Edward A. Hartshorn

Methotrexate and Nonsteroidal Antiinflammatory Drug Interactions

OBJECTIVE: To determine if the coadministration of methotrexate (MTX) and nonsteroidal antiinflammatory drugs (NSAIDs) results in a clinically significant drug interaction. DATA SOURCES: A case report of hematologic toxicity following the administration of MTX and flurbiprofen at our institution is presented. Six previously published case reports and five pharmacokinetic studies regarding MTX and NSAID interactions are available to assist in the evaluation of this potential interaction. DATA SYNTHESIS: Cases of various clinical manifestations during concomitant MTX and NSAID administration, including acute renal failure and pancytopenia, have been reported. The exact mechanism of the interaction has not been fully elucidated. Suggested theories to explain the mechanism of MTX toxicity include reduction in MTX clearance secondary to renal capillary constriction induced by NSAIDs, displacement of MTX or its metabolite from plasma proteins, competition between MTX and NSAIDs for renal tubular excretion, or impairment of hepatic metabolism of MTX by NSAIDs. Studies comparing MTX pharmacokinetics with or without concurrent NSAID therapy have not shown statistical differences in the parameters evaluated. However, one study did demonstrate differences in the pharmacokinetics of 7-hydroxymethotrexate, the active metabolite of MTX, when MTX was administered with aspirin. CONCLUSIONS: Although a clinically significant interaction does not occur in all patients, numerous case reports are available that demonstrate possible problems following the coadministration of MTX and NSAIDs. To date, the specific circumstances during which the reaction may occur have not been well defined.

A Review of Cyclic Antidepressant-Induced Blood Dyscrasias

OBJECTIVE: To review the literature for cases of blood dyscrasias associated with cyclic antidepressants. Several types of blood dyscrasias are discussed. DATA SOURCES: All references were selected through the use of MEDLINE. Indexing terms were blood, abnormalities, dyscrasias, antidepressants, agranulocytosis, and eosinophilia. The only constraints were English language and human subjects. STUDY SELECTION: All cases were included except for letters to the editor of various journals when pertinent data such as doses and additional medications were omitted. DATA SYNTHESIS: The review provides a table listing the different blood dyscrasias and the drug the patient was receiving. The table also includes time of onset, time to recovery, and several symptoms for each patient. CONCLUSIONS: Common symptoms of various blood dyscrasias are discussed. The chemical structures of the antidepressants are related to phenothiazines, which are also implicated in causing blood dyscrasias. Recommendations for treatment of both the dyscrasia and depression are discussed.

Interactions of CNS Drugs Psychotherapeutic Agents — The Antianxiety Drugs

A review of the literature of drug interactions of the antianxiety agents yields little of clinical significance. Recorded drug interactions of this group involve primarily meprobamate, chlordiazepoxide, and diazepam. The only interaction of note with meprobamate is the development of tolerance partially as a result of microsomal enzyme induction by meprobamate, chronic alcohol ingestion, and possibly some other agents. Of the benzodiazepine interactions, the one of most serious note is the incidence of respiratory depression and/or hypotension which occurs when diazepam is given intravenously for convulsions after prior parenteral administration of a barbiturate. The benzodiazepine derivatives may inhibit diphenylhydantoin metabolism. Hence, patients on diphenylhydantoin therapy should be closely monitored when the benzodiazepine anti-anxiety agents are introduced to or deleted from the therapeutic regimen.

Interactions of CNS Drugs Psychotherapeutic Agents — Antidepressants

which converts monoamine compounds into acids ( C N H = > C O O H ) by oxidative deamination. The enzyme is most commonly known for its ability to metabolize norepinephrine to its inactive metabolite, 3,4dihydroxymandelic acid. Presence of MAO in the gut is important in preventing absorption of pharmacologically active substances found in foods. The monoamine oxidase inhibitors (MAOI) are a group of heterogeneous drugs which have in common the ability to block the action of MAO on naturally occurring amines. The relationship between MAO inhibition and

Drug Interactions Analgesics—Salicylates

ASPIRIN IS A WEAK ACID BOUND TO THE ALBUMIN MOLEcule in the serum. This statement regarding some simple properties of aspirin explains the basis of a number of potential interactions involving salicylates. Few, however, have been documented, possibly indicating that adverse effects arise only occasionally or, if there is an interaction, it either is of little concern to the physician or the reaction is considered an extension of the pathology rather than a reaction to the drugs. Of interest primarily as a toxological matter is the fact that salicylates are weak acids and the degree of ionization and lipid solubility may be markedly affected by urinary pH. Forced diuresis with alkalinizing solutions will enhance salicylate excretion. l e Perhaps related to change in urinary pH is the report that administration of a constant dose of salicylate during tapering of corticosteroid dose resulted in a significant increase in blood salicylate levels in four patients, but simultaneous administration of corticosteroid and salicylate resulted in a blood salicylate level lower than expected. A suggested

