Drug metabolism, action, and effects

Metabolism

Metabolism is a series of chemical processes whereby enzymes change drugs in the body. Metabolism is necessary so that medications can be cleared from the body. Active forms of drugs may be converted into water-soluble compounds, which are eventually excreted.

Most drug metabolism occurs in the liver. Younger children, older adults, and those with liver disease may have problems metabolizing medications. These populations could be at risk for drug toxicity. The dose of medication is adjusted for at-risk populations to prevent toxicity.

Prodrugs

Prodrugs are medications that are administered in an inactive form. Through the normal metabolic processes, the medication is changed into an active form of a drug. The liver and the intestines are sites that can convert prodrugs to active forms of drugs. For instance, sulfasalazine (Azulfidine) is an anti-inflammatory drug that is used to treat ulcerative colitis. It is also a prodrug because it is ingested in an inactive form. Bacteria in the colon change the drug into an active drug that the body will use.

Excretion

Excretion is the movement of metabolites out of the body. Most drugs are excreted through the large intestine and kidneys. The large intestine excretes the undigested drug products in the stool. The kidneys excrete metabolites in the urine. Clinical Laboratory Improvement Amendments (CLIA)–waived urine drug screening tests can detect certain metabolites.

Drugs can also be excreted in breast milk. This is critical information to have when a mother is breastfeeding her baby. As with pregnancy, only a limited number of drugs are safe with breastfeeding. Most drug references indicate if medications pass into the breast milk. Other ways drugs can be excreted are through sweat, exhaled air, and saliva.

Young children, older adults, and those with kidney disease are at risk for the buildup of metabolic drug by-products in the body. These populations are at greater risk for symptoms of toxicity.

Drug action

Drugs are chemicals that can cause changes in the cells. There are four main drug actions:

• Depressing: Slows down the cell’s activity. For example, narcotic medications reduce the activity in the brain’s respiratory center. This action slows the respiration rate.
• Stimulating: Increases the cell’s activity. For instance, caffeine increases brain activity.
• Destroying: Kills cells or disrupts parts of cells. For example, chemotherapy medications destroy cancer cells.
• Replacing substances: Substances required by the body can be given as medications. For instance, patients with type 1 diabetes mellitus take insulin.

Factors influencing drug action

One might think that a drug works the same for everyone. This is not so. Personal characteristics can cause minor differences in how a drug works from one person to another. Many factors influence drug action:

• Age: Infants and older adults have problems metabolizing and excreting medications. Their liver and kidneys are less effective. This can lead to possible drug accumulation and toxicity.
• Body size: A person’s size affects the amount of drug needed. Children’s dosages are calculated based on body weight. Thinner people require less medication than heavier people.
• Sex: Women have a higher proportion of body fat. Hormonal differences can affect metabolism. Women can react differently to some medications compared to men.
• Genetics: Genetic makeup can affect how a person responds to drugs. (This is discussed in more depth in the Pharmacogenomics section.)
• Diseases: Poor circulation, liver disease, and kidney disease can alter drug action.
• Diet: Certain foods can affect a drug’s action. For instance, milk products can diminish the effects of tetracycline, an antibiotic.
• Drug dosage, route, and timing of administration: The greater the amount of drug taken, the greater the effect will be. The route will also affect drug action. Drugs are absorbed, distributed, and metabolized differently based on the administration route. Some drugs work better when taken with food, whereas others do not.
• Mental state: People with positive attitudes tend to do better than those with negative attitudes.
• Environmental temperature: In hot weather, heat relaxes blood vessels. This can speed up the distribution of medication, thus speeding up the drug’s action.

Pharmacogenomics

Most medications are dosed as “one size fits all.” Each person’s genetic makeup affects how that person responds to medications. Pharmacogenomics or pharmacogenetics is the study of how genetic factors influence a person’s metabolic response to a specific medication.

Pharmacogenomics testing usually requires a small blood or saliva sample. The sample is analyzed to determine if a specific medication will be an effective treatment for an individual. Testing can determine the best dose of medication and if the person could have serious adverse reactions (unexpected or life-threatening reactions) to the medication. A different test is required for each medication. Pharmacogenomics is largely used in cancer treatments, but it is becoming more common in other areas of medicine.

Therapeutic effects

Medications can have local or systemic effects. Medication effects that are seen at the site of administration are local effects. Medication effects that are seen throughout the body are systemic effects. Each medication has one or more therapeutic effects, or desired effects. This is the intended action of the medication. For instance, the therapeutic effect of a pain reliever is to reduce pain.

Sometimes multiple doses are needed to achieve the therapeutic effect. Other times just one dose of medication can achieve the therapeutic effect. The provider may prescribe a higher initial dose for some medications, called a loading dose. This helps to quickly increase the medication level in the blood. A loading dose helps the person achieve the therapeutic range sooner. A maintenance dose is the amount of medication needed to keep the blood levels within the therapeutic range. If the blood levels go beyond the therapeutic range, the person can experience signs and symptoms of toxicity. This is considered a toxic dose of medication. A lethal dose is the amount of medication that could kill a person.

Adverse reactions

Most of the time, when a medication is correctly administered, the therapeutic effect occurs. However, sometimes issues arise, and the person has problems with the medication. The person can experience an unexpected or life-threatening reaction called an adverse reaction.

Common adverse reactions

ADVERSE REACTION	DESCRIPTION
Allergy	allergy occurs when a person develops antibodies against a specific drug. When the drug is taken, the antibodies attack the antigens from the drug. Tissues are damaged during this process, and histamines are released. Histamines cause the allergic reactions.
Anaphylaxis	xtreme hypersensitivity to a specific drug (antigen) can cause life-threatening symptoms, including swelling of the mouth and airway, difficulty breathing (dyspnea), wheezing, loss of consciousness, and death.
Idiosyncrasy	A peculiar response to a certain drug. For instance, Benadryl causes drowsiness. However, when it is given to children, they often get extremely agitated.
Cumulative effect	For medications taken routinely, often the prior dose is not completely metabolized and excreted before the next dose is given. This can lead to a buildup of medication or by-products that can produce toxic effects.
Toxicity	The harmful and possibly deadly effects of a medication that can develop due to the buildup of medication or by-products in the body. People with liver or kidney disease, young children, older adults, and those who overdose are at risk for toxicity.
Drug interactions	When two or more drugs are taken, sometimes a drug-drug interaction can occur. The interactions can be helpful or harmful. Three types of drug interactions can occur: • Antagonism: One drug reduces or blocks the effect of another drug. For example, naloxone is given for narcotic overdosage. • Synergism: The combined effect of two drugs used together is greater than the sum of each drug’s effect (e.g., 1 + 1 > 2). Example of a harmful interaction: Alcohol has a synergistic effect on antidepressants. • Potentiation: A type of synergism; one drug increases the effect of the second drug. With L-dopa and carbidopa, one drug has no effect but increases the effect of the other drug (e.g., 0 + 1 > 1).
Tolerance	The need for a larger dose to get the same therapeutic or desired effect. Tolerance can be seen when narcotic pain medications are taken with anticonvulsants.
Drug dependence	Strong psychological or physical need to take a certain drug. Withdrawal symptoms can be experienced when a person stops using a drug. Drug dependence can occur with or without addiction.