Adverse Drug Reactions PDF

Adverse Drug Reactions Module: Fundamentals B Dr. Mayers-Aymes, PharmD [email protected] Office hours: https://calendly.com/nmayers-aymes/office-hours Learning Objectives 1. Define the terms "side effect" and “adverse effect” of a drug. 2. Adverse effects are often categorized as pharmacolog...

Adverse Drug Reactions Module: Fundamentals B Dr. Mayers-Aymes, PharmD [email protected] Office hours: https://calendly.com/nmayers-aymes/office-hours Learning Objectives 1. Define the terms "side effect" and “adverse effect” of a drug. 2. Adverse effects are often categorized as pharmacological, immunological or cytotoxic. What are the principal features of each of these categories? 3. Describe the main features of overdose toxicity of a drug. 4. Define the terms LD50, TD50 and ED50. Estimate the TD50 and ED50 from a given set of data. 5. Define the term "therapeutic index". Estimate the therapeutic index of a drug from a given set of data 6. Describe the main features of drug idiosyncrasy. a. List the most common instances of drug idiosyncrasy. b. Explain the mechanisms that can underlie drug idiosyncrasy. 2 Learning Objectives 7. a. 8. a. b. c. 9. a. 10. a. Define the term "drug allergy". Describe the main features of drug allergy. List the most common types of allergic reaction to drugs. Define the term "teratogen" and "teratogenesis". Give examples of drugs proven or highly suspected to be teratogens in humans. Relate the prenatal effects of drugs to the stage of embryo-fetal development. Explain the most likely mechanisms underlying drug teratogenesis. Describe the main features of drug carcinogenesis. Give examples of drugs proven or highly suspected to be carcinogenic in humans. Define the terms "drug misuse", "drug abuse", “drug addiction” and "physical dependence". Describe the main features of drug addiction and physical dependence. 3 LO 1 Side Effects and Adverse Effects • Side effects: o undesirable, non deleterious drug effects occurring after administration of standard therapeutic doses. o Related to the pharmacological properties of the drug (usually due to interaction with drug receptors). • Adverse effects are undesirable deleterious drug effects occurring after administration of standard therapeutic doses which may be: o predictable or unpredictable o dose-dependent o mild, moderate or severe 4 LO 2 Classification of Adverse Effects Pharmacological (~80%): • Results from one of more of the specific effects of the drug or of its metabolites • Can be predicted and related to a drug’s MOA • Example: excessive bleeding caused by warfarin C y t o tox i c (~10%) • drug causes cell damage • Example: Liver injury caused by acetaminophen overdose Immunological (~10%) • the drug activates the immune system • Example: Penicillin allergy 5 LO 3 Overdose Toxicity • Adverse effects appearing after administration of doses higher than therapeutic doses. • Depends mainly on the administered dose. • May be an extension of a therapeutic effect OR a side effect. • May be caused by interaction with drug receptors OR may not be related to specific actions of the drug (cytotoxic). 6 Toxic Doses LO 4 • Minimum toxic dose (the dose which provokes a given toxic effect in 1% of subjects) • Median toxic dose (the dose that causes the same effect in 50% of subjects) • Maximum toxic dose (the dose that provokes the same effect in 99% of subjects) 7 LD50, TD50 and ED50 Dose The minimum The median The maximum Lethal LD1 LD50 LD99 Toxic TD1 TD50 TD99 LO 4,5 Effective ED1 ED50 ED99 Therapeutic Index: The ratio between a median harmful dose and a median effective dose of a drug. Examples: LD50/ED50; TD50/ED50 8 TD50 and ED50 LO 4,5 9 Drug Idiosyncrasy LO 6 • Idiosyncratic an unusual, abnormal or exceptional response to a drug. • Idiosyncrasy is also defined as “a genetically based, abnormal response to a drug”. • The incidence of idiosyncratic drug reactions is low. • Idiosyncratic reactions: o are generally dose-dependent o occur in genetically susceptible individuals o may become more severe when the dose is increased 10 Drug Allergy • Drug allergy can be defined as an immunologically mediated, adverse drug effect that reoccurs when the patient is re-exposed to the drug. • Allergic reaction only after a previous sensitizing contact with the same drug or drug closely related in chemical structure (cross-sensitization). • After sensitization, 7 to 14 days of time usually is needed for the production of sufficient and specific antibodies (or of specific receptors on the surface of T-cells). • A second triggering contact with the same drug will provoke the production of an antigen-antibody complex (or the activation of the sensitized T-cells). LO 7 11 Drug Allergy LO 7 • A drug may cause an allergic reaction only if: o it has a MW higher of 6000 o it can function as hapten, that is, it is capable of binding covalently to a macromolecule, for example a protein, to form a larger product that has immunogenic properties. 12 Drug Allergy • The Gell and Coombs classification of allergic reactions: 1. 2. 3. 4. Type I (immediate reactions) Type II (antibody-dependent cytotoxicity) Type III (immune complex-mediated reaction) Type IV (delayed or cell-mediated reaction) LO 7 13 LO 8 Teratogenesis • A teratogen may be defined as any agent that (when administered during pregnancy) is able to cause abnormal in utero development or the appearance of malformations. • Examples of teratogens are several chemical agents (e.g., alcohol), ionizing radiations, intrauterine infections, RH incompatibility, etc. • Drugs can have direct or indirect effects on the fetus • To be considered a teratogen, the drug must: o o o cause a characteristic set of malformations; exert its effect at a particular stage of development; show a dose-dependent incidence. 