Neuroleptic malignant syndrome

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Libby Zion’s Lesson:
Serotonin Syndrome
and P450 Drug Interactions
Laurence J. Kinsella, MD, FAAN
SSM St Clare
Neuroscience Institute
Saint Louis University
Disclosures
 Dr Kinsella is a consultant for Therapath
laboratories and Cross Country Education.
 No relationships with pharmaceutical industry
 Stock ownership in Passnet Air Ambulance
 2009 Teacher of the Year,
US Psychiatric Congress
You Should Know
 mechanism of drug-drug
interactions (DDI)
 common DDIs in neurologic
practice
 how to predict and manage
interactions
Question 1
In 1984, a young woman died from a fatal drugdrug interaction (DDI). Her death was blamed on
poor judgment of sleep-deprived house staff, and
led to the 80 hour work week restriction for
residents. What was the DDI and the name of the
syndrome?
a.
b.
c.
d.
Haloperidol and Chlorpromazine - Neuroleptic
malignant Syndrome
Penicillamine and Gentamicin - Myasthenic Crisis
Phenelzine and meperidine - Serotonin Syndrome
Carbamazepine and acetaminophen - Stevens
Johnson Syndrome
Case 1: 54 Year-Old Female
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


Admitted for GI distress, vomiting, chest pain
On phenelzine (Nardil®) for depression
Given meperidine for chest wall discomfort q6hrs
Developed shivering, rigidity, tremor, confusion,
mutism, hyperthermia and tachycardia
Case 1
 Meperidine, phenelzine held
 Given cyproheptadine 12 mg per NG, then 2
mg q 2 hrs
 Ativan 1 mg IV q 2-4 hours
 EEG - no seizures, diffuse slowing
 CPK wnl
 Gradual resolution after 3 days
Case 2
 35 year old woman
 Admitted with confusion
 Has baseline mental retardation,
schizophrenia, but is able to live
independently
 Noted to be confused, less verbal by her
mother
 No longer able to care for self
Case 2
 Meds
 Exam - resting
tachycardia 104 bpm
 Fine tremor in hands
 MMSE - 12/27
 Trazodone (Desyrel®)
Clonazepam (Klonopin®)
Venlafaxine (Effexor®)
Citalopram (Celexa®)
Risperidone (Risperdal®)
Aripiprazole (Abilify®)
Olanzapine (Zyprexa®)
Chlorpromazine (Thorazine®)
Oxcarbazepine (Trileptal®)
Case 2
 Confusion and tremulousness resolved
over 3 days when holding just 3 meds  Citalopram, venlafaxine and trazodone
 Mental status returned to baseline
 MMSE - 24/30
 HR 81
Serotonin Syndrome:
Features
Clinical
 Mental status changes
 Agitation, hypervigilence, confusion
 Autonomic hyperactivity
 Tachycardia, fever, hypertension,
diaphoresis
 Hyperkinetic motor activity
 Tremor, clonus, hyperreflexia
New York Hospital, 1984
 Libby Zion, an 18 year old college student,
dies in New York Hospital
 Rcvd meperidine (Demerol®) and haloperidol (Haldol®) for
sedation and pain control.
 Home meds included phenelzine (Nardil®), an MAOI
 Her father, Sidney Zion, indicts the
medical training system, overworked and
poorly supervised residents
 1995 – Zion vs New York Hospital
 Jury assigns partial blame to MDs and Zion
 Traces of cocaine found in autopsy samples
http://www.courttv.com/archive/casefiles/verdicts/zion.html
Asch DA. “The Libby Zion Case”, New England Journal of Medicine 1988;318:771-775.
www.ethicsconsultant.com/system/files/Zion-Case-White3.ppt
The Bell Commission 1987
 Indictment of residency work hours
and poor supervision
 Led to current 80 hour workweek
mandate
 Adopted by ACGME in 2003 for all
US residencies
 Recent data supports a link
between poor decision making and
sleep deprivation
 Poor attention following sleep
deprivation
 Poor/dangerous order writing by ICU
residents post-call.
Lockley et al. NEJM 2004;351:1829-1837
