Genetic Makeup
Differences in genetic (inherited) makeup among individuals affect what the body does to a drug and what the drug does to the body. The study of genetic differences in the response to drugs is called pharmacogenetics.
Because of their genetic makeup, some people process (metabolize) drugs slowly; as a result, a drug may accumulate in the body, causing toxicity. Other people metabolize drugs so quickly that after they take a usual dose, drug levels in the blood never become high enough for the drug to be effective. Still others metabolize a drug given at the usual dose normally, but if the drug is given at a high dose or with another drug metabolized by the same enzyme system, the system may be overloaded, resulting in toxic levels of the first drug.
In about half of the people in the United States, N-acetyltransferase, a liver enzyme that metabolizes certain drugs, works slowly. In such people (called slow acetylators), drugs that are metabolized by this enzyme tend to reach higher blood levels and remain in the body longer than they do in people in whom this enzyme metabolizes drugs rapidly (fast acetylators).
About 1 of 1,500 people have low levels of pseudocholinesterase, a blood enzyme that inactivates drugs such as succinylcholine, which is given with an anesthetic during many surgical procedures to temporarily relax muscles. If succinylcholine is not rapidly inactivated, muscle relaxation may be prolonged, and people may not be able to breathe on their own as soon after surgery as is usual. They may need a ventilator for an extended time.
About 10% of black men and fewer black women have a deficiency of glucose-6-phosphate dehydrogenase (G6PD), an enzyme that protects red blood cells from certain toxic chemicals. For example, in people with G6PD deficiency, some drugs (such as chloroquine and primaquine, which are used to treat malaria) destroy red blood cells and cause hemolytic anemia (see Section 14, Chapter 172).
About 1 of 20,000 people have a genetic defect that makes muscles overly sensitive to anesthetics such as halothane, isoflurane, and sevoflurane. When such people are given one of these anesthetics with a muscle relaxant (usually succinylcholine), a life-threatening disorder called malignant hyperthermia may develop. It produces a very high fever. Muscles stiffen, the heart races, and blood pressure falls.
Some people have low levels of P-450 liver enzymes, which inactivate many drugs (see Section 2, Chapter 11). In such people, a drug's effects may be increased and prolonged. For example, the sedative effects of the sleep aid flurazepam can last much longer than usual and can cause drowsiness during the day.
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