282

Understanding Medication Interactions

11. Pickett P, Masand P, Murray GB: Psychostimulant treatment of geriatric depression disorders secondary to medical illness. J Geriatr Psychiatry Neurol 3(3):146-151, 1990. 12. Spencer T, et al: Pharmacotherapy of attention-deficit hyperactivity disorder across the life cycle. J Am Acad

Child Adolesc Psychiatry 35:409-432, 1996. 13. Woods SW, Tesar GE, Murray GB, Cassem NH: Psychostimulant treatment of depressive disorders secondary to medical illness. J Clin Psychiatry 47:12-15, 1986.

53 . UNDERSTANDING MEDICATION INTERACTIONS

Dee Opp, R.Ph., BCPP,and Lyle Laird, Phccv~zD, BCPP

1. Why are drug interactions important to consider? To maximize therapeutic outcome and minimize adverse side effects, a prescriber needs to understand how a drug works, how it is metabolized, and what side effects are common with the use of the medication. When you consider a new medication for use, you must know how it will interact both dynamically and kinetically with other medications. For example, if a patient is currently on clonidine for hypertension, and a tricyclic antidepressant (TCA) is being considered for therapy, the prescriber should know that the TCA could antagonize the alpha-2 agonist property of the clonidine and negate its antihypertensive effects. This is an example of a pharmacodynamic interaction. Thus, it is important to have an understanding of the mechanisms of action of medications to determine if one is likely to antagonize or block the therapeutic effect of another. In many therapeutic regimens, physicians are faced with using more than one agent to treat or ameliorate symptoms. All combinations need to be assessed for the presence of both kinetic and dynamic interactions. 2. What are the mechanisms of psychotropic medication metabolism? Most of the psychotropic medications are metabolized by a process known as phase I metabolism. This type of metabolism is carried out hepatically by a group of enzymes known as the cytochrome P450 (CYP450) mixed oxidase system. CYP450 enzymes break down the medications into more water-soluble metabolites, which then are more easily excreted into the urine and eliminated from the body. In addition, phase I1 metabolism involves another group of enzymes in the liver. This system primarily results in glucuronidation of drugs, which also allows them to be excreted in the urine. A clinically important example is the interaction between the anticonvulsants, lamotrigine and valproic acid. When these two medications are used together, valproic acid inhibits the phase 11 process of glucuronidation, causing up to a 50% decrease in lamotrigines clearance and a significant increase in its half-life. This effect on the pharmacokinetic parameters of lamotrigine can increase blood levels and, hence, side effects (most significantly, increasing the risk of StevenJohnsons syndrome).

3. Are there other ways medications interact beside via metabolism in the liver?
Medications can interact through multiple mechanisms, and all concurrently. The difficult task is to evaluate which one will influence the success of drug treatment the most. There are two main types of drug interactions: pharmacokineticand pharmacodynamic.Pharmacokinetic interactions involve how one drug influences the normal movement of another drug in the body. For example, one medication may inhibit the absorption of another. Ascorbic acid inhibits the absorption of amphetamines and therefore decreases their effectiveness in the treatment of attention deficit hyperactivity disorder. Another type of interaction is how one medication may influence the

Understanding Medication Interactions

283

volume of distribution of another. If one medication like warfarin is highly protein bound and another highly protein-bound medication is added (e.g., valproic acid or carbamazepine), they could interact via a competition for albumin-binding sites, resulting in a rise in unbound, active components of one of the medications in the blood. If the medication freed from its protein binding sites from this interaction is warfarin, the patient could be at risk for bleeding episodes. With carbamazepine, after the initial increase in blood levels and INR values secondary to protein binding displacement, metabolic effects will occur due to the enzyme induction properties of this anticonvulsant. Warfarin will then be metabolized more readily, and INR values will drop. Valproic acid on the other hand can initially bump INR values and may continue to increase warfarins effect through inhibition of warfarins main route of metabolism (the CYP450 isoenzyme, 2C9). Excretion is another mode of interaction and occurs when one medication interferes with the excretion of another. For example, nonsteroidal antiinflammatory drugs (NSAIDs) inhibit prostaglandin synthesis, which is responsible for normal renal function. If NSAIDs (except sulindac) are used with lithium, one could observe a 30% or higher increase in lithium levels. Given lithiums narrow therapeutic index, such a consequence could result in lithium toxicity. Other medications that also affect lithium disposition in this way are the so-called ACE inhibitors and thiazide diuretics. Mechanisms
PHARMACOKINETIC

ofDrug Interactions
PHARMACODYNAMIC

Absorption Distribution Metabolism (includes the ability of medications to induce or inhibit P-450isoenzymes) Excretion

Duplication in effect or antagonistic interactions between medications Side effects common with medications (can exacerbate or complicate other medical symptoms or disease states)