Landrigan et al. Effect of reducing interns’ work hours on
serious medical errors in intensive care units. NEJM
2004;351:1838-1848.
Libby Zion’s Lesson
 Would today’s well-rested resident
have recognized the problem that
killed Libby Zion?
Serotonin Syndrome:
Pathophysiology
 Hyperstimulation of
post synaptic 5-HT
receptors
 Brain, GI tract and
vessels
 Drugs may stimulate
receptors directly
 Tryptophan
 Sumatriptan
 Buspirone
 Or block reuptake
and metabolism
 SSRIs
 Meperidine (Demerol®)
 MAOIs
Boyer, E. W. et al. N Engl J Med 2005;352:1112-1120
Serotonin Syndrome
 1960: tryptophan and MAOIs
 1984: Libby Zion - Demerol and phenelzine
(and cocaine?)
 15% incidence in patients overdosing SSRIs
 Toxic Exposure surveillance system 2002
 7349 patients reported in 2002
 93 deaths
 0.4 cases/1,000 patient-months on SSRIs
Oates JA, Neurology, 1960; Asch DA, NEJM 1988
Spectrum of Clinical Findings
Akathisia, restlessness
Tremor
Altered mental status
Multifocal myoclonus
Hypertonicity
Hyperthermia
Coma
Boyer, E. W. et al. N Engl J Med 2005;352:1112-1120
Drugs Associated With
Serotonin Syndrome
 SSRIs: sertraline, fluoxetine,
fluvoxamine, paroxetine,
citalopram
 Antidepressants:
trazodone, nefazodone,
buspirone, clomipramine,
venlafaxine
 MAOI: phenelzine,
isocarboxazid
 AEDs: valproate
 Analgesics: meperidine,
fentanyl, tramadol and
pentazocine
 Antiemetics:
ondansetron,
metoclopramide†
 Migraine: sumatriptan*
 ABx: linezolid, ritonavir
 Dietary supplements:
tryptophan, St John’s Wort,
Ginseng
 Lithium, dextromethorphan
† FDA boxd warning 2/26/09 – Long-term or highdose use of metoclopramide has been linked to
tardive dyskinesia
* FDA warning re. Triptans and SSRIs 2006;
http://www.fda.gov/cder/drug/InfoSheets/HCP/ve
nlafaxineHCP.pdf
Question 2
The serotonin syndrome and neuroleptic
malignant syndrome are distinguished by all
of the following EXCEPT:
a. Movements are hyperkinetic in SS, bradykinetic
in NMS.
b. Bowel sounds are diminished in NMS.
c. Agitation is more likely in SS.
d. Both SS and NMS respond to bromocriptine.
Manifestations of Severe Serotonin Syndrome
and Neuroleptic Malignant Syndrome
Condition
Medication
History
Serotonin
syndrome
Pro
< 12 hours
serotonergic
drug
Neuroleptic Dopamine
malignant
antagonist
syndrome
Time
Needed
1-3 days
Vital signs
Bowel
sounds
Hypertension, Hyperactive
tachycardia,
tachypnea,
hyperthermia
Hypertension, decreased
tachycardia,
tachypnea,
hyperthermia
SS vs NMS
Condition
Mental
Status
Pupils
Neuromusc
ular tone
Reflexes
Serotonin
syndrome
Agitation,
coma
Mydriasis
Hyperreflexia,
clonus
Neuroleptic
malignant
syndrome
Stupor,
alert mutism,
coma
normal
Increased,
mainly in
lower
extremities
Lead pipe
rigidity, all
muscle
groups
Hyporeflexia
Treatment
 Mild cases - withdraw meds; low doses
benzodiazepines
 Severe cases - benzos, cyproheptadine,
olanzapine, intubation, neuromuscular
blockade
 Cyproheptadine binds 5-HT receptors
 Give by NG 12 mg, then 2 mg q 2 hours
 Avoid
 Propranolol (hypotension)
 Bromocriptine (may worsen serotonin syndrome)
 Dopamine (rqs conversion to epinephrine)
Question 3
The following are true statements about drug
interactions EXCEPT:
a. It is among hospitalized patients’ chief concerns
b. Drug interactions increase exponentially above
4 medications
c. Competition for protein binding sites is a more
important mechanism of DDI than P450
interactions.
d. Elderly have a 3 fold risk of drug interactions
and adverse effects due to altered metabolism
and increased sensitivity.
Drugs withdrawn for excessive
Adverse Drug Reactions






