Anticholinergic Drugs

Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic
receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the
parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract,
vascular system, urinary tract, GI tract, and pupils of the eyes. These medications are used in the
management of a wide range of diseases, most notably in the treatment of overactive bladder,
irritable bowel syndrome, chronic obstructive pulmonary disease (COPD), and allergic rhinitis.
Atropine specifically is used in emergency medicine in the advanced cardiac life support (ACLS)
protocol for severe bradycardia and as an antidote to organophosphate poisoning with insecticides or
chemical warfare agents. Atropine is also used in anesthesiology as an antisialagogue or to reverse
neuromuscular blocking agents. The term “anticholinergic” is often used to describe the adverse
effects of drugs with anticholinergic properties (e.g., tricyclic antidepressants); these include dry
mouth, constipation, blurred vision, and orthostatic hypotension.

Last updated: January 17, 2023

CONTENTS

Chemistry and Pharmacodynamics

Pharmacokinetics
Indications
Adverse Effects, Contraindications, Drug–Drug Interactions, and Toxicity
Comparison of Mechanism of Action and Indications in Different Anticholinergics
References

Chemistry and Pharmacodynamics

Atropine is the prototypical anticholinergic drug owing to its antagonism of acetylcholine (ACh)
receptors.

Overview
Also called:
Antimuscarinics/muscarinic receptor antagonists
Cholinergic blockers
Parasympatholytics
Chemistry of anticholinergics:
Have a primary point of attachment to cholinergic receptors through their cationic
(positively charged) nitrogen atom
Are either tertiary amines or quaternary ammonium compounds
A hydroxyl group enhances antimuscarinic activity over that of similar compounds without
a hydroxyl group.
Anticholinergic actions of chemicals:
Block the activity of ACh receptors → prevent transmission of signals through certain
parts of the nervous system
Atropine (prototypical drug) antagonizes ACh receptors (anticholinergic).

Mechanism of action and physiologic effects

Mechanism of action:
Competitively inhibit the neurotransmitter ACh at receptor sites within the cholinergic
system
This inhibition leads to blockade of the parasympathetic nervous system.
Physiologic effects:
Decreased production of secretions:
Salivary glands
Bronchial tree
GI tract
Bronchodilation
Smooth muscle relaxation in the GI tract and bladder
Drug classes used for their anticholinergic activity:
Antispasmodics for GI conditions:
Antagonize ACh at muscarinic receptors
Relax smooth muscle
Inhibit histamine-induced spasms
Urinary antispasmodics:
Antagonize ACh at muscarinic receptors
Relax bladder smooth muscle
Inhibit involuntary detrusor muscle contractions
Inhaled long-acting muscarinic antagonists (LAMAs):
Bronchodilation
Decrease bronchial secretions
Used for individuals with chronic obstructive pulmonary disease (COPD)
Mydriatics in ophthalmology (eye drops):
Inhibit response of iris sphincter
Inhibit response of the ciliary body muscles
1st-generation antihistamines:
Act on histamine receptors
Inhibit muscarinic receptors and have anticholinergic effects (used therapeutically
for motion sickness)
Antiparkinson drugs (largely replaced by newer medications)
Acetylcholinesterase (AChE) regenerators stimulate the breakdown of acetylcholine →
anticholinergic effect on cholinergic excess:
Pralidoxime (2-pyridine aldoxime methyl chloride (2-PAM)): antidote for
organophosphate toxicity seen with insecticide poisoning and nerve agents in
bioterrorism (AChE inhibitors)
Because AChE breaks down ACh, the AChE inhibitors cause cholinergic poisoning
and AChE regenerators (antidote) → net decrease in ACh
Cholinergic terminal neurotransmission and mechanism of action of anticholinergics:
Acetylcholine (ACh) is terminated in the synaptic cleft by AChE (acetylcholinesterase).
Anticholinergic drugs antagonize different muscarinic receptors throughout the body depending on their
selectivity.
LEMS (Lambert-Eaton myasthenic syndrome) produces antibodies that block presynaptic calcium channels →
decreased ACh release and muscle weakness.
Neuromuscular blockers antagonize nicotinic receptors at neuromuscular junctions.
Galantamine: AChE inhibitor used in Alzheimer dementia; inhibits the breakdown of ACh for a net increase in ACh
in the synaptic cleft
Pralidoxime (2-PAM): AChE regenerator, allows ↑ breakdown of ACh → net decrease in ACh in the synaptic cleft.
CHT: choline transporter
VAChT: vesicular acetylcholine transporter

Image by Lecturio.

