Toxicology – Cholinergic Agonist Medications

Core concept

Direct cholinergic agonists produce toxicity by stimulating acetylcholine receptors directly rather than by inhibiting acetylcholinesterase.

The characteristic syndrome is predominantly:

Muscarinic receptor stimulation → salivation + lacrimation + diaphoresis + vomiting/diarrhea + miosis + bradycardia + bronchospasm/bronchorrhea

The most important severe manifestations are:

Bronchospasm/bronchial secretions + bradycardia/hypotension → respiratory and cardiovascular compromise

The principal antidote is:

Atropine

A crucial distinction from organophosphate poisoning is:

Pralidoxime has no mechanistic role in an isolated direct cholinergic agonist overdose

because acetylcholinesterase has not been inhibited.

Classification

Cholinergic drugs are divided into:

1. Direct-acting cholinergic agonists

These drugs bind directly to cholinergic receptors.

Important examples include:

Choline esters

• Acetylcholine
• Bethanechol
• Carbachol
• Methacholine

Alkaloid/direct muscarinic agonists

• Pilocarpine
• Cevimeline
• Muscarine
• Arecoline

Current reviews classify acetylcholine, methacholine, carbachol, bethanechol, pilocarpine, muscarine, and cevimeline as direct-acting parasympathomimetics.

2. Indirect cholinergic agonists

These increase acetylcholine by inhibiting acetylcholinesterase.

Examples include:

• Neostigmine
• Pyridostigmine
• Physostigmine
• Donepezil
• Rivastigmine
• Organophosphates
• Carbamate insecticides
• Nerve agents

These are different toxicologic entities, particularly because oximes such as pralidoxime act on inhibited AChE and therefore apply principally to selected anticholinesterase poisonings, not direct receptor agonists.

Important Current Agents

Acetylcholine

Current U.S. MIOCHOL-E contains acetylcholine chloride for:

Intraocular use to produce rapid miosis during ophthalmic surgery.

Acetylcholine is rapidly hydrolyzed by cholinesterases, so systemic toxicity from correct intraocular use is unusual.

It activates both:

• Muscarinic receptors
• Nicotinic receptors

but has an extremely short duration.

Bethanechol

Bethanechol is primarily a:

Muscarinic receptor agonist

It is relatively resistant to acetylcholinesterase and has little clinically important nicotinic action.

Current oral dosing remains approximately:

10–50 mg three or four times daily

for selected urinary-retention indications.

Typical adverse/toxic effects include:

• Salivation
• Sweating
• Flushing
• Abdominal cramping
• Diarrhea
• Urinary urgency
• Miosis
• Bronchoconstriction
• Hypotension

Current labeling explicitly identifies atropine as the antidote for bethanechol overdose.

Carbachol

Carbachol is distinctive because it has:

Both muscarinic and nicotinic cholinergic agonist activity

Current MIOSTAT 0.01% is used intraocularly to:

• Produce miosis during surgery
• Reduce early postoperative intraocular-pressure elevation after cataract surgery.

2026 update

A new ophthalmic combination:

YUVEZZI — carbachol 2.75% + brimonidine 0.1%

received U.S. approval in 2026 for treatment of:

Presbyopia in adults.

Therefore the older view of carbachol solely as an intraoperative/glaucoma medication is incomplete.

Methacholine

Methacholine is primarily a:

Muscarinic agonist

and the old description grouping methacholine with strongly nicotinic drugs is misleading.

Current PROVOCHOLINE is used for:

Methacholine bronchial-challenge testing

to diagnose airway hyperresponsiveness in adults and children ≥5 years without clinically apparent asthma.

It is deliberately administered to provoke:

M3 receptor activation → bronchial smooth-muscle contraction → bronchoconstriction

Current labeling carries a boxed warning for:

Severe bronchoconstriction

even at low doses.

It is contraindicated when baseline:

• FEV₁ <60% predicted
• or
• Adult FEV₁ <1.5 L.