terfenadine (Seldane®) - February 1998
mibefradil (Posicor®) - June 1998
astemazole (Hismanal®) - July 1999
cisapride (Propulsid®) - January 2000
Fluvoxamine (Luvox®) - 2005
All relate to P450 enzymatic interactions with
other drugs
http://www.fda.gov/cder/drug/drugReactions/default.htm
Adverse Drug Interactions





2.2 million severe reactions/yr
7000 deaths/yr (institute of medicine)
Some claim 100,000+/yr
1.75 billion in increased medical costs
Largest reason for malpractice payouts
Lazarou J. JAMA 1998
“Top Ten” Drug Interactions
1. MAOIs, meperidine, and
SSRIs → Serotonin
Syndrome
2. Chinese w/ HLA B1502 and
carbamazepine →
SJS/TEN
3. Clopidogrel and
omeprazole → poor stroke
prophylaxis
4. Phenytoin and topiramate
→ phenytoin toxicity
5. Valproate and Lamotrigine
(1/2 life^x3) → rash
6. AEDs and OCPs →
pregnancy
7. AEDs and warfarin → low
INR
8. Grapefruit juice and statins
→ myalgias
9. TPMT deficiency and
Azathioprine → toxicity
10. Imitrex and fluoxetine →
Serotonin Syndrome (rare)
Why So Many ADRs?
 64% of patient visits result in Rx
 2.8 billion outpatient Rxs (10/person in U.S.)
in 2000
 ADRs increase dramatically over 4 medications
Jacubeit T. Agents Actions 1990
Polypharmacy in the Elderly
 Average older person takes 4.5 prescription
medications and 2 OTC
 Average person aged 65-69 fills 13.6 rx/yr
 Average person aged 80-84 fills 18.2 rx/yr
GAO, 1996; Senior Care Pharmacist, 2005
Beers Criteria
Hgh Severity: Should be avoided in elderly












Amiodarone
Amphetamine
Anorexants
Anticholinergics
Antihistamines
Antispasmodics
Barbiturates
Benzodiazepines
Indomethacin
Bisacodyl
Clonidine
Dessicated thyroid
Fick DM. Arch Intern Med













