ANTICHOLINERGIC SYNDROMEBY DR. ANJEANNETTE REECE

IntroductionAAPCC National Poison Data System Annual Report (2007)1:

88,582 single exposures to anticholinergic drugs• Unintentional ingestions – 83,352 • Intentional ingestions -5,230• Adverse reactions occurred in 1,274 cases - Moderate morbidity - 463 - Major morbidity- 186 - Deaths- 75• Numbers only included pure anticholinergic e.g. atropine and scopolamine• Numerous OTC medications have anticholinergic properties - not their primary

pharmacologic activity2

- toxicity can occur with these medications and their is anticholinergic burden is additive.• Especially important in children and the elderly

Physiology

• Anticholinergics reversibly antagonize the action of acetylcholine. 3

• Two major subtypes of cholinergic receptors: muscarinic receptors and nicotinic receptors.

Muscarinic receptors3

• G protein-coupled • found on - autonomic effector cells innervated by peripheral postganglionic parasympathetic nerves, - ganglia- brain

Muscarinic receptors (continued)3

M1

• Found in autonomic ganglia, the brain, salivary glands, and stomach. Stimulation decreases activity in autonomic ganglia but increases secretion of saliva and gastric acid, from the salivary glands and stomach, respectively.

M2

• Found mainly in the heart. Stimulation decreases the sinus node rate, slowing conduction through the AV node, and decreases the force of atrial contraction, and possibly ventricular contraction.

M3

• Found on smooth muscle, endocrine and exocrine glands, and the iris. Stimulation produces bronchospasm, causes mild vasodilation, increases saliva and gastric acid production, and constricts the pupil.

M4 & M5

• M4 is found in the central nervous system where stimulation of the receptor subtype produces a diversity of actions; Parkinson Disease, Schizophrenia and Neuropathic pain. M5 may be involved in schizophrenia and drug dependence.

Nicotinic Receptors3

Complex structure of several subunits encoded by multiple genes. Combined into four main families of nicotinic receptors - the muscle-type- neuromuscular junction - the ganglion-type, autonomic ganglia; - two brain-types, CNS * Roles in neuronal development, learning and memory formation, and reward

• Anticholinergic generally refers to drugs and plant toxins that act as muscarinic receptor antagonists2

• Muscarinic receptor antagonists block of acetylcholine binding 3

• Effects from antagonism of the nicotinic cholinergic system is not a component of Anticholinergic Syndrome/ Toxidrome.

Types of Anticholinergics

Classification 3,6

Natural alkaloids Atropine (from the plant Atropa belladonna/ Deadly nightshade)Hyoscine (Scopolamine) (from Hyoscyamus niger/ henbane)

Datura stramonium (plant- Jimson weed/ Angel’s Trumpet)

Semi synthetic derivatives Homatropine – eye dropsTiotropium bromide- Spiriva

Synthetic compounds a) Mydriatics

Tropicamide – eye drops b) Antisecretory -antispasmodics Quaternary compounds

- Glycopyrrolate Tertiary amines

- Oxybutynin c) Antiparkinsonian drugs

- Benzhexol - Benztropine

Miscellaneous Tricyclic antidepressants e.g. AmitriptylinePhenothiazines e.g. Prochlorperazine Antihistamines e.g. Cyclizine

Neuroleptics e.g. Olanzapine

Anticholinergic Syndrome

Most common causes (in Australia)7 are:

AntihistaminesAnticholinergic drugs including

atropinebenztropinebenzhexol procyclidineorphenadrine

Tricyclic antidepressants (TCAs)Neuroleptics (in particular thioridazine and chlorpromazine)CarbamazepineAnticholinergic plants

Datura (Brugmansia) stramonium (Angel's trumpet)Atropa belladonna (Deadly Nightshade)

Toxidrome may be caused by5 - intentional overdose,- inadvertent ingestion,- medical noncompliance, and- polypharmacy. - Systemic effects have also resulted

from topical eye drops.

The range of toxicity is highly variable and unpredictable. in healthy adults

• Rate of absorption varies depending on the drug and the route of exposure

-e.g. the duration of toxic effects in benztropine intoxication may last for 2–3 days• Onset usually within 30 mins to 2 hours.

Symptoms are dose-dependant, - usually last between 2 to 7 days (up to 1 month)

Clinical Presentation

Central anticholinergic syndrome 6

- central effects of muscarinic receptor antagonism predominate, with fever, agitation, delirium, and coma.

Peripheral anticholinergic syndrome - peripheral effects such as tachycardia, flushed dry skin, dry mouth, ileus, and urinary retention.

The Mnemonic

(Apologies in advance)

Hot as a Hare6

Anhydrotic hyperthermia

• Suppression of thermoregulatory sweating via inhibition of sweat glands (innervated by sympathetic cholinergic fibers)

Skin becomes hot and dry

• In adults, body temperature is elevated by this effect only if large doses are administered or at high environmental temperatures, but in infants and children even ordinary doses may cause "atropine fever”

• Hyperthermia may be significantly potentiated by agitation and status epilepticus.