Severe methacholine-induced bronchospasm should be reversed promptly with a:

Rapid-acting inhaled β₂ agonist

such as albuterol/salbutamol.

Pilocarpine

Pilocarpine is predominantly a:

Direct muscarinic agonist

Current systemic oral pilocarpine is indicated for:

• Xerostomia following radiotherapy for head/neck cancer
• Xerostomia associated with Sjögren syndrome.

Ophthalmic pilocarpine remains used in selected ophthalmologic settings.

Systemic effects can include:

• Profuse sweating
• Salivation
• Nausea
• Diarrhea
• Urinary frequency
• Bradycardia
• Hypotension
• Bronchospasm

Current labeling notes historical fatal overdoses at doses presumed to exceed approximately:

100 mg

and regards 100 mg as potentially fatal, although this should not be interpreted as a precise clinical threshold.

Cevimeline

Cevimeline should be added to the modern list.

It is a direct muscarinic agonist currently used for:

Dry mouth in Sjögren syndrome.

It can cause:

• Sweating
• Salivation
• Nausea
• Bronchoconstriction
• Bradycardia/hemodynamic changes

Current labeling warns that it may:

• Increase airway resistance
• Increase bronchial smooth-muscle tone
• Increase bronchial secretions

and it is contraindicated in uncontrolled asthma.

Natural Cholinergic Agonists

The older source mixes several natural products together; these require correction.

Pilocarpus

Pilocarpus plants contain pilocarpine, not arecoline.

Areca Nut

The seed of:

Areca catechu

contains:

Arecoline

Arecoline is predominantly a muscarinic partial agonist but also has activity at selected nicotinic acetylcholine receptors.

Acute areca-nut exposure can produce:

• Salivation
• Sweating
• GI hyperactivity
• Tachycardia or bradycardia
• Tremor
• CNS stimulation

Important terminology correction

“Betel quid” commonly contains:

• Areca nut
• Betel leaf
• Lime
• Sometimes tobacco

The principal source of arecoline is the areca nut, not the Piper betle leaf itself.

Muscarine-Containing Mushrooms

Muscarinic mushroom poisoning is classically associated with:

• Inocybe
• Clitocybe

species.

The older inclusion of Boletus as a principal muscarine-containing genus is not appropriate for the classic muscarinic mushroom syndrome.

Symptoms usually begin rapidly—often within:

30 minutes to 2 hours

and include:

• Salivation
• Lacrimation
• Diaphoresis
• Miosis
• Vomiting/diarrhea
• Bronchospasm
• Bradycardia/hypotension

Atropine produces rapid improvement when muscarinic symptoms are clinically significant.

Pathophysiology

Muscarinic receptors

Five muscarinic receptor subtypes exist:

M1–M5

The most clinically important toxic effects involve:

M2 — heart

Activation causes:

• Reduced SA-node firing
• Reduced AV conduction
• Bradycardia

M3 — glands/smooth muscle

Activation causes:

• Salivation
• Lacrimation
• Sweating
• Bronchoconstriction
• Bronchial secretion
• GI hypermotility
• Bladder contraction
• Miosis

Thus:

M3 activation → wet patient

while:

M2 activation → slow heart

Nicotinic Receptors

Nicotinic receptor stimulation may cause:

• Ganglionic autonomic activation
• Tachycardia
• Hypertension
• Skeletal-muscle fasciculations
• Weakness

However:

Pronounced nicotinic neuromuscular toxicity is much more characteristic of anticholinesterase poisoning than of most therapeutic direct muscarinic agonists.

Carbachol has meaningful nicotinic activity.

Arecoline also has some nicotinic activity.

By contrast:

• Bethanechol → predominantly muscarinic
• Methacholine → predominantly muscarinic
• Pilocarpine → predominantly muscarinic

Therefore the old chapter overstates expected nicotinic toxicity from methacholine.