Disopyridine
Fluoxetine
Ketorolac
Long acting NSAIDs
Meperidine
Meprobamate
Methyldopa
Muscle relaxants
Nifedipine
Nitrofurantoin
Certain Sulfonylureas
Typical antipsychotics
Tricyclic antidepressants
©
What Causes Drug Interactions?
 Age - > 65 have 3 fold increase
 Polypharmacy
 Genetic variability in drug metabolism
 Lack of awareness of CYP450 system
 Protein binding site competition - not
clinically relevant (except in renal failure)
Brown CS, US Pharmacist, 2000
Phase I Drug Oxidation
NADP +
Reduced
Oxidized
Fe
NADPH
Reductase
P450
Oxidized
Reduced
Drug
+
O2
Drug-OH
+
H2O
 Majority of drug interactions occur during phase 1 metabolism
(oxidation, hydroxylation, methylation)
 Phase 2 metabolism prepares the compound for elimination
by making it water soluble (i.e. glucuronidation)
P450 Enzyme System
 Located in liver, kidney, intestine, lungs,
brain
 6 Individual enzymes metabolizing > 95%
of all drugs:
 1A2, 2B6, 2C9, 2C19, 2D6, 3A4
www.fftc.agnet.org/library/image/tb159f1.html
Pharmacogenetic Effect
of Cytochrome Genotypes
©
A. Poor metabolizer (PM)
no functioning alleles
B. Intermediate metabolizer (IM)
Heterozygous for normal and
reduced activity allele
C. Extensive metabolizer (EM)
2 functioning alleles- normal
D. Ultra Metabolizer (UM)
Greatly increased activity due
to 3 or more alleles (2D6
only)
http://www.healthanddna.com/professional/pharmacogeneticsofpain.html
 7-10% of Caucasian
population have
polymorphisms of CYP2D6
isoform
 20-30% Asians CYP2C19
 PM - poor metabolizers
 EM - extensive metabolizers
Number of Subjects
Polymorphic Distribution
PM
EM
URM
 URM - ultrarapid metabolism
Center for Drug Evaluation
and Research.
www.fda.gov
Increasing Metabolic Capacity
Question 4
Genetic variants increase the likelihood of
drug toxicity. Which of the following drugs
have clinically relevant genetic variations in
metabolism?
a)
b)
c)
d)
e)
Warfarin
Clopidogrel
Carbamazepine
Azathioprine
All of the above
Is Pharmacogenomics Important for
Physicians to Know About?
 TMPT (thiopurine
methyltransferase) and
azathioprine >> toxicity
 Enzyme activity absent in
1/300 Caucasians, 1% reduced
 CYP2C9 and VKORC1
warfarin >> hemorrhage
 1-14% caucasians poor
metabolizers (FDA Alert)
 2-3% on Clopidogrel will
lack benefit due to 2C19
 HLA B*1502 and
inactivity
carbamazepine>>Stevens
 UGT inhibition –
Johnson Syndrome (SJS)
lamotrigine and
 Present in 15% of Asians and
valproate >> skin rash
South Asian Indians (FDA Alert)
and SJS
Pharmacogenet. Genomics 2006;16(4):297-306;
http://www.fda.gov/CDER/drug/infopage/carbamazepine/default.htm#top;
http://www.fda.gov/cder/drug/infopage/warfarin/qa.htm; Parmacol Ther 1996;60:145156; Pharmacogenetics 1999;9:37-42. NEJM December 2008
Genetic Testing
 Commercial labs offer analysis of whole
blood for
 1A2, 2D6, 2C9, 2C19
 NAT (“slow acetylators” of isoniazid, others)
 VKORC1
 $200-250/test, $1,250 for the entire panel
 Insurance coverage - ”some do, some don’t”
 Detailed printout of drugs to avoid based on
patient’s genetic polymorphisms
CYP1A2
 15% of all drugs metabolized by CYP1A2
 Genetic polymorphism
 Induced (rapid metabolism) by smoking tobacco
 Omeprazole, rifampin, smoking, char grilled meats
 Substrates  theophylline, tricyclics, clozapine, other antipsychotics,
caffeine, benzodiazepines, zolmitriptan
 Inhibitors  Fluvoxamine, ciprofloxacin, cimetidine
75 Year-Old Male With Seizures






Admitted with COPD exacerbation
Meds; theophylline 300 mg BID
Begun on levaquin for pneumonia
Developed confusion, ataxia, over next two days
Seizure, encephalopathy 3 days after admission
What caused the seizure?
Levaquin/Theophylline Interaction
 Theophylline is
substrate of
CYP1A2
 Fluoroquinolones
are inhibitors of
CYP1A2
 Theo levels
 8.9 mg/dl (12/14)
 16.2 (12/17)
 6.2 (12/18) after
levaquin stopped,
theo held
18
16
14
12
10
8
6
4
2
0
Theo levels
CYP2D6
 25% of all drugs metabolized by CYP2D6
 Significant genetic polymorphism-copies
of alleles
 7-10% of whites are poor metabolizers (≤ 1 allele)
 4% of African-Americans, < 1% of Asians
 1-7% whites, 25% Ethiopians ultrarapid (> 3 alleles)
 Deficient patients cannot metabolize codeine
(no analgesic effect)
 Phenothiazines cannot metabolize, leading to
toxicity at therapeutic doses
CYP2D6
 Substrates
 TCAs, SSRIs,
Venlafaxine,
Phenothiazines,
Risperidone,
codeine, morphine,
tramadol
 Inhibited by:
 SSRIs, Haldol,
thioridazine,
amiodarone,
fluvoxamine
 Induced by:
 None
Codeine intoxication associated with
ultrarapid CYP2D6 metabolism
 62 yo M w/ cough, pneumonia
 PMHx-CLL, Epilepsy, on Valproate
 Begun on ceftriaxone (Rocephin®), clarithromycin
(Biaxin®), voriconazole (Vfend®)
 codeine 25 mg TID for cough suppression
Gasche Y. NEJM 2004;351:2827-2831.
NEJM 2004




