Drug Interactions with emphasis on o-t-c drugs

with emphasis on o-t-c drugs ...

drug interactions by Lawrence H. Block and Peter P. Lamy few years ago, drug interactions were considered to result from the concurrent administration of two drugs with either the same or with antagonistic pharmacologic effects. This anachronistic conception is fast being discarded in favor of a broader concept which also considers a drug interaction to arise whenever the absorption, distribution, biotransformation andl or excretion of one drug is altered by the prior or concomitant administration of another drug. In addition, some drugs can interfere with the interpretation of diagnostic tests, resulting in misdiagnosis or in an inapplicable therapeutic regimen.1,2 Recent publications 3 - 1o have been concerned with either the incidence or source of adverse drug reactions in hospitals where continual observation and control of the patient is a normal function of the staff. It is unfortunate that a similar concern with adverse reactions has not been as vigorously expressed with regard to outpatients or patients seen in private practice. Frequently, the ambulatory patient requires greater supervision and surveillance as control of diet and self-medication are left up to the patient. These two f.actors, diet and self-medication, can significantly influence the effectiveness of a particular therapeutic regimen. Self-medication implies self-diagnosis and relegation of posology to the consumer. However, no drug is innocuous. Friend'sll description of drugs as "two-edged swords" is an apt one. Self-medication can be a boon to the patient by yielding symptomatic relief, at least temporarily, but it can also do irreparable harm bv masking more serious conditions, 'delaying medical attention or directly resulting in some untoward reaction. In a report on undesirable reactions to drug therapy, Lasagna 12 commented-

A

202

It is apparent not only that a prob· lem exists but also that, despite the fairly high frequency of reported trouble from drugs, the publicized cases constitute merely the floating tip of an iceberg, with much of the difficulty remaining hidden beneath the surface of our awareness. Although Lasagna's comment was applied to adverse drug reactions involving legend drugs, it would not seem unreasonable to apply this comment equally to interactions between legend and o-t-c drugs or diet. O-t-c drugs represent a special problem to the physician attempting to avoid therapeutic mishaps(1) The composition and strength of

o-t-c drugs are often vague or cannot be ascertained . (2) The same drug, in a somewhat higher dose, may be available only on prescription. As a result of (1), it may be difficult to predict the effect of selfmedication on a given therapeutic regimen. As a consequence of (2), the patient employing an o-t-c drug without supervision may actually treat himself with doses that could give rise to untoward reactions. The proliferation of o-t-c products, in turn, will make these problems even more serious in the future. Table I shows the number of new o-t-c drugs that have been introduced in recent years." Table II lists some o-t-c preparations and the active ingredient (s) in the particular dosage form which could be the cause of an interaction • If specific inforlllation on products is lacking, the practitioner may find the following re ferences helpful(l) Martindale's Extra Pharmacopeia, Rittenhouse Bookstore, Rittenhouse Square, Philadelphia, Pa. (2) Clinical Toxicology of Commercial Products, Will-iams and Wilkins Company, Baltimore. Md. (3) Handbook of Non-Prescription Drugs, American Pharmaceutkal Association, Washington, D.C.

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

with a prescription drug (see page 203). How many o-t-c products are being marketed? There is probably no complete list available. The Pink Book (Topics Publishing Company, 330 West 34th Street, New York 10001) lists about 3,000 manufacturers, 600 classifications and approximately 6,000 products, although these are not a'II o-t-c drugs. The book also includes toiletries, baby items and others. But, the book does give an indication of the vast number of preparations available. Classification of o-t-c products by use would be helpful in anticipating interactions or possible side effects. Table III lists a number of categories.