Clinical Syndrome

A useful mnemonic remains:

DUMBELS

• D — Diarrhea / diaphoresis
• U — Urination
• M — Miosis
• B — Bradycardia / bronchospasm / bronchorrhea
• E — Emesis
• L — Lacrimation
• S — Salivation

Another practical approach is:

Wet + wheezy + slow

HEENT

Possible findings:

• Miosis
• Blurred vision
• Lacrimation
• Salivation
• Rhinorrhea

Ophthalmic exposure may produce:

• Ciliary spasm
• Brow ache/headache
• Miosis
• Blurred vision
• Reduced night vision

Dermatologic

Muscarinic stimulation of eccrine sweat glands causes:

Profuse diaphoresis

The patient may therefore be:

• Wet
• Cool
• Clammy

rather than dry as in an anticholinergic toxidrome.

Cardiovascular

Possible findings include:

• Bradycardia
• Hypotension
• AV block
• Reduced cardiac output

Low-dose vasodilatory effects may sometimes produce:

Hypotension → reflex tachycardia

so tachycardia does not absolutely exclude a muscarinic drug exposure.

Pilocarpine and cevimeline labeling both warn that cholinergic effects may alter heart rate and hemodynamics, particularly in patients with underlying cardiovascular disease.

Respiratory

The most immediately dangerous manifestations are:

Bronchospasm + increased bronchial secretions

Patients may develop:

• Cough
• Wheezing
• Chest tightness
• Dyspnea
• Hypoxemia

Patients with:

• Asthma
• COPD
• Other obstructive lung disease

are at higher risk.

Pilocarpine can increase airway resistance, bronchial tone, and secretions.

Methacholine is deliberately bronchoconstrictive and can cause severe bronchospasm even during properly conducted diagnostic testing.

Gastrointestinal

Typical findings:

• Nausea
• Vomiting
• Abdominal cramping
• Borborygmi
• Diarrhea

Severe vomiting/diarrhea can produce:

• Volume depletion
• Electrolyte abnormalities

Genitourinary

Muscarinic stimulation can cause:

• Urinary urgency
• Increased bladder contraction
• Incontinence

Bethanechol’s therapeutic effect itself depends on increasing detrusor activity.

Neurologic

Most direct peripheral muscarinic agonists produce less dramatic CNS toxicity than organophosphate poisoning.

Possible manifestations include:

• Headache
• Dizziness
• Tremor
• Confusion

Seizures and coma are uncommon in isolated routine direct-agonist overdose and should prompt consideration of:

• Massive exposure
• Hypoxia
• Coingestant
• Alternative diagnosis
• Anticholinesterase poisoning

The older chapter likely overstates seizure/coma as routine manifestations of this medication class.

Neuromuscular Findings

Significant:

• Fasciculations
• Generalized weakness
• Flaccid paralysis

should raise suspicion for:

Organophosphate/carbamate anticholinesterase poisoning

rather than a straightforward bethanechol or pilocarpine overdose.

Carbachol and arecoline can have some nicotinic effects, but profound neuromuscular paralysis is not the usual syndrome of therapeutic direct muscarinic agonists.

Toxic Dose

There is no useful class-wide statement that:

“Two or three times the daily dose is toxic.”

The agents vary greatly in:

• Potency
• Route
• Absorption
• Duration
• Receptor selectivity

For example:

• Methacholine is inhaled in tightly controlled diagnostic doses
• Acetylcholine is predominantly intraocular
• Pilocarpine is orally systemically active
• Carbachol is commonly ophthalmic/intraocular
• Bethanechol is oral
• Cevimeline is oral

Therefore:

Risk assessment must be agent-specific.

Diagnosis

Diagnosis is primarily clinical:

Known direct cholinergic exposure + predominantly muscarinic toxidrome

Look for:

Salivation + diaphoresis + GI hyperactivity + miosis + bronchospasm ± bradycardia

Cholinesterase Levels

This is an important distinction from pesticide poisoning.

RBC acetylcholinesterase and plasma butyrylcholinesterase levels are not useful for direct cholinergic agonist poisoning.

These drugs stimulate receptors directly.