Deteriorating LOC, became unresponsive
Glasgow Coma Scale 6/15
pO2 56 mmHg, pCO2 80 mmHg
Recovered after 2 doses naloxone
Codeine metabolism
 Requires 2D6 (to morphine) and 3A4 (to codeine-6 phosphate)
 Normal ratio of codeine to morphine 10 to 1.
 Clarithromycin and voriconazole are potent inhibitors
of 3A4, leaving more codeine available for
conversion to morphine
 Patient had genetic testing showing an additional
allele of 2D6 -> ultrarapid conversion to morphine.
Gasche Y. NEJM 2004;351:2827-2831.
68 Year-Old Male With Neuropathic Pain




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
5 years of severe small fiber neuropathy
Gabapentin 5600 mg day
Tramadol 300 mg day
Acetaminophen 2350 mg day
Duloxetine (Cymbalta®) added 60 mg day
Pain worsens, why?
Duloxetine and Tramadol
 Tramadol converted to morphine by 2D6
 Duloxetine is an inhibitor of 2D6
 Adding duloxetine reduces the efficacy of
tramadol by inhibiting conversion to morphine
Skinner MH, et al. Duloxetine is both an inhibitor and a substrate
of cytochrome P4502D6 in healthy volunteers; Clin Pharmacol
Ther. 2003 Mar;73(3):170-7
Diphenhydramine inhibits metoprolol
metabolism, prolonging negative inotropy
 Benadryl a potent CYP2D6 inhibitor
 Inhibits metoprolol metabolism in extensive (rapid)
metabolizers
 Prolonged the effects of metoprolol due to
inhibited metabolism
Hamelin BA, Bouayad A, Methot J, Significant interaction between the
nonprescription antihistamine diphenhydramine and the CYP2D6 substrate
metoprolol in healthy men with high or low CYP2D6 activity. Clinical
pharmacology and therapeutics. 67(5):466-77, 2000.
2C9
 5-10% on warfarin experience ADRs
 Dominant metabolic enzyme pathway for warfarin
 17% have polymorphisms
 Non-significant increase in INRs in excess of 4
 VKORC1 (Vitamin K epoxide reductase C1)
 14% of whites, no blacks with polymorphisms
 INRs rise 2.5x as fast, and 19% more time in excess of INR > 4
 FDA Alert – VKORC1 and 2C9 mutations need less drug
 30-60% of variability due to 2C9 and VKORC1 mutations
Schwarz UI et al. Genetic determinants of response to warfarin during initial
anticoagulation; N Engl J Med 2008 Mar 6; 358:999
CYP2C19
 Deficient in 15-30%
of Asians
 May lead to benzo
toxicity at usual doses
 Primary metabolism of:
 Diazepam
 Phenytoin
 Omeprazole
 Inhibited by:
 Omeprazole
 Isoniazid
 Ketoconazole
 Induced by
 Carbamazepine
 Rifampin
http://www.esrf.fr/UsersAndScience/Publications/Highlights/ 2003 /MX/MX06;
Ghoneim MM, Clin Pharmacol Ther 1981.
35 yo F with epilepsy
 Topamax 50 BID recently added to regimen of
phenytoin 300 mg daily and carbamazepine ER
400 BID
 Developed ataxia, tremulousness, malaise
 Phenytoin level 29.
 Topiramate is a potent inhibitor of 2C19
metabolism, the primary pathway for phenytoin
metabolism
Caution in Asian populations
 15-30% 2C19 deficient
 - watch diazepam, phenobarbital, primidone
 15% have HLA B*1502 allele
 High risk of Stevens-Johnson (SJS) with
carbamazepine FDA Alert 12/12/07
 SJS 10x more frequent in Asia
Hung, S.I. et al. Genetic susceptibility to carbamazepine-induced cutane
adverse drug reactions. Pharmacogenet. Genomics.2006;16(4):297-306.
http://www.fda.gov/CDER/drug/InfoSheets/HCP/carbamazepineHCP.h
Cytochrome P450 (CYP) 3A4
 Metabolizes 60% of currently available meds
 Ca channel blockers, benzodiazepines, HIV, statins,
cyclosporin, antihistamines, cisapride





