SELECTED LIST OF DRUG-INDUCED EFFECTS

The following list of selected drug-induced side effects has been compiled for use in conjunction with the drug interactions section of USP DI monographs. This listing gives examples of certain substances that may contribute to additive effects of the medication being referred to where such an effect has been identified as posing a potential clinically significant problem with the concurrent use of two or more medications. The listing of drugs is not meant to be inclusive.

Anticholinergics

Anisotropine
Atropine
Belladonna
Clidinium
Dicyclomine
Glycopyrrolate
Homatropine
Hyoscyamine
Ipratropium
Mepenzolate
Methantheline
Methscopolamine
Pirenzepine
Propantheline
Scopolamine
Other medications with anticholinergic activity
Antihistamines, H1-receptor (except for non-sedating ones)
Benztropine
Biperiden
Buclizine
Carbamazepine
Clozapine
Cyclizine
Cyclobenzaprine
Digoxin
Disopyramide
Dronabinol
Ethopropazine
Loxapine
Maprotiline
Meclizine
Molindone
Orphenadrine
Oxybutynin
Phenothiazines
Pimozide
Procainamide
Procyclidine
Quinidine
Trihexyphenidyl
Thioxanthenes

Blood dyscrasia–causing medications—Defined as those drugs causing unpredictable myelotoxicity that usually occurs in a minority of patients and is not dose-dependent

Acetazolamide
Alemtuzumab
Aminopyrine
Amodiaquine
Amphotericin B lipid complex
Angiotensin-converting enzyme (ACE) inhibitors
Anticonvulsants, hydantoin
Anticonvulsants, succinimide
Antidepressants, tricyclic
Antidiabetic agents, sulfonylurea
Anti-inflammatory drugs, nonsteroidal (NSAIDS), especially phenylbutazone
Antithyroid agents
Bexarotene
Carbamazepine
Cetirizine and Pseudoephedrine
Chloramphenicol
Clozapine
Dapsone
Divalproex
Epirubicin
Felbamate
Flecainide
Foscarnet
Gemtuzubam Ozogamicin
Gold compounds
Levamisole
Loxapine
Maprotiline
Mirtazapine
Peginterferon alfa-2B
Penicillamine
Pentamidine
Phenothiazines
Pimozide
Primaquine
Primidone
Procainamide
Propafenone
Propylthiouracil
Pyrimethamine (with high doses)
Rifampin
Rifapentine
Rituximab
Sulfasalazine
Sulfamethoxazole and Trimethoprim
Sulfonamides, systemic
Temozolomide
Thioxanthenes
Ticlopidine
Tiopronin
Tocainide
Trastuzumab
Trimethobenzamide
Trimethoprim
Valproic acid

Bone marrow depressants—Defined as those drugs producing a predictable dose-related myelotoxicity

Abacavir, Lamuvudine and Zidovudine
Aldesleukin
Altretamine
Amphotericin B, systemic
Amphotericin B cholesteryl complex
Amphotericin B lipid complex
Amphotericin B liposomal complex
Anastrazole
Azathioprine
Bexarotene
Busulfan
Capecitabine
Carboplatin
Carmustine, systemic
Chlorambucil
Chloramphenicol
Clozapine
Cisplatin
Cladribine
Colchicine
Cyclophosphamide
Cytarabine
Dacarbazine
Dactinomycin
Daunorubicin
Daunorubicin, liposomal
Didanosine
Docetaxel
Doxorubicin
Doxorubicin, liposomal
Eflornithine
Epirubicin
Etoposide
Floxuridine
Flucytosine
Fludarabine
Fluorouracil, systemic
Ganciclovir
Gemcitabine
Gemtuzumab Ozogamicin
Hydroxyurea
Idarubicin
Ifosfamide
Imatinib
Interferon, gamma
Interferons, alpha
Irinotecan
Lomustine
Mechlorethamine, systemic
Melphalan
Mercaptopurine
Methotrexate
Mitomycin
Mitoxantrone
Paclitaxel
Pegaspargase
Pentostatin
Plicamycin
Procarbazine
Sodium iodide I 131
Sodium phosphate P 32
Strontium 89 chloride
Streptozocin
Temozolomide
Teniposide
Thioguanine
Thiotepa
Topotecan
Trimetrexate
Uracil mustard
Valganciclovir
Valrubicin
Vidarabine, systemic (with high doses)
Vinblastine
Vincristine
Vinorelbine
Zidovudine
Zidovudine and Lamivudine
Zoledronic Acid

