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Drug-Drug Interactions in Mental Illnesses

By Susan Chen, RPh, PharmD, MS, CGP

tsuhuachen@gmail.com

507-301-mtmp(6867)

www.mtmpatmankato.com

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What is drug interaction?

Co-administration of two or more drugs; which has influence on the drug effectiveness, drug metabolism, drug excretion, drug protein binding, and produce adverse drug reactions.

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Change in Mental Health Payment by Provider 1993 vs. 2003

http://www.nimh.nih.gov/statistics/4CHANGE_PROV9303.shtml

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Why drug interactions matter?

Drug interactions contribute about 3-5% of preventable adverse drug reactions in hospital settings(1).
Drug interaction is a significant reason of ER visit (2).

More than 5 drugs taking together increases drug interactions related adverse reaction up to 50 %.

Some drug interactions can be predicted.

1. JAMA 1995;274(1):35–43
2. Eur J Clin Pharmacol 1999;54(12):959–963.

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Drug Interaction Mechanism-�Liver Enzymes p450

There are at least eight liver cytochrome p450 enzymes involved in medication metabolism. Each subtype enzyme will metabolize a group of medications. One medication can be a substrate (the material is metabolized by an enzyme), an inhibitor of the enzyme, or an inducer of the enzyme ---it can be complicated !!!!
% Slower metabolizers of each enzyme are found in various individuals and races due to genetics variation

p450 2 C19 (up to 20% of Japanese and Africa-American are slower metabolizers compared with white population).
P450 2D6: slower metabolizers are more in white than Asians and Africa-Americans.
Variations are even found between persons-personalized regiment

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Drug Interaction Mechanism-Substrate, Inhibitor, and Inducer of CYP 450 Enzymes

Inhibitor, make substrate metabolize slower, and accumulates higher drug concentration

Inducer, make substrate metabolize faster, and accumulates less drug concentration

Inhibitors

Inducers

Substrates

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Drug interaction mechanism-Substrate, inhibitor, and inducer of CYP 450 Enzymes

Inducer: barbiturates, carbamazepine, St. John's Wort, phenytoin, tobacco, and alcohol

Inhibitors

Inducers

Inhibitors:

Fluoxetine, paroxetine, bupropion,

nefazodone, fluvoxamine,

and Grapefruit juice

Substrate

Examples: 2D6 substrate inhibitor (venlafaxine, Effexor), drug concentration will be increased by inhibitor (paroxetine, Paxi), and reduces concentration by inducer (rifampin, Rafadin).

3A4 inhibitors: indinavir, nelfinavir, ritonavir, clarithromycin, itraconazole¹, ketoconazole, nefazodon, saquinavir, suboxon, telithromycin, erythromycin, fluconazole, grapefruit juice� ,verapamil², diltiazem, cimetidine

2C19 inhibitors: PPIs:esomeprazole, lansoprazole,omeprazole, pantoprazole

2D6 inducers:dexamethasone, Rifampin

3A4 inducers:barbiturates, carbamazepine, Glucocorticoids, oxcarbazepine, phenobarbital²,Phenytoin², rifampin¹, St. John's Wort

2C19 inducers: carbamazepine, efavirenz, norethindrone, prednisone, rifampicin¹, ritonavir, St. John's Wort

2D6 substrate:Antidepressants:,amitriptyline, clomipramine, desipramine, fluoxetine, imipramine, paroxetine,venlafaxine

Antipsychotics:haloperidol,perphenazine,risperidone→9-OH,

3A4 substrates:Benzodiazepines:alprazolam, diazepam→3OH, midazolam¹,triazolam ²^,,buspirone, carbamazepine, haloperidol, quetiapine, risperidone, trazodone

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Why Psychiatric Medications (PM) Have Noxious Drug �Interaction Profiles?

1. Most of PM are metabolized by liver enzymes- Cytochrome P450 series. Many of PM are strong substrates and inhibitors of P450>>> over dose and toxic effects are very common.
2. Higher protein binding and metabolism via drug transporters are common in PM>> Adjust dose on plasma protein concentration.
3. PM metabolism heavily rely on liver or renal excretions. Adjust doses are usually necessary based on liver or renal functions. >>>Special alert in elderly population.