table I new o-t-c products, 1959-1965 category analgesics antacids and gastrointestinal products cough and cold products laxatives and evacuants sleeping aids and tranquilizers tonics vitamins and hematinics

number of new drugs 112

137 343 70 29 106

529

The Committee on Safety of Drugs for 1965 (England) statedThe public should be made increasingly aware that no effective drug is entirely without hazard, even a drug which can be bought without a prescription order. Physicians, for their part, should bear in mind that druginduced illnesses may be the result of self-medication by the patient. Some of the possible pathways for drug disposition are shown in figure I on page 204.

table II selected o-t-c products which could cause interactions with legend drugs ingredient(s) analgesics

3 3 3 3 3 3 3 2,3

product

3 3 3 3 3 3 3 3

A.S.A. Compound Alka·Seltzer Anacin Ascriptin Aspirin B.C. Bufferin Cope

remedies for bronchial asthma, (a) inhalation products: cough and cold. hay fever and rhinitis 4 Adrenalin Chloride 4 AsthmaNefrin 4 Breatheasy 4 Bronkaid Mist 4 Epinephrine Solution 4 Medihaler·Epi 4 Primatene Mist (b) liquids: 2, 3, 4 Coldene 1 Creo·Terpin (25% alcohol) 2,4 2, 4

4 2 2,4 4

2 1

sleeping aids

2 2 2 2, 5

antimotion sickness

ingredient(s)

product Doan's Pills Ecotrin Empirin Compound Excedrin Fizrin Measurin Midol Pabirin

3 2

3 5 3 3 3 3

product P·A·C Compound Pamprin Phensal Pre·Mens Resolve Stanback Vanquish Zarumin

(d) tablets and capsules (continued) 2, 4 Bronitin 2, 4 Triaminic 2,4 Triaminicol 4 Bromo·Quinine 4 Trind 2, 4 Bronakaid (c) nasal sprays and nose drops: 2, 3, 4 Cheracol Cold Capsules 2,4 Chexit 4 Alconefrin 2, 4 Bena·Fedrin 2, 4 Citrisun 2,4 Colchek 2, 4 Contac 2, 4, 5 Contac 2, 4 Drilitol 2, 3 Coricidin 2,4 NTZ 4 Neo·Synephrine 2,3,4 Coricidin·D 4 Paredrine Sulfathiazole Susp. 2,4 Coryban·D 2,4 Dondril Noscomel 2 Privine 2, 3, 4 Dristan Novahistine, Novahistine DH 2,4 Sinex 2, 4 Fedrazil 4 St. Joseph's Nose Drops for 2 Thephorin Children Orthoxicol 2, 4 Super Anahist 2, 3 Thephorin·AC 2, 4 Theracin Robitussin·AC 4 Vasoxyl Romilar CF (d) tablets and capsules: 2, 3, 4 Triaminicin Sudafed 3,4 4·Way Cold Tablets 2, 4 Tri·Span Super Anahist Cough Syrup 2, 4 Tussagesic 2,4 Allerest 2,3,4 Ursinus Inlay·Tabs Terpin Hydrate, Terpin Hy· drate with Codeine, Terpin 4 Zantrate Hydrate with Dextro· methorphan (42% alcohol)

2, 5

Dormin Nytol Relax·U·Caps San ·Man Sleep · Eze Sominex

2 2 2 5

Bonine Dramamine Marezine Mothersill's Remedy

2, 5

ingredient(s)

(b) liquids (continued)

Key: l ·alcohol; 2·antihistamin e; 3·aspirin, salicylates; 4·sympathomimetic amines; 5·belladonna alkaloids a nd related compounds

alteration of drug absorption

The rate and/ or extent of drug absorption from the gastrointestinal tract may be markedly affected when other preparations are used concurrently. Most drugs are weak organic electrolytes. As a result, alterations of pH-e.g., by antacids, acidiRerscan bring about a shift in the proportion of drug present as the unionized moiety. The pH-partition hypothesis of Shore et al,13 considers the biological barrier between the gastrointestinal lumen and the plasma to be permeable only to the undissociated form of the weak electrolyte. Therefore, absorption is dependent upon the concentration of the unionized drug moiety which is pH-dependent. Another way in which the concentration of the drug moiety available for absorption can be altered is by adsorption onto the surface of solids. Finely divided solids in suspension-e.g. , aluminum hydroxide gel, milk of magnesia, chalk mixture, kaolin, charcoal, etc.-could adsorb a por-