CNS depression–producing medications

Alcohol
Aminoglutethimide
Anesthetics, general
Anesthetics, parenteral-local
Anticonvulsants
Antidepressants, monoamine oxidase (MAO) inhibitor
Antidepressants, tricyclic
Antidyskinetics (except amantadine)
Antihistamines, H1-receptor (except cetirizine, fexofenadine, and loratadine)
Apomorphine
Azelastine
Baclofen
Barbiturates
Benzodiazepines
Beta-adrenergic blocking agents
Brimonidine
Buclizine
Carbamazepine
Cetirizine (dose related)
Cetirizine and Pseudoephedrine (dose related)
Chlophedianol
Chloral hydrate
Chlorzoxazone
Clonidine
Clozapine
Cyclizine
Difenoxin and atropine
Diphenoxylate and atropine
Disulfiram
Donepezil
Dronabinol
Ethchlorvynol
Ethinamate
Etomidate
Glutethimide
Guanabenz
Guanfacine
Haloperidol
Hydroxyzine
Ifosfamide
Interferons
Ketamine
Levomethadyl
Loratadine (dose related)
Loxapine
Magnesium sulfate, parenteral
Maprotiline
Meclizine
Meprobamate
Methyldopa
Methyprylon
Metoclopramide
Metyrosine
Mirtazapine
Mitotane
Molindone
Nabilone
Nefazodone
Olanzapine
Opioid (narcotic) analgesics
Oxcarbazepine
Paraldehyde
Paregoric
Pargyline
Peginterferon alfa-2B
Phenothiazines
Pimozide
Procarbazine
Promethazine
Propiomazine
Propofol
Quetiapine
Rauwolfia alkaloids
Risperidone
Scopolamine
Skeletal muscle relaxants (centrally acting)
Thalidomide
Thioxanthenes
Trazodone
Trimeprazine
Trimethobenzamide
Zolpidem

CNS stimulation–producing medications

Amantadine
Amphetamines
Anesthetics, local
Appetite suppressants, sympathomimetic
Bronchodilators, theophylline
Bupropion
Caffeine
Chlophedianol
Cocaine
Corticosteroids (in moderate to large doses)
Doxapram
Dronabinol
Dyphylline
Fluoroquinolones
Meropenem
Methylphenidate
Modafinil
Nabilone
Pemoline
Selegiline
Sympathomimetics

Enzyme inducers, hepatic, cytochrome P450

Alcohol (with chronic use)
Aminoglutethimide
Barbiturates, especially phenobarbital
Carbamazepine
Efavirenz
Glutethimide
Griseofulvin
Modafinil
Nevirapine
Phenylbutazone (mixed inducing and inhibiting effect)
Phenytoin (and possibly other hydantoins)
Primidone
Rifabutin
Rifampin
Rifapentine
Troglitazone

Enzyme inhibitors, hepatic, various

Note: The following agents may affect single or multiple enzymes.
Alcohol (with acute, high-dose use)
Allopurinol
Antidepressants, monoamine oxidase (MAO) inhibitor
Antifungals, azole
Chloramphenicol
Cimetidine
Clarithromycin
Contraceptives, estrogen-containing, oral
Diltiazem
Disulfiram
Divalproex
Efavirenz
Erythromycins
Fluoroquinolones
Fluoxetine
Fluvoxamine
Indinavir
Isoniazid
Letrozole
Metoprolol
Mibefradil
Modafinil
Nefazodone
Nelfinavir
Omeprazole
Paroxetine
Phenylbutazone (mixed inducing and inhibiting effect)
Propranolol
Quinidine
Quinupristin and Dalfopristin
Ritonavir
Saquinavir
Sertraline
Tamoxifen
Valproic acid
Venlafaxine
Verapamil

