents with signs of muscarinic excess (nausea, vomiting, excessive salivation, excessive perspiration, diarrhea, urinary urgency, bronchospasm, excessive tracheobronchial secretions and miosis), central nervous system signs (cognitive disturbances, convulsions, coma) and peripheral nicotinic effects (depolarizing neuromuscular blockade).

Miosis

Image: “A 25 year old Caucasian male with miosis due to opiate (i.e., codeine) use.” by Anonymous. License: CC0 1.0

Central nervous system side effects are more common with physostigmine than with neostigmine or pyridostigmine as physostigmine enters the CNS while the others cannot.

Compared to direct-acting cholinomimetics, poisoning with cholinesterase inhibitors has the following differences: vasodilation is uncommon and bradycardia is more common than tachycardia.

  • The most common organophosphate is malathion. Malathion is a cholinesterase inhibitor, a diverse family of chemicals that includes sarin and carbaryl. Carbaryl enters the CNS where it irreversibly oxidizes acetylcholinesterase. All organophosphates interfere with the cholinergic nervous system and cause death because the effects of the neurotransmitter acetylcholine cannot be terminated by carbamoylated acetylcholinesterase. Upon uptake into the target organism, it binds irreversibly to several random serine residues on the cholinesterase enzyme, with a peroxide as the leaving group. The resultant phosphoester group is strongly bound to the cholinesterase, and irreversibly deactivates the enzyme which leads to rapid build-up of acetylcholine at the synapse.
  • Parathion is a cholinesterase inhibitor. It generally disrupts the nervous system by inhibiting acetylcholinesterase. Parathion acts on the enzyme acetylcholinesterase indirectly. After an insect (or a human) ingests parathion, an oxidase replaces the double bonded sulfur with oxygen to give paraoxon. Parathion and related organophosphorus pesticides are used in hundreds of thousands of poisonings annually, especially suicides. It is known as “Schwiegermuttergift” (mother-in-law poison) in Germany. For this reason, most formulations contain a blue dye providing warning.
  • Nerve toxicity can also develop 1-4 days after exposure to organophosphate insecticides, which is known as intermediate syndrome. It is also characterized by muscular weakness; the mechanism of toxicity is thought to be related to cholinesterase inhibition, but there is no proof.
  • As cholinesterase inhibitors are used as chemical weapons in wars, soldiers and civilians are provided with autoinjection syringes containing carbamate, pyridostigmine and atropine. Pyridostigmine prevents prolonged inhibition of cholinesterase by impeding binding of the chemical agent; however, it does not enter the central nervous system.
  • Tacrine, an anticholinesterase used in treatment of Alzheimer’s disease, is replaced by other drugs due to its hepatotoxicity.
  • Important adverse effect of donepezil, rivastigmine and galantamine, anticholinesterase drugs used in treatment of Alzheimer’s disease, is gastrointestinal distress.
  • Chronic exposure to triorthocresyl phosphate, used as an additive in lubricating oils, can cause delayed demyelinating neuropathy 1-2 weeks after exposure by inhibiting neuropathy target esterase (NTE). Clinical presentation includes weakness of limbs and unsteadiness of gait.

    Cataract in human eye

    Image: “Cataract in human eye” by Rakesh Ahuja, MD – Own work, License: CC BY-SA 3.0

  • Important adverse effects associated with echothiophate (previously used topically in treatment of glaucoma) are brow ache, uveitis, blurred vision and cataract formation.

Treatment of Cholinomimetic Toxicity

Management of acute anticholinesterase poisoning

  • Maintenance of vital signs, with special importance to respiration.
  • Prevention of further absorption of the agent (removal of clothing and washing of skin when exposure is through skin, etc.).
  • Management of other symptoms (control of seizures by benzodiazepines, etc.).
  • Specific antidotes: atropine & cholinesterase reactivators.

Atropine

  • Very effective for treatment of muscarinic symptoms;
  • Higher doses are necessary to counteract central actions;
  • Peripheral muscular paralysis cannot be reversed by atropine as it is a nicotinic effect.

Cholinesterase reactivators

Cholinesterase reactivators are composed of substituted oximes that regenerate active cholinesterase from the organophosphorus-cholinesterase complex. They attach to the anionic site of cholinesterase, which is unoccupied by organophosphates. The anionic site is not free in case of carbamates—cholinesterase reactivators are ineffective and contraindicated in carbamate poisoning as they also have a weak anti-cholinesterase activity.

Cholinesterase reactivators are most effective when administered as early as possible, before the phosphorylated cholinesterase has undergone aging.

Pralidoxime can reverse both muscarinic and nicotinic peripheral effects but cannot reverse CNS effects as it cannot penetrate the CNS.

Other important cholinesterase reactivators are obidoxime (more potent than pralidoxime) and diacetyl-monoxime (DAM) (a lipophilic cholinesterase reactivator).

Myasthenic Crisis versus Cholinergic Crisis

Myasthenic Crisis Cholinergic Crisis
Pathophysiologic cause is insufficient cholinesterase inhibitors in presence of reduced number of acetylcholine receptors Pathophysiologic cause is excess of acetylcholine due to excessive cholinesterase inhibitors
External ophthalmoplegia present External ophthalmoplegia absent
Pupils normal and reactive to light Pupils reactive to light but miosis present
Ptosis usually present Ptosis usually absent
Fasciculations absent in skeletal muscles Fasciculations present in skeletal muscles
Increased blood pressure Decreased blood pressure
Bowel and bladder incontinence Abdominal cramps, nausea, vomiting, diarrhea
Edrophonium gives temporary relief Edrophonium has no effect but may worsen symptoms
Atropine does not improve symptoms Atropine improves symptoms

Review Questions on Cholinomimetic Agent Toxicity

The correct answers can be found below the references.

1. Which of the following clinical features of acute cholinomimetic poisoning cannot be effectively treated by administration of parenteral atropine?

A.    Muscular paralysis

B.     Hyperlacrimation

C.     Miosis

D.    Hypersalivation

E.     Diarrhea

2. Due to which of the following adverse effects has tacrine been replaced by other cholinesterase inhibitors for management of Alzheimer’s disease?

A.    Nephrotoxicity

B.     Retinal damage

C.     Neurotoxicity

D.    Hepatotoxicity

E.     Cardiotoxicity

3. In acute poisoning due to which of the following compounds will pralidoxime not be effective?

A.     Malathion

B.     Parathion

C.     Carbaryl

D.     Sarin

E.     Metrifonate

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