Adverse Drug Reactions Supplemental Reading PDF

Adverse Effects of Drugs Pharmacology, Ross University School of Medicine Adverse Effects of Drugs STOP and read the Learning Objectives. Use your current knowledge to address each one. Then use the information provided or alternative resources to supplement your current knowledge. Learning Objec...

Adverse Effects of Drugs Pharmacology, Ross University School of Medicine Adverse Effects of Drugs STOP and read the Learning Objectives. Use your current knowledge to address each one. Then use the information provided or alternative resources to supplement your current knowledge. 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. List the most common instances of drug idiosyncrasy. Explain the mechanisms that can underlie drug idiosyncrasy. 7. Define the term "drug allergy". Describe the main features of drug allergy. List the most common types of allergic reaction to drugs. Explain the 4 main mechanisms underlying drug allergy. 8. 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. 9. Describe the main features of drug carcinogenesis. Give examples of drugs proven or highly suspected to be carcinogenic in humans. 10. Define the terms "drug misuse", "drug abuse", “drug addiction” and "physical dependence". Describe the main features of drug addiction and physical dependence. 1 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine Define the terms "side effect" and “adverse effect” of a drug. Even if the aim of the administration of a drug is to obtain a useful effect for the patient, (nearly?) all drugs provoke unwanted effects. Therefore, the physician needs to know that the use of drugs involves some risks. Unwanted drug effects are usually classified according to different criteria: either the frequency of their appearance (frequent or rare effects), seriousness (light or serious effects) or their underlying mechanisms. With respect to mechanisms of adverse effects, these may or may not be related to the desired pharmacological actions of the drug. Although in the RUSM curriculum we use the terms “side effect” and “adverse effect” interchangeably, a distinction can be made between them: Side effects are undesirable, non-deleterious drug effects occurring after administration of standard therapeutic doses and are related to the pharmacological properties of the drug. Adverse effects are undesirable deleterious drug effects occurring after administration of standard therapeutic doses. Some adverse effects are predictable and dose-dependent, and may be mild, moderate or severe. Some adverse effects are unpredictable. As side effects are non-deleterious, in most cases the patient is advised to continue taking the drug. Generally, side effects resolve after taking the drug for several weeks. The prescriber should advise the patient of likely side effects and that they are expected to diminish with continued therapy. Since a drug rarely produces only a single effect, the definition of side effect often depends on the therapeutic use of the drug. For instance, if an anticholinergic drug is used to treat diarrhea, the appearance of tachycardia is considered a side effect, but if the same drug is used to counteract sinus bradycardia, the appearance of constipation is regarded as a side effect. Since such effects are related to pharmacological actions of the drug (even if these effects are not sought by the therapist) in many cases the mechanism will be the interaction with drug receptors. Examples of side effects related to drug receptor interaction are the constipation due to anticholinergic drugs (blockade of intestinal muscarinic receptors), the gastrointestinal damage induced by nonsteroidal anti-inflammatory drugs (blockade of cyclooxygenase), the tachycardia induced by beta-stimulant drugs (activation of cardiac beta-receptors), the hypokalemia due to loop diuretics (blockade of cotransport of Na+, K+ and Cl- in the thick ascending limb of Henle), the constipation due to calcium antagonists (blockade of voltage-gated Ca++ channels in the smooth muscle). In several cases however the mechanisms of drug side effects remain obscure. For example, many drugs can cause headache, but the molecular basis of this is unknown. Adverse effects are often categorized as pharmacological, immunological or cytotoxic. What are the principal features of each of these categories? The mechanisms of adverse drug reactions are many (see below). In the majority of cases they are pharmacological (~80%), meaning that they result from one of more 2 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine of the specific effects of the drug or of its metabolites. In the remaining cases they are either cytotoxic (~10%), meaning that the drug causes cell damage, or immunological (~10%), meaning that the drug has activated the immune system. Most unwanted pharmacological drug effects can be predicted, by understanding mechanisms of action of the drug. Reducing the drug dosage may be sufficient to avoid these effects. In contrast, cytotoxic and immunological adverse effects are usually unrelated to the mechanisms of action of the drug. • Excessive bleeding caused by an anticoagulant is an example of a pharmacological drug adverse effect. • Liver injury caused by acetaminophen overdose is an example of cytotoxic adverse effect. • Penicillin allergy is an example of an immunological adverse effect. Describe the main features of overdose toxicity of a drug. Drug overdose toxicity can be defined as an adverse effect appearing after the administration of doses higher than therapeutic doses. Chemical compounds, if introduced into the body in excessive amount, can lead to toxic effects that may be very serious or even lethal (poisoning). It is therefore evident that overdose toxicity of drugs depends mainly on the administered dose. Therefore, the seriousness of overdose toxicity in a patient will be directly proportional to the administered dose. There are two kinds of overdose toxicity. In many cases the toxic effect is an extension of the therapeutic effect or of a side effect and therefore the most frequent mechanism is the interaction with drug receptors. Examples of toxic effects related to drug receptor interaction are the hemorrhage due to anticoagulants, cardiac failure due to beta-blockers, coma due to hypnotic drugs, paralytic ileus due to anticholinergic drugs, etc. In other cases, the toxic effect is not related to the specific actions of the drug but is cytotoxic, which means an unspecific cell damage produced by the drug or (more often) by highly reactive intermediates made during the biotransformation of the parent compound. These intermediates can form covalent or non-covalent