Pharmacokinetics
The pharmacokinetic properties of anticholinergic drugs are diverse, as they are available in
many forms for different medical uses, such as IV atropine for severe bradycardia, oral tablets for
GI and bladder antispasmodic use, inhaled forms of LAMAs for bronchodilation, and eye drops
for cycloplegia.

Eye drops
Short-acting mydriatics dilate the pupils (e.g., cyclopentolate, tropicamide) and are preferred for
ophthalmic diagnostic procedures.
Cycloplegics produce mydriasis, but they also paralyze the ciliary muscle in the treatment of
uveitis and other painful ophthalmic conditions.

Table: Comparison of anticholinergic eye drops

Drug Maximum mydriasis Duration of cycloplegia

Atropine 30–40 minutes 7–12 days

Cyclopentolate ophthalmic 30 minutes 24 hours

Homatropine 40–60 minutes 24 hours

Tropicamide 30 minutes 6 hours

Oral anticholinergic agents

The lipophilicity of a drug correlates with its penetration into the CNS; ↑ lipophilicity causes
dizziness, drowsiness, and cognitive impairment.
GI antispasmodics: dicyclomine and hyoscyamine
Used for irritable bowel syndrome, biliary colic
Excretion: primarily in urine
Half-life: 2–3.5 hours; extended-release form, 7.5 hours
Both are lipophilic.
Metabolism: hepatic cytochrome P450 enzymes
Urologic anticholinergic drugs/antispasmodics:
Used for overactive bladder
Excretion: mostly in urine (except for trospium: 85% feces and 6% urine)
 Table: Half-lives, lipophilicity, and metabolism of urinary anticholinergics

Drug Half-life Lipophilicity Metabolism

(CNS
penetration)

Darifenacin 13–19 hours Moderate Hepatic

(Enablex) CYP3A4
CYP2D6

Fesoterodine 7 hours Low Hepatic

(Toviaz) CYP3A4
CYP2D6

Oxybutynin Short-acting: Lipophilic Hepatic

(Ditropan, Ditropan 2.5 hours CYP3A4
XL, Oxytrol patch, XL form: 13 High 1st-pass
Gelnique topical hours metabolism
gel) Patch: 7 hours Patch and gel
avoid 1st-pass
metabolism

Solifenacin 45–68 hours Lipophilic Hepatic CYP3A4

(Vesicare)

Tolterodine (Detrol Short-acting: Low Hepatic

IR, LA, and ER 2–3 hours CYP3A4
forms) Long-acting: 7 CYP2D6
hours, plus
active
metabolites

Trospium (Sanctura, 20–35 hours None Hepatic

also XR form)

ER, XR, and XL: extended-release

IR: immediate-release (short-acting)
LA: long-acting
CYP: cytochrome P450

Atropine (IV)
 Nonselective muscarinic blocker
Tertiary amine:
Lipid-soluble
Crosses the blood–brain barrier (BBB)
Used IV in advanced cardiac life support (ACLS) protocol for symptomatic bradycardia to
increase HR
Onset of action: 30 seconds
Duration of action: approximately 4 hours
Maximum effect (IV): 2–6 minutes

Indications
Anticholinergic drugs are used in many forms. They are used via eye drops in ophthalmology as
mydriatics/cycloplegics, included in inhalers as bronchodilators and to dry up secretions as
LAMAs for individuals with COPD, and used in oral pill form as antispasmodics. Atropine is also
used IV for severe bradycardia and is part of the ACLS protocol.

