In therapeutics, a drug typically produces numerous effects, but usually only one is sought as the primary goal of treatment; most of the other effects are referred to as undesirable effects of that drug for that therapeutic indication. Side effects of drugs usually are nondeleterious; they include effects such as dry mouth occurring with tricyclic antidepressant therapy. Some side effects may be adverse or toxic. Mechanistic categorization of toxic effects is a necessary prelude to their avoidance or, if they occur, to effect their rational and successful management.
types of toxic reactions Toxic effects of drugs may be classified as pharmacological, pathological, or genotoxic (alterations of DNA), and their incidence and seriousness are related, at least over some range, to the concentration of the toxic chemical in the body. An example of a pharmacological toxicity is excessive depression of the central nervous system (CNS) by barbiturates; of a pathological effect, hepatic injury produced by acetaminophen; of a genotoxic effect, a neoplasm produced by a nitrogen mustard. If the concentration of chemical in the tissues does not exceed a critical level, the effects usually will be reversible. The pharmacological effects usually disappear when the concentration of drug or chemical in the tissues is decreased by biotransformation or excretion from the body. Pathological and genotoxic effects may be repaired. If these effects are severe, death may ensue within a short time; if more subtle damage to DNA is not repaired, cancer may appear in a few months or years in laboratory animals or in a decade or more in humans.
Local toxicity occurs at the site of first contact between the biological system and the toxicant. Systemic toxicity requires absorption and distribution of the toxicant; most substances, with the exception of highly reactive chemical species, produce systemic toxic effects. The two categories are not mutually exclusive. Tetraethyl lead, for example, injures skin at the site of contact and deleteriously affects the CNS after it is absorbed into the circulation (see Chapter 65).
Most systemic toxicants predominantly affect one or a few organs. The target organ of toxicity is not necessarily the site of accumulation of the chemical. For example, lead is concentrated in bone, but its primary toxic action is on soft tissues; DDT (chlorophenothane) is concentrated in adipose tissue but produces no known toxic effects there.
The CNS is involved in systemic toxicity most frequently because many compounds with prominent effects elsewhere also affect the brain. Next in order of frequency of involvement in systemic toxicity are the heart and circulatory system; the blood and hematopoietic system; visceral organs such as liver, kidney, and lung; and the skin. Muscle and bone are least often affected. With substances that have a predominantly local effect, the frequency of tissue reaction depends largely on the portal of entry (skin, GI tract, or respiratory tract).
The effects of drugs on humans, whenever possible, must be reversible; otherwise, the drugs would be prohibitively toxic. If a chemical produces injury to a tissue, the capacity of the tissue to regenerate or recover largely will determine the reversibility of the effect. Injuries to a tissue such as liver, which has a high capacity to regenerate, usually are reversible; injury to the CNS is largely irreversible because the highly differentiated neurons of the brain have a more limited capacity to divide and regenerate.
Most toxic effects of drugs occur at a predictable (usually short) time after administration. However, such is not always the case. For example, aplastic anemia caused by chloramphenicol may appear weeks after the drug has been discontinued. Carcinogenic effects of chemicals usually have a long latency period: 20—30 years may pass before tumors are observed. Because such delayed effects cannot be assessed during any reasonable period of initial evaluation of a chemical, there is an urgent need for reliably predictive short-term tests for such toxicity, as well as for systematic surveillance of the long-term effects of marketed drugs and other chemicals (see Chapter 5).
chemical carcinogens Chemical carcinogens are classified as genotoxic or nongenotoxic. Genotoxic carcinogens interact with DNA; nongenotoxic carcinogens do not. Chemical carcinogenesis is a multistep process. Most genotoxic carcinogens are themselves unreactive (procarcinogens or proximate carcinogens) but are converted to primary or ultimate carcinogens in the body. The drug-metabolizing enzymes often convert the proximate carcinogens to reactive elec-trophilic intermediates (see Chapter 3). These reactive intermediates can interact with nucleophilic centers in DNA to produce a mutation. Such interaction of the ultimate carcinogen with DNA in a cell is thought to be the initial step in chemical carcinogenesis. The DNA may revert to normal if DNA repair mechanisms operate successfully; if not, the transformed cell may grow into a tumor that becomes apparent clinically.
