Libby Zion’s Lesson: Serotonin Syndrome

and P450 Drug Interactions

Laurence J. Kinsella, MD, FAANSSM St Clare

Neuroscience InstituteSaint 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

In 1984, a young woman died from a fatal drug-drug 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?

Question 1

a. Haloperidol and Chlorpromazine - Neuroleptic malignant Syndrome

b. Penicillamine and Gentamicin - Myasthenic Crisis

c. Phenelzine and meperidine - Serotonin Syndrome

d. Carbamazepine and acetaminophen - Stevens Johnson Syndrome

Case 1: 54 Year-Old Female

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 Trazodone (Desyrel®)

Clonazepam (Klonopin®) Venlafaxine (Effexor®) Citalopram (Celexa®) Risperidone (Risperdal®) Aripiprazole (Abilify®) Olanzapine (Zyprexa®) Chlorpromazine (Thorazine®) Oxcarbazepine (Trileptal®)

Exam - resting tachycardia 104 bpm

Fine tremor in hands MMSE - 12/27

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: Clinical Features

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 sampleshttp://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;351:1829-1837Landrigan 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

Boyer, E. W. et al. N Engl J Med 2005;352:1112-1120

Spectrum of Clinical Findings

Akathisia, restlessness

Tremor

Altered mental status

Hypertonicity

Multifocal myoclonus

Coma

Hyperthermia

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 warning re. Triptans and SSRIs 2006; http://www.fda.gov/cder/drug/InfoSheets/HCP/venlafaxineHCP.pdf

† FDA boxd warning 2/26/09 – Long-term or high-dose use of metoclopramide has been linked to tardive dyskinesia

The serotonin syndrome and neuroleptic malignant syndrome are distinguished by all of the following EXCEPT:

Question 2

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

Time Needed

Vital signs Bowel sounds

Serotonin

syndrome

Pro

serotonergic

drug

< 12 hours Hypertension, tachycardia, tachypnea, hyperthermia

Hyperactive

Neuroleptic

malignant

syndrome

Dopamine

antagonist

1-3 days Hypertension, tachycardia, tachypnea, hyperthermia

decreased

SS vs NMS

Condition Mental Status

Pupils Neuromuscular tone

Reflexes

Serotonin

syndrome

Agitation, coma

Mydriasis Increased, mainly in lower extremities

Hyperreflexia, clonus

Neuroleptic

malignant

syndrome

Stupor, alert mutism, coma

normal 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)

The following are true statements about drug interactions EXCEPT:

Question 3

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 drugshttp://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 CriteriaHgh Severity: Should be avoided in elderly

Amiodarone Amphetamine Anorexants Anticholinergics Antihistamines Antispasmodics Barbiturates Benzodiazepines Indomethacin Bisacodyl Clonidine Dessicated thyroid

Disopyridine Fluoxetine Ketorolac Long acting NSAIDs Meperidine Meprobamate Methyldopa Muscle relaxants Nifedipine Nitrofurantoin Certain Sulfonylureas Typical antipsychotics Tricyclic antidepressants

Fick DM. Arch Intern Med 2003;163:2716

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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

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)

NADP +

NADPH Oxidized

Fe

P450

Oxidized

Reductase

Reduced

Reduced Drug-OH+

H2O

Drug+O2

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

http://www.healthanddna.com/professional/pharmacogeneticsofpain.html

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 dueto 3 or more alleles (2D6 only)

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Polymorphic Distribution

7-10% of Caucasian population have polymorphisms of CYP2D6 isoform

20-30% Asians CYP2C19 PM - poor metabolizers EM - extensive metabolizers URM - ultrarapid metabolism

Center for Drug Evaluation and Research.

www.fda.gov

Increasing Metabolic Capacity

URMEMPMNu

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Genetic variants increase the likelihood of drug toxicity. Which of the following drugs have clinically relevant genetic variations in metabolism?

Question 4

a) Warfarin

b) Clopidogrel

c) Carbamazepine

d) Azathioprine

e) 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

HLA B*1502 and carbamazepine>>Stevens Johnson Syndrome (SJS) Present in 15% of Asians and

South Asian Indians (FDA Alert)

CYP2C9 and VKORC1 warfarin >> hemorrhage 1-14% caucasians poor

metabolizers (FDA Alert)

2-3% on Clopidogrel will lack benefit due to 2C19 inactivity

UGT inhibition – lamotrigine and valproate >> skin rash 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;60:145-156; 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

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12/1

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6/20

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7/20

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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

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

http://www.fda.gov/CDER/drug/InfoSheets/HCP/carbamazepineHCP.htm

Hung, S.I. et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet. Genomics.2006;16(4):297-306.

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

Moderate Interaction

Weak Interaction

diazepam buspirone lovastatin simvistatin

Nicardipine felodipine atorvastatin vincristine vinblastine

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

Which statement is TRUE of the cytochrome P450 system?

Question 5

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