Drug Metabolism/Interactions

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Drug Metabolism/Interactions

Definition

Drug metabolism is the process by which the body breaks down and converts medication into active chemical substances.

Precautions

Drugs can interact with other drugs, foods, and beverages. Interactions can lessen or magnify the desired therapeutic effect of a drug, or may cause unwanted or unexpected side effects. There are thousands of possible drug-to-drug and drug-to-food interactions, and many medications and supplements are contraindicated (not recommended) under certain conditions or in patients with specific diseases and disorders. This is why it is imperative that patients always keep their physician fully informed about all drugs and dietary supplements (including herbal remedies) they are taking.

Description

The primary site of drug metabolism is the liver, the organ that plays a major role in metabolism, digestion, detoxification, and elimination of substances from the body. Enzymes in the liver are responsible for chemically changing drug components into substances known as metabolites. Metabolites are then bound to other substances for excretion through the lungs, or bodily fluids such as saliva, sweat, breast milk, and urine, or through reabsorption by the intestines. The primary mode of excretion is through the kidneys.

The family of liver isoenzymes known as cytochrome P-450 are crucial to drug metabolism. These enzymes (labeled CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) have a catabolic action on substances, breaking them down into metabolites. Consequently, they also act to lower the concentration of medication in the bloodstream.

Drug interactions can occur when one drug inhibits or induces a P-450 that acts on another drug. An example is nicotine, a drug contained in tobacco, and known to induce P-450s. Individuals with liver disease (e.g., cirrhosis ) may also have insufficient levels of P-450 enzymes. As a result, the concentration of drugs metabolized by these enzymes (e.g., amprenavir and other protease inhibitors ) remains high and can build up to toxic levels in the bloodstream. In addition, certain medications and foods, such as grapefruit juice, can inactivate or lessen the metabolic activity of P-450s. Changing the drug dosage can alleviate the problem in some cases.

The metabolic rate can vary significantly from person to person, and drug dosages that work quickly and effectively in one individual may not work well for another. Factors such as genetics, environment, nutrition, and age also influence drug metabolism; infants and elderly patients may have a reduced capacity to metabolize certain drugs, and may require adjustments in dosage.

Causes and symptoms

Drugs that commonly interact with other medications include:

Diuretics. Diuretics such as hydrochlorothiazide can reduce serum potassium and sodium electrolyte levels when taken with digoxin and lithium, respectively.
Monoamine oxidase inhibitors (MAOIs). MAOI antidepressants can cause convulsions and other serious side effects when used with tricyclic antidepressants (e.g., Imipramine, Nortriptyline), selective serotonin reuptake inhibitors (SSRIs), or sympathomimetic drugs (e.g., amphetamines).
Antibiotics. Antibiotics may reduce the efficiency of oral contraceptives.
Metals. Medications containing metals, such as antacids with aluminum additives and iron supplements, can reduce the absorption of tetracyclines and fluoroquinolones.
Drugs that inhibit liver enzyme function. Drugs that slow drug metabolism include ciprofloxacin, erythromycin, fluoxetine, nefazodone, paroxetine, and ritonavir. The therapeutic effect of other medications taken with these drugs may be amplified. Warfarin, a blood thinner, should be used with great caution in individuals taking these drugs.

Foods and beverages that may interact with drugs include:

Grapefruit juice. Grapefruit juice inhibits the metabolism of many medications, including cyclosporine, felodipine, nifedipine, nitrendipine, nisoldipine, carbamazepine, triazolam, and midazolam.
Foods and beverages with tyramines. Red wine, malted beers, smoked foods (e.g., fish and meats), dried fruits, and aged cheeses may contain tyramines, and can cause a severe and dangerous elevation in blood pressure when taken with MAOI inhibitors (a class of antidepressants).
Dairy products. Milk, cream, and other dairy products containing calcium can prevention the absorption of antibiotics such as tetracycline, doxycycline, and ciprofloxacin when they are taken with the drug. In addition, whole milk with vitamin D can cause milk-alkali syndrome in patients taking aluminum hydroxide antacids.
Caffeinated beverages. The caffeine contained in coffee and colas can influence drug metabolism.
Alcohol. Alcohol is a central nervous system depressant, and should not be taken with other CNS depressants (e.g., antipsychotics, antihistamines ). In addition, certain fermented beverages may contain tyramines.