• A markedly elevated body temperature may lead to multisystem organ dysfunction and rhabdomyolysis, resulting in liver, kidney, and brain injury, and coagulopathy.

Dry as a bone6

Dry skin and dry mucous membranes are the typical peripheral clinical manifestations

Due to impaired - sweat gland secretory and- salivary gland secretory activity. - Particularly sensitive to inhibition with complete abolishment of the saliva by parasympathetic stimulation. Mouth becomes dry, and swallowing and talking may become difficult.

Severe case of xerostomia from the antimuscarinic effects of Jimsonweed ingestion. Note the associated erythema on the patient's cheek

Red as a beet 6

Due to cutaneous vasodilation - likely to dissipate heat by shunting blood to the skin - compensates for the loss of sweat production. Mechanism is unknown

Blind as a bat6

(non-reactive mydriasis)

Block the cholinergic responses of the pupillary sphincter muscle of the iris and the ciliary muscle controlling lens curvature. - Causes dilation of the pupil (mydriasis) and paralysis of

accommodation (cycloplegia). - Leads to photophobia; - Lens is fixed for far vision so near objects are blurred, - Objects may appear smaller than they are.

Normally, anticholinergics do not change intraocular pressure, but with narrow-angle glaucoma, they may precipitate an episode of acute glaucoma

Mydriasis and flushing are some of the characteristic findings of anticholinergic toxidrome

Mad as a Hatter6 Manifestations may include:

Anxiety

Agitation and Delirium

Psychosis (usually paranoia)

Confusion

Disorientation

Dysarthria - staccato speech pattern that’s difficult-to-comprehend . May be exacerbated by severe dysphasia from decreased mucous secretion. High-pitched cries may sometimes be heard

Visual and Auditory hallucinations:Hallucinations are often described as Alice in Wonderland or Lilliputian type, where people appear to become larger and smaller. Bizarre behaviour Repetitive picking at the bed clothes or imaginary objects. Patients may also exhibit jerking movements of the extremities (Choreoathetosis) Seizures- rare with pure antimuscarinic agents, although they may result from other pharmacologic properties of the drug (eg, tricyclic antidepressants and antihistamines).

Full as a Flask6

Anticholinergics 1) reduce detrusor muscle contraction and2) prevent normal opening of the urethral sphincterLeading to urinary retention

Other manifestations7

1) TachycardiaEarliest and most reliable sign of anticholinergic toxicityRanges from 120 to 160 beats/minDue to blockade of M2 receptors on the SA nodal pacemaker cells - Antagonizes parasympathetic tone and increases heart rate More malignant dysrhythmias are less common

2) Decreased or absent bowel soundssecondary to decreased peristalsis and GI motility

3) Postural HypotensionIn very large overdoses, a small degree of neuromuscular blockade maybe observed causing postural hypotension.

4) DeathFatalities are usually characterised by severe agitation, status epilepticus, hyperthermia, wide-complex tachydysrhythmias, coma and respiratory paralysis secondary to eventual circulatory failure They can also be due to environmental hazards secondary to delirium (e.g. drowning)

The severity of the symptoms and signs of poisoning is generally dose dependent6:

Management 6-9

- Majority of cases require only supportive care.

- Initial management should follow the same approach regardless of the poison involved: - A B C D Es

AirwayProtect airway early in patients with severe intoxication (e.g. seizures, severe delirium). Hypoactive gut increases risk of aspiration. BreathingShould be assessed byObservation Pulse OximetryABGs (1) Hypoxia may result in brain damage, cardiac arrhythmias, and cardiac arrest.(2) Hypercarbia results in acidosis, which may contribute to arrhythmias, especially in patients with salicylate or tricyclic antidepressant overdoses. Patients with respiratory insufficiency should be intubated and mechanically ventilated. CirculationIV access should be securedContinuous monitoring of - pulse rate, - blood pressure- urinary output, and - evaluation of peripheral perfusion. Obtain an ECG and institute continuous cardiac monitoring in patients with moderate to severe toxicity (e.g, agitation, delirium, seizures, coma and hypotension).

Disability:Blood glucose test for hypoglycaemia Assessment of altered level of consciousness Environment Temperature(Hyperthermia is expected) Active cooling by removing patient clothing , covering with damp sheets, ice application and large fans with cool mist to maximize evaporative cooling are life-saving measures that should be aggressively performed. Antipyretics not helpful.

HistoryPatient may be unreliable Get corroborative statements from family members, police, fire department and paramedics about the environment Any syringes, empty bottles, household products, or OTC medications in the immediate vicinity of the patient should be brought in if possible. Physical ExaminationEmphasise those areas most likely to give clues to the toxicological diagnosis. These include vital signs, eyes and mouth, skin, abdomen, and nervous system

The signs as per the mnemonic we discussed previously outline the basis for this in the case of anticholinergics TestsNo specific diagnostic studies exist for anticholinergic overdoses.