Anticholinergic drugs
Antimuscarinic agents:
Atropine: used IV in ACLS protocol for symptomatic bradycardia
Glycopyrrolate:
Used as an anesthesia adjunc
Used as an antisialagogue
Medications for dystonia/Parkinson disease (largely replaced by newer drugs):
Benztropine: antagonizes ACh and histamine receptors
Trihexyphenidyl: antagonizes ACh receptors
GI antispasmodics: used in the treatment of irritable bowel syndrome (IBS)
Urinary antispasmodics: used in the treatment of overactive bladder (OAB)
Anticholinergics in eye drops:
Drugs that cause pupillary dilation (mydriatics):
Affect only the iris, not the ciliary muscle
Used during ophthalmic exam of the posterior segment and fundus
Drugs that cause ciliary muscle paralysis and inhibit accommodation or focusing ability:
cycloplegic
Used in ophthalmic exams and the evaluation of hyperopia
Used for prevention and release of posterior synechiae in individuals with uveitis
Treat pain associated with ciliary body spasm in the eye
Also used to treat amblyopia (lazy eye) in infants
Names of ophthalmic preparations:
Cyclopentolate
Homatropine
Tropicamide
Bronchodilators: used in the treatment of COPD

Drugs with major anticholinergic side effects

 Low-potency 1st-generation antipsychotic drugs (FGAs):
Work primarily on dopamine receptors
Also have an affinity for muscarinic receptors → anticholinergic side effects
Examples of low-potency FGAs:
Chlorpromazine
Thioridazine
Tricyclic antidepressants: inhibit norepinephrine and serotonin reuptake
Antihistamines (1st generation):
Used for motion sickness (nausea), allergic rhinitis, and dizziness/vertigo
Examples of 1st-generation antihistamines:
Chlorpheniramine
Dimenhydrinate (Dramamine)
Diphenhydramine
Doxylamine
Hydroxyzine
Ipratropium bromide (Atrovent nasal spray)
Meclizine (Antivert)
Promethazine
Scopolamine (patch)
Centrally acting skeletal muscle relaxants:
Cyclobenzaprine
Metaxalone
Methocarbamol
Orphenadrine
Tizanidine

Adverse Effects, Contraindications, Drug–Drug

Interactions, and Toxicity
Adverse effects are due to effects on the CNS and also to reduced activity of the
parasympathetic nervous system. Anticholinergics must be used with caution or avoided in the
elderly owing to the risks of side effects.

Adverse effects
Neuropsychiatric:
Drowsiness
Hallucinations
Memory impairment
Exocrine glandular secretion → dry mouth
Smooth muscle contraction →:
Urinary retention
Constipation
Pupils →:
Blurred vision
Photophobia
Warnings/contraindications
Beers criteria (medications be used with caution or avoided in elderly individuals):
Includes all anticholinergics
Elderly individuals are more vulnerable to anticholinergic adverse effects due to:
Increased permeability of the BBB
Decreased ACh-induced transmission within the CNS
Strong anticholinergics have a cumulative dose–response relationship with the development of
Alzheimer dementia.

Comparison of adverse effects, contraindications, and drug–drug

interactions
Table: Adverse effects, warnings/contraindications, and drug-drug interactions for
anticholinergic medications

Adverse effects Warnings/contraindications Drug–drug

interactions

Atropine Tachycardia Caution with: Avoid with:

Palpitations Elderly individuals Cholinomim
Anxiety Recent myocardial Concomita
Drowsiness infarction use of card
Dizziness Chronic lung disease stimulants
Dry mouth Acute angle-closure Other
Constipation glaucoma anticholine
Urinary Prostatic hypertrophy or agents
retention obstructive uropathy Concomita
Blurred vision (may cause urinary use of opio
Mydriasis retention) can lead to
Pyloric stenosis constipatio

GI Antimuscarinic Warnings similar to atropine Similar to atro

antispasmodics: effects similar to drug interacti
Dicyclomine and atropine
Hyoscyamine

Urinary Blurred vision Warnings similar to Anticholine

antispasmodics: Cognitive atropine agents
Darifenacin impairment Rare risk of angioedema Strong CYP
Fesoterodine Sedation Constipation and CYP3A
Oxybutynin Dry mouth Urinary retention inhibitors
Solifenacin Hallucinations Narrow-angle glaucoma
Tolterodine Dizziness
Trospium
Toxicity/overdose
A cholinergic crisis may occur with an overdose or with using multiple drugs that have
cholinergic effects.