They do not require inhibition of acetylcholinesterase.

Therefore:

Normal cholinesterase activity is expected and does not argue against direct muscarinic-agonist toxicity.

Laboratory Testing

Mild toxicity

No routine laboratory testing may be necessary.

Moderate/severe toxicity

Consider:

• Glucose
• Electrolytes
• Bicarbonate
• BUN
• Creatinine

For significant vomiting/diarrhea:

• Potassium
• Magnesium

For severe respiratory illness:

• Blood gas
• Lactate

For repeated seizures/prolonged immobilization:

• CK

ECG

Obtain an ECG and cardiac monitoring for:

• Bradycardia
• Syncope
• Hypotension
• Significant systemic overdose
• Cardiovascular symptoms

Possible abnormalities include:

• Sinus bradycardia
• AV block
• Reflex tachycardia

Respiratory Assessment

Patients with:

• Wheezing
• Dyspnea
• Bronchospasm

should have:

• Pulse oximetry
• Serial lung examination

Peak flow/spirometry may be helpful in selected cooperative patients.

Chest radiography is not routine but may be appropriate with:

• Persistent hypoxemia
• Aspiration
• Suspected pulmonary edema
• Alternative pulmonary diagnosis

Differential Diagnosis

Most important toxicologic differential

Organophosphate poisoning

Produces:

• Muscarinic excess
• Nicotinic weakness/fasciculations
• CNS effects

and typically causes cholinesterase inhibition.

Carbamate insecticides

Also inhibit acetylcholinesterase, usually reversibly.

Therapeutic AChE inhibitors

Examples:

• Donepezil
• Rivastigmine
• Galantamine
• Neostigmine
• Pyridostigmine

Muscarinic mushrooms

Especially:

• Inocybe
• Clitocybe

Nicotine

May produce a mixed:

• Cholinergic
• Adrenergic
• Neuromuscular

syndrome.

Treatment

1. Airway and breathing

Assess immediately:

• Ability to handle secretions
• Bronchospasm
• Work of breathing
• Oxygenation
• Ventilation

Provide:

• Suction
• Oxygen when indicated
• Assisted ventilation if necessary

Intubate for:

• Severe respiratory failure
• Inability to protect airway
• Refractory bronchospasm with fatigue
• Severe CNS depression

2. Atropine

Atropine is the specific pharmacologic antagonist for dangerous muscarinic toxicity.

It competitively blocks muscarinic receptors.

Atropine improves:

• Bronchial secretions
• Bronchospasm
• Salivation
• Bradycardia
• Muscarinic hypotension
• GI hyperactivity

It does not directly reverse nicotinic skeletal-muscle weakness.

Current references specifically recommend parenteral atropine for overdose of direct parasympathomimetic drugs.

Atropine Dosing

Direct muscarinic-agonist poisonings often require much less atropine than severe organophosphate poisoning.

Current product labeling provides examples:

Pilocarpine overdose

Atropine 0.5–1 mg IV or SC, titrated to clinical response.

Bethanechol overdose

Current labeling recommends approximately:

0.6 mg atropine in adults

with repeat dosing according to response.

In severe poisoning

When clinically important:

• Bronchorrhea
• Bronchospasm
• Bradycardia
• Hypotension

persist, IV atropine should be repeated and titrated clinically rather than limited by an arbitrary maximum dose.

Atropine Endpoint

Treat the dangerous physiology rather than the pupils.

The most useful endpoints are:

Adequate ventilation + controlled bronchial secretions + improvement in bronchospasm + adequate perfusion

Do not continue atropine simply to produce:

• Complete mouth dryness
• Mydriasis
• A particular heart rate

Avoid Over-Atropinization

Because most direct agonist overdoses are shorter and milder than organophosphate poisoning, excessive atropine can easily produce an anticholinergic toxidrome:

• Tachycardia
• Dry flushed skin
• Hyperthermia
• Urinary retention
• Ileus
• Agitation
• Delirium

Thus:

Use enough atropine to control dangerous muscarinic effects—not automatically massive organophosphate-style doses in every patient.