Autonomic Drugs: Skeletal Muscle Relaxants

THE SKELETAL MUSCLE RELAXANTS MAY BE DIVIDED INTO two groups, the centrally-acting relaxants (carisoprodol, chlormezanone, chlorphenesin, chlorzoxazone, mephenesin, metaxalone, methocarbamol, styramate and the discontinued zoxazolamine) and the peripheral-acting relaxants. The latter may be further divided into the depolarizing relaxants (decamethonium, succinylcholine chloride) and the non-depolarizing agents (demethylcurarine, gallamine, hexafluorenium, tubocurarine chloride). The centrally-acting relaxants are, for the most part, propanediol derivatives related to meprobamate and mephenesin. They are generally administered orally in the treatment of acute muscle spasm of local origin or certain other conditions such as bursitis and spondylitis in which muscular spasm is present. They are thought to act on the intermmcial neurons of the spinal cord, reducing multisynaptic spinal reflexes, and perhaps depressing neurons of the brain stem, thalamus and basal ganglia. The peripheral acting agents are generally administered intravenously as adjuncts to anesthesia to produce the muscular relaxation necessary for abdominal and other operation. Although the end result of neuromuscular blockade is essentially the same, the non-depolarizers act by competing with acetylcholine at its site of action, thus preventing the acetylcholine-induced depolarization of the motor end-plate that results in muscle fiber contraction. The other group, the depolarizers, depolarize the motor end-plate, producing an initial brief period of muscle fibrillation and twitching. However, these agents are not metabolized as rapidly as acetylcholine; they delay repolarization of the myoneural junction, and a period of flaccid paralysis develops. This difference in action explains why the cholinesterase inhibitors neostigmine, edrophonium, etc. counteract the paralyzing action of the non-depolarizing drugs but potentiate the muscle paralyzing action of the depolarizing drugs.

Dr. Hartshorn Replies

Propoxyphene Napsylate Chemistry and Experimental Design, Toxicol. Appl. Pharmacol. 79:423-426, 1971. 5. Lilly Research Laboratories, Division of Eli Lilly and Company, Indianapolis, Indiana 46202 (October, 1974, personal communication ). 6. Emerson, John L., Gibson, W. R., Harris, R. N., Todd, G. C, Pierce, E. C. and Anderson, R. C. : Short Term Toxicity of Propoxyphene Salts in Rats and Dogs, Toxicol. Appl. Pharmacol. 19:452-470, 1971. 7. Emerson, John L., Gibson, W. R. and Anderson, R. C. : Acute Toxicity of Propoxyphene Salts, Toxicol. Appl. Pharmacol. 79:445-451, 1971. 8. McBay, Arthur J. and Hudson, P. : Propoxyphene Overdose Deaths, /. Am. Med. Assoc. 233:1257, 1975.

