Книги фарма 2 / Bertram G. Katzung-Basic & Clinical Pharmacology(9th Edition)

1Passive immunotherapy or immunoprophylaxis should always be administered as soon as possible after exposure. Prior to the administration of animal sera, patients should be questioned and tested for hypersensitivity.

2See the following references for an analysis of additional uses of intravenously administered immune globulin: Ratko TA et al: Recommendations for off-label use of intravenously administered immunoglobulin preparations. JAMA 1995;273:1865; and Dalakas MC: Intravenous immune globulin therapy for neurologic diseases. Ann Intern Med 1997;126:721.

3Centers for Disease Control and Prevention, 404-639-3670 during weekday business hours; 404- 639-2888 during nights,

weekends, and holidays (emergency requests only).

Legal Liability for Untoward Reactions

It is the physician's responsibility to inform the patient of the risk of immunization and to employ vaccines and antisera in an appropriate manner. This may require skin testing to assess the risk of an untoward reaction. Some of the risks described above are, however, currently unavoidable; on the 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 United States, 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 Food and Drug Administration, "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.

Katzung PHARMACOLOGY, 9e > Section X. Special Topics > Appendix I: Vaccines, Immune Globulins, & Other Complex Biologic Products >

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://www.cdc.gov/travel/vaccinat.htm. The Medical Letter on Drugs and Therapeutics also offers periodically updated recommendations for international travelers (see issue of April 15, 2002). 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.

Appendix II: Important Drug Interactions & Their Mechanisms

Katzung PHARMACOLOGY, 9e > Section X. Special Topics > Appendix II: Important Drug Interactions & Their Mechanisms >

Important Drug Interactions & Their Mechanisms: Introduction

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, or combined interactions. 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.

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. One must distinguish between effects on adsorption 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 will be clinically important if it results in subtherapeutic serum levels.

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. Induction (stimulation) of cytochrome P450 isozymes in the liver and small intestine can be caused by drugs such as barbiturates, carbamazepine, efavirenz, glutethimide, nevirapine, phenytoin, primidone, rifampin, and rifabutin. 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 drug is long, it may take a week or more to reach a new steady-state serum level. Drugs that may inhibit cytochrome P450 metabolism of other drugs include allopurinol, amiodarone, androgens, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, grapefruit juice, indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexiletine, miconazole, nefazodone, omeprazole, paroxetine, phenylbutazone, propoxyphene, quinidine, ritonavir, sulfonamides, verapamil, 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 Chapter 1: Introduction 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. The ABC transporter P-glycoprotein is involved in active tubular secretion of some drugs, and inhibition of this transporter can inhibit renal elimination with attendant increase in serum drug concentrations.

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. 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 countermeasures 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.

Katzung PHARMACOLOGY, 9e > Section X. Special Topics > Appendix II: Important Drug Interactions & Their Mechanisms >

Predictability of Drug Interactions

The designations listed in Table II–1 will be 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 do not always mean that the interaction is likely to produce an adverse effect. Whether the interaction occurs and produces an adverse effect or not depends upon (1) the presence or absence of factors that predispose to the adverse effects of the drug interaction (diseases, organ function, dose of drugs, etc) and (2) awareness on the part of the prescriber, so that appropriate monitoring can be ordered or preventive measures taken.

Table II–1. Important Drug Interactions.

HP = Highly predictable. Interaction occurs in almost all patients receiving the interacting combination.

P = Predictable. Interaction occurs in most patients receiving the combination.

NP = Not predictable. Interaction occurs only in some patients receiving the combination.

NE = Not established. Insufficient data available on which to base estimate of predictability.

Drug or Drug Properties Promoting Drug Clinically Documented Interactions Group Interaction

clotting factor catabolism?

Disulfiram: [P] Decreased warfarin metabolism.

Erythromycin: [NP] Probably inhibits anticoagulant metabolism.

Fluconazole: [P] Decreased warfarin metabolism.

Gemfibrozil: [NE] Mechanism not established.

Lovastatin: [NE] Probably decreased anticoagulant metabolism.

Metronidazole: [P] Decreased warfarin metabolism.

Miconazole: [NE] Decreased warfarin metabolism.

Nonsteroidal anti-inflammatory drugs: [P] Inhibition of platelet function, gastric erosions; some agents increase hypoprothrombinemic response (unlikely with diclofenac, ibuprofen, or naproxen).

Propafenone: [NE] Probably decreased anticoagulant metabolism.

Quinidine: [NP] Additive hypoprothrombinemia.

Salicylates: [HP] Platelet inhibition with aspirin but not with other salicylates; [P] large doses have hypoprothrombinemic effect.

Sulfinpyrazone: [NE] Inhibits warfarin metabolism.

Sulfonamides: [NE] Inhibit warfarin metabolism; displace protein binding.

Thyroid hormones: [P] Enhance clotting factor catabolism.

Trimethoprim-sulfamethoxazole: [P] Inhibits warfarin metabolism; displaces from protein binding.

See also Alcohol; Allopurinol.

Drugs that may decrease anticoagulant effect:

Aminoglutethimide: [P] Enzyme induction.

Barbiturates: [P] Enzyme induction.