Pralidoxime (2-PAM)

Pralidoxime is NOT indicated for an isolated direct cholinergic agonist overdose.

Mechanism:

Pralidoxime → reactivates inhibited acetylcholinesterase

But with:

• Bethanechol
• Pilocarpine
• Methacholine
• Carbachol
• Cevimeline

there may be no inhibited enzyme to reactivate.

Therefore:

Direct agonist → atropine

not:

Direct agonist → atropine + pralidoxime

When Pralidoxime May Still Be Appropriate

If the exposure is unclear and the patient could instead have:

• Organophosphate poisoning
• Mixed pesticide exposure
• Nerve-agent exposure

then manage according to the suspected anticholinesterase syndrome, which may include pralidoxime.

Methacholine-Specific Bronchospasm

If severe bronchoconstriction follows methacholine challenge:

Give a rapid-acting inhaled β₂ agonist immediately

such as:

• Albuterol
• Salbutamol

This is specifically required by current Provocholine labeling.

Atropine may be appropriate if there are broader systemic muscarinic manifestations, but inhaled β₂ agonist treatment is central to reversing methacholine-provoked bronchoconstriction.

Bronchospasm From Other Muscarinic Agonists

Treat with:

• Atropine
• Inhaled β₂ agonist as an adjunct

Oxygen and ventilatory support are added according to severity.

Do not rely on albuterol alone if marked:

• Secretions
• Bradycardia
• Generalized cholinergic toxicity

are present.

Hypotension

First assess whether hypotension reflects:

• Muscarinic bradycardia
• Vasodilation
• Volume depletion from vomiting/diarrhea

Initial therapy

• Atropine when bradycardia/cholinergic excess is contributing
• Isotonic crystalloid if volume responsive

If persistent shock remains:

Norepinephrine is generally an appropriate contemporary vasopressor.

The historical use of Trendelenburg positioning as therapy is obsolete.

Seizures

Although uncommon with isolated therapeutic direct agonists, toxin-induced seizures should be treated with:

Benzodiazepines first-line

Examples:

• Midazolam
• Lorazepam
• Diazepam

For refractory seizures:

• Phenobarbital
• Propofol in an intubated patient

Also correct:

• Hypoxia
• Hypoglycemia
• Electrolyte abnormalities

Gastrointestinal Decontamination

Do not induce vomiting

No ipecac or induced emesis.

Spontaneous vomiting and respiratory secretions increase aspiration risk.

Activated Charcoal

Activated charcoal is not routinely necessary for every direct cholinergic drug exposure.

A single dose may be considered after a:

• Recent
• Clinically significant
• Oral ingestion

if:

• The airway is intact/protected
• Vomiting is not severe
• Aspiration risk is acceptable

Airway and respiratory treatment always take priority.

Gastric Lavage

The older recommendation for routine gastric lavage after a significant ingestion is outdated.

Routine gastric lavage is not recommended.

Only an extraordinary:

• Immediately life-threatening
• Very recent

ingestion could justify considering lavage after:

• Airway protection
• Specialist toxicology consultation

Eye / Skin Exposure

For significant inadvertent topical exposure:

• Remove contaminated clothing
• Wash skin with soap and water

For inappropriate ocular exposure to a non-ophthalmic preparation:

• Irrigate with water/saline
• Evaluate persistent ocular symptoms

Therapeutic miotic eye drops themselves are not managed by simply “washing them out” once absorbed; treatment is symptom directed.

Succinylcholine – Important Distinction

Anticholinesterase poisoning can prolong succinylcholine paralysis because cholinesterase activity is inhibited.

However:

An isolated direct receptor agonist does not inhibit cholinesterase.

Therefore the blanket warning to avoid succinylcholine in every “cholinergic” drug poisoning does not automatically apply to a confirmed direct muscarinic agonist exposure.

If organophosphate/carbamate poisoning is possible, a nondepolarizing paralytic such as rocuronium remains preferable.

