The following article on pharmacology are detailed and technical and may be unnecessarily complex for some visitors to this site.
Nonetheless because the use of multiple medications has become the standard of care for bipolar disorder, both in children and in adults, it may be important for some parents or professionals to master these complexities in order to understand what makes some combinations safe and others dangerous.
In most cases the prescribing physician or the pharmacist can give you a warning about drugs that interact dangerously. Still, some parents want to know for themselves.
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DRUG INTERACTIONS
Part I: METABOLISM OF PSYCHIATRIC MEDICATIONS
The CYP-450 System:
For the most part, psychiatric drugs are metabolized in the liver. In order to be psycho-active a drug must have a certain chemical activity and must be partially fat soluble, so it can pass through the blood-brain barrier and on into the central nervous system where it can affect the action of neurons.
Metabolism in the liver inactivates and eliminates a drug: that is, the enzymes in the liver change a drug’s chemical activity and make it water soluble in preparation for elimination either by the kidneys in urine or in the bowel in feces.
There are, however, different pathways for the metabolism of different drugs. One set of pathways is made up of an array of different enzymes, present in the gut and the liver, known as the CYP-450 system. Different drugs are metabolized by different CYP-450 enzymes, and some drugs are metabolized by more than one enzyme. When several medications are being used, it is important to know if their metabolisms interact in some way: to know if one drug slows down, inhibits, or speeds up the metabolism of the other.
Below is a chart showing some of the most important CYP-450 Enzymes and the drugs they metabolize. The chart also indicates which drugs inhibit the enzyme and which drugs induce an enzyme.
- If two drugs are metabolized by the same enzyme they compete for metabolism. The drugs must take turns with one another, waiting on line to be metabolized.
- If one drug inhibits the enzyme, the line moves more slowly for that drug and for any other drug metabolized by that enzyme.
- If a drug induces the enzyme the line moves more quickly for that drug and any other drug metabolized by that enzyme.
- An enzyme can also be inhibited or induced by a substance that is not usually considered to be a drug: for example grapefruit juice strongly inhibits one enzyme (3A4) and cigarette smoke induces another (1A2).
When an enzyme is inhibited or when two drugs compete for metabolism the circulating levels of those drugs go up. In some cases this can be dangerous or uncomfortable, so the dose of one or both medications may need to be lowered.
When an enzyme is induced, the circulating levels of drugs metabolized by that enzyme fall. That fall can cause a medication to lose its therapeutic effect. So the dose of those drugs metabolized by the enzyme may need to be raised.
For example:
Fluoxitine (Prozac) strongly inhibits the enzyme (2D6) that metabolizes metoprolol (Lopressor) a drug that lowers blood pressure and slows heart rate. The combination of these drugs will cause an increase in the level of metoprolol and consequently lower blood pressure; the increased level of metoprolol will also slow the heart rate possibly leading to a dangerously low blood pressure and even circulatory collapse.
Carbamazepine (Tegretol) induces the enzyme (2D6) that metabolizes hormones contained in oral contraceptives. When carbamazepine is combined with an oral contraceptive in a sexually active woman an unexpected pregnancy can occur.
Grapefruit juice strongly inhibits an enzyme (3A4) that metabolizes erythromycin and a similar antibiotic clarithromycin (Biaxin). If the level of either of those medicines is raised sharply nausea and vomiting can result, which can be uncomfortable but not dangerous.
In order to use the chart:
- Locate the medications being used (generic names are given).
- Determine if they are metabolized by the same enzyme (compete).
- or if one inhibits or induces another’s metabolism
- This can be done with two or three or more medications.
- If more information is desired use the links below the chart.
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METABOLISM BY CYTOCHROME P450 ENZYMES
(an asterisk * indicates a drug is metabolized by more than one enzyme)
| 1A2 | 2C9 | 2C19 | 2D6 | 2E1 | 3A4 |
| PSYCHOACTIVEAntidepressantsamitriptyline*
clomipramine* fluvoxamine* imipramine=>N-DeMe* Major Tranquilizers clozapine* haloperidol* olanzepine* ——- cyclobenzaprine riluzole verapamil* OTHER SUBSTRATES: acetaminophen- =>NAPI* caffeine estradiol* mexilletine naproxen ondansetron phenacetin=> propafenone* propranolol* ropivacaine tacrine theophylline * tizanidine (R)warfarin zileuton zolmitriptan propranalol* theophyll INDUCED BY broccoli brussel sprouts chargrilled-meat insulin methyl- cholanthrene modafinil nafcillin beta-naptho-flavone omeprazole tobacco INHIBITED BY amiodarone cimetidine ciprofloxacin fluoro-quinolones furafylline interferon methoxsalen mibefradil |
PSYCHOACTIVE Antidepressantsamitrypteline*