4. How do patient-specific factors play a role in predicting clinical significance of drug-drug interactions? Age, gender, race, and co-morbid medical conditions can complicate medication outcomes. Age plays an important role in how we choose medications and dose them. The elderly tend to become more easily toxic on water-soluble medications or medications with a low volume of distribution. Hence, lithium should be prescribed in lower doses in a geriatric patient than in a younger patient. These lower than expected doses can readily result in therapeutic blood levels. Blood levels will require closer monitoring. Liver function can be decreased in the elderly, especially phase 1type reactions. If benzodiazepines are used that undergo phase I metabolism (e.g., temazepam), this may cause toxicity and increased risk of falls. Phase I1 reactions such as glucuronidation are usually intact. Lorazepam and oxazepam are better benzodiazepine choices in the elderly because they undergo phase I1 metabolism and have shorter half-lives. Race is also important to consider when prescribing psychotropics. Phase I hepatic metabolism can be influenced by genetic polymorphism of an isozyme. For example, some racial groups are more likely to be poor metabolizers of drugs that require the isozyme, CYP450 2D6. It has been found that 5 1 0 % of Causcasians and I-3% of Asians and African-Americans possess genetic polymorphism for this isozyme. Clinically this could mean that if individuals who are poor metabolizers at CYP450 2D6 are given medications (substrates) that rely on this isozyme for metabolism, they could be at risk for elevated levels of these drugs with the resultant clinical consequences (be that enhanced therapeutic effects or adverse effects and toxicity). Certain antipsychotics (e.g., phenothiazines, clozapine, and risperidone) rely on CYP 2D6 to varying degrees for their metabolism. Another type of a clinically significant CYP450-related interaction is the case of codeine, a prodrug that requires CYP450 2D6 to be metabolized to the active analgesic component. If the 2D6 enzyme is inhibited, for example by a drug such as paroxetine, codeine will not be an effective analgesic medication. Finally, comorbid medical diseases can greatly influence how a patient responds to medication. A patient with impaired renal function clears lithium less effectively than the patient without

284

Understanding Medication Interactions

kidney impairment. In this example, the renally compromised individual has a greatly increased chance of becoming lithium toxic. Similarly, patients with severe liver dysfunction (e.g., cirrhosis) are more likely to become toxic on many medications, since the majority of them rely on intact hepatic function for effective elimination from the body.

5. When assessing patient medication regimens, what are two important mechanisms of metabolic interaction? There are two drug interaction mechanisms that are crucial to determining whether medications will interact. Induction is the propensity of certain substances to increase the production of isozymes in the liver. For example, phenytoin (relying on CYP450 1A2, 2C9, 3A4 for metabolism), carbamazepine (relying on 2C9, 3A4), and phenobarbital (relying on 1A2, 2B6, 2C9, 2C19, and 3A4) are enzyme-inducing antiepileptics. When these medications are used, they increase production of certain subfamilies of isozymes in the liver. This enzyme induction effect reaches its full potential when the inducer medication itself reaches steady-state conditions (based on the half-life of each inducer) and adequate time has elapsed for the new production of enzymes. Carbamazepine, for instance, takes at least 2 weeks to see an induction effect. Other inducers include caffeine ( 1 A2), omeprazole (1A2), nicotine ( I A2), rifampin (2C9, 2C19, 3A4), ritonavir (1A2, 3A4), and phenobarbital ( 1 A2, 2C9, 3A4). Once more enzymes are produced, they metabolize substrates more efficiently, resulting in decreased levels of the substrate compared to the pre-induction period. Thus, to maintain therapeutic effects of the substrate drugs, their doses need to be increased. The opposite hoids true if an inducer is discontinued from a patients regimen, necessitating a reduction in the dose of the substrate medication to avoid potential toxicity. This type of interaction may take awhile to diminish until the inducer is completely eliminated from the body. An example is the discontinuation of carbamazepine from a regimen that includes haloperidol. Once induction has subsided, increased haloperidol blood levels could place the client at greater risk of adverse drug effects. In contrast to induction, inhibition can occur and is usually competitive in nature. It results from one substrate having greater affinity for an isozyme in the liver than another medication. For example, erythromycin is an effective inhibitor of the 3A4 isozyme. If cisapride is given along with erythromycin, the metabolism of cisapride is effectively impaired, resulting in an increased probability of cardiac toxicity, such as Torsades de pointes, from the cisapride. Thus, toxicity of certain medications can be greatly increased by the concomitant administration with medications that inhibit CYP450 isozymes. Inhibition can be immediate, but is dose dependent. The higher the dose of inhibitor, the more likely the interaction with other substrates (medications). The full effect can be seen after one dose, but does not reach full effect until the inhibitor has reached steady-state levels.
6. Discuss the implications of therapeutic index. Therapeutic index refers to the range of blood level concentrations of a medication in which the probability of desired clinical benefits is relatively high and risk of unacceptable side effects (toxicity) is relatively low. A wide therapeutic index is preferable. Not all psychotropic medications have well-established therapeutic indices. Selective serotonin reuptake inhibitors (SSRIs; fluoxetine, sertraline) have broad therapeutic indices; hence, severe toxicity is unlikely. Tricyclic antidepressants (e.g., nortriptyline, imipramine) and lithium carbonate have narrow therapeutic indices; hence, greater caution is needed (e.g., blood level monitoring) to avoid toxicity. It is well established that therapeutic blood levels of lithium of 0.5-1.2 mEq/L are needed for clinical response. This narrow range can easily be exceeded by dehydration, age, or adjunctive medications, resulting in potentially dangerous toxicity.
7. What are common psychotropic drug interactions? Interactions involving the CYP450 system are currently receiving a great deal of attention because of burgeoning discoveries regarding how these metabolic systems function and the potential for drug-drug interactions within these systems. For example, we now know that some of the SSRIs (e.g., fluoxetine, paroxetine) are potent inhibitors of the CYP450, 2D6, and/or CYP450, 3A4 systems.