bonds with biological macromolecules, which can lead to cytotoxic effects (e.g. breakage of cell membrane, block of enzymatic reactions, etc.) that can cause cell death. Examples of drug-induced cytotoxicity are the nephrotoxicity and ototoxicity due to aminoglycoside antibiotics, the hepatotoxicity due to isoniazid, the cardiotoxicity due to tricyclic antidepressants, etc. Define the terms LD50, TD50 and ED50. Estimate the TD50 (or LD50) and ED50 from a given set of data. Different toxic doses can be estimated from quantal log dose-response curves: a minimum toxic dose (e.g. the dose which provokes a given toxic effect in 1% of subjects), a median toxic dose (the dose that causes the same effect in 50% of subjects) and a maximum toxic dose (e.g. the dose that provokes the same effect in 99% of subjects). In laboratory 3 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine animals the toxic effect can be the death of the animal (minimum lethal dose, median lethal dose and maximum lethal dose). In humans, the lethal dose can be only approximately estimated from the incidence of acute poisoning. The knowledge of the toxic doses of a drug is of great practical importance since it concentrates in a single number the information about the safety of that drug. Dose The minimum The median The maximum Lethal LD1 LD50 LD99 Toxic TD1 TD50 TD99 Effective ED1 ED50 ED99 Define the term "therapeutic index". Estimate the therapeutic index of a drug from a given set of data. The ratio between the median dose provoking a toxic or lethal effect and the median dose provoking the desired therapeutic effect is named therapeutic Index. Note that the therapeutic index of a drug will depend on the chosen toxic effect. In laboratory animals the therapeutic index is usually calculated as the ratio between median lethal dose and median effective dose. In a clinical setting different doses can be chosen. Once a given toxic effect and the desired therapeutic effect have been determined, the therapeutic index can be calculated as the ratio between median toxic dose and median therapeutic dose. While a therapeutic index can be calculated for any adverse effect, typically it is reserved for clinically significant adverse effects, such as organ damage. The therapeutic index gives information only about overdose toxicity and therefore it is not useful to predict other adverse drug effects. For instance, all penicillins have very high therapeutic indexes but often they provoke allergic reactions, some of them very serious. 4 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine THERAPEUTIC INDEXES OF DRUGS The ratio between a median harmful dose and a median effective dose of a drug. Examples: LD50/ED50; TD50/ED50 Note that TD1/ED99 is sometimes called the margin of safety Describe the main features of drug idiosyncrasy. List the most common instances of drug idiosyncrasy. Explain the mechanisms that can underlie drug idiosyncrasy. Individual variability is an important factor influencing the magnitude of a pharmacological effect of a drug. This variability is often Gaussian (bell curve) in shape. However, in some patients, the biological response to a given drug is completely unusual, either because it is qualitatively different from the effects usually observed or because it is quantitatively outside (above or below) of the range that includes most responses. In the past any unusual response to a drug was named idiosyncratic, which means unusual, abnormal or exceptional. Today, idiosyncrasy is defined as “a genetically based, abnormal response to a drug” although the genetic explanation for the reaction is often not known. As a rule, (even if there are some exceptions) an idiosyncratic response is dangerous for the patient and therefore idiosyncrasy must be considered a form of drug toxicity. Pharmacogenetics is the branch of pharmacology which studies the genetic basis for variation in drug response. The incidence of idiosyncratic drug reactions is low. Idiosyncratic reactions are generally dose-dependent, but they only occur in genetically susceptible individuals. In these patients, idiosyncratic reactions become more severe when the dose is increased. Define the term "drug allergy." Describe the main features of drug allergy. List the most common types of allergic reaction to drugs. Explain the 4 main mechanisms underlying drug allergy. Drug allergy is an important class of adverse drug effects as it has potential for serious clinical consequences. Drug allergy can be defined as an immunologically mediated, adverse drug effect that reoccurs when the patient is re-exposed to the drug. Drug allergies are produced by essentially the same mechanisms as other allergies. A drug can produce an allergic reaction in a patient only after a previous sensitizing contact with the same drug or with another drug closely related in chemical structure (the latter case is named cross sensitization). After sensitization, a certain period of time (usually from 7 to 14 days) is needed for the production of a sufficient number of specific antibodies (or of specific receptors on the surface of T-cells). Later 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). Drug administration does not need to be interrupted between the first and 5 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine second exposure. In fact, allergic sensitization can occur early and allergic response later on, during the same therapeutic cycle. The relative frequency of allergic reactions to a specific drug depends on many factors. The chemical structure of the drug is especially important. It is well known that some drugs cause allergic reactions very rarely (e.g, in spite of the great consumption of caffeine containing drinks, allergic reactions to caffeine are extremely rare) while other compounds (obviously not used as drugs) can cause sensitization in all exposed subjects. Moreover, the seriousness of an allergic reaction is not dose-dependent, in most cases. In fact, in sensitized individuals, extremely low doses of a drug (even in the nanogram range) may be able to elicit a life-threatening reaction (e.g. an anaphylactic shock), where for other drugs standard therapeutic doses may trigger only a slight allergic response. Allergic drug reactions involve immunological defense against foreign substances. In order to induce an allergic response, the drug must have immunogenic properties, i.e. it must behave as an antigen. This property is mainly linked to the molecular weight (MW) of the drug as it has been shown that, in general, only molecules with a MW greater than about 6000 can be immunogenic. This is because small MW drugs are not easily recognized by the cells