- Drug screeningPerform screening for e.g. paracetamol level in all intentional poisonings because combination medication preparations and multiple ingestions often occur.  - Consider blood and urine cultures in febrile patients.- Serum chemistry and electrolyte analysis may provide clues to the intoxicating agents and co-ingestants. - Obtain a creatine kinase (CK) and monitor renal function and urine output in patients with psychomotor agitation and seizures to rule out associated rhabdomyolysis.

Physostigmine10

• A trial dose of physostigmine can be used to confirm the presence of anticholinergic toxicity in a patient whose history of drug ingestion is unclear;

• Rapid reversal of signs and symptoms is consistent with the diagnosis. • (t ½= 16 minutes and duration of action= 1 hour)• Tertiary amine• Crosses the blood-brain barrier • Both central and peripheral acetylcholine antagonism. • 10 mechanism of action - reversibly inhibits acetylcholinesterase

boosting acetylcholine levels to overcome the toxicity. • Has been associated with severe complications, including bradycardia,

heart block, and seizures. Atropine should be readily available if it is used, and ECG monitoring is necessary.

Treatment13-14

GI DecontaminationEarly presenters (4 hours) with large ingestions should receive a single dose of activated charcoalOnly in patients who can protect their airway or who are intubated.

Enhanced eliminationHemodialysis, hemoperfusion, peritoneal dialysis, and repeat-dose charcoal are not effective in removing anticholinergic agents.

SeizuresIntravenous benzodiazepines; add propofol or barbiturates if seizures persist or recur

DeliriumControl agitation with benzodiazepines. Large doses may be required. Continue observation in a calming, dark environment.

ArrhythmiasIt would be reasonable to try any of the following treatments, which have been used in other drugs with antiarrhythmic drug effects:Na bicarbonatelignocaineMagnesium

Urinary catherisation - for urinary retention

Very important to remember:

Consult on-call Toxicology Registrar or Consultant at the Mater Hospital or the NSW Poisons Information Centre for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear

.

Differential Diagnosis

Includes life-threatening presentations such as • viral encephalitis, • Reye syndrome, • head trauma, • alcohol and sedative-hypnotic withdrawal, • postictal state,• other intoxications, • neuroleptic malignant syndrome, • acute psychotic disorder.

PROGNOSIS - FOLLOW UP

Delirium and other signs may persist for some days up to a month

Patients must be monitored for 8 hours following exposure for onset or worsening of symptoms.

If asymptomatic at the end of the observation period (i.e. ECG is normal or unchanged from previous and gastric motility is also normal), they should be:

discharged into the care of a reliable caregiver with instructions to return should any further symptoms developorReferred for psychological assessment

More information

Contact the Toxicology Registrar or Consultant on call- MaterNSW Poisons Information Centre 131 126

Websites to use

Via CIAP- Mims- Australian based- Australian Medical Handbook- Australian pharmacopoeia- Micromedex- US based- Toxinz- Australian based- Toxinet- US based

References1.Bronstein AC, Spyker DA, Cantilena LR Jr, Green JL, Rumack BH, Heard SE. 2007 Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 25th Annual Report. Clin Toxicol (Phila). Dec 2008;46(10):927-1057.

2. Boustani MA, Campbell NL, Munger S et al. Impact of anticholinergics on the aging brain: A review and practical application. Aging Health 2008;4:311–320.

3. Chapter 8. Cholinoceptor-Blocking Drugs by Achilles J. Pappano in Basic & Clinical Pharmacology 11e Bertram G., Katzung, SB & Masters, A. Wiley-Blackwell, 2007: 1033-1045.

4. Caulfield MP. Muscarinic receptors--characterization, coupling and function. Pharmacol Therapeutics 1993 Jun; 58 (3): 319-79.

5.Kemmerer DA Anticholinergic syndrome. Journal of Emergency Nursing Vol 33, Issue 1 (February 2007) Pages 76 - 78

6. Chapter 23. Anticholinergics in Poisoning & Drug Overdose, 5e Olsen. K. McGraw-Hill, 2007: 1100-1120.

7. Toxinet website http://toxnet.nlm.nih.gov/

8. Toxinx http://www.toxinz.com/

9. Feldman MD. The syndrome of anticholinergic intoxication. Am Fam Physician 1986 Nov; 34 (5): 113-6.

10. Listwania,L & Whealy NG. Mental symptoms in poisoning with atropine and its derivatives. Med J Aust 1953 Apr 25; 1 (17): 581-3.

11. Tenenbein M. Whole bowel irrigation as a gastrointestinal decontamination procedure after acute poisoning. Med Toxicol Adverse Drug Exp 1988 Mar-Apr; 3 (2): 77-84.

12. Burns MJ, et al. A comparison of physostigmine and benzodiazepines for the treatment of anticholinergic poisoning. Ann Emerg Med 2000; 35:374..

13. Schneir AB et al.: Complications of diagnostic physostigmine administration to emergency department patients. Ann Emerg Med 2003;42:14–19.

14. WikiTox http://curriculum.toxicology.wikispaces.net/

15. Tintinalli J, Kelen G, Stapcznski JS: Emergency medicine: a comprehensive study guide, 6th ed McGraw-Hill New York 2004: 1143-1146.