Download Case History - Children`s Hospital of Michigan

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COW EDITOR
G. Patrick Daubert
ASST EDITOR
Susan Smolinske
CASE CONTRIBUTORS
POISON CENTER STAFF (HERD)
Suzanne White
Cynthia Aaron
Susan Smolinske
Lydia Baltarowich
Janet Eng
Kirk Mills
Matthew Hedge
Saima Qureshi
FELLOWS
G. Patrick Daubert
Abhi Katiyar
Case
History
CASES FROM THE DETROIT PCC
A teenager calls the poison control center stating
that a friend took 20 “Cor” about an hour ago and
is now acting very strange. The PCC advised the person to
take her friend to the nearest emergency department (ED)
for evaluation.
The patient is an 18-year-old male presenting to the ED in an
agitated state. He appears confused with slurred speech.
The patient is not able to give a reliable history. The friend
claims the patient was using Coricidin HBP to get ‘high‘. She
also states that he (the patient) has taken Coricidin in the
past but does not normally take this many pills. No other
drugs/medication was reported to be ingested. The patient
is placed on a monitor and an IV is established. Blood is sent
for preliminary studies. He is given activated charcoal and
benzodiazepines for sedation.
PMHx/SurgHx: None Allergies: None
Meds: None
Soc. Recent graduate from high school. No reported
tobacco or illicit drug use. Occasional alcohol use.
Mad Cow…
Who was Mickey Finn?
Micky Finn was the owner and bartender of a Chicago bar called the Lone Star Saloon and Palm
Garden Restaurant. It operated from 1896 to 1903 in the city's South Loop neighborhood on the
west side of South State Street north of Harrison Street. Mickey would put chloral hydrate in
unsuspecting patron’s drinks and proceed to rob them after they passed out. Mickey's saloon was
ordered closed on December 16, 1903 (note: there are several variations to this story!).
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©2005 Children’s Hospital of Michigan Regional Poison Control Center
4160 John R • Suite 616
Detroit • Michigan • 48201
Physical
Exam
Wt 170 lbs, BP-180/81, HR-139, Resp-20, Temp-38.3, Pulse Ox 97% RA
General: Agitated, delirious.
HEENT: Pupils dilated to 6 mm; no signs of trauma; mucous membranes dry
Neck: No meningismus
Chest: Clear to auscultation bilaterally with good air entry; breathing not labored
Cardiac: S1, S2 noted; tachycardic with regular rhythm; no murmurs
Abdomen: Soft; bowel sounds diminished; no liver or spleen enlargement; bladder
not palpable
Skin: Warm and dry; no rashes or lesions; skin is flushed
Musculoskeletal: No edema; normal pulses; no acute trauma
Neurologic: Agitated; speech slurred; normal strength; no rigidity, tremor or
clonus; DTRs normal; not able to follow commands
Labs
Na 137, K 3.1, Cl 100, bicarb 26 Bun 15, Cr 1.3, glc 100, Ca 9.1
AST 36, WBC 6.6, Hb 16.8, Plt 198
Aspirin/Acetaminophen negative
Questions
1. What are the active ingredients in Coricidin HBP
(Figure 1)?
This product is an over-the-counter cough and cold
medication marketed toward patients with
hypertension. Several products are on the market.
1) Coricidin HBP Cold and Flu
325 mg acetaminophen (APAP)
2 mg chlorpheniramine
2) Coricidin HBP Cough and Cold
30 mg DXM HBr
4 mg chlorpheniramine
3) Coricidin HBP Maximum Strength Flu
500 mg APAP
15 mg DXM HBr
2 mg chlorpheniramine
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Figure 1. Coricidin HBP
©2005 Children’s Hospital of Michigan Regional Poison Control Center
4160 John R • Suite 616
Detroit • Michigan • 48201
Chlorpheniramine is an antihistamine. People abuse Coricidin for the DXM but one
of the products doesn’t contain DXM and two others contain APAP. Therefore,
users are at risk for acute and/or chronic APAP toxicity in addition to the acute
antihistamine intoxication. Coricidin is one of the more popular products among
teens seeking DXM. However, there are at least 92 other products on the market
that contain DXM in 15-30 mg dosages.
2. Why are young adults abusing this medication? How common is Coricidin
abuse?