No genetic polymorphisms
CYP3A4 is present in intestinal mucosa and liver
Accounts of majority of first-pass metabolism
Induced by St John’s Wort, carbamazepine
Several drugs inhibited by grapefruit juice
(bioflavinoids)
 Amlodipine, lovastatin, buspirone, benzodiazepines
CYP3A4
 Substrates
 Steroids, TCAs, SSRIs, benzodiazepines,
Ca2+ Channel blockers, warfarin, oral
contraceptives
 Inhibitors
 Ketoconazole, metronidazole, AZT,
omeprazole, cimetidine, statins, macrolides,
verapamil, grapefruit juice
 Inducers
 Rifampin, AEDs, dexamethasone, isoniazid
The Grapefruit Effect
 Furanocoumarins in grapefruit inhibit 3A4
 Reduces/eliminates first pass metabolism
Strong
Interaction
diazepam
buspirone
lovastatin
simvistatin
Moderate
Interaction
Nicardipine
felodipine
atorvastatin
vincristine
vinblastine
Weak
Interaction
Sertraline
fexofenadine
omeprazole
guaifenesin
sildenafil
Center for Food-Drug Research and Education, University of Florida
P-Glycoprotein
 Transporter proteins in the small intestine, blood
brain barrier,liver, kidney, gonads
 Encoded by ABCB1 gene, ethnic polymorphisms
 ATP-dependent cell membrane transporter
 Similar substrates, inducers, inhibitors as 3A4
 Example- loperamide, an opioid antidiarrheal,
does not cross the BBB due to P-glycoprotein
 Quinidine inhibits Pgp, leading to respiratory
depression and somnalence from loperamide
toxicity
Sirot EJ. Drug Safety 2006; 29 (9): 735-768
Question 5
Which statement is TRUE of the cytochrome
P450 system?
a. Drug-drug interactions are likely to occur when a
P450 substrate is combined with a P450
inhibitor
b. Anticonvulsants tend to be P450 inhibitors.
c. P450 enzymes are located primarily in the
stomach and small intestine.
d. Cigarette smoking has no effect on drug
metabolism.
DDI: A Stepwise Approach
1. Take a medication history
 Mnemonic; avoid mistakes
2. Identify high risk patients
> 3 medications
 Red flag drugs
anticonvulsants, SSRIs,
antifungals, quinolones,
digoxin, warfarin,
amiodarone
3. Check pocket
reference card
4. Consult pharmacist/
drug specialist
5. Check computer programs
 www.epocrates.com
 Medical letter drug
interaction program
www.fda.gov/cder/drug/drugReactions/default.htm
Mnemonic: Avoid Mistakes
 Allergies?
 Vitamins and dietary supplements
 Grapefruit juice, St Johns Wort, tobacco,
char-grilled meats
 Old drugs and OTC?
 Interactions risk?
 Dependence?
 Mendel: any family history of drug sensitivity
When to suspect a genetic variant
 Pt requires very low doses of coumadin (<5 mg
daily) for therapeutic INR
 Pt receives no analgesia from codeine, tramadol
 Long drug allergy list
 High sensitivity to drugs
Websites on DDI, CYP450, and drug
transporting proteins




http://medicine.iupui.edu/flockhart
www.epocrates.com
http://www.themedicalletter.com/
http://www.druginteractioninfo.org/
Conclusions
 Serotonin syndrome may present with mild
symptoms of tremor confusion, and tachycardia
and is frequently missed
 Drug interactions are extremely common
 An understanding of the P450 system is useful in
predicting who is at risk for drug interactions or
adverse reactions
 Suspect a genetic susceptibility to DDI when





Patients have history of multiple drug sensitivities
Long drug allergy lists
Those who receive no analgesia from codeine
Those on > 4 medications
Asian descent

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