This list is not all-inclusive and individuals should always let their doctor and pharmacist know when they are taking other medications, herbal remedies, or dietary supplements. Anyone who experiences a serious reaction to a drug that is not consistent with its product labeling should report the event to their doctor and/or the MedWatch adverse event reporting system of the United States Food and Drug Administration (FDA).

Alternative treatment

The growing use of herbal supplements has also increased the opportunity for adverse drug and herbal interactions. In 2000, the FDA issued a warning on the popular herb St. John's wort (Hypericum perforatum ). The supplement was found to inhibit the effect of indinavir, a protease inhibitor used in the treatment of HIV. It may also affect the action of cyclosporine and other protease inhibitors (e.g., amprenavir, ritonavir). Further clinical studies are still necessary to determine the full metabolic effects of the herb.

Other herbs which may interact with allopathic medications include gingko bilboa, ginseng, and garlic, which may all heighten the blood thinning effect of the anticoagulant warfarin. Because herbs are regulated by the FDA as dietary supplements, they do not require the same extensive clinical trials and premarket testing as drugs do before they are cleared for sale in the United States. As such, there is still much to learn about the potential interactions and adverse effects associated with herbal supplements. Individuals who experience serious side effects from dietary supplements should report them to FDA's MedWatch program.

Diagnosis

Drug interactions can be difficult to detect. In some cases, adverse reactions may closely resemble the symptoms of the disease or condition the medication was prescribed to treat. Patients who take a number of medications or self-treat with over-the-counter drugs and/or herbal remedies may not be able to determine which drug actually triggered the interaction. A 2001 study by University of Florida researchers found that less than half of the women participating disclosed their use of herbal therapies to their healthcare providers. In cases where a serious drug or herb interaction occurs, withholding this information can delay diagnosis and put the patient at increased risk.

Treatment

Treatment of a drug interaction is dependant on a number of factors, including the medication(s) or supplements used and the medical history of the patient. A dosage adjustment may reverse the effects of some interactions. Serious or life-threatening interactions will require more aggressive therapies.

Prevention

Patients with chronic health conditions, particularly those with liver disorders, should always inform their healthcare professional before taking any over-the-counter (OTC) medications or dietary supplements. Because of the risk for a drug-to-drug interaction, individuals should also let their doctor know if they are taking drugs prescribed by other physicians. Individuals should closely follow instructions for use and package directions on both prescription and over-the-counter drugs. Consulting with a pharmacist and/or physician may be beneficial if package directions are unclear to the patient.

As a rule, grapefruit juice should not be taken with medication unless recommended by a doctor. Patients taking MAOI inhibitors should always check food and beverage labels to ensure tyramines are not included, and should avoid all fermented drinks.

KEY TERMS

Catabolism— A process of metabolism that breaks down complex substances into simple ones.

Cirrhosis— Liver disease characterized by the widespread disruption of the normal liver structure and function.

CNS depressant— Anything that depresses, or slows, the sympathetic impulses of the central nervous system (i.e., respiratory rate, heart rate).

Drug interaction— A chemical or physiological reaction that can occur when two different drugs are taken together.

Enzymes— Organic substances (proteins) composed of amino acids that trigger and regulate chemical reactions in the body. There are over 700 identified human enzymes.

Liver— A solid organ located on the right in the upper abdomen. It plays a major role in metabolism, digestion, detoxification, and elimination of substances from the body.

Metabolism— The sum of all the physical and chemical processes occurring in the body to organize and maintain life.

Metabolites— Substances produced by metabolism or by a metabolic process.

Milk-alkali syndrome— Elevated blood calcium levels and alkalosis caused by excessive intake of milk and alkalis. Usually occurs in the treatment of peptic ulcer.