14 LO 8 Direct Effects of Drugs on the Fetus • Toxic: o The same effects that a drug causes also in adults if given in too high of doses. o Toxic effects on the fetus are generally reversible (as well as in adults) once the drug is withdrawn. • Teratogenic o Morphological damage is the appearance of one or more malformations. o Functional damage is the alteration of one or more physiological functions. o A teratogenic effect is usually irreversible. 15 LO 8 Indirect Effects of Drugs on the Fetus • Indirect effects on the fetus can be caused by: 1. 2. A decrease in blood flow to the placenta (owing to an oxytocic action on the uterus or to a constriction of placental vessels or to a negative inotropic action on the heart). A disease of the mother that compromises fetal growth and development. 16 LO 8 Prenatal Effects of Drugs • Germinal stage (weeks 0-2) in which cells are still undifferentiated and totipotent (i.e., can form any one of the organism's differentiated cell type), exposure to harmful agents may cause death of the embryo. • If the exposure is less severe, those cells that survive can recover and normal embryogenesis may ensue. • The effect of teratogenic agents at the germinal stage is all or none. 17 LO 8 Prenatal Effects of Drugs • The embryonic stage (weeks 3-8) is the most sensitive to morphological teratogenic effects. • If the doses are very high, death of the embryo may ensue, while lower doses may cause gross malformations. • In this stage, functional damage is rarer since tissue maturation is only beginning. 18 LO 8 Prenatal Effects of Drugs • The fetal stage (weeks 9-38) is the most sensitive to functional teratogenic effects. These effects may become evident only after many years. • Abortion and gross malformations are much rarer in the fetal stage, as the organs are already formed. 19 Drug Carcinogenesis LO 9 • The effects of carcinogens are in general dose- dependent, additive and irreversible. • There is always a long latent period between exposure to the agent that causes tumors and the detection of cancer. • Most cancer-causing chemicals probably are not carcinogenic in the form in which they enter the body but are metabolically activated into reactive intermediates that are toxic and carcinogenic (epoxides, nitrosamines, etc.). 20 LO 10 Drug Misuse, Drug Addiction, Substance Use Disorder • Drug misuse: o Is the use of a substance for a purpose not consistent with legal or medical guidelines. o Examples include taking a higher dose than what was prescribed or taking an antibiotic that was prescribed for a previous condition. • Drug abuse, drug addiction and substance use disorder are terms that refer to repetitive drug taking for non-medical (“recreational”) purposes. 21 Drug Addiction LO 10 • The main variables that affect addiction to a given drug are: o The dose of the drug. Since the rewarding effect of the drug is pharmacological, it is dose-dependent o The development of tolerance. Tolerance is defined as the need for more drug to get the same effect. Since tolerance leads to dose increases, it is an important factor in the development of addiction for many drugs o The route of administration. A general rule of behavior is that a rewarding effect is more powerful when it is immediate. Therefore, IV administration of a drug is more likely than oral administration to initiate the chain of events that leads to loss of control over drug taking. o The frequency of administration. Addiction is the consequence of frequent and strongly reinforced drug-taking behavior. 22 Physical Dependence LO 10 • Physical dependence: o an altered physiological state produced by the repeated administration of a drug o necessitates the continued administration of the drug to prevent the appearance of intense unpleasant symptoms called withdrawal (or abstinence) syndrome • Tolerance: needing more drug to get the same effect (or alternatively, observing reduced effect with the same dose). 23 Learning Objectives 1. Define the terms "side effect" and “adverse effect” of a drug. 2. Adverse effects are often categorized as pharmacological, immunological or cytotoxic. What are the principal features of each of these categories? 3. Describe the main features of overdose toxicity of a drug. 4. Define the terms LD50, TD50 and ED50. Estimate the TD50 and ED50 from a given set of data. 5. Define the term "therapeutic index". Estimate the therapeutic index of a drug from a given set of data 6. Describe the main features of drug idiosyncrasy. a. List the most common instances of drug idiosyncrasy. b. Explain the mechanisms that can underlie drug idiosyncrasy. 24 Learning Objectives 7. a. 8. a. b. c. 9. a. 10. Define the term "drug allergy". Describe the main features of drug allergy. List the most common types of allergic reaction to drugs. Define the term "teratogen" and "teratogenesis". Give examples of drugs proven or highly suspected to be teratogens in humans. Relate the prenatal effects of drugs to the stage of embryo-fetal development. Explain the most likely mechanisms underlying drug teratogenesis. Describe the main features of drug carcinogenesis. Give examples of drugs proven or highly suspected to be carcinogenic in humans. Define the terms "drug misuse", "drug abuse", “drug addiction” and "physical dependence". a. Describe the main features of drug addiction and physical dependence. 25