Anticholinergic Syndrome - PowerPoint Presentation

Slide1

Anticholinergic Syndrome

By Dr. Anjeannette ReeceSlide2

Introduction

AAPCC National Poison Data System Annual Report (2007)1:88,582 single exposures to anticholinergic drugsUnintentional ingestions – 83,352 Intentional ingestions -5,230Adverse 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

activity

2

- toxicity can occur with these medications and their is anticholinergic

burden is additive.

Especially important in children and the elderlySlide3

Physiology

Anticholinergics reversibly antagonize the action of acetylcholine. 3Two major subtypes of cholinergic receptors: muscarinic receptors and nicotinic receptors. Muscarinic receptors3G protein-coupled found on autonomic effector cells innervated by peripheral postganglionic parasympathetic nerves, gangliabrain Slide4

Muscarinic receptors (continued)3

M1Found 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. M2Found 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. 

M

3

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.

M

4

& M

5

M

4

is

found in the central nervous system where stimulation of the receptor subtype produces a diversity of

actions;

Parkinson Disease,

Schizophrenia

and Neuropathic

pain.

M

5

may be involved in schizophrenia and drug dependence.Slide5
Slide6

Nicotinic Receptors

3Complex 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

rewardSlide7

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

Muscarinic receptor antagonists block of acetylcholine binding 3Effects from antagonism of the nicotinic cholinergic system is not a component of Anticholinergic Syndrome/ Toxidrome. Slide8

Types of AnticholinergicsSlide9

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- SpirivaSlide10

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. OlanzapineSlide11

Anticholinergic SyndromeSlide12

M

ost common causes (in Australia)7 are:AntihistaminesAnticholinergic drugs including atropinebenztropinebenzhexol procyclidineorphenadrine

Tricyclic antidepressants (TCAs)

Neuroleptics (in particular

thioridazine

and chlorpromazine)

Carbamazepine

Anticholinergic plants

Datura

(

Brugmansia

)

stramonium

(Angel's trumpet)

Atropa

belladonna (Deadly Nightshade

)Slide13

Toxidrome

may be caused by5 intentional overdose,inadvertent ingestion,medical noncompliance, andpolypharmacy. Systemic effects have also resulted from topical eye drops.

The

range of toxicity is highly variable and unpredictable.

in

healthy

adultsSlide14

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 daysOnset usually within 30 mins to 2 hours. Symptoms are dose-dependant,

- usually

last between 2 to 7

days (up to 1

month)Slide15

Clinical PresentationSlide16

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.Slide17
Slide18

The Mnemonic

(Apologies in advance)Slide19
Slide20

Hot as a Hare6

Anhydrotic hyperthermiaSuppression of thermoregulatory sweating via inhibition of sweat glands (innervated by sympathetic cholinergic fibers) Skin becomes hot and dryIn 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.

 Slide21
Slide22

Dry as a bone

6Dry skin and dry mucous membranes are the typical peripheral clinical manifestationsDue to impaired sweat gland secretory andsalivary 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.Slide23

S

evere case of xerostomia from the antimuscarinic effects of Jimsonweed ingestion. Note the associated erythema on the patient's cheekSlide24
Slide25

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 Slide26
Slide27

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 Slide28

Mydriasis

and flushing are some of the characteristic findings of anticholinergic toxidromeSlide29
Slide30

Mad as a Hatter

6 Manifestations may include:AnxietyAgitation and DeliriumPsychosis (usually paranoia)ConfusionDisorientationDysarthria - 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).

 Slide31
Slide32

Full as a Flask

6Anticholinergics 1) reduce detrusor muscle contraction and2) prevent normal opening of the urethral sphincterLeading to urinary retentionSlide33

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 common2) Decreased or absent bowel soundssecondary to decreased peristalsis and GI motility3) Postural HypotensionIn 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)

 Slide34

The severity of the symptoms and signs of poisoning

is generally dose dependent6:Slide35

Management 6-9Slide36

- Majority of cases require only supportive care.

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

 Slide37

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.Slide38

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

. Slide39

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 amineCrosses 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

.Slide40

Treatment

13-14‍GI 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.

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 retentionSlide41

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.Slide42

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.Slide43

PROGNOSIS - FOLLOW UP

Delirium and other signs may persist for some days up to a monthPatients 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 assessmentSlide44

More information

Contact the Toxicology Registrar or Consultant on call- MaterNSW Poisons Information Centre 131 126Websites to use Via CIAP- Mims- Australian based- Australian Medical Handbook- Australian pharmacopoeia- Micromedex- US based

-

Toxinz

-

Australian based

-

Toxinet

-

US based

 Slide45

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/

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Tintinalli

J, 

Kelen

G, 

Stapcznski

JS:  Emergency medicine: a comprehensive study guide,   6th

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McGraw-Hill New York 2004: 1143-1146.