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September 9, 1974, Vol 229, No. 11 >
ARTICLE | September 9, 1974

Pharmacokinetic Drug Interactions: Title and subTitle BreakSedative, Hypnotic, and Antianxiety Agents FREE

Mary Ellen Kosman, PhD
[+] Author Affiliations

Reprint requests to Department of Drugs, American Medical Association, 535 N Dearborn St, Chicago, IL 60610.


JAMA. 1974;229(11):1485-1488. doi:10.1001/jama.1974.03230490069036
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Article
References

MOST clinically observed drug interactions—both beneficial and adverse— are probably caused by additive, synergistic, or antagonistic effects of agents that act at the same site or on the same physiologic system. There has been more emphasis in the literature, however, on those interactions that occur when one drug affects the activity of another by altering its absorption, distribution, metabolism, or excretion (the so-called "pharmacokinetic,"1 "ADME",2 or "indirect"3 interactions). These complex mechanisms have been extensively studied in laboratory animals, but less is known of their incidence or importance in man. The pharmacokinetic interactions of widely used drugs could be of major clinical importance. This review focuses on a commonly prescribed group, the sedative, hypnotic, and antianxiety agents.

MECHANISMS OF INTERACTIONS 

Enhancement of Metabolism.—  Most drugs and many naturally occurring compounds are metabolized into water-soluble derivatives before excretion, and this biotransformation is effected mainly by microsomal enzymes of the