DXM abuse continues to be a growing
problem among teens. Although 80% of
teen users abuse DXM less than twice
a month, the rate of abuse has doubled
since the year 2000. In a recent
survey released by the Partnership
for a Drug Free America in 2004, 9%
(2.3 million) of high school teens had
abused an OTC cough and cold
medication. This is a similar number
reported for Ecstasy use. DXM is
reported to produce a dissociative high and some experience hallucinations. Not
all users experience the desired effects of DXM, however. (See BBQ below). In
reference to cough syrup, about one third of first time users like the effects
enough to try it again. Another third can’t get past the taste of the cough syrup
to want to try it again. And the last third can tolerate the taste but don’t
experience the desired effect. The chlorpheniramine has antimuscarinic
properties that may potentiate the desired effects in abusers, making Coricidin a
favorite product among teens. In addition, some chronic users experience a mild
histamine release from DXM causing the “robo itch”. Chlorpheniramine may be an
added bonus for these users helping to alleviate this symptom.
3. What is the pharmacology of dextromethorphan (DXM)?
DXM is often considered an opioidW, although its pharmacology is much more
complex. Although DXM will bind to opioid receptors, at high doses it is devoid of
analgesic properties. DXM is the methylated dextro-isomer of levorphanol (see
Figure 2). Levorphanol is a relatively old, long-acting synthetic opioid with an
equivalence of about 1 mg levorphanol to 5 mg of morphine. Unlike levophanol,
however, DXM has no analgesic and possesses minimal addictive properties.
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©2005 Children’s Hospital of Michigan Regional Poison Control Center
4160 John R • Suite 616
Detroit • Michigan • 48201
DXM is well absorbed from the GI tract. Erratic and slower absorption may occur
with high-dose ingestions or with the concomitant ingestion of a drug with
antimuscarinic properties (decreased gut motility) such as chlorpheneramine.
DXM is metabolized extensively by the liver by the P450 system (CYP2D6) and
has an elimination half-life of 2 to 4 hours. Dextrorphan is the major active
metabolite generated via CYP2D6. DXM is most commonly used as a cough
suppressant and achieves this effect by elevating the cough threshold in the
Levorphanol
Dextromethoorphan
Figure 2. Levorphanol and its dextro-isomer DXM
medulla oblongata. DXM is, however, what one might call a ‘dirty drug’ and
possesses a number of additional unique properties. DXM inhibits the reuptake of
serotonin and may cause a serotonin syndrome, especially when used concurrently
with monoamine oxidase inhibitors (MAO-I). DXM and dextrorphan have also
been shown to antagonize the action of glutamate (anticonvulsant property of
DXM). Dextrorphan blocks the NMDA receptor (calcium channel) by binding to
the PCP (phencyclidine) site. In fact, the structural similarities between DXM
and PCP may cause a false positive drug screen for PCP. DXM has also been shown
to block N- and L-type voltage-dependent calcium channels and nicotinic
receptors. In addition to the NMDA receptor, dextrorphan binds to sigma
receptors in the brain. Sigma receptors are not opioid receptors and their true
function remains obscure. However, the sigma receptors (σ1 and σ2) have been
associated with psychosis (similar to the dysophoria seen with PCP) via modulation
of synthesis and release of neurotransmitters such as acetylcholine and dopamine.
The σ1 receptor is also postulated to elevate the cough threshold. Again, DXM
will bind to opioid receptors at high doses producing the classic triad of opioid
toxicity with CNS depression, depressed respiratory drive, and miosis. Naloxone
may inhibit these effects similar to other opioid overdoses.
Note: The term opiate is reserved for naturally occurring chemicals derived from opium
(morphine, codeine). Synthetic derivates (ie, heroin) are termed opioids.
W
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©2005 Children’s Hospital of Michigan Regional Poison Control Center
4160 John R • Suite 616
Detroit • Michigan • 48201
4. What toxidrome does this patient have and why does he have it?
The patient is confused with dilated pupils; has tachycardia; is hypertensive; is
hyperthermic with hot, flushed skin; and demonstrates decreased bowel sounds.
This is the antimuscarinic toxidrome that has developed due to the antihistamine
chlorpheneramine. Antihistamines commonly antagonize muscarinic receptors in
addition to their primary antihistaminic effects. The sympathomimetic toxidrome
would demonstrate diaphoresis and active bowel sounds.