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Clinical and Economic Impact of Variation in Psychiatric Medications Metabolism

one meta-analysis demonstrated a reduction in ∼50% in the average dose for most tricyclic antidepressants in patients who are CYP2D6 poor metabolizers (1)
It was estimated from retrospective assessments that patients with psychiatric disorders who are poor or ultra rapid metabolizer of CYP2D6 cost US$ 4000–6000 more per year than extensive metabolizers.(2, 3)
1. . Mol. Psychiatry 2004;9:442-473.
2. Clin Pharmacol Ther 1996; 60: 522–534.
3. J Clin Psychopharmacol 2000; 20: 246–251

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Genomic Tests for Psychiatric Medications

1. CYP 450 2D6
2. CYP 2C19
3. The Serotonin transporter gene (SLC6A4)
4. The Serotonin Receptor 2A gene (HTR2A)
5. The Serotonin Receptor 2C gene ( HTR2C)
6. Dopamine Transporter (DAT)
7. Norepinphrine Transporter ( NET)
8. GABA Transporter 1, 2, 3, 4 (GAT)

Dialogues Clin Neurosci. Mar2010; 12(1): 69-76
Stahl’s Essential Psycopharmacology online, chapter 2

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Examples of Drug �Interactions

Examples

Fluvoxamine (inhibitor of 3A4) and zolpidem (substrate of 3A4)-monitor therapy
Fluvoxamine (inhibitor of 1A2) and cyclobenzaprine (substrate of 1A2)-modify therapy, serotonin syndrome
Fluvoxamine (inhibitor of 1A2) and duloxetine (substrate of 1A2)-modify therapy, serotonin syndrome

Examples

MAOI (selegiline, phenelzine, etc.) and dextromethorphan (OTC antitussive) (X)-Serotonin syndrome
Fluoxetine (long half-life about 4-16 days), highly protein bound (95%), strong 2D6 inhibitor, adjust dose at severe liver and renal functions. Highest QT interval prolonging agents increase risk with other QT prolonging agents (methadone, Haldol, etc.)

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Predictions of SSRI �Drugs Interactions

Drugs/Drugs

SSRI with MAOI or SNRI (X)

Example: fluoxetine and phenelzine, selegiline, or venlafaxine

SSRI with Tricyclic antidepressant (TCA)

Example: amitriptyline and fluvoxamine

Adverse Drug Reactions

Serotonin syndrome

Prolong QT interval (arrhythmia, e.g. Torsades de pointes).
Serotonin syndrome

Selective serotonin reuptake inhibitors: citalopram( Celexa), escitalopram(lexapro), fluoxetine (prozac), fluvoxamine( Luvox), paroxetine (Paxil), sertraline (zoloft), vilazodone (Vilbryd), vortioxetine(Brintella)

MAOImonoamine oxidease inhibitors:isocarboxazid (marplan), phenelzine (Nardil), selegiline (Eldepryl, zelapar),tranylcypromine(Parmate).

SSRI and MAOI Serotonin syndrome:mental change, restlessness, myoclonus, hyperreflexia, diaphoreisis, SNRI:Effexor (venlafaxine), cymbalta (duloxetine)

Tertiary amine TCA: impramine, amitriptyline, trimipramine, doxepin, clomipramine

Secondary amine TCA: desiramine, nortriptyline, and protriptyline

3A4 inhibitors:atazanavir, chloramphenicol, delavirdine, fosamprenavir, indinavir, itraconazole, ketoconazole, lopinavir, nefazodone, nelfinavir, nicardipine, ritonavir, saquuinarvir, voriconazole,clarithromucin,

ACE inhibitors and cough �Antibiotics and diarrhea �β-Blockers and bradycardia �Calcium channel blockers and peripheral edema �Digoxin and nausea �Diuretics and hyponatremia �Diuretics and hypotension �Hypoglycemics and hypoglycemia �Hypoglycemics and tremor �NSAIDs and bleeding �NSAIDs and gastrointestinal tract complaints �NSAIDs and nausea �NSAIDs and renal insufficiency/failure �Opioids and constipation �Proton pump inhibitors and diarrhea �Selected antidepressants and anorexia �Selected antidepressants and constipation �Selected antidepressants and dry mouth �Selected antidepressants and hypotension �Selected antidepressants and insomnia �Selected antidepressants and nervousness �Warfarin and bleeding

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Common Drugs-Diet �Interactions

Drugs-Diet

Grapefruit juice (strong inhibitor of 3A4)- increase AUC (total drug exposure over time) of all 3A4 substrates.
MAOI and foods rich in tyramine, dopamine, tyrosine, trytophan or caffeine

Reactions

Toxic and over dose: buspirone (9-20x) carbamazepine (40%), clomipramine (3x), sertraline, etc.

Hypertension crisis (tyramine toxicity)

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Common Drugs-Diet Interactions

Drugs-Diet

Foods increase AUC: quetiapine (Seroquel), Lurasidone (Latuda) by 2-3 times, ziprasidone (Geodon) by 2 fold

Drug cause weight gain: Olanzapine (Zyprexa)> = TCA>SSRI

What to do?

Take with empty stomach or light meals

BMI at 4, 8, 12 weeks after initial therapy.

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Common Drugs-chronic conditions interactions

Drugs-chronic conditions

Clozapine-concurrent of chemotherapy agents, severe liver, renal impairment, infections, hypotension, agranulocytosis, effects bone marrow functions, and syncope.
Bupropion: severe stroke, seizure, liver impairment
MAOI: hypertension, liver, and renal impairment

Monitor parameters

BP, WBC, vital sign, sign/symptoms of infection(myocarditis), BMI, involuntary movements, A1C, lipid profile.