Extrapyramidal reaction–causing medications

Amoxapine
Haloperidol
Loxapine
Metoclopramide
Metyrosine
Molindone
Olanzapine
Phenothiazines
Pimozide
Rauwolfia alkaloids
Risperidone
Tacrine
Thioxanthenes

Folate antagonists

Anticonvulsants, hydantoin
Anticonvulsants, succinimide
Divalproex
Methotrexate
Phenobarbital (with long-term use)
Pyrimethamine
Sulfonamides
Triamterene (with high doses or prolonged use)
Trimethoprim
Trimetrexate
Valproic acid

Hemolytics

Acetohydroxamic acid
Antidiabetic agents, sulfonylurea
Doxapram
Furazolidone
Mefenamic acid
Menadiol
Methyldopa
Nitrofurans
Primaquine
Procainamide
Quinidine
Quinine
Sulfonamides, systemic
Sulfones

Hepatotoxic medications

Abacavir, Lamivudine and Zidovudine
Acetaminophen (with long-term, high-dose use or acute overdose)
Acitretin
Alcohol
Aldesleukin
Amiodarone
Amsacrine
Anabolic steroids
Androgens
Angiotensin-converting enzyme (ACE) inhibitors
Anti-inflammatory drugs, nonsteroidal (NSAIDS)
Asparaginase
Bexarotene
Carbamazepine
Carmustine
Cytarabine
Dantrolene
Dapsone
Daunorubicin
Disulfiram
Divalproex
Epirubicin
Erythromycins
Estrogens
Ethionamide
Etretinate
Fat emulsions, intravenous (with prolonged use)
Felbamate
Fluconazole
Flutamide
Gold compounds
Halothane
HMG-CoA reductase inhibitors
Imatinib
Iron (overdose)
Isoniazid
Itraconazole
Ketoconazole, oral
Labetalol
Mercaptopurine
Methimazole
Methotrexate
Methyldopa
Metronidazole
Naltrexone (with long-term, high-dose use)
Nevirapine
Niacin (with high doses, sustained release, and antihyperlipidemic use)
Nilutamide
Nitrofurans
Pemoline
Phenothiazines
Phenytoin
Plicamycin
Propylthiouracil
Rifampin
Rosiglitazone
Sulfamethoxazole and Trimethoprim
Sulfonamides, systemic
Tacrine
Tenofovir
Tizanidine
Tolcapone
Toremifene
Tretinoin
Troleandomycin
Valproic acid
Vitamin A (with chronic overdose)
Zidovudine
Zidovudine and Lamivudine

Hyperkalemia-causing medications

Amiloride
Angiotensin-converting enzyme (ACE) inhibitors
Anti-inflammatory drugs, nonsteroidal (NSAIDS), especially indomethacin
Anti-thymocyte globulin (rabbit)
Cyclosporine
Digitalis glycosides (with acute overdose)
Diuretics, potassium-sparing
Heparin
Penicillins, potassium-containing (with high doses)
Pentamidine
Phosphates, potassium-containing
Potassium citrate-containing medications
Potassium iodide
Potassium supplements (including OTC salt substitutes)
Succinylcholine chloride
Tacrolimus

Hypokalemia-causing medications

Alcohol
Amphotericin B, systemic
Amphotericin B cholestryl complex
Amphotericin B lipid complex
Amphotericin B liposomal complex
Bronchodilators, adrenergic, beta-2
Capreomycin
Carbenicillin, parenteral
Carbonic anhydrase inhibitors
Corticosteroids, systemic
Diuretics, loop
Diuretics, thiazide
Edetate disodium (with prolonged use)
Fludrocortisone
Foscarnet
Indapamide
Insulin
Insulin lispro
Laxatives (with acute overdose or chronic misuse)
Mannitol
Mezlocillin
Piperacillin
Piperacillin and Tazobactam
Salicylates
Sodium bicarbonate
Sodium polystyrene sulfonate
Ticarcillin
Ticarcillin and Clavulanate
Urea, systemic