tion of the drug and render it unavailable for absorption. Sorby and Liu 14 showed the rate and extent of absorption of promazine to be decreased significantly when an attapulgite clay-citrus pectin mixture was administered concurrently. Complexation with metal ions-e.g.,

from milk, antacids-might render a drug unavailable for absorption-e.g., tetracycline-di or tri-valent metal complexes. 15 Surfactants-e.g., polysorbate 80, dioctyl sodium sulfosuccinate-may affect the rate and/ or extent of absorption by solubilizing the drug or by

table III selected categories of o-t-c drugs which may cause interaction category

interacting ingredient(s)

ana lgesics

aspirin, salicylates

antacids

aluminum, calcium, magnesium , bicarbonate, citrate

antihistamines cold tablets and capsules

antihistamines, aspirin, belladonna alkaloids

cough syrups, elixirs, expectorants

alcohol, antihistamines, ammonium chloride

diarrhea remedies

clays and other adsorbents

laxatives

surfactants

motion sickness products

antihistamines, belladonna alkaloids

nasal sprays and drops

sympathomimetic amines

sleeping aids

antihistamines

tonics

alcohol

Vol. NS9, No. 5, May 1969

203

affecting the p enneability of the gastrointestinal epithelium. In the case of solid dosage fonns or susp ensions, the surfactant might increase the rate of dissolution of the solid by increasing the contact between the particulate matter and the bulk fluid of the gut. This would result in an increase in the total amount of drug available for absorption.

chlorpropamide, or one of the other sulfonylurea derivatives, may lead to hypoglycemia. Hemorrhagic crises can result in patients maintained on anticoagulants who are treated with other agents which displace the anticoagulant from its protein binding sites. Drug distribution in the tissues of the body also is affected by binding of the drug to tissue componentsproteins, phospholipids, etc. The cardiovascular action of norepinephrine can be potentiated by certain antihistaminic agents.18- 21 Isaac and Goth 20 attributed this to an inhibition of the uptake of norepinephrine by various tissues resulting in an increase in the concentration of unbound norepinephrine. There is a potential hazard in the administration of antihistaminic agents to patients already receiving monoamine oxidase inhibitors in that a hypertensive crisis might ensue. Table IV lists some of the drugs bound to plasma or tissue components whose binding is affected by the administration of other agents.

alteration of drug distribution

Pharmacologic response to a drug is related to the unbound concentration of the d rug in the plasma. H ence, changes in the prop ortion of drug bound to plasma protein can directly influence drug therapy. Drugs bound to plasma protein can be displaced from their binding sites by substances with a greater affinity for the sites resulting in an increase in the plasma concentration of the unbound drug. 0 An increase in the plasma concentration of the free drug could lead to untoward effects. For example, aspirin can reduce the extent of plasma protein binding of penicillin analogues 16 resulting in higher levels of the unbound drug. Aspirin also has been implicated17 in the alteration of p rotein binding of chlorpropamide. A reduction of chlorpropamide dosage was p ossible when aspirin was administered concurrently. Self-medication with aspirin by patients maintained on

alteration of biotra nsformation

In recent years, attention has been directed towards the stimulation or inhibition of drug metabolizing enzymes. Certain drugs will change the metabolism of other drugs or become less effective themselves due to stimulation of metabolism. Drugs which interfere with enzymatic pathways can enhance and/ or prolong the effect of other drugs. This is of particular concern with drugs that are extensively modified prior to excretion. A classic example of this is the

o One must keep in mind that most drug binding to plasma protein is reversible. Drugs with

approximately the same affinity for a particular binding site could displace one another. The degree of displacement would depend upon the relative affinity for the site and the relative concentration of the drugs.