Enhanced Elimination

There is no established routine role for:

• Hemodialysis
• Hemoperfusion
• Urinary alkalinization
• Forced diuresis

for typical direct cholinergic agonist medication poisoning.

Pilocarpine labeling specifically states that whether it is dialyzable is unknown.

Supportive care and atropine are generally sufficient.

Monitoring

Symptomatic patients should have:

• Respiratory monitoring
• Pulse oximetry
• Frequent lung examinations
• Blood-pressure monitoring

Continuous ECG monitoring is appropriate with:

• Bradycardia
• Hypotension
• Syncope
• Significant systemic poisoning

Reassess:

• Secretions
• Wheezing
• Heart rate
• Blood pressure
• Mental status

after every atropine dose.

Observation

The old statement that toxicity routinely:

“peaks within 6–12 hours and may take days to recover”

is too broad for this diverse class.

Duration depends heavily on the agent.

For example:

• Acetylcholine has extremely brief activity
• Methacholine challenge effects are generally short and actively reversed
• Bethanechol commonly acts for several hours or less
• Oral pilocarpine/cevimeline can produce more sustained systemic effects
• Natural-product ingestion may have a different time course

Therefore:

Observation should be agent- and symptom-specific rather than a fixed 4–6-hour rule.

Admission

Hospital admission is appropriate for:

• Clinically important bronchospasm
• Persistent bronchial secretions
• Recurrent atropine requirement
• Significant bradycardia
• Hypotension
• AV block/dysrhythmia
• Hypoxemia
• Severe vomiting/diarrhea with dehydration
• Altered mental status
• Seizure

ICU-level care is appropriate for:

• Respiratory failure
• Intubation
• Severe bronchospasm
• Hemodynamic instability
• Recurrent serious dysrhythmia

Not every mildly symptomatic patient requires ICU admission, contrary to the older recommendation.

Discharge

Patients may be discharged when:

• Symptoms have fully resolved
• Oxygenation is normal
• No clinically important bronchospasm remains
• Heart rate/BP are stable
• No recurrent atropine is required
• Oral intake is tolerated when appropriate
• The expected duration of the specific agent has been considered

Intentional overdose also requires appropriate psychiatric/safety assessment.

Pregnancy

The historical FDA Pregnancy Category C system is obsolete.

Pregnancy safety data vary considerably between individual drugs.

For acute poisoning:

Maternal airway, oxygenation, and circulation take priority.

Atropine should not be withheld when needed to treat life-threatening muscarinic toxicity.

The potential maternal and fetal consequences of:

• Severe bronchospasm
• Hypoxia
• Bradycardia
• Hypotension

are more immediately dangerous than appropriate antidotal atropine therapy.

Prognosis

Most isolated direct cholinergic medication exposures have:

Good prognosis with prompt supportive care and atropine when required.

Severe morbidity is more likely when:

• Bronchospasm is not recognized
• Excess secretions compromise ventilation
• Profound bradycardia/hypotension develops
• Exposure is massive
• Coingestants are present

Direct agonist medication poisoning generally resolves faster than severe organophosphate poisoning because there is no persistent AChE phosphorylation or aging process.

Important Pitfalls

1. Treating all cholinergic poisonings as organophosphate poisoning

Direct agonists stimulate receptors.

Organophosphates inhibit AChE.

This fundamentally changes the role of pralidoxime.

2. Giving pralidoxime for confirmed bethanechol or pilocarpine overdose

There is no inhibited AChE enzyme for pralidoxime to reactivate.

Use atropine.

3. Checking cholinesterase levels to diagnose direct agonist toxicity

Cholinesterase levels are not expected to fall.

A normal level is therefore unsurprising.

4. Calling methacholine a major nicotinic agonist

Methacholine’s clinically important action is:

Muscarinic bronchoconstriction

Current Provocholine specifically warns about severe bronchospasm.

5. Missing severe methacholine bronchospasm

Treat rapidly with:

Inhaled β₂ agonist

rather than waiting for spontaneous recovery.