Hypotension-producing medications

Alcohol
Aldesleukin
Alprostadil
Amantadine
Amifostine
Anesthetics, general
Angiotensin-converting enzyme (ACE) inhibitors
Antidepressants, monoamine oxidase (MAO) inhibitor
Antidepressants, tricyclic
Antihypertensives
Benzodiazepines used as preanesthetics
Beta-adrenergic blocking agents
Bretylium
Brimonidine
Bromocriptine
Cabergoline
Calcium channel blocking agents
Calcium supplements, parenteral
Carbidopa and levodopa
Clozapine
Contrast agents, radiopaque, water-soluble organic iodides (with intravascular use)
Contrast agents, paramagnetic
Contrast agents, superparamagnetic
Deferoxamine (when given IV at doses >15 mg/kg/hr)
Diuretics
Droperidol
Edetate calcium disodium
Edetate disodium
Gadopentetate
Haloperidol
Hydralazine
Levodopa
Lidocaine, systemic
Loxapine
Magnesium sulfate, parenteral
Mirtazapine
Molindone
Nabilone (with high doses)
Nefazodone
Nitrates
Nitric Oxide
Nitrites
Olanzapine
Opioid (narcotic) analgesics (including alfentanil, fentanyl, and sufentanil)
Paclitaxel
Pentamidine
Pentoxifylline
Phenothiazines
Pimozide
Pramipexole
Procainamide
Propofol
Protamine (with too rapid administration)
Quetiapine
Quinidine
Risperidone
Rituximab
Ropinirole
Sildenafil
Thioxanthenes
Thrombolytic agents
Tizanidine
Tocainide
Tolcapone

Hypothermia-producing medications

Alcohol, ethyl
Alpha-adrenergic blocking agents (dihydroergotamine, ergotamine, labetalol, phenoxybenzamine, phentolamine, prazosin, tolazoline)
Anesthetics, general
Barbiturates (with high doses or acute overdose)
Beta-adrenergic blocking agents
Clonidine
Insulin
Minoxidil, systemic
Opioid analgesics (with overdose)
Phenothiazines
Polyethylene glycol and electrolytes (with large amounts of refrigerated solution)
Vasodilators

Methemoglobinemia-causing medications

Acetanilid
Aminosalicylic acid
Articaine
Benzocaine
Castellani solution
Cetrimide
Chloroquine
Coal tar
Dapsone
Flutamide
Lidocaine
Mafenide
Methylene blue (with high doses)
Nitrates
Nitric oxide
Nitrites
Nitrofurantoin
Nitroglycerin
Nitroprusside
Pamaquine
Phenacetin
Phenobarbital
Prilocaine
Primaquine
Quinine
Silver nitrate
Sulfonamides
Thiopental
Triclocarban

Nephrotoxic medications

Acetaminophen (in acute high doses)
Acyclovir, parenteral
Aldesleukin
Aminoglycosides, parenteral and topical irrigation (only on denuded surfaces or mucous membranes)
Amphotericin B, systemic
Amphotericin B cholestryl complex
Amphotericin B lipid complex
Amphotericin B liposomal complex
Analgesic combinations containing acetaminophen and aspirin or other salicylates (with chronic high-dose use)
Anti-inflammatory drugs, nonsteroidal (NSAIDS)
Bacitracin, parenteral
Carmustine
Capreomycin
Chlorpropamide
Cholecystographic agents, oral
Cidofovir
Ciprofloxacin
Cisplatin
Contrast agents, radiopaque, water-soluble organic iodides (with intravascular administration)
COX 2 inhibitors
Cyclosporine
Deferoxamine (with long-term use)
Demeclocycline (in nephrogenic diabetes insipidus)
Edetate calcium disodium (with high doses)
Edetate disodium (with high doses)
Foscarnet
Gallium nitrate
Gold compounds
Ifosfamide
Imipenem
Lithium
Methotrexate (with high-dose therapy)
Methoxyflurane
Neomycin, oral
Pamidronate
Penicillamine
Pentamidine
Phenacetin
Plicamycin
Polymyxins, parenteral
Rifampin
Streptozocin
Sulfamethoxazole and Trimethoprim
Sulfonamides, systemic
Tacrolimus
Tetracyclines, other (except doxycycline and minocycline)
Tiopronin
Tretinoin
Vancomycin, parenteral