figure I possible pathways of drug disposition A BSORPTION

I BIOTRANSFORMA TION I T ISSUE

BOUND DRUG

===

FREE

DRUG ~=j:=== FREE

DRUG

META BOLI TE S

H

I

I

PLASMA

LOCUS OF ACTION -re cept or S it e FREE DRUG

IEXC RETI ON I 204

Journal of t he AMERICAN PHARMACEUTICAL ASSOCIATI ON

B OUN D ~

DRUG

inhibition of acetaldehyde dehydrogenase by disulfiram-subsequent exposure of the patient to alcohol produces the usual acetaldehyde-accumulation syndrome. However, disulfiram also can interfere with the metabolism of other drugs. Olesen 22 reported excessively high serum levels of the anticonvulsant, diphenylhydantoin in patients maintained on disulfiram. (Only about one percent of a given dose of phenytoin is excreted unchanged by the kidneys.) When a drug is employed which alters a metabolic pathway in some manner, caution should be exercised in the administration of other drugs that might undergo modification via the same enzyme system. An increased elaboration of drug metabolizing enzymes ( enzyme induction) is important clinically in that a shortened duration of action or a decreased effectiveness of the drug may result. Particularly serious are the interactions of enzyme inducing agents with anticoagulants. One illustration of this involves the release, from the hospital, of cardiovascular patients previously titrated with anticoagulants. Not infrequently, these patients may be placed on a barbiturate regimen. Interactions may occur before the next scheduled visit to the physician. Robinson and MacDonald 23 showed that sedative doses of phenobarbital significantly antagonize the effect of warfarin in man. Concurrent administration of coumarin anticoagulants and barbiturates could reduce anticoagulant effectiveness and lead to fluctuations in prothrombin levels. This might necessitate discontinuance of the anticoagulant or if the barbiturate were discontinued, result in less rapid metabolism of the anticoagulant and subsequent hemorrhage. The problem of enzyme induction is one which continues to expand. Carcinogenic air pollutantse.g., benzypyrene-halogenated pesticides-e.g., DDT, chlordane, dieldrin, aldrin-herbicides and food additives, in addition to drugs, have been shown to stimulate their own metabolism or the metabolism of other compounds. 24 A concern for the patient's total environment is becoming increasingly more important. Drugs also may have an effect on a coenzyme system. Salicylates, for example, interfere with vitamin K utilization in prothrombin synthesis. Drug metabolism may be affected by an alteration in the concentration of substances involved in biotransfonnation. Contrary to the usual metabolic pathways, acetylation of sulfonamides generally gives rise to derivatives which are less soluble than the parent compound. Deposition of the in-

soluble acetylated sulfonamide in the kidney tubules gives rise to crystalluria. The potential for crystalluria may be enhanced when paraldehyde is administered concomitantly due to the resultant increase in acetate levels. A listing of those compounds whose metabolism in man has been shown to be affected by the administration of other agents is given in table V.

table IV drugs whose binding to plasma or tissue components may be affected by other agents bound drug

displacing agent

analgesics e.g., sa licylates

[indomethacin phenylbutazone, oxyphenbutazone

[,,"m..," '""~""',""

