Drug interactions

CHAPTER 6


Drug interactions


In this chapter we consider the interactions of drugs with other drugs, with foods, and with dietary supplements. Our principal focus is on the mechanisms and clinical consequences of drug-drug interactions and drug-food interactions. Drug-supplement interactions are discussed briefly here and at greater length in Chapter 108.




Drug-drug interactions


Drug-drug interactions can occur whenever a patient takes two or more drugs. Some interactions are both intended and desired, as when we combine drugs to treat hypertension. In contrast, some interactions are both unintended and undesired, as when we precipitate malignant hyperthermia in a patient receiving halothane and succinylcholine. Some adverse interactions are well known, and hence generally avoidable. Others are yet to be documented.


Drug interactions occur because patients frequently take more than one drug. They may take multiple drugs to treat a single disorder. They may have multiple disorders that require treatment with different drugs. They may take over-the-counter drugs in addition to prescription medicines. And they may take caffeine, nicotine, alcohol, and other drugs that have nothing to do with illness.


Our objective in this chapter is to establish an overview of drug interactions, emphasizing the basic mechanisms by which drugs can interact. We will not attempt to catalog the huge number of specific interactions that are known. For information on interactions of specific drugs, you can refer to the chapters in which those drugs are discussed.



Consequences of drug-drug interactions


When two drugs interact, there are three possible outcomes: (1) one drug may intensify the effects of the other, (2) one drug may reduce the effects of the other, or (3) the combination may produce a new response not seen with either drug alone.



Intensification of effects

When a patient is taking two medications, one drug may intensify the effects of the other. This type of interaction is often termed potentiative. Potentiative interactions may be beneficial or detrimental. A potentiative interaction that enhances therapeutic effects is clearly beneficial. Conversely, a potentiative interaction that intensifies adverse effects is clearly detrimental. Examples of beneficial and detrimental potentiative interactions follow.





Reduction of effects

Interactions that result in reduced drug effects are often termed inhibitory. As with potentiative interactions, inhibitory interactions can be beneficial or detrimental. Inhibitory interactions that reduce toxicity are beneficial. Conversely, inhibitory interactions that reduce therapeutic effects are detrimental. Examples follow.






Basic mechanisms of drug-drug interactions


Drugs can interact through four basic mechanisms: (1) direct chemical or physical interaction, (2) pharmacokinetic interaction, (3) pharmacodynamic interaction, and (4) combined toxicity.



Direct chemical or physical interactions

Some drugs, because of their physical or chemical properties, can undergo direct interaction with other drugs. Direct physical and chemical interactions usually render both drugs inactive.


Direct interactions occur most commonly when drugs are combined in IV solutions. Frequently, but not always, the interaction produces a precipitate. If a precipitate appears when drugs are mixed together, that solution should be discarded. Keep in mind, however, that direct drug interactions may not always leave visible evidence. Hence you cannot rely on simple inspection to reveal all direct interactions. Because drugs can interact in solution, never combine two or more drugs in the same container unless it has been established that a direct interaction will not occur.


The same kinds of interactions that can take place when drugs are mixed together in a bottle can also occur when drugs are mixed together in the patient. However, since drugs are diluted in body water following administration, and since dilution decreases chemical interactions, significant interactions within the patient are much less likely than in a bottle.



Pharmacokinetic interactions

Drug interactions can affect all four of the basic pharmacokinetic processes. That is, when two drugs are taken together, one may alter the absorption, distribution, metabolism, or excretion of the other.



Altered absorption.

Drug absorption may be enhanced or reduced by drug interactions. In some cases, these interactions have great clinical significance. There are several mechanisms by which one drug can alter the absorption of another:



• By elevating gastric pH, antacids can decrease the ionization of basic drugs in the stomach, thereby increasing the ability of basic drugs to cross membranes and be absorbed. Antacids have the opposite effect on acidic drugs.


• Laxatives can reduce absorption of other oral drugs by accelerating their passage through the intestine.


• Drugs that depress peristalsis (eg, morphine, atropine) prolong drug transit time in the intestine, thereby increasing the time for absorption.