REFERENCES

1 +
Prescott LF:  Pharmokinetic drug interactions . Lancet 2:1239-1243, 1969;.
2 +
Hansten PD: Drug Interactions , ed 2. Lea & Febiger Publishers, Philadelphia, 1973;.
3 +
 Adverse drug interactions, Boston Collaborative Drug Surveillance Program . JAMA 220:1238-1239, 1972;.
4 +
Conney AH, Burns V:  Metabolic interactions among environmental chemicals and drugs . Science 178:576-586, 1972;.
5 +
Koch-Weser J, Sellers EM:  Drug interactions with coumarin anticoagulants: (part 2.) N Engl J Med 285:547-558, 1971;.
6 +
Alexanderson B, Evans DAP, Sjoqvist F:  Steady-state plasma levels of nortriptyline in twins: Influence of genetic factors and drug therapy . Br Med J 4:764-768, 1969;.
7 +
O'Reilly RA, Aggeler PM:  Determinants of response to oral anticoagulant drugs in man . Pharmacol Rev 22:35-96, 1970;.
8 +
Hussar DA:  Drug interactions . Amer J Pharm 145:65-116, 1973;.
9 +
Levy G, et al:  Pharmacokinetic analysis of effect of barbiturate on anticoagulant action of warfarin in man . Clin Pharmacol Ther 11:372-377, 1970;.
10 +
Aggeler PM, O'Reilly RA:  Effect of heptabarbital on the response to bishydroxycoumarin in man . J Lab Clin Med 74:229-238, 1969;.
11 +
MacDonald MG, Robinson DS:  Clinical observations of possible barbiturate interference with anticoagulation . JAMA 204:97-100, 1968;.
12 +
MacDonald MG, et al:  The effects of phenobarbital, chloral betaine and glutethimide administration on warfarin plasma levels and hypoprothrombinemic response in man . Clin Pharmacol Ther 10:80-84, 1969;.
13 +
Johansson SA:  Apparent resistance to oral anticoagulant therapy and influence of hypnotics on some coagulation factors . Acta Med Scand 184:297-300, 1968;.
14 +
Udall JA:  Warfarin therapy not influenced by meprobamate. A controlled study in nine men . Curr Ther Res 12:724-728, 1970;.
15 +
Gould L, et al:  Prothrombin levels maintained with meprobamate and warfarin: A controlled study . JAMA 220:1460-1462, 1972;.
16 +
Sellers EM, Koch-Weser J:  Potentiation of warfarin-induced hypoprothrombinemia by chloral hydrate . N Engl J Med 283:827-831, 1970;.
17 +
Sellers EM, et al:  Enhancement of warfarin-induced hypoprothrombinemia by triclofos . Clin Pharmacol Ther 13:911-915, 1972;.
18 +
Koch-Weser J, Sellers EM:  Chloral hydrate and warfarin therapy . Ann Intern Med 75:141, 1971;.
19 +
 Interaction between chloral hydrate and warfarin: Report from Boston Collaborative Drug Surveillance Program . N Engl J Med 286:53-55, 1972;.
20 +
Griner PF, et al:  Chloral hydrate and warfarin interaction: Clinical significance ? Ann Intern Med 74:540-543, 1971;.
21 +
Lackner H, Hunt VE:  The effect of Librium on hemostasis . Am J Med Sci 256:368-372, 1968;.
22 +
Robinson DS, Sylvester D:  Interaction of commonly prescribed drugs and warfarin . Ann Intern Med 72:853-856, 1970;.
23 +
Solomon HM, Barakat MJ, Ashley CJ:  Mechanisms of drug interaction . JAMA 216:1997-1999, 1971;.
24 +
Orme M, Breckenridge A, Brooks RV:  Interactions of benzodiazepines with warfarin . Br Med J 3:611-614, 1972;.
25 +
Robinson DS, Amidon EL:  Interaction of benzodiazepines with warfarin in man , in Garattini S, Randall LO (eds): The Benzodiazepines . New York, Raven Press, 1973;, pp 641-646.
26 +
Bieger R, deJonge H, Loeliger EA:  Influence of nitrazepam on oral anticoagulation with phenprocoumon . Clin Pharmacol Ther 13:361-365, 1972;.
27 +
Burrows GD, Davies B:  Antidepressants and barbiturates . Br Med J 4:113, 1971;.
28 +
Silverman G, Braithwaite R:  Interaction of benzodiazepines with tricyclic antidepressants . Br Med J 4:111, 1972;.
29 +