6. Assuming all direct cholinergic agents cause paralysis

Profound:

• Fasciculations
• Weakness
• Flaccid paralysis

are more suggestive of substantial nicotinic excess from anticholinesterase poisoning.

7. Using massive organophosphate atropine doses automatically

Direct muscarinic agonist overdose often responds to much smaller atropine doses.

Titrate to the patient.

8. Titrating atropine to pupil size

Treat:

• Bronchial secretions
• Bronchospasm
• Bradycardia/perfusion

not persistent miosis.

9. Forgetting atropine toxicity

Over-treatment can transform:

Cholinergic toxicity → anticholinergic delirium

especially because direct agonist poisoning is often relatively short-lived.

10. Assuming methacholine is a treatment for asthma

It does the opposite.

Methacholine is a:

Diagnostic bronchoprovocation agent

and current labeling carries a boxed warning for severe bronchoconstriction.

11. Using the old natural-product classification

Correct associations:

• Pilocarpus → pilocarpine
• Areca catechu nut → arecoline
• Inocybe/Clitocybe → muscarine

The betel leaf itself is not the primary source of arecoline.

12. Forgetting cevimeline

Cevimeline is an important modern direct muscarinic agonist used for:

Sjögren-associated xerostomia.

13. Missing new carbachol ophthalmic formulations

As of 2026, YUVEZZI (carbachol + brimonidine) is FDA-approved for adult presbyopia, expanding current therapeutic exposure beyond the older intraoperative preparations.

14. Using routine gastric lavage

Modern poisoning management does not support routine lavage for these pharmaceutical ingestions.

Supportive care and atropine matter far more.

High-Yield Toxicology Pearls

Direct cholinergic agonists = primarily muscarinic toxidrome

Think:

Wet + wheezy + slow

Typical syndrome:

Salivation + lacrimation + diaphoresis + diarrhea/vomiting + miosis + bronchospasm + bradycardia

Key points:

• Direct agonists bind cholinergic receptors directly
• They do not require acetylcholinesterase inhibition
• Important agents:
• Acetylcholine
• Bethanechol
• Carbachol
• Methacholine
• Pilocarpine
• Cevimeline
• Bethanechol → predominantly muscarinic
• Methacholine → predominantly muscarinic
• Pilocarpine → predominantly muscarinic
• Carbachol → muscarinic + nicotinic
• Arecoline → mainly muscarinic partial agonist with some nicotinic activity
• Major dangerous manifestations:
• Bronchospasm
• Bronchial secretions
• Bradycardia
• Hypotension
• Main antidote:
• ATROPINE
• Direct agonist overdose often needs much less atropine than severe OP poisoning
• Pilocarpine label example:
• Atropine 0.5–1 mg IV/SC, titrated
• Treat to:
• Controlled bronchial secretions
• Improved bronchospasm
• Adequate perfusion
• Do not titrate atropine to pupil size
• Pralidoxime is NOT indicated for confirmed isolated direct agonist poisoning
• Cholinesterase measurements are not clinically useful
• Severe methacholine bronchospasm:
• Rapid-acting inhaled β₂ agonist
• Methacholine challenge:
• Approved for airway-hyperreactivity testing in patients ≥5 years
• Contraindicated when baseline FEV₁ <60% predicted
• Pilocarpine:
• Used for xerostomia after head/neck radiation and Sjögren syndrome
• Cevimeline:
• Used for Sjögren-associated xerostomia
• Carbachol:
• Intraocular miotic
• 2026: carbachol/brimonidine YUVEZZI approved for presbyopia
• Natural sources:
• Areca nut → arecoline
• Inocybe/Clitocybe mushrooms → muscarine
• Pilocarpus → pilocarpine
• Do not induce vomiting
• Activated charcoal only for selected recent oral exposures with a protected airway
• Routine gastric lavage is obsolete
• No routine role for dialysis
• Most isolated direct-agonist poisonings recover completely with prompt supportive care and atropine