Basic and Clinical Pharmacology, 13th Ed.

Important Drug Interactions & Their Mechanisms

John R. Horn, PharmD, FCCP

One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorized as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic (additive, synergistic, or antagonistic effects), or combined interactions. The general principles of pharmacokinetics are discussed in Chapters 3 and 4; the general principles of pharmacodynamics in Chapter 2.

Botanical medications (“herbals”) may interact with each other or with conventional drugs. Unfortunately, botanicals are much less well studied than other drugs, so information about their interactions is scanty. Pharmacodynamic herbal interactions are described in Chapter 64. Pharmacokinetic interactions that have been documented (eg, St. John’s wort) are listed in Table 66–1.

TABLE 66-1 Important drug interactions.

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Knowledge of the mechanism by which a given drug interaction occurs is often clinically useful, since the mechanism may influence both the time course and the methods of circumventing the interaction. Some important drug interactions occur as a result of two or more mechanisms.

image PREDICTABILITY OF DRUG INTERACTIONS

The designations listed in Table 66–1 are used here to estimate the predictability of the drug interactions. These estimates are intended to indicate simply whether or not the interaction will occur, and they do not always mean that the interaction is likely to produce an adverse effect. Whether or not the interaction occurs (precipitant drug produces a measurable change in the object drug) and produces an adverse effect depends on both patient- and drug-specific factors. Patient factors can include intrinsic drug clearance, genetics, gender, concurrent diseases, and diet. Drug-specific factors include dose, route of administration, drug formulation, and the sequence of drug administration. The most important factor that can mitigate the risk of patient harm is recognition by the prescriber of a potential interaction followed by appropriate action.

PHARMACOKINETIC MECHANISMS

The gastrointestinal absorption of drugs may be affected by concurrent use of other agents that (1) have a large surface area upon which the drug can be adsorbed, (2) bind or chelate, (3) alter gastric pH, (4) alter gastrointestinal motility, or (5) affect transport proteins such as P-glycoprotein and organic anion transporters. One must distinguish between effects on absorption rate and effects on extent of absorption. A reduction in only the absorption rate of a drug is seldom clinically important, whereas a reduction in the extent of absorption is clinically important if it results in subtherapeutic serum concentrations.

The mechanisms by which drug interactions alter drug distribution include (1) competition for plasma protein binding, (2) displacement from tissue binding sites, and (3) alterations in local tissue barriers, eg, P-glycoprotein inhibition in the blood-brain barrier. Although competition for plasma protein binding can increase the free concentration (and thus the effect) of the displaced drug in plasma, the increase will be transient owing to a compensatory increase in drug disposition. The clinical importance of protein binding displacement has been overemphasized; current evidence suggests that such interactions are unlikely to result in adverse effects. Displacement from tissue binding sites would tend to transiently increase the blood concentration of the displaced drug.

The metabolism of drugs can be stimulated or inhibited by concurrent therapy, and the importance of the effect varies from negligible to dramatic. Drug metabolism primarily occurs in the liver and the wall of the small intestine, but other sites include plasma, lung, and kidney. Induction (stimulation) of cytochrome P450 isozymes in the liver and small intestine can be caused by drugs such as barbiturates, bosentan, carbamazepine, efavirenz, nevirapine, phenytoin, primidone, rifampin, rifabutin, and St. John’s wort. Enzyme inducers can also increase the activity of phase II metabolism such as glucuronidation. Enzyme induction does not take place quickly; maximal effects usually occur after 7–10 days and require an equal or longer time to dissipate after the enzyme inducer is stopped. Rifampin, however, may produce enzyme induction after only a few doses. Inhibition of metabolism generally takes place more quickly than enzyme induction and may begin as soon as sufficient tissue concentration of the inhibitor is achieved. However, if the half-life of the affected (object) drug is long, it may take a week or more (three to four half-lives) to reach a new steady-state serum concentration. Drugs that may inhibit the cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexiletine, miconazole, omeprazole, paroxetine, quinidine, ritonavir, sulfamethizole, sulfamethoxazole, verapamil, voriconazole, zafirlukast, and zileuton.

The renal excretion of active drug can also be affected by concurrent drug therapy. The renal excretion of certain drugs that are weak acids or weak bases may be influenced by other drugs that affect urinary pH. This is due to changes in ionization of the drug, as described in 1 under Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation. For some drugs, active secretion into the renal tubules is an important elimination pathway. P-glycoprotein, organic anion transporters, and organic cation transporters are involved in active tubular secretion of some drugs, and inhibition of these transporters can inhibit renal elimination with attendant increase in serum drug concentrations. Drugs that are partially eliminated by P-glycoprotein include digoxin, cyclosporine, dabigatran, colchicine, daunorubicin, and tacrolimus. The plasma concentration of these drugs can be increased by inhibitors of P-glycoprotein including amiodarone, clarithromycin, erythromycin, ketoconazole, ritonavir, and quinidine.