 Plasma levels of psychopharmaceuticals . Int Drug Ther Newsletter 9( (1) ):1-4, Jan 1974;.
30 +
Hammer W, Idestrom CM, Sjoqvist F:  Chemical control of antidepressant drug therapy , in Garattini S, Dukes MNG (eds): Antidepressant Drugs . Amsterdam, Excerpta Medica Foundation, 1966;, pp 301-310.
31 +
Crocker J, Morton B:  Tricyclic (antidepressant) drug toxicity . Clin Toxicol 2:397-402, 1969;.
32 +
Silverman G, Braithwaite RA:  Benzodiazepine and tricyclic antidepressant plasma levels . Br Med J 3:18-20, 1973;.
33 +
 Interaction of barbiturate and non-barbiturate hypnotics and benzodiazepines with tricyclic antidepressants . Int Drug Ther Newsletter 8( (4) ):13-14, Apr 1973;.
34 +
Forrest FM, Forrest IS, Serra MT:  Modification of chlorpromazine metabolism by some other drugs frequently administered to psychiatric patients . Biol Psychiatry 2:53-58, 1970;.
35 +
Morselli PL, Rizzo M, Garattini S:  Interaction between phenobarbital and diphenylhydantoin in animals and in epileptic patients . Ann NY Acad Sci 179:88-107, 1971;.
36 +
Buchanan RA, Heffelfinger JC, Weiss CF:  The effect of phenobarbital on diphenylhydantoin metabolism in children . Pediatrics 43:114-116, 1969;.
37 +
Cucinell SA, et al:  Drug Interactions in man: I. Lowering effect of phenobarbital on plasma levels of bishydroxycoumarin (Dicoumarol) and diphenylhydantoin (Dilantin) . Clin Pharmacol Ther 6:420-429, 1965;.
38 +
Garrettson LK, Dayton PG:  Disappearance of phenobarbital and diphenylhydantoin from serum of children . Clin Pharmacol Ther 11:674-679, 1970;.
39 +
Kutt H, et al:  The effect of phenobarbital on plasma diphenylhydantoin level and metabolism in man and in rat liver microsomes . Neurology 19:611-616, 1969;.
40 +
Booker HE, Tormey A, Toussaint J:  Concurrent administration of phenobarbital and diphenylhydantoin: Lack of an interference effect . Neurology 21:383-385, 1971;.
41 +
Diamond WD, Buchanan RA:  A clinical study of the effect of phenobarbital on diphenylhydantoin plasma levels . J Clin Pharmacol 10:306-311, 1970;.
42 +
Kokenge R, Kutt H, McDowell F:  Neurological sequelae following Dilantin overdose in a patient and in experimental animals . Neurology 15:823-829, 1965;.
43 +
Vajda FJE, Prineas RJ, Lovell RRH:  Interaction between phenytoin and the benzodiazepines . Br Med J 1:346, 1971;.
44 +
Kutt H, McDowell F:  Management of epilepsy with diphenylhydantoin sodium . JAMA 203:969-972, 1968;.
45 +
Kariks J, Perry SW, Wood D:  Serum folic acid and phenytoin levels in permanently hospitalized epileptic patients receiving anticonvulsant therapy . Med J Aust 2:368-371, 1971;.
46 +
Solomon HM, Abrams WB:  Interactions between digitoxin and other drugs in man . Am Heart J 83:277-280, 1972;.
47 +
Kaldor A, et al:  Enhancement of methyldopa metabolism with barbiturate . Br Med J 3:518-519, 1971;.
48 +
Kristensen M, Jorgenson M, Hansen T:  Barbiturates and methyldopa metabolism . Br Med J 1:49, 1973;.
49 +
Burstein S, Klaiber EL:  Phenobarbital-induced increase in 6β-hydroxycortisol excretion: Clue to its significance in human urine . J Clin Endocrinol Metab 25:293-296, 1965;.
50 +
Brooks SM, et al:  Adverse effects of phenobarbital on corticosteroid metabolism in patients with bronchial asthma . N Engl J Med 286:1125-1128, 1972;.
51 +
Falliers CJ:  Corticosteroids and phenobarbital in asthma . N Engl J Med 287:201, 1972;.
52 +
Riegelman S, Rowland M, Epstein WL:  Griseofulvin-phenobarbital interaction in man . JAMA 213:426-431, 1970;.
53 +
Busfield D, et al:  An effect of phenobarbitone on blood levels of griseofulvin in man . Lancet 2:1042-1043, 1963;.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Prescott LF:  Pharmokinetic drug interactions . Lancet 2:1239-1243, 1969;.