Neurotoxic medications

Altretamine
Aminoglycosides, parenteral and topical irrigation (only on denuded surfaces or mucous membranes)
Anticonvulsants, hydantoin
Asparaginase
Capreomycin
Carbamazepine
Chloramphenicol, systemic
Chloroquine
Cilastatin
Ciprofloxacin
Cisplatin
Contrast agents (ionic and some nonionic; with intrathecal administration)
Cycloserine
Cyclosporine
Cytarabine
Didanosine
Disulfiram
Docetaxel
Ethambutol
Ethionamide
Fludarabine
Hydroxychloroquine
Imipenem
Interferon, gamma
Interferons, alpha
Isoniazid
Lincomycins
Lindane, topical
Lithium
Methotrexate, intrathecal
Metronidazole
Mexiletine
Nitrofurantoin
Oxamniquine
Pemoline
Penicillins, parenteral
Polymyxins, parenteral
Pyridoxine (with long-term, high-dose use)
Quinacrine
Quinidine
Quinine
Stavudine
Tacrolimus
Tetracyclines
Thalidomide
Vincristine
Zalcitabine

Ototoxic medications

Aminoglycosides, parenteral and topical irrigation (only on denuded surfaces or mucous membranes)
Anti-inflammatory drugs, nonsteroidal (NSAIDS)
Bumetanide, parenteral
Capreomycin
Carboplatin
Chloroquine
Cisplatin
Deferoxamine (with long-term, high-dose use)
Erythromycins (with high doses and renal function impairment)
Ethacrynic acid
Furosemide
Hydroxychloroquine
Quinidine
Quinine
Salicylates (especially with long-term, high-dose use or overdose)
Vancomycin, parenteral (with elevated plasma concentration)

Platelet aggregation inhibitors or other medications with platelet aggregation–inhibiting activity

Abciximab
Alprostadil, systemic
Anagrelide
Anti-inflammatory drugs, nonsteroidal (NSAIDS)
Aspirin
Clopidogrel
Contrast agents, radiopaque, water-soluble organic iodides (with intravascular administration)
Dextran
Dipyridamole
Divalproex
Epoprostenol
Eptifibatide
Mezlocillin
Pentoxifylline
Piperacillin
Plicamycin
Sulfinpyrazone
Thrombolytic agents
Ticarcillin
Ticlopidine
Tirofiban
Valproic acid

Serotonergics

Citalopram
Clomipramine
Fluoxetine
Fluvoxamine
Lysergic acid diethylamide (LSD)
Methylenedioxymethamphetamine (MDMA ["ecstasy"])
Moclobemide
Monoamine oxidase inhibitors, irreversible (furazolidone, phenelzine, procarbazine, selegiline, tranylcypromine)
Nefazodone
Paroxetine
Sertraline
Sibutramine
Tryptophan
Venlafaxine

Other medications or substances with serotonergic activity

Ademetionine
Almotriptan
Amitriptyline
Bromocriptine
Buspirone
Dextromethorphan
Imipramine
Levodopa
Lithium
Marijuana
Meperidine
Naratriptan
Pentazocine
Sumatriptan
Tramadol
Trazodone
Zolmitriptan

THERAPEUTIC GUIDELINES

Hyperlipidemia

In the second report of the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II), the following guidelines for the treatment of high blood cholesterol are recommended:

Nonpharmacologic management, especially reduction in dietary intake of saturated fat and cholesterol, weight reduction, increase in physical activity, and cessation of smoking, is recommended initially for all patients and as an adjunct to all pharmacologic therapy.

If an adequate response is not achieved after 6 months of dietary therapy, then medication therapy is recommended to be added to dietary therapy. The combination of nonpharmacologic and medication therapy should be started earlier in patients with severe elevations in low density lipoprotein (LDL) cholesterol or in patients with established coronary heart disease or other clinical atherosclerotic disease.