5. Have there been any deaths reported from Coricidin abuse? Are there
prognostic indicators for who is at risk for serious toxicity or mortality?
Death from DXM abuse is uncommon but reported deaths have been increasing
since 1999. There are 3 major causes of mortality from DXM abuse. First, DXM
at high doses will cause CNS and respiratory depression similar to that of other
opioids. Second, an altered sensorium leads to risky behavior. For instance, in
2003, a 14-year-old boy in Colorado who abused DXM died when he was hit by two
cars as he attempted to cross a highway. Third, cough and cold medications
commonly contain other active ingredients such as antihistamines,
pseudoephedrine, and acetaminophen. Patients who develop dysrhythmias (Na+
channel blockade), hyperthermia, and/or agitation are at a higher risk of
morbidity (rhabdomyolysis, renal failure) and mortality. There is also a remote
possibility of bromide toxicity since many cold remedies use DXM HBr as the
water-soluble formulation.
6. What is the sigma plateau?
DXM abusers ingest various amounts of the drug depending on their body weight
and the effect or plateau that they are attempting to achieve. The recommended
therapeutic dose for DXM is 10-20 mg every 4 hours or 30 mg every 6-8 hours.
There are traditionally four plateaus achieved based on the amount of DXM
ingested. Users will consume 600 mg to achieve the second plateau. Most users
stick to the first two plateaus. There are some who claim a 5th plateau exists –
the sigma plateau (named after the receptor and the sum of the other plateaus).
Most DXM abusers state that the sigma plateau is achieved by stacking doses
which would achieve a second plateau experience over a period of several hours.
It is obviously a dangerous trial, particularly if users attempt to achieve higher
plateaus with APAP or antihistamine containing products. A brief description of
the other plateaus is given below.
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©2005 Children’s Hospital of Michigan Regional Poison Control Center
4160 John R • Suite 616
Detroit • Michigan • 48201
First Plateau: (1.5 to 2.5 mg/kg) Mild inebriation. Many users develop tolerance to
the effects of DXM at this dose range.
Second Plateau: (2.5 to 7.5 mg/kg) An effect similar to alcohol intoxication and,
occasionally, mild hallucinations. The abuser's speech can become slurred, and
short-term memory may be temporarily impaired. Users have described this
plateau as feeling “stoned.”
Third Plateau: (7.5 to 15 mg/kg) An altered state of consciousness. The abuser's
senses, particularly vision, can become impaired. Frank psychosis may develop in
naïve users. Cognitive function is severely impaired.
Fourth Plateau: (> 15 mg/kg) Mind and body dissociation or an "out-of-body"
experience. The abuser can lose some or all contact with his or her senses. The
effects at this plateau are comparable to the effects caused by ketamine or PCP.
7. How would you treat this patient?
The vast majority of patients require only supportive care. The patient’s airway
must be closely evaluated. Naloxone may reverse CNS and respiratory
depression. Benzodiazepines should be used liberally for agitation. They may also
be effective for the hypertension seen in these cases. Remember to address
potential APAP toxicity. Antihistamines commonly possess Na+ channel blocking
properties and an ECG is warranted early in the course of management. Patients
demonstrating a wide QRS rhythm (QRS > 100 ms) should be treated with sodium
bicarbonate similar to a TCA overdose. Patients may develop rhabdomyolysis
requiring aggressive IV hydration and an evaluation of their CK and creatinine.
BBQ
1. Why don’t some first time users of DXM experience the psychoactive effects
of this drug?
Recall that dextrorphan is likely the molecule responsible for binding to the sigma
receptor leading to dysphoria. Also, remember that dextrorphan is generated via
CYP2D6. CYP2D6 is a polymorphic enzyme, meaning that its rate of activity varies
among individual people. Persons with a very active CYP2D6 generate more
dextrorphan and therefore experience more of the dysphoria associate with
DXM. Individuals who are poor CYP2D6 metabolizers (5 to 10% of the Caucasian
population) generate very little dextrorphan. These first time users get nothing
but cough medicine breath. The majority of the population (> 80%) are fast or
extensive CYP2D6 metabolizers, suggesting at least one reason why DXM has
become so popular among our youth.
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©2005 Children’s Hospital of Michigan Regional Poison Control Center
4160 John R • Suite 616
Detroit • Michigan • 48201