• Drugs that induce vomiting can decrease absorption of oral drugs.


• Cholestyramine and certain other adsorbent drugs, which are administered orally but do not undergo absorption, can adsorb other drugs onto themselves, thereby preventing absorption of the other drugs into the blood.


• Drugs that reduce regional blood flow can reduce absorption of other drugs from that region. For example, when epinephrine is injected together with a local anesthetic (as is often done), the epinephrine causes local vasoconstriction, thereby reducing regional blood flow and delaying absorption of the anesthetic.



Altered distribution.

There are two principal mechanisms by which one drug can alter the distribution of another: (1) competition for protein binding and (2) alteration of extracellular pH.










Alteration of extracellular pH.


Because of the pH partitioning effect (see Chapter 4), a drug with the ability to change extracellular pH can alter the distribution of other drugs. For example, if a drug were to increase extracellular pH, that drug would increase the ionization of acidic drugs in extracellular fluids (ie, plasma and interstitial fluid). As a result, acidic drugs would be drawn from within cells (where the pH was below that of the extracellular fluid) into the extracellular space. Hence, the alteration in pH would change drug distribution.


The ability of drugs to alter pH and thereby alter the distribution of other drugs can be put to practical use in the management of poisoning. For example, symptoms of aspirin toxicity can be reduced with sodium bicarbonate, a drug that elevates extracellular pH. By increasing the pH outside cells, bicarbonate causes aspirin to move from intracellular sites into the interstitial fluid and plasma, thereby minimizing injury to cells.




Altered metabolism.

Altered metabolism is one of the most important—and most complex—mechanisms by which drugs interact. Some drugs increase the metabolism of other drugs, and some drugs decrease the metabolism of other drugs. Drugs that increase the metabolism of other drugs do so by inducing synthesis of hepatic drug-metabolizing enzymes. Drugs that decrease the metabolism of other drugs do so by inhibiting those enzymes.


As we discussed in Chapter 4, the majority of drug metabolism is catalyzed by the cytochrome P450 (CYP) group of enzymes, which is composed of a large number of isozymes (closely related enzymes). Of all the isozymes in the P450 group, five are responsible for the metabolism of most drugs. These five isozymes of CYP are designated CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Table 6–1 lists major drugs that are metabolized by each isozyme, and indicates drugs that can inhibit or induce those isozymes.



TABLE 6–1 


Drugs That Are Important Substrates, Inhibitors, or Inducers of Specific CYP Isozymes













