Mnemonic: “Dry as a bone, hot as a pistol, red as a beet, mad as a hatter”

Dry: excess of the antisialagogue effect
Hot: anhidrosis and inability to regulate body temperature → hyperthermia
Red: due to peripheral vasodilation
Mad: psychosis
Treatment: physostigmine (antidote)

Comparison of Mechanism of Action and

Indications in Different Anticholinergics
Table: Anticholinergics mechanism of action and indications

Group Drug Mechanism of Indications

action
Group Drug Mechanism of Indications
action

Antimuscarinic agents Atropine Antagonizes Used IV in

muscarinic ACLS proto
receptors of: symptomat
Exocrine bradycardi
glands Preanesthe
Eyes medication
GI tract salivation a
Heart respiratory
Respiratory secretions
tract (aspiration
Stimulates the prophylaxi
CNS Antidote fo
↑ HR nerve agen
organopho
insecticide
poisoning
Emergency
treatment o
mushroom
poisoning
cholinergic
excess

Glycopyrrolate Antagonizes ACh Anesthesia

receptors adjunct; fo
(anticholinergic) neuromusc
blockade (
reversal
Hyperhidro
and as an
antisialago
Emergency
treatment o
mushroom
poisoning
cholinergic
excess
Group Drug Mechanism of Indications
action

Antiparkinson drugs Benztropine Antagonize Parkinsonis

Trihexyphenidyl muscarinic adjunct the
receptors in the rigidity and
striatum tremor
Drug-induc
extrapyram
symptoms
dystonia (e
tardive
dyskinesia

Antiemetics Scopolamine Nonselective Motion sick

(patch) muscarinic scopolamin
receptor mediates t
antagonism vestibular
in the inne
which prov
its antieme
effect
Prevention
postoperat
nausea an
vomiting
Group Drug Mechanism of Indications
action

GI antispasmodics Dicyclomine Antagonism of IBS

muscarinic
receptors →
relaxation of GI
smooth muscle
and ↓ GI motility

Hyoscyamine Nonselective Symptom r

muscarinic functional
receptor disorders:
antagonist— neurogenic
blocks ACh at Also used
postganglionic urinary
muscarinic antispasmo
acetylcholine
receptors
(mAChRs) at:
GI smooth
muscle
Bronchial
smooth muscle
Exocrine glands

Urinary antispasmodics Darifenacin Antagonize OAB

Fesoterodine ACh at
Oxybutynin muscarinic
Solifenacin receptors
Tolterodine Relax bladder
Trospium smooth muscle,
inhibit
involuntary
detrusor muscle
contractions
 Group Drug Mechanism of Indications
action

Cycloplegics/mydriatics Atropine Relaxation of Amblyopia

(ophthalmic solutions) Cyclopentolate the sphincter penalizatio
Homatropine muscle of the the healthy
Tropicamide iris → pupil Cycloplegi
dilation mydriasis
(mydriasis) Uveitis
Weakens
contraction of
the lens ciliary
muscle → loss
of
accommodation
(cycloplegia)

Bronchodilators (oral Aclidinium Muscarinic M3 COPD

inhalation) Ipratropium receptor
Tiotropium antagonism
Umeclidinium causes
bronchodilation.
Also called
long-acting
muscarinic
antagonists
(LAMAs)

AChE regenerator Pralidoxime Reactivates the Antidote for n

cholinesterase agent or
enzyme AChE organophosp
to reverse insecticide
excess poisoning
acetylcholine
levels
Net effect is
reducing the
amount of ACh
in the synaptic
cleft.

References