The Antipsychotic Drugs Comprehension Quiz

1967 ( O H ) . 89. Deykin, C.: Current Concepts: Warfarin Therapy (Second of Two Parts), New Engl. J. Med. 283:801-803 (Oct. 8) 1970 (R) . 90. Dornfest, F. D . : Drug Interaction, S. Afr. Med. J. 46: 1104 (Aug. 5) 1972 (Letter) ( C H ) . 91. Farman, J. V.: Desipramine and Hypertensive Episodes, Lancet 2:436 (Aug. 20) 1966 (Letter) ( C H ) . 92. Murray, K. M. F. and Smith, S. E.: Desipramine and Hypertensive Episodes, Lancet 2:591-592 (Sept. 10) 1966 (Letter). 93. Westervelt, F. B. Jr. and Atuk, N. O. : Methyldopainduced Hypertension, / . Am. Med. Assoc. 227:557 (Feb. 4) 1974 (Letter) ( C H ) . 94. Shapiro, S. et al. : The Epidemiology of Digoxin. A Study in Three Boston Hospitals, / . Chron. Dis. 22:361-371 (5) 1969 (R) . 95. Ayd, F. J. Jr. : Current Status of Thiothixene, Int. Drug Ther. Newsletter 2:27 (Sept.) 1967 (R) . 96. Oakley, D. P. and Lautch, H. : Haloperidol and Anticoagulant Treatment, Lancet 2:1231 (Dec. 7) 1963 ( C H ) . 97. Dobkin, A. B. : Potentiation of Thiopental Anaesthesia: with Tigan®, Panectyl®, Benadryl®, Gravol®, Marezine®, Histadyl®, Librium®, and Haloperidol (R 1625), Canad. Anaesth. Soc. J. S:265-269 (May) 1961 (OA) . 98. Wauquier, A., Niemegeers, C. J. E. and Lai, H. : Differential Antagonism by Naloxone of Inhibitory Effects of Haloperidol and Morphine on Brain Self-Stimulation, Psychopharmacologia 37:303-310, 1974 (OA). 99. Anon : Lithium-induced Diabetes Insipidus, Brit. Med. J. 2:726 (June 24) 1972 (R) . 100. Ramsey, T. A. et al.: Lithium Carbonate and Kidney Function. A Failure in Renal Concentrating Ability, / . Am. Med. Assoc. 2/9:1446-1449 (Mar. 13) 1972 ( C H ) . 101 Hynie, S. and Sharp, G. W. G.: Inhibition by Manganese of the Action of Antidiuretic Hormone on Adenyl Cyclase in Toad Bladder, / . Endrocrinology 50:231-235 (June) 1971 (OA) . 102. Demers, R. G. and Heniger, G. R.: Sodium Intake and Lithium Treatment in Mania, Amer. J. Psychiat 128: 100-104 (July) 1971 ( O H ) . 103. Linjaerde, O. : Synergistic Effect of Tricyclic Antidepressants and Lithium Carbonate in Endogenous Depression, Lancet 2:1260 (Dec. 1) 1973 (Letter) ( O H ) . 104. Young, D. S. et al.: Effects of Drugs on Clinical Laboratory Tests, Clin. Chem. 78:1041-1303 (Oct.) 1972 ( R ) . 105. Ravel, R., Riekers, H. G. and Goldstein, B. J. : Effects of Certain Psychotropic Drugs on Immunologie Pregnancy Tests, Am. J. Obstet. Gyn. 705:1222-1225 (Dec. 15) 1969 ( O H ) . 106. Craven, E. M. : Falsely Positive Pregnosticon Tests, J. Pediat. 72:106-108 (Jan.) 1968 ( C H ) . 107. Fine, G., Morales, A. R. and Horn, R. C. Jr. : Immunologie and Frog Pregnancy Tests. Comparative Study of Sensitivity and Accuracy, and Consideration of Factors Influencing Immunologie Methods, Am. J. Clin. Path. 45:171182 (Feb.) 1968 ( O H ) . 108. Paoletti, F. et al.: Positive Pregnancy Test in an 82Year-Old-Woman, Am. J. Med. Set. 252:570-572 (Nov.) 1966 ( C H ) . 109. Metcalf, M. G. and Beaven, D. W. : The Metopirone Test of Pituitary Corticotropin Release. Evaluation of 101 Tests, Am. J. Med. 45:176-186 (Aug.) 1968 ( O H ) . 110. Borushek, S. and Gold, J. J.: Commonly Used Medications that Interfere with Routine Endocrine Laboratory Procedures, Clin. Chem. 70:41-52 (Jan.) 1964 ( O H ) . 111. McEvoy, D. et al.: The Interference of Chlorpromazine in the Measurement of Urinary 17-hydroxycorticosteroids, Steroids 75:153-166 (Jan.) 1970 ( O T H ) . 112. Cacace, L. : Elevated Serum CPK after Drug Injections, New Engl. J. Med. 287:309-310 (Aug. 10) 1972 (Letter) ( R ) . 113. Mefferd, R. B. Jr. et al.: Influence of Chlorpromazine on Certain Biochemical Variables of Chronic Male Schizophrenics, / . Nerv. Ment. Dis. 727:167-179 (Aug.) 1958 ( O H ) .

Pyrazolone Derivatives (Antipyrine, Aminopyrine, Phenylbutazone, Oxyphenbutazone)

butazone, are pyrazole derivatives used as analgesics, antipyretic and anti-inflammatory agents. Their antiinflammatory effect is reportedly comparable to adrencorticosteroids in activity but the mechanism in man is unknown. Because of high incidence of side effects, some of which are life threatening, these agents are frequently reserved for treating arthritis. Phenylbutazone is a weakly acidic lipid-soluble substance highly bound (98 percent at therapeutic doses) to the albumin molecule in the plasma. It competes for the same binding site on human plasma albumin with sulfonamides, warfarin, tolbutamide, indomethacin and corticosteroids. Phenylbutazone is almost completely metabolized by hydroxylating enzymes found in the microsomal fraction of hepatic (and other) cells. It is converted to oxyphenbutazone (active as and more toxic than, parent compound) and gamma-hydroxyphenylbutazone. Both metabolites are extensively bound to plasma protein. Phenylbutazone apparently also has the property of stimulating these hydroxylating enzymes, which may account for alteration of its own metabolism as well as the metabolism of other drugs. Neither phenylbutazone

Book Review: A Documented Cross-Indexed Manual to Human Drug InteractionsA DOCUMENTED CROSS-INDEXED MANUAL TO HUMAN DRUG INTERACTIONS by SawyerN. J., KingC. M.Jr. and HeliumB. A., University of Alabama, Birmingham, Alabama, 1971, Ed. 2.

The author claims that the aim of this book is to fill the vast gap between laboratory and clinic. After reviewing the pertinent nerve physiology for the mode of action of local anesthetics and the mechanics of impulse generation the author discusses the membrane actions of local anesthetics and their effects on individual axons and on the whole nerves. Other chapters deal with narrower and more specific topics. The book is divided into 13 chapters some of which are: site and mode of action of local anesthetics; structureactivity relationships; systemic effects of local anesthesics; fate and disposition of local anesthesics; and toxicity. The material presented usually can not be found in general textbooks of pharmacology or physiology. The author has been very successful in presenting the material which is equally important to the clinician and the basic scientist. Twenty-three clear tables and 47 instructive figures contribute to the well-organized presentation. The book can be recommended to anesthesists, pharmacologists, physiologists, biochemists and all those concerned with drug development and evaluation.