Nongenotoxic carcinogens, or promoters, do not produce tumors alone but do potentiate the effects of genotoxic carcinogens. The time from initiation to the development of a tumor probably depends on the presence of such promoters; for many human tumors, the latent period is 15-45 years.
Two main types of laboratory tests are used to screen for potential carcinogenicity. One is performed to determine whether the chemical is mutagenic, since many carcinogens are also mutagens. Such studies often use assays such as the Ames test. This reverse mutation test uses a strain of Salmonella typhimurium that has a mutant gene for the enzyme phosphoribosyl adenosine triphosphate (ATP) synthetase. This enzyme is required for histidine synthesis, and the bacterial strain is unable to grow in a histidine-deficient medium unless a reverse mutation is induced. Because many chemicals are not mutagenic or carcinogenic unless activated by enzymes on the endoplasmic reticulum, rat hepatic microsomes usually are added to the medium containing the mutant bacteria and the drug. The Ames test is rapid and sensitive; its usefulness for the prediction of genotoxic carcinogens is widely accepted; it does not, however, detect nongenotoxic carcinogens (promoters). The second type consists of feeding laboratory rodents the chemical at high dosages for their entire life span, after which autopsies and histopathologi-cal examinations are performed on each animal. This latter study can detect both promoters and genotoxic carcinogens.
allergic reactions Chemical allergy is an adverse reaction that results from previous sensitization to a particular chemical or to one that is structurally similar. Such reactions are mediated by the immune system. The terms hypersensitivity and drug allergy often are used to describe the allergic state.
For a low-molecular-weight chemical to cause an allergic reaction, it or its metabolic product usually acts as a hapten, combining with an endogenous protein to form an antigenic complex. Such antigens induce the synthesis of antibodies, usually after a latent period of at least 1-2 weeks. Subsequent exposure of the organism to the chemical results in an antigen-antibody interaction that provokes the typical manifestations of allergy. Dose-response relationships usually are not apparent for the provocation of allergic reactions.
Allergic responses have been divided into four general categories based on the mechanism of immunological involvement. Type I, or anaphylactic, reactions are mediated by immunoglobulin (IgE) antibodies. The Fc portion of IgE can bind to receptors on mast cells and basophils (see Chapter 27). If the Fab portion of the antibody molecule then binds antigen, various mediators (e.g., histamine, leukotrienes, and prostaglandins) are released and cause vasodilation, edema, and an inflammatory response. The main targets of this type of reaction are the GI tract (food allergies), the skin (urticaria and atopic dermatitis), the respiratory system (rhinitis and asthma), and the vasculature (anaphylactic shock). These responses tend to occur quickly after challenge with an antigen to which the individual has been sensitized and are termed immediate hypersen-
Type II, or cytolytic, reactions are mediated by both IgG and IgM antibodies and usually are attributed to their ability to activate the complement system. The major target tissues for cytolytic reactions are the cells in the circulatory system. Examples of type II allergic responses include penicillin-induced hemolytic anemia, methyldopa-nduced autoimmune hemolytic anemia, quinidine-induced thrombocytopenic purpura, and sulfonamide-induced granulocytopenia. These autoimmune reactions to drugs usually subside within several months after removal of the offending agent.
Type III, or Arthus, reactions are mediated predominantly by IgG; the mechanism involves the generation of antigen-antibody complexes that subsequently fix complement. The complexes are deposited in the vascular endothelium, where a destructive inflammatory response called serum sickness occurs. This phenomenon contrasts with the type II reaction, in which the inflammatory response is induced by antibodies directed against tissue antigens. The signs and symptoms of serum sickness include urticarial skin eruptions, arthralgia or arthritis, lymphadenopathy, and fever. These reactions usually last for 6-12 days and then subside after the offending agent is eliminated. Several drugs (e.g., sulfonamides, penicillins, certain anticonvulsants, and iodides) can induce serum sickness. Stevens-Johnson syndrome, such as that caused by sulfonamides, is a more severe form of immune vasculitis; manifestations include erythema multiforme, arthritis, nephritis, CNS abnormalities, and myocarditis.
Type IV, or delayed-hypersensitivity, reactions are mediated by sensitized T-lymphocytes and macrophages. When sensitized cells come in contact with antigen, an inflammatory reaction is generated by the production of lymphokines and the subsequent influx of neutrophils and macrophages. An example of type IV or delayed hypersensitivity is the contact dermatitis caused by poison ivy.
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