The study of heritable factors that determine how drugs are chemically metabolized in the body is called pharmacogenetics. This field addresses genetic differences among population segments that are responsible for variations in both the therapeutic and adverse effects of drugs. Investigations in pharmacogenetics are important not only because they may lead to more rational approaches to therapy, but also because they facilitate a deeper understanding of drug pharmacology. For further discussion, see Part V, Ocular Pharmacology.
The drug isoniazid provides an example of how pharmacogenetics works. This antituberculosis drug is normally inactivated by the liver enzyme acetyltransferase. A large segment of the population, which varies by geographic distribution, has a reduced amount of this enzyme; these individuals are termed slow inactivators. When they take isoniazid, the drug reaches higher-than-normal concentrations, causing a greater incidence of adverse effects. Family studies have shown that a reduced level of acetyltransferase is inherited as an autosomal recessive trait.
Several other well-documented examples demonstrate how pharmacogenetics works. An X-linked recessive trait, present in 10% of the African American male population, a high percentage of male Sephardic Jews (originally from around the Mediterranean Sea), and males from a number of other ethnic groups, causes a deficiency in the enzyme glucose-6-phosphate dehydrogenase in the erythrocytes of affected males. As a consequence, a number of drugs (including sulfacetamide, vitamin K, acetylsalicylic acid, quinine, chloroquine, dapsone, and probenecid) may produce acute hemolytic anemia in these individuals. Pharmacogenetic causes have also been ascribed to variations in response to ophthalmic drugs, such as the increased IOP noted in a segment of the population after prolonged use of topical corticosteroids.
Several drugs have been shown to cause greater reaction in children with Down syndrome than in children without the syndrome. As a result of hypersensitivity, some children with Down syndrome have died after systemic administration of atropine. This hypersensitivity is also found with topical use of atropine in some of these children. In these patients, atropine exerts a greater-than-normal effect on pupillary dilation. In several children with Down syndrome being treated for strabismus, hyperactivity occurred several hours after local instillation of echothiophate iodide, 0.125%.
One of the earliest examples of an inherited deficit in drug metabolism involved succinylcholine, a strong muscle relaxant that interferes with acetylcholinesterase, the enzyme that catabolizes acetylcholine at neuromuscular junctions. Normally, succinylcholine is rapidly destroyed by plasma cholinesterase (sometimes called pseudocholinesterase), so that its effect is short-lived—usually no more than a few minutes. Some individuals are homozygous for a recessive gene that codes for a form of cholinesterase with a considerably lower substrate affinity. Consequently, at therapeutic doses of succinylcholine, almost no destruction occurs, and the drug continues to exert its inhibitory effect on acetylcholinesterase, resulting in prolonged periods of apnea.
Excerpted from BCSC 2020-2021 series: Section 2 - Fundamentals and Principles of Ophthalmology. For more information and to purchase the entire series, please visit https://www.aao.org/bcsc.