Understanding Medication Interactions

285

Hence when used concomitantly with medications metabolized by the enzyme systems (e.g., cisapride, nortriptyline, some antipsychotic medications) significant toxicity can occur. With complex, multi-medication regimens it may be prudent to consult with a clinical pharmacist or pharmacologist to understand the relative risks with different drug choices, or if problems arise with side effects. Keeping track of trends in side effects (e.g., time course) after adding a new medication may provide clues to these drug interactions. Educating patients and family members about these risks (including risks with over-the-counter and nontraditional medications) and conferring with other prescribers are essential in providing safe, effective pharmacologic treatment. The following table is not complete, but provides a guideline to assessing potential drug interactions (see next page).

8. How do psychiatrists minimize adverse effects secondary to drug interactions? As a rule of thumb, it is prudent to add only one medication at a time. While in practice this is often difficult to do given the enormous number of variables with any given patient, it does allow the practitioner to observe which medication is working while minimizing chances of drug-drug interactions. Likewise, it is advisable to titrate dosages of only one medication at a time. If one medications dosage has been maximized for an adequate period of time but the patient is not clinically benefitting, consider the possibility of a drug-drug interaction complicating the situation. When you find yourself adding medications to treat side effects, always ask yourself if lowering or discontinuing another medication is warranted before the addition. Consider antidepressant-induced sleep disturbance. If a patient being treated for depression is complaining of sleeplessness, evaluate drug-induced reasons for this occurrence as well as sleep hygiene issues before the addition of a sleep medication. The reason may be as simple as changing the time of administration of a medication. For example, fluoxetine, bupropion, and venlafaxine should not be given at bedtime secondary to the risk of activation and insomnia. The addition of another medication is prevented which in turn decreases the likelihood of drug-drug interactions.
BIBLIOGRAPHY 1. Anderson G: A mechanistic approach to antiepileptic drug interactions. Ann Pharmacother 32554-563, 1998. 2. Evans WE, Schentag JJ, Jusko WJ: Applied Pharmacokinetics, 3rd ed. Vancouver, Washington Applied Therapeutics, Inc., 1992. 3. Jefferson J: Drug interactions-Friend or foe? J Clin Psychiatry 59(suppl4):3747, 1998. 4. Michalets EL: Update: Clinically significant cytochrome P-450 drug interactions. Pharmacotherapy 18(1):83112, 1998. 5 . Shen W The metabolism of psychoactive drugs: A review of enzymatic biotransformations and inhibition. Biol Psychiatry 41:814-826, 1997. 6. Winans E, Cohen L: Assessing the clinical significance of drug interactions in psychiatry. Psychiatric Ann 28(7):399405, 1998.

Potential DruR Interactions

SUBSTRATES INHIBITORS INDUCERS

ISOENZYME

CYPIA2

Caffeine * Clomipramine Clozapine Cyclobenzaprine Fluvoxamine * Imipramine

Methadone (racemic mix) Mirtazapine Olanzapine Ondansetron Propranolol Sibutramine

Tacrine * Tamoxifen Theophylline R-Warfarin Valproic acid Zileuton

Isoniazid (INH) Mexilitine Norethindrone Tacrine Verapamil Zileuton Itraconazole Ketoconazole Metronidazole Ritonavir Sulfinpyrazone Ticlopidine Zafirlukas t Omeprazole Paroxe tine Sertraline Ticlipodine Tranylcypromine Barbiturates Carbamzepines Phenytoin Primidone Rifampin

Caffeine & Smoking Charcoal-broiled meat Cruciferous Veggies Omeprazole Phenytoin & Barbiturates Ritonavir