Mental status, LFT, BP
BP, HR, tyramine-free diet

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Common Drugs-Chronic Conditions Interactions

Drugs-chronic conditions

SSRI- severe liver, renal impairment, risk of seizure, hyponatremia, CYP slow metabolizer, electrolyte imbalance (K and Mg), and elderly.
TCA-Constipation, arrhythmia, gastroparesis, hypotension/hypertension, with other sedatives

Monitor Parameter

QT interval prolonging
Serotonin syndrome
SIADH (syndrome of inappropriate antidiuretic hormone)

Worsen the anticholinergic effects, especially in elderly

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Common Drugs-Disease� Interactions

Drugs-diseases

Need adjust dose by renal function: Lurasidone (Latuda), paliperidone (Invega), risperidone (Risperdal),and lithium

Monitor Parameters

Elderly increase risk sudden death of dementia-related psychosis treatment (cardiovascular diseases).

Example: Ziprasidone (Geodon)

Psychiatry (Edgmont). Oct 2010; 7(10): 25–29.

Published online Oct 2010.

In addition to arrhythmias, other proposed mechanisms for sudden death include the following: 1) peripheral vasodilation leading to cardiovascular collapse,12 2) congestive failure,5 3) respiratory dyskinesia with asphyxia,13 4) oral-laryngeal-pharyngeal dystonia with airway obstruction,14 5) acute myocarditis or cardiac myopathy,15 and 6) infections (e.g., pneumonia).5

Beside cardiac concerns, antipsychotic drugs appear to escalate the risk for cerebrovascular events like syncope and stroke.7,16 Reportedly, there is a 50-percent rise in such adversities among geriatric subjects with dementia when treated with either the first- or second-generation agents.

Thus, patients taking either first- or second-generation antipsychotic drugs have nearly a two-fold increase in the likelihood of sudden cardiac death, and both medication classes evidence an escalating risk at higher doses.5–8 Sudden death also increases with age among geriatric populations.22(5. Wang P, Schneeweiss S, Avorn J, Fischer M. Risk of death in elderly users of conventional vs. atypical antipsychotic medications. N Engl J Med. 2005;353(22):2335–2342. [PubMed]

6. Kuehn B. FDA warns antipsychotic drugs may be risky for elderly. JAMA. 2005;293(20):2462. [PubMed]

7. Gill S, Bronskill S, Rochon P. Antipsychotic drug use and mortality in older adults with dementia. Ann Intern Med. 2007;146:775–786. [PubMed]

8. Ray WA, Chung CP, Murray KT, et al. Atypical antipsychotic drugs and the risk of sudden cardiac death. N Engl J Med. 2009;360:225–235. [PMC free article] [PubMed]; 22. Ballard C, Hanney ML, Theodoulou M, et al. The dementia antipsychotic withdrawal trial (DART-AD): long-term follow-up of a randomized placebo-controlled trial. Lancet Neurol. 2009;8(2):151–157. [PubMed])

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Vulnerable Population of Drug Interactions (Risk factors)

Malnutrition (high protein bound drug-phenytoin)
Liver dysfunctions
Renal dysfunctions
Elderly (lipid soluble and water soluble medications, liver enzymes, renal/liver dysfunctions, and less plasma protein, etc.)
Identify who takes multiple drugs (including over-the-counters and prescriptions).
Identify who takes narrow therapeutic drugs (theophylline, warfarin, carbamazepine etc.)

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Vulnerable Population of Drug Interactions (Risk factors)

Who are slow or ultra-rapid metabolizer
Who has new medications adding to regimen
Who are chronic alcohol or tobacco users (inducer)
Who are illicit drugs users
http://medicine.iupui.edu/clinpharm/ddis/main-table/

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What We Need to Do to Avoid Drug Interactions?�

Understand the medications, knowing potential drug interactions ( prediction).
Simplify drug regimen, simple and effective, lowest effective dose as possible, take away un-unnecessary medications, too high of doses, duplications, right dose interval (between dose timing).
Identify the risk factors of drug

Interaction.

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Comprehensive Medication Review (CMR) Can Help to Reduce Drug Interactions (drug-drug/drug-diet and drug-disease)

CMR can:

1. Monitor side/adverse drug effects, and drug interactions

2. Medication educations

3. Simplify regimens

4. Personalize medication therapy (Effective? Right dose? Timing? Safety? And reduce cost)

5. Screening potential interactions between drug and diet, drug and diseases.

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Summary

More PM are used to treat patients nowadays.
Drug interactions increased along with the number medications (>4 medications / day) .
PM have noxious and complicated drug interactions profile.
Mechanism of drug interactions can be used to predict some of the drug interactions.
Risk factors of drug interactions.
Comprehensive medication review is able to prevent drug-drug, drug-diseases, drug-food interactions, and reduce hospitalization morbidity.