fluoxitene* OTHER SUBSTRATES: NSAIDs: diclofenac ibuprofen lornoxicam meloxicam S-naproxen piroxicam suprofen tenoxicam Oral Hypoglycemic Agents: tolbutamide glipizide Angiotensin II Blockers: losartan* irbesartan Sulfonylureas: glyburide glibenclamide glipizide glimepiride tolbutamide celecoxib fluvastatin glyburide nateglinide phenytoin=>4-OH rosiglitazone tamoxifen torsemide S-warfarin dapsone INDUCED BY rifampin secobarbital INHIBITED BY amiodarone fenofibrate fluconazole fluoxitine 2+ fluvastatin fluvoxamine isoniazid lovastatin phenylbutazone probenicid sertraline sulfamethoxazole sulfaphenazole teniposide voriconazole zafirlukast |
PSYCHOACTIVE Antidepressantsamytriptyline*citalopram clomiprimine* escitalopram imiprimine=>N-DeMe* meclobemide ——- hexobarbital R-mephobarbital omeprazole progesterone Anti-epileptics carbamazepine* diazepam=>Nor* oxcarbamazepine* phenytoin(O) S-mephenytoin phenobarbitone primidone OTHER SUBSTRATES: lansoprazole omeprazole pantoprazole rabeprazole E-3810 carisoprodol cyclophosphamide indomethacin nelfinavir nilutamide progesterone proguanil propranalol* teniposide R-warfarin=>8-OH tolbutamid INDUCED BY carbamazepine norethindrone prednisone rifampin INHIBITED BY amiodarone bupropion celecoxib chlorpromazine chlorpheniramine cimetidine citalopram clomipramine cocaine doxepin doxorubicin duloxetine escitalopram fluoxetine halofantrine red-haloperidol levomepromazine metoclopramide methadone mibefradil midodrine moclobemide paroxetine perphenazine quinidine ranitidine ritonavir sertraline terbinafine ticlopidine Antihistamines diphenhydramine chlorpheniramine* clemastine hydroxyzine tripelennamine cimetadine felbamate fluoxitine 1+ fluvoxamine 4+ indomethacin ketoconazole modafanil |
PSYCHOACTIVE amphetamineAntidepressants
amitriptyline* clomiprimine* desiprimine duloxetine fluoxitine* fluvoxamine* imiprimine nortriptyline paroxitine venlafaxin Major Tranquilizers chlorpromazine haloperidol* perphenazine quietapine risperidone=>9OH thioridazine zuclopenthixol OTHER SUBSTRATES: Beta Blockers: alprenalol carvedilol S-metoprolol propafenone timolol atomoxetine bufuralol chlorpheniramine* codeine* (=>O-desMe) debrisoquine dexfenfluramine dextromethorphan* encainide flecainide lidocaine metoclopramide methoxy- amphetamine mexilletine minaprine nebivolol ondansetron oxycodone perhexiline phenacetin phenformin promethazine propafenone* propranolol* quanoxan sparteine tamoxifen tramadol INDUCED BY dexamethasone rifampin INHIBITED BY amiodarone bupropion2+ celecoxib chlorpromazine chlorpheniramine cimetidine citalopram clomipramine cocaine doxepin doxorubicin duloxetine 2+ escitalopram fluoxetine 4+ halofantrine red-haloperidol levomepromazine metoclopramide methadone mibefradil midodrine moclobemide paroxetine 4+ quinidine ranitidine ritonavir sertraline 1+ terbinafine ticlopidine Antihistamines diphenhydramine chlorpheniramine clomastine perphenazine hydroxyzine tripelennamine |
PSYCHOACTIVE ethanolAnesthetics
enflurane halothane isoflurane methoxyfluranes evoflurane ——- acetaminophen* =>NAPQI aniline benzene chlorzoxazone N,N-dimethyl formamide theophylline=>8-OH* INHIBITORS diethyl- dithiocarbamate disulfiram INDUCERS ethanol isoniazid |
PSYCHOACTIVE Antidepressantssertraline*
St. John’s Wort trazodone Minor Tranquilizers alprazolam diazepam*=>3OH midazolam triazolam Hypnotics (for sleep) zaleplon zolipidem Major Tranquilizers aripiprisol haloperidol* quietepine risperidone ziprasidone pimozide Anti-epileptics carbamazepine* zonisamide tiagabine ——- buspirone Narcotics fentanyl methadone* OTHER SUBSTRATES: Macrolide antibiotics: clarithromycin erythromycin telithromycin Anti-arrhythmics: quinidine=>3-OH Immune Modulators: cyclosporine tacrolimus-(FK506) HIV Antivirals: indinavir nelfinavir ritonavir saquinavir Prokinetic: cisapride Antihistamines: astemizole* chlorpheniramine* terfenidine Calcium Channel Blockers: amlodipine diltiazem felodipine lercanidipine nifedipine nisoldipine nitrendipine verapamil* HMG CoA Reductase Inhibitors: atorvastatin cerivastatin lovastatin simvastatin Steroid6beta-OH: estradiol* hydrocortisone progesterone* testosterone Miscellaneous: alfentanyl aprepitant cafergot caffeine=>TMU cilostazol cocaine codeine-N-demethylation dapsone dextromethorphan docetaxel domperidone eplerenone fentanyl finasteride gleevec irinotecan LAAM lidocaine methadone nateglinide odanestron propranolol quinine salmeterol sildenafil sirolimus tamoxifen taxol vincristine vinblastin INDUCED BY HIV Antivirals: efavirenz nevirapine ——- barbiturates Anticonvulsants carbamazepine phenetoin phenobarbitol oxcarbamazepine ——- glucocorticoids dexamethasone modafanil pioglitazone rifampin rifabutin St John’s Wort troglitazone INHIBITED BY Grapefruit juice 4+ Star Fruit 4+ Antidepressants norfluoxetine fluvoxamine delaviridine indinavir nelfinavir ritonavir ——- Macrolid Antibiotics Antifungals fluconazole voriconazole ——- amiodarone aprepitant chloramphenicol cimetidine diethyl- dithiocarbamate diltiazem gestodene imatinib mifepristone norfloxacin mibefradil verapamil |
Click Here for a thorough Guide to the CPY-450 System
Cick Here for a Guide to the Names and Properties of Drugs
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