Transcript anticholinergic-toxicityx

Introduction
AAPCC 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 drops
Tiotropium 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. Amitriptyline
Phenothiazines e.g. Prochlorperazine
Antihistamines e.g. Cyclizine
Neuroleptics e.g. Olanzapine
Anticholinergic Syndrome
Most common causes (in Australia)7 are:
Antihistamines
Anticholinergic drugs including
atropine
benztropine
benzhexol
procyclidine
orphenadrine
Tricyclic antidepressants (TCAs)
Neuroleptics (in particular thioridazine and
chlorpromazine)
Carbamazepine
Anticholinergic 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
6
bat
(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
6
Flask
Anticholinergics
1) reduce detrusor muscle
contraction and
2) prevent normal opening of the
urethral sphincter
Leading to urinary retention
Other manifestations7
1) Tachycardia
Earliest and most reliable sign of anticholinergic toxicity
Ranges from 120 to 160 beats/min
Due 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 sounds
secondary to decreased peristalsis and GI motility
3) Postural Hypotension
In very large overdoses, a small degree of neuromuscular blockade maybe
observed causing postural hypotension.
4) Death
Fatalities 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
Airway
Protect airway early in patients with severe intoxication (e.g. seizures, severe delirium).
Hypoactive gut increases risk of aspiration.
Breathing
Should be assessed by
Observation
Pulse Oximetry
ABGs
(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.
Circulation
IV access should be secured
Continuous 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.
History
Patient 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 Examination
Emphasise 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
Tests
No specific diagnostic studies exist for anticholinergic overdoses.
- Drug screening
Perform 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 Decontamination
Early presenters (4 hours) with large ingestions should receive a single dose of activated charcoal
Only in patients who can protect their airway or who are intubated.
Enhanced elimination
Hemodialysis, hemoperfusion, peritoneal dialysis, and repeat-dose charcoal are not effective in removing
anticholinergic agents.
Seizures
Intravenous benzodiazepines; add propofol or barbiturates if seizures persist or recur
Delirium
Control agitation with benzodiazepines. Large doses may be required. Continue observation in a calming,
dark environment.
Arrhythmias
It would be reasonable to try any of the following treatments, which have been used in other drugs with
antiarrhythmic drug effects:
Na bicarbonate
lignocaine
Magnesium
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
develop
or
Referred for psychological assessment
More information
Contact the Toxicology Registrar or Consultant on call- Mater
NSW 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
References
1.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.