CYP Substrates Inhibitors Inducers
CYP1A2 CNS Drugs: amitriptyline, clomipramine, clozapine, desipramine, duloxetine, fluvoxamine, haloperidol, imipramine, methadone, ramelteon, rasagiline, ropinirole, tacrine
Others: theophylline, tizanidine, warfarin		 Acyclovir
Ciprofloxacin
Ethinyl estradiol
Fluvoxamine
Isoniazid
Norfloxacin
Oral contraceptives
Zafirlukast
Zileuton		   Carbamazepine
Phenobarbital
Phenytoin
Primidone
Rifampin
Ritonavir
Tobacco
St. John’s wort
CYP2C9 Diazepam, phenytoin, ramelteon, voriconazole, warfarin Amiodarone
Azole antifungals
Efavirenz
Fenofibrate
Fluorouracil
Fluoxetine		 Fluvastatin
Fluvoxamine
Gemfibrozil
Isoniazid
Leflunomide
Zafirlukast		 Aprepitant
Carbamazepine
Phenobarbital
Phenytoin
Primidone
Rifampin
Rifapentine
Ritonavir
St. John’s wort
CYP2C19 Citalopram, clopidogrel, methadone, phenytoin, thioridazine, voriconazole Chloramphenicol
Cimetidine
Esomeprazole
Etravirine
Felbamate
Fluconazole
Fluoxetine		 Fluvoxamine
Isoniazid
Ketoconazole
Lansoprazole
Modafinil
Omeprazole
Ticlopidine
Voriconazole		 Carbamazepine
Phenobarbital
Phenytoin
St. John’s wort
Tipranavir/ritonavir
CYP2D6 CNS Drugs: amitriptyline, atomoxetine, clozapine, desipramine, donepezil, doxepin, duloxetine, fentanyl, haloperidol, iloperidone, imipramine, meperidine, nortriptyline, propoxyphene, tetrabenazine, thioridazine, tramadol, trazodone
Antidysrhythmic Drugs: flecainide, mexiletine, propafenone
Beta Blocker: metoprolol
Opioids: codeine, dextromethorphan, hydrocodone		 Amiodarone
Cimetidine
Darifenacin
Darunavir/ritonavir
Duloxetine
Fluoxetine
Methadone		 Paroxetine
Propoxyphene
Propranolol
Quinidine
Ritonavir
Sertraline
Tipranavir/ritonavir		 Not an inducible enzyme
CYP3A4 Antibacterials/Antifungals: clarithromycin, erythromycin, ketoconazole, itraconazole, rifabutin, telithromycin, voriconazole,
Anticancer Drugs: busulfan, dasatinib, doxorubicin, erlotinib, etoposide, ixabepilone, lapatinib, paclitaxel, pazopanib, romidepsin, sunitinib, tamoxifen, vinblastine, vincristine
Calcium Channel Blockers: amlodipine, felodipine, isradipine, nifedipine, nimodipine, nisoldipine, verapamil
Drugs for HIV Infections: amprenavir, darunavir, etravirine, indinavir, maraviroc, nelfinavir, ritonavir, saquinavir, tipranavir
Drugs for Erectile Dysfunction: sildenafil, tadalafil, vardenafil
Drugs for Urge Incontinence: darifenacin, fesoterodine, solifenacin, tolterodine
Immunosuppressants: cyclosporine, everolimus, sirolimus, tacrolimus
Opioids: alfentanil, alfuzosin, fentanyl, methadone, oxycodone
Sedative-Hypnotics: alprazolam, eszopiclone, midazolam, ramelteon, triazolam		 Amiodarone
Amprenavir
Aprepitant
Atazanavir
Azole antifungals
Chloramphenicol
Cimetidine
Clarithromycin
Conivaptan
Cyclosporine
Darunavir/ritonavir
Delavirdine
Diltiazem
Dronedarone
Erythromycin
Fluvoxamine
Fosamprenavir
Grapefruit juice		 Indinavir
Isoniazid
Methylprednisolone
Nefazodone
Nelfinavir
Nicardipine
Nifedipine
Norfloxacin
Pazopanib
Prednisone
Quinine
Ritonavir
Saquinavir
Synercid
Telithromycin
Tipranavir/ritonavir
Verapamil		 Amprenavir
Aprepitant
Bosentan
Carbamazepine
Dexamethasone
Efavirenz
Ethosuximide
Etravirine
Garlic supplements
Nevirapine
Oxcarbazepine
Phenobarbital
Phenytoin
Primidone
Rifabutin
Rifampin
Rifapentine
Ritonavir
St. John’s wort
  Statins: atorvastatin, lovastatin, simvastatin
Antidysrhythmics Drugs: disopyramide, dronedarone, lidocaine, quinidine
Others: aprepitant, bosentan, cinacalcet, cisapride, colchicine, conivaptan, dihydroergotamine, dronabinol, eplerenone, ergotamine, estrogens, ethosuximide, fluticasone, guanfacine, iloperidone, ondansetron, oral contraceptives, pimozide, ranolazine, saxagliptin, sertraline, silodosin, tiagabine, tolvaptan, trazodone, warfarin		 (See p. 61) (See p. 61)
< div class='tao-gold-member'>

Related posts:

  1. Orientation to pharmacology
  2. Drug therapy during pregnancy and breast-feeding
  3. Drug abuse III: nicotine and smoking
  4. Review of the immune system

Stay updated, free articles. Join our Telegram channel
Tags:
Jul 24, 2016 | Posted by in NURSING | Comments Off on Drug interactions

Full access? Get Clinical Tree
Get Clinical Tree app for offline access