The major classes of medications available for pharmacologic therapy are: bile acid sequestrants (cholestyramine, colestipol), nicotinic acid, HMG-CoA reductase inhibitors (atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin), fibric acid derivatives (clofibrate, gemfibrozil), and probucol. Bile acid sequestrants are especially useful for treatment of isolated elevations of LDL cholesterol. Nicotinic acid is useful in patients in whom LDL cholesterol concentrations are moderately elevated combined with an increase in triglycerides and low high density lipoprotein (HDL) cholesterol concentrations. The HMG-CoA reductase inhibitors are particularly useful in achieving substantial LDL cholesterol reduction in patients with severe forms of hypercholesterolemia or in patients with established coronary heart disease and lesser degrees of LDL cholesterol elevation. The fibric acid derivatives are primarily effective in lowering triglyceride concentrations and, to a lesser extent, increasing HDL cholesterol concentrations. Therapy with probucol is generally reserved for patients who do not tolerate or respond to other cholesterol-lowering medications.

If patient response to initial medication therapy is not adequate, the patient may be switched to another class of medications or to a combination of two medications. Most antihyperlipidemic agents may be used in combination. The combination of a bile acid sequestrant with either nicotinic acid or an HMG-CoA reductase inhibitor may be particularly effective. However, the use of an HMG-CoA reductase inhibitor plus a fibric acid derivative or nicotinic acid may increase the risk of myopathy.

Consultation with a lipid specialist may be necessary in cases of unusually severe, complex, or refractory lipid disorders.

In postmenopausal women who qualify for consideration of medication therapy to lower LDL cholesterol, estrogen replacement therapy may be considered. Estrogen may decrease LDL and increase HDL concentrations. An individualized approach to selection of patients for estrogen replacement therapy is recommended, taking into consideration risk of coronary heart disease and potential risks of prolonged estrogen therapy.

References: National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994; 89(3): 1329-445.

National Cholesterol Education Program. Cholesterol lowering in the patient with coronary heart disease. Physician monograph. NIH Publication No. 97-3794 (September) 1997.

Hypertension

Initial treatment—In the sixth report of the Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI), a varied selection of antihypertensive agents is recommended for the initial treatment of essential hypertension. A choice is presented from 7 classes of agents: diuretics, beta-adrenergic blocking agents, angiotensin-converting enzyme (ACE) inhibitors, calcium channel blocking agents, alpha-1 adrenergic blocking agents, angiotensin II receptor blockers, and the alpha-beta receptor blocking agents. The medications in each of these classes are effective in reducing and controlling arterial pressure. However, the diuretics and beta-adrenergic blocking agents are preferred since a reduction in cardiovascular morbidity and mortality have been demonstrated with these classes of agents in controlled clinical trials. The ACE inhibitors, calcium channel blocking agents, alpha-1 adrenergic blocking agents, angiotensin II receptor blockers, and the alpha-beta adrenergic blocking agents have not been tested to demonstrate a reduction in morbidity and mortality. Factors such as the cost of medication, side effects, drug interactions, concomitant diseases, additional risk factors, and other prescribed medications should be considered in choosing an initial antihypertensive agent. In addition, special population groups and situations such as ethnic, demographic, and other clinical situations should be considered in that choice. The direct-acting smooth muscle vasodilators, the alpha-2 agonists, and the peripherally acting adrenergic blocking agents are considered supplemental antihypertensive agents but may be used for initial monotherapy in selected patients.

If an adequate response (achieved goal blood pressure or progress towards goal) is not achieved after reaching full dose of initial monotherapy, an agent from another class may be substituted, or a second agent from another class may be added. If addition of a second agent produces adequate blood pressure control, withdrawal of the first agent may be considered. If an adequate response is still not achieved, a second or third agent and/or diuretic, if not already prescribed, may be added. If blood pressure has been effectively controlled for 1 year, a deliberate, slow, and progressive reduction in antihypertensive medication therapy may be attempted.

Life-style modifications, including weight reduction, increased physical activity, smoking cessation, and moderation of dietary sodium and alcohol intake, are important therapeutic modalities in the treatment of hypertension. Life-style modifications alone may adequately control hypertension in some cases. However, even when not adequate in themselves, they may reduce the number and doses of antihypertensive medications required to manage hypertension. Furthermore, life-style modifications may be particularly helpful in hypertensive patients with additional cardiovascular risk factors.

Reference: The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Arch Intern Med 1997; 157(24):2413-2446.

 

 

 

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