antibiotics, antibacteria ls e.g., peniciIJin long-acting su Ifona m ides

indomethacin phenylbutazone, oxyphenbutazone salicylates sulfinpyrazone

alteration of drug excretion

Laxatives or cathartics might enhance the excretion of a drug and decrease its availability by promoting an expulsion of the intestinal contents. Drug excretion also may be markedly affected by changes in urinary pH. If the urine is at a pH at which the drug is present primarily in the ionized form, the possibility of passive reabsorption of the drug may be considerably reduced resulting in a diminution of drug levels and lowered therapeutic effectiveness. If the urine is at a pH at which the drug is unionized, the possibility of passive reabsorption is enhanced resulting in higher plasma levels and the onset of side-effects. In addition to agents such as ammonium chloride, sodium bicarbonate and the citrates which have been used to alter urinary pH, the thiazide diuretics and acetazolamide also can alter urinary pH." One example of the importance of pH was provided by Beckett et al,25-after administration of a single dose of dextroamphetamine, 54.5 percent of the drug was excreted in the urine after 16 hours at pH 5.0 and only 2.9 percent after 16 hours at pH 8.0. Urinary pH is a parameter which should be followed routinely when potent medicaments are employed whose excretion is susceptible to relatively small changes in pH. The variation in the percent of the non-reabsorbed drug with urinary pH is shown in table VI on page 206. An additional pathway which may be affected involves the blockage of tubular transport of drugs-e.g., urate transport can be blocked by probenecid. The same transport mechanism is involved with penicillin. Salicylates can interfere with the uricosuric effect of probenecid. Field et al,26 reported the potentiation of acetohexamide hypoglycemia by phenylbutazone and attributed it to an interference with renal excretion of the active metabolite, hydroxyhexamide. (Conversion of acetohexamide""'" hydroxyhexamide was unchanged.)

"Alteration of the diet of the patient can often be responsible for changes in the urinary pH. It would not seem unreasonable to expect vegetarians to have a considerably different urinary pH-time profile than non-vegetarians.

[O",","''''"'''',"b"~''O ,," '"' '" .".. '0"'''''',' indomethacin

anticoagulants e.g., coumarin derivatives indanedione derivatives

phenylbutazone, oxyphenbutazone salicylates sulfonamides d-thyroxine

antidiabetic agents e .g . , sulfonylureas (acetohexamide, chlorpropamide, tolbutamide)

[,,"m..," '"'''~'"''"''

indomethacin phenylbutazone,oxyphenbutazone salicylates sultonamides

cardiovascular agents e .g., norepinephrine (levarterenol) guanethidine

antihistamines, sympathomimetic amines sympathomimetic amines

misceIJaneous mepacrine

pamaquine and other 8-aminoquinolines

table V drugs whose metabolism in man has been altered by the administration of other agents (a) metabolic inhibition d rug affected tricyclic antidepressants (e.g., imipramine, desipramine, amitriptyline) eNS depressants hypotensive agents sympathomimetics antihistamines anticonvulsants, hydantoin anticoagulants, coumarin oxyphenbutazone

J

agent monoamine oxidase inhibitors (e.g. , tranylcypromine, phenelzine, isocarboxazid, nialamide, pargyline)

disulfiram oxyphenbutazone, phenyramidol methandrostenolone

(b) metabolic stimulatiQn drug affected griseofulvin anticoagulants, coumarin

anticoagulants, indanedione anticonvu Isa nts, hyda ntoin aminopyrine; dipyrone meprobamate digitoxin

agent phenobarbital phenobarbital chloral hydrate griseofulvin [ heptabarbital haloperidol phenobarbital glutethimide, phenylbutazone meprobamate phenobarbital

(c) miscellaneous drug affected anticoagulants

agent salicylates

conclusion **

The physician may find the tables of legend drug-o-t-c drug and legend drug-food interactions published by Block and Lamy"" "27 of help in keeping abreast of developments. In ad-

•• Articles of interest that have appeared since the manuscript was submitted include one on drug-induced modifications of laboratory test values (Am. J. Hasp . Pharm., 25, 484-519, 1968), and a report of oral anticoagulant potentiation by acetaminophen (Current Therap. Res., 10, 501 - 507, 1968) ••• Available from the authors

dition, information on adverse reactions is available in the following publications(a) FDA Clinical Experience Ab· stracts; FDA Reports of Suspected Adverse Reactions to Drugs and Therapeutic Devices-both available from the Food and Drug Administra· tion (b) The Medical Letter (c) Clin·Alert (d) Drug Intelligence (e) Academy /GP