2 +
Hansten PD: Drug Interactions , ed 2. Lea & Febiger Publishers, Philadelphia, 1973;.
3 +
 Adverse drug interactions, Boston Collaborative Drug Surveillance Program . JAMA 220:1238-1239, 1972;.
4 +
Conney AH, Burns V:  Metabolic interactions among environmental chemicals and drugs . Science 178:576-586, 1972;.
5 +
Koch-Weser J, Sellers EM:  Drug interactions with coumarin anticoagulants: (part 2.) N Engl J Med 285:547-558, 1971;.
6 +
Alexanderson B, Evans DAP, Sjoqvist F:  Steady-state plasma levels of nortriptyline in twins: Influence of genetic factors and drug therapy . Br Med J 4:764-768, 1969;.
7 +
O'Reilly RA, Aggeler PM:  Determinants of response to oral anticoagulant drugs in man . Pharmacol Rev 22:35-96, 1970;.
8 +
Hussar DA:  Drug interactions . Amer J Pharm 145:65-116, 1973;.
9 +
Levy G, et al:  Pharmacokinetic analysis of effect of barbiturate on anticoagulant action of warfarin in man . Clin Pharmacol Ther 11:372-377, 1970;.
10 +
Aggeler PM, O'Reilly RA:  Effect of heptabarbital on the response to bishydroxycoumarin in man . J Lab Clin Med 74:229-238, 1969;.
11 +
MacDonald MG, Robinson DS:  Clinical observations of possible barbiturate interference with anticoagulation . JAMA 204:97-100, 1968;.
12 +
MacDonald MG, et al:  The effects of phenobarbital, chloral betaine and glutethimide administration on warfarin plasma levels and hypoprothrombinemic response in man . Clin Pharmacol Ther 10:80-84, 1969;.
13 +
Johansson SA:  Apparent resistance to oral anticoagulant therapy and influence of hypnotics on some coagulation factors . Acta Med Scand 184:297-300, 1968;.
14 +
Udall JA:  Warfarin therapy not influenced by meprobamate. A controlled study in nine men . Curr Ther Res 12:724-728, 1970;.
15 +
Gould L, et al:  Prothrombin levels maintained with meprobamate and warfarin: A controlled study . JAMA 220:1460-1462, 1972;.
16 +
Sellers EM, Koch-Weser J:  Potentiation of warfarin-induced hypoprothrombinemia by chloral hydrate . N Engl J Med 283:827-831, 1970;.
17 +
Sellers EM, et al:  Enhancement of warfarin-induced hypoprothrombinemia by triclofos . Clin Pharmacol Ther 13:911-915, 1972;.
18 +
Koch-Weser J, Sellers EM:  Chloral hydrate and warfarin therapy . Ann Intern Med 75:141, 1971;.
19 +
 Interaction between chloral hydrate and warfarin: Report from Boston Collaborative Drug Surveillance Program . N Engl J Med 286:53-55, 1972;.
20 +
Griner PF, et al:  Chloral hydrate and warfarin interaction: Clinical significance ? Ann Intern Med 74:540-543, 1971;.
21 +
Lackner H, Hunt VE:  The effect of Librium on hemostasis . Am J Med Sci 256:368-372, 1968;.
22 +
Robinson DS, Sylvester D:  Interaction of commonly prescribed drugs and warfarin . Ann Intern Med 72:853-856, 1970;.
23 +
Solomon HM, Barakat MJ, Ashley CJ:  Mechanisms of drug interaction . JAMA 216:1997-1999, 1971;.
24 +
Orme M, Breckenridge A, Brooks RV:  Interactions of benzodiazepines with warfarin . Br Med J 3:611-614, 1972;.
25 +
Robinson DS, Amidon EL:  Interaction of benzodiazepines with warfarin in man , in Garattini S, Randall LO (eds): The Benzodiazepines . New York, Raven Press, 1973;, pp 641-646.
26 +
Bieger R, deJonge H, Loeliger EA:  Influence of nitrazepam on oral anticoagulation with phenprocoumon . Clin Pharmacol Ther 13:361-365, 1972;.
27 +
Burrows GD, Davies B:  Antidepressants and barbiturates . Br Med J 4:113, 1971;.
28 +
Silverman G, Braithwaite R:  Interaction of benzodiazepines with tricyclic antidepressants . Br Med J 4:111, 1972;.
29 +
 Plasma levels of psychopharmaceuticals . Int Drug Ther Newsletter 9( (1) ):1-4, Jan 1974;.
30 +
Hammer W, Idestrom CM, Sjoqvist F:  Chemical control of antidepressant drug therapy , in Garattini S, Dukes MNG (eds): Antidepressant Drugs . Amsterdam, Excerpta Medica Foundation, 1966;, pp 301-310.
31 +
Crocker J, Morton B:  Tricyclic (antidepressant) drug toxicity . Clin Toxicol 2:397-402, 1969;.
32 +
Silverman G, Braithwaite RA:  Benzodiazepine and tricyclic antidepressant plasma levels . Br Med J 3:18-20, 1973;.
33 +
 Interaction of barbiturate and non-barbiturate hypnotics and benzodiazepines with tricyclic antidepressants . Int Drug Ther Newsletter 8( (4) ):13-14, Apr 1973;.
34 +
Forrest FM, Forrest IS, Serra MT:  Modification of chlorpromazine metabolism by some other drugs frequently administered to psychiatric patients . Biol Psychiatry 2:53-58, 1970;.
35 +
Morselli PL, Rizzo M, Garattini S:  Interaction between phenobarbital and diphenylhydantoin in animals and in epileptic patients . Ann NY Acad Sci 179:88-107, 1971;.
36 +
Buchanan RA, Heffelfinger JC, Weiss CF:  The effect of phenobarbital on diphenylhydantoin metabolism in children . Pediatrics 43:114-116, 1969;.
37 +
Cucinell SA, et al:  Drug Interactions in man: I. Lowering effect of phenobarbital on plasma levels of bishydroxycoumarin (Dicoumarol) and diphenylhydantoin (Dilantin) . Clin Pharmacol Ther 6:420-429, 1965;.
38 +
Garrettson LK, Dayton PG:  Disappearance of phenobarbital and diphenylhydantoin from serum of children . Clin Pharmacol Ther 11:674-679, 1970;.
39 +
Kutt H, et al:  The effect of phenobarbital on plasma diphenylhydantoin level and metabolism in man and in rat liver microsomes . Neurology 19:611-616, 1969;.
40 +
Booker HE, Tormey A, Toussaint J:  Concurrent administration of phenobarbital and diphenylhydantoin: Lack of an interference effect . Neurology 21:383-385, 1971;.
41 +
Diamond WD, Buchanan RA:  A clinical study of the effect of phenobarbital on diphenylhydantoin plasma levels . J Clin Pharmacol 10:306-311, 1970;.
42 +
Kokenge R, Kutt H, McDowell F:  Neurological sequelae following Dilantin overdose in a patient and in experimental animals . Neurology 15:823-829, 1965;.
43 +
Vajda FJE, Prineas RJ, Lovell RRH:  Interaction between phenytoin and the benzodiazepines . Br Med J 1:346, 1971;.
44 +
Kutt H, McDowell F:  Management of epilepsy with diphenylhydantoin sodium . JAMA 203:969-972, 1968;.
45 +
Kariks J, Perry SW, Wood D:  Serum folic acid and phenytoin levels in permanently hospitalized epileptic patients receiving anticonvulsant therapy . Med J Aust 2:368-371, 1971;.
46 +
Solomon HM, Abrams WB:  Interactions between digitoxin and other drugs in man . Am Heart J 83:277-280, 1972;.
47 +
Kaldor A, et al:  Enhancement of methyldopa metabolism with barbiturate . Br Med J 3:518-519, 1971;.
48 +
Kristensen M, Jorgenson M, Hansen T:  Barbiturates and methyldopa metabolism . Br Med J 1:49, 1973;.
49 +
Burstein S, Klaiber EL:  Phenobarbital-induced increase in 6β-hydroxycortisol excretion: Clue to its significance in human urine . J Clin Endocrinol Metab 25:293-296, 1965;.
50 +
Brooks SM, et al:  Adverse effects of phenobarbital on corticosteroid metabolism in patients with bronchial asthma . N Engl J Med 286:1125-1128, 1972;.
51 +
Falliers CJ:  Corticosteroids and phenobarbital in asthma . N Engl J Med 287:201, 1972;.
52 +
Riegelman S, Rowland M, Epstein WL:  Griseofulvin-phenobarbital interaction in man . JAMA 213:426-431, 1970;.
53 +
Busfield D, et al:  An effect of phenobarbitone on blood levels of griseofulvin in man . Lancet 2:1042-1043, 1963;.

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