CYP2C9 Genetic Polymor-phisrn: I-3% Caucasians & 18% AA

Clozapine Diclofenac Dronabinol Fluvastin Glipizide Ibuprofen Omeprazole * Pentamidine Propranolol R-Warfarin Valproic acid Citalopram Felbamate Fluconazole Fluoxetine Fluvoxamine Amiodarone Cimetidine Citalopram (weak) Fluoxetine Fluphenazine * Haloperidol Methadone Paroxetine

Indomethacin Losartan Naproxen Nelfinavir Phenytoin Piroxicam

S i butramine Tolbutamide Torsemide S-Warfarin * potent anticoagulant form * Valproic acid

Cimetidine Ciprofloxacin Disulfiram Ethinyl Estradiol Fluvoxamine Grapefruit Juice Cimetidine Cotrimoxazole Disulfiram Fluconazole Fluoxetine Fluvoxamine Isoniazid (INH) Rifampin

CYP2C19 Genetic Polyrnorphism: 18-20% Asians & 3-5% Caucasians

* Amitriptyline Carispodol Chlordiazepoxide Citalopram * Clomipramine

Clorazepate Diazepam * Imipramine Lansoprazole Mephenytoidphenytoin

CYP2D6 Not liver specjfic, extrahepatic locations include the brain

Genetic Polymorphism: 5-10% Caucasians & l-3% Asians/AA

* Perphenazine Propafenone Propoxyphene * Quinidine Ramitidine Ritonavir Sertraline (weak) Yohimbine * Thioridazine
Oxycodone Olanzapine Paroxitine * Perphenazine Propafenone Propranolol * Risperidone Sertraline * Thioridazine Tramadol Trazodone Venlafexine

Note: CYP2D6 appears to be relatively resistant to enzyme induction

* Amitriptyline Buspirone (&3A4) Carvedilol Citalopram (minor) * Clomipramine Clozapine Codeine-Morphine (prodwid * Despiramine Dextromethorphan Donepad(& 3A4) Fluoxetine

Fluvoxamine * Haloperidol Hydrocodone * Irnipramine * Maprotiline Methamphetamine Metoprolol Mexilitine Mirtazapine m-CCP (metabolite of nefazadone & trazodone) * Nortriptyline

Table continued on following page

Potential Drug Interactions (Continued)

SUBSTRATES 1NHIBITORS INDUCERS
~~ ~

ISOENZYME

CYP3A4 Most abundant in liver and intestinal mucosa

No genetic polymorphism known

5 a
n

Alfentanil Alprazolam Amlodipine Amiodarone Atorvastatin * Bedepril Bromocryptine Carbarnazepine Chlordiazepoxide * Cisupride Ci talopram Clarithromycin Clorazepate Clozapine Cocaine & metabolite Cyclophosphamide Cyclosporine Dupsone Delaviridine Dexamethasone Diazepam Diltiazem Disopyramide Doxorubicin Ergotamine

* Erythromycin Ethinyl Estradiol Etoposide Felodipine Fexofenadine Fentanyl Finasteride Flutamide Ifosfamide (podrug) Indinavir Isradipine Itraconazole Ketoconazole Lidocaine Loratidine Losartan Lovastatin Methadone Methy lprednisolone Miconazole Miduzolam Nefazodone Nicardipine Nifedipine Nimodipine
Nisoldipine Nitrendipine Paclitaxel * Pimozide Prednisolone Quetiapine * Quinidine Quinine Rifabutin Ritonavir Saquinavir Sertraline Sibutrumine Sildenafil Simvastatin Tacrolinus + Tamoxifen Testosterone Trazadone Triuzolam Verapurnil Vinblastine Vincristine R-Warfarin Ziprasidone Zolpidem Cimetidine Clarithrom ycin Cyclosporin Danazol Delaviridine Diltiazem Erythromycin Ethinyl Estradiol Fluconazole (weak) Fluoxetine Fluvoxamine Grapefruit juice Indinavir Isoniazid Itraconazole Ketoconazole Methadone Metronidazole Methylprednisolone Mibefradil Miconazole Nefazodone Nelfinavir Nicardipine Nifedipine Norethindrone Norfloxacin Norfluoxetine (Prozac metb) Omeprazole Oxicanozxole Prednisone Quinine Ritonavir Saquinavir Troleandom y cin UAO) Valproic acid Inhibits 2C9 and 2C129 & epoxide hydrolase Verapamil Zafirlukast

Aminoglutethimide Barbiturates Carbamazepine Dexamethasone Efavirenz Ethanol (with chronic use) Glutethimide Griseofulvin Nafcillin Nalfinavir Nevirapine Phenytoin Primidone Rifabutin Rifampin Ritonavir

% -.

0 I

~~~

~~~

Italic substrate =main route of metabolism Boldface = drug is a potent inhibitor * = risk of QTc prolongation