The consideration of therapeutic incompatibilities is now emerging as an Vol. NS9, No.5, May 1969

205

the Results of Some Common Laboratory Diagnostic Procedures," Am. J. Hasp. Pharm., 23, 235 (1966) 2. Block, L.H., and Lamy, P.~., "These Drugs Discolor Feces or Urine, Am. Professio rw! Pharmacist, 34, 2, 27 ( 1968) " 3. Lasagna, L., HThe Diseases Drugs Cause, Perspectives Biol. Med., 7, 457 (19631964) 4. C luff, L.E., Thornton, G .F:, a,;,d Seidl, L.G., " Studies on the Epidemiology of Adverse Drug Reactions. I. Methods of Surveillance," JAMA, 188, 976 (1964)

Lawrence H. Block is assistant professor of pharmaceutics at the University of Pittsburgh school of pharmacy. He studied for his PhD at the University of Maryland where he earned his BS in 1962 and MS in 1966. He has been a consultant to the Aerosol Pharmacal Company in Baltimore. A former graduate fellow in pharmacy, AFPE, Block's 'research interests Ue in biopharmaceutics and in surface and colloid chemistry. He is a member of APhA, Academy of Pharmaceutical Sciences, AAAS, American Oil Chemists' Society and Society of Cosmetic Chemists.

Peter P. Lamy is associate professor of pharmacy and director of institutional pharmacy programs at the University of Maryland. He earned his BS, MS and PhD from the Philadelphia College of Pharmacy and Science and was an instructor there from 1956 to 1963. He also has taught pharmacology at the Woman's Hospital in Philadelphia and has been consultant to the USPHS Hospital in Baltimore. Lamy is a member of APhA, ASHP, Academy of Pharmaceutical Sciences and a fellow of AAAS. Currently he is vice president of the Maryland Society of Hospital Pharmacists.

area where close cooperation between physicians and pharmacists is absolutely essential. The maintenance of patient records with a complete breakdown of drug usage (both prescription drugs and o-t-c drugs) and sensi-

tivities can only serve to reduce the incidence of undesirable drug interactions . • references 1. Cross, F .C., Canada, A.T., Jr., and Davis, N.M., "The Effect of Certain Drugs on

table VI some drugs whose renal excretion could vary with changes in urinary pHa drug atropine

approximate pKa

percent of drug in ionized form b when urinary pH is 8.0 4.0 6.0

4.4

71.53

2.45

0.02

9.5 11.2

99.99 99.99

99.97 99.99

96.94

8.7

99.99

99.80

phenylbutazone

7.8 4.4

99.98 28.47

98.44 97.55

quinine

8.4

99.99

99.60

salicylic acid

3.0

sulfadiazine su Ifamethylth iad iazole

6.5 5.2 4.8

90.91 0.32

99.90 24.04

5.93

86.32 94.06

96.94 99.84 99.94

99.99

99.50

imipramine

mecamylamine meperidine perphenazine

su Ifisoxazole tolazoline

10.3

13.68 99.99

99.94 83.37 63.09 99.98 71.53 99.99

" Drugs with a pKa >~9 .0, such as imipramine, mecamylamine and tolazoline, will not generally show a marked change in passive urinary excretion as urinary pH rarely exceeds a value of 8.0 b Calculated from the followingfor bases, percent ionized = 100/(1 antilog (pH-pKa)) for acids, percent ionized = 100/(1 antilog (pKa-pH))

+ +

206

Journal of the AMERICAN PHARMACEUTICAL ASSOCIATION

5. Seidl, L.G., Thornton, G.~., and Cluff, L.E., "Epidemiological Studl~s of Adverse Drug Reactions," Am. J. Public Health, 55, 1170 (1965) 6. Seidl, L.G., Thornton, G.F .• Smit~, J.yv'., and Cluff, L.E., "Studies on the Epldenuology of Adverse Drug Reactions in Patients on a General Medical Service," Bull. Johns Hopkins Hosp., 119,299 (1966) 7. Modell, W., "Drul1:-Induced Diseases," Ann. Rev. Pharmacol., 5, 285 (1965) 8. Lancaster, W.J., "Adverse Drug Reactions:~ Am. J. Hosp. Ph arm., 22, 524 (1965) 9 . Smith, J.W., "A Hospital A~verse I?rug Reaction Reporting Program, Hospttals, 40, No.4, 90, 92, 94, 96 (1966) 10. Cluff, L.E., "Clinical Predictiveness of Therapeutic Incompatibilities." Paper presented at annual meeting, Am. Assoc. Adv. Sci., Washington, D.C. (Dec. 30, 1966) 11. Friend, D.G., "Drugs Are Douhle-Edged Swords," JAPhA, NS4, 221 (1964) 12. Lasagna, L., HThe Diseases Drugs Cause,'~ Perspectives BioI. Med., 7, 457 (19631964) 13. Shore, P.A., Brodie, B.B., and Hogben, C.A.M., "The Gastric Secretion of Drugs: A pH Partition Hypothesis," J. Pharmacol. Ex". Therap., 119, 361 (1957) 14. Sorby, D .L., and Liu, G., "Effects of Adsorbents on Drug Ahsorption. II. Effect of an Antidiarrhea Mixture on Promazine Ahsorption," J. Pharm. Sci., 55, 504 (1966) 15. Kunin, C.M., and Finland, M., "Clinical Pharmacology of the Tetracycline Antibiotics," Clin. Pharmacol. Therap., 2, 51 (1961 ) 16. Kunin, C.M., "Clinifal Pharmacology of the New Penicillins. II. Effect of Drugs Which Interfere With Binding to Serum Prote ins," Clin. Pharmacol. Th erap., 7, 180 (1966) 17. Silver, A.A., personal commun ication (May 12,1967) 18. Innes, I.R., "Sensitization of the Heart and Nictitating Memhrane of the Cat to Sympathomimetic Amines by Antihistamine Drugs," Brit. J. Pharmacol., 13, 6 (1958) 19. Sherrod, T.R., Loew, E.R., and Schloemer. H.F ., "Pharmacological Properties of Antihistamine Drugs, Benadryl, Pyribenzamine and Neoantergan/' J. Pharmacol. Exp. Thera"., 89, 247 (1947) 20. Isaac, L., .lnd Goth, A., "Interaction of Antihistaminics with Norepinephrine Uptake: A Cocaine-Like Effect," Life Sci., 4, 1899 (1965) 21. Jori, A., "Potentiation of Noradrenaline Toxicity by Drugs With Antihistamine Activity," J. Pharm. Pharmacol., 18, 824 (1966) 22. Olesen, O .V., "Disulfiram (Antabuse) as Inhibitor of Phenytoin Metabolism," Acta. Pharmacol. Toxico!., 24, 317 (1966) 23. Robinson, D .S., a nd MacDonald, M.G., "The Effect of Phenobarbital Administration on the Control of Coagulation Achieved During Warfarin Therapy in Man," J. Pharmacol. Exp. Therap., 153, 250 (1966) 24. Conney, A.H., "Pharmacological Implications of Microsomal Enzyme Induction ," Pharmacol. Rev., 19, 317 (1967) 25. Beckett, A.H., Rowland, M., and Turner, P ., Hlnfluence of Urinary pH on Excretion of Amphetamine," Lancet, 1, 303 (1965) 26. Fie ld, I.B. , Ohta, M .• Boyle, C., and Remer, T.A., "Potentiation of Acetohexamide Hypoglycemia by Phenylbutazone," New Engl. J. Med., 277, 889 (1967) ".7. Block, L.H., and Lamy, P.P., "Legend Drugs With O-t-c Drugs . . . Therapeutic Incompatibilities," JAPhA, NS8, 66, 82 ( 1968)