PHARMACODYNAMIC MECHANISMS

When drugs with similar pharmacologic effects are administered concurrently, an additive or synergistic response is usually seen. The two drugs may or may not act on the same receptor to produce such effects. In theory, drugs acting on the same receptor or process are usually additive, eg, benzodiazepines plus barbiturates. Drugs acting on different receptors or sequential processes may be synergistic, eg, nitrates plus sildenafil or sulfonamides plus trimethoprim. Conversely, drugs with opposing pharmacologic effects may reduce the response to one or both drugs. Pharmacodynamic drug interactions are relatively common in clinical practice, but adverse effects can usually be minimized if one understands the pharmacology of the drugs involved. In this way, the interactions can be anticipated and appropriate counter-measures taken.

COMBINED TOXICITY

The combined use of two or more drugs, each of which has toxic effects on the same organ, can greatly increase the likelihood of organ damage. For example, concurrent administration of two nephrotoxic drugs can produce kidney damage, even though the dose of either drug alone may have been insufficient to produce toxicity. Furthermore, some drugs can enhance the organ toxicity of another drug, even though the enhancing drug has no intrinsic toxic effect on that organ.

REFERENCES

Boobis A et al: Drug interactions. Drug Metab Rev 2009;41:486.

DeGorter MK et al: Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol Toxicol 2012;52:249.

DuBuske LM: The role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions. Drug Saf 2005;28:789.

Hansten PD, Horn JR: Drug Interactions Analysis and Management. Facts & Comparisons. 2013. [Quarterly.]

Hansten PD, Horn JR: The Top 100 Drug Interactions. A Guide to Patient Management. H&H Publications, 2014.

Hillgren KM et al: Emerging transporters of clinical importance: An update from the international transporter consortium. Clin Pharmacol Ther 2013;94:52.

Horn JR et al: Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41:674.

Hukkanen J: Induction of cytochrome P450 enzymes: A view on human in vivo findings. Expert Rev Clin Pharmacol 2012;5:569.

Juurlink DN et al: Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003;289:1652.

Leucuta SE, Vlase L: Pharmacokinetics and metabolic drug interactions. Curr Clin Pharmacol 2006;1:5.

Lin JH, Yamazaki M: Role of P-glycoprotein in pharmacokinetics: Clinical implications. Clin Pharmacokinet 2003;42:59.

Pelkonen O et al: Inhibition and induction of human cytochrome P450 enzymes: Current status. Arch Toxicol 2008;82:667.

Roberts JA, et al: The clinical relevance of plasma protein binding changes. Clin Pharmacokinet 2013;52:1.

Tatro DS (editor): Drug Interaction Facts. Facts & Comparisons. 2011. [ Quarterly.]

Thelen K, Dressman JB: Cytochrome P540-mediated metabolism in the human gut wall. J Pharm Pharmacol 2009;61:541.

Williamson EM: Drug interactions between herbal and prescription medicines. Drug Saf 2003;26:1075.

Appendix: Vaccines, Immune Globulins, & Other Complex Biologic Products

Harry W. Lampiris, MD, & Daniel S. Maddix, PharmD

Vaccines and related biologic products constitute an important group of agents that bridge the disciplines of microbiology, infectious diseases, immunology, and immunopharmacology. A list of the most important preparations is provided here. The reader who requires more complete information is referred to the sources listed at the end of this appendix.

ACTIVE IMMUNIZATION

Active immunization consists of the administration of antigen to the host to induce formation of antibodies and cell-mediated immunity. Immunization is practiced to induce protection against many infectious agents and may utilize either inactivated (killed) materials or live attenuated agents (Table A–1). Desirable features of the ideal immunogen include complete prevention of disease, prevention of the carrier state, production of prolonged immunity with a minimum of immunizations, absence of toxicity, and suitability for mass immunization (eg, cheap and easy to administer). Active immunization is generally preferable to passive immunization—in most cases because higher antibody levels are sustained for longer periods of time, requiring less frequent immunization, and in some cases because of the development of concurrent cell-mediated immunity. However, active immunization requires time to develop and is therefore generally inactive at the time of a specific exposure (eg, for parenteral exposure to hepatitis B, concurrent hepatitis B IgG [passive antibodies] and active immunization are given to prevent illness).

TABLE A–1 Materials commonly used for active immunization in the United States.1

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Current recommendations for routine active immunization of children are given in Table A–2.

TABLE A–2 Recommended routine childhood immunization schedule.

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PASSIVE IMMUNIZATION

Passive immunization consists of transfer of immunity to a host using preformed immunologic products. From a practical standpoint, only immunoglobulins have been used for passive immunization, because passive administration of cellular components of the immune system has been technically difficult and associated with graft-versus-host reactions. Products of the cellular immune system (eg, interferons) have also been used in the therapy of a wide variety of hematologic and infectious diseases (see Chapter 55).

Passive immunization with antibodies may be accomplished with either animal or human immunoglobulins in varying degrees of purity. These may contain relatively high titers of antibodies directed against a specific antigen or, as is true for pooled immune globulin, may simply contain antibodies found in most of the population. Passive immunization is useful for (1) individuals unable to form antibodies (eg, congenital agammaglobulinemia); (2) prevention of disease when time does not permit active immunization (eg, postexposure); (3) for treatment of certain diseases normally prevented by immunization (eg, tetanus); and (4) for treatment of conditions for which active immunization is unavailable or impractical (eg, snakebite).

Complications from administration of human immunoglobulins are rare. The injections may be moderately painful and rarely a sterile abscess may occur at the injection site. Transient hypotension and pruritus occasionally occur with the administration of intravenous immune globulin (IVIG) products, but generally are mild. Individuals with certain immunoglobulin deficiency states (IgA deficiency, etc) may occasionally develop hypersensitivity reactions to immune globulin that may limit therapy. Conventional immune globulin contains aggregates of IgG; it will cause severe reactions if given intravenously. However, if the passively administered antibodies are derived from animalsera, hypersensitivity reactions ranging from anaphylaxis to serum sickness may occur. Highly purified immunoglobulins, especially from rodents or lagomorphs, are the least likely to cause reactions. To avoid anaphylactic reactions, tests for hypersensitivity to the animal serum must be performed. If an alternative preparation is not available and administration of the specific antibody is deemed essential, desensitization can be carried out.

Antibodies derived from human serum not only avoid the risk of hypersensitivity reactions but also have a much longer half-life in humans (about 23 days for IgG antibodies) than those from animal sources (5–7 days or less). Consequently, much smaller doses of human antibody can be administered to provide therapeutic concentrations for several weeks. These advantages point to the desirability of using human antibodies for passive protection whenever possible. Materials available for passive immunization are summarized in Table A–3.

TABLE A–3 Materials available for passive immunization.1

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LEGAL LIABILITY FOR UNTOWARD REACTIONS

It is the physician’s responsibility to inform the patient of the risk of immunization and to use vaccines and antisera in an appropriate manner. This may require skin testing to assess the risk of an untoward reaction. Some of the risks previously described are, however, currently unavoidable; on balance, the patient and society are clearly better off accepting the risks for routinely administered immunogens (eg, influenza and tetanus vaccines).

Manufacturers should be held legally accountable for failure to adhere to existing standards for production of biologicals. However, in the present litigious atmosphere of the USA, the filing of large liability claims by the statistically inevitable victims of good public health practice has caused many manufacturers to abandon efforts to develop and produce low-profit but medically valuable therapeutic agents such as vaccines. Since the use and sale of these products are subject to careful review and approval by government bodies such as the Surgeon General’s Advisory Committee on Immunization Practices and the FDA, “strict product liability” (liability without fault) may be an inappropriate legal standard to apply when rare reactions to biologicals, produced and administered according to government guidelines, are involved.

RECOMMENDED IMMUNIZATION OF ADULTS FOR TRAVEL

Every adult, whether traveling or not, should be immunized with tetanus toxoid and should also be fully immunized against poliomyelitis, measles (for those born after 1956), and diphtheria. In addition, every traveler must fulfill the immunization requirements of the health authorities of the countries to be visited. These are listed in Health Information for International Travel, available from the Superintendent of Documents, United States Government Printing Office, Washington, DC 20402. A useful website is http://wwwnc.cdc.gov/travel/The Medical Letter on Drugs and Therapeutics also offers periodically updated recommendations for international travelers (see Treatment Guidelines from The Medical Letter, 2012;10:45). Immunizations received in preparation for travel should be recorded on the International Certificate of Immunization. Note: Smallpox vaccination is not recommended or required for travel in any country.

REFERENCES

Ada G: Vaccines and vaccination. N Engl J Med 2001;345:1042.

Advice for travelers. Treat Guidel Med Lett 2012;10:45.

Avery RK: Immunizations in adult immunocompromised patients: Which to use and which to avoid. Cleve Clin J Med 2001;68:337.

CDC websites: http://www.cdc.gov/vaccines/ and http://wwwnc.cdc.gov/travel/

Centers for Disease Control and Prevention: Advisory Committee on Immunization Practices (ACIP) recommended immunization schedules for persons aged 0 through 18 years and adults aged 19 years and older—United States, 2013. MMWR Morb Mortal Wkly Rep 2013:62(Suppl 1):1.

Dennehy PH: Active immunization in the United States: Developments over the past decade. Clin Micro Rev 2001;14:872.

Gardner P, Peter G: Vaccine recommendations: Challenges and controversies. Infect Dis Clin North Am 2001;15:1.

Gardner P et al: Guidelines for quality standards for immunization. Clin Infect Dis 2002;35:503.

General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2011;60(2):1.

Hill DR et al: The practice of travel medicine: Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1499.

Keller MA, Stiehm ER: Passive immunity in prevention and treatment of infectious diseases. Clin Microbiol Rev 2000;13:602.

Pickering LK et al: Immunization programs for infants, children, adolescents, and adults: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:817.

Zumula A et al: Travel medicine. Infect Dis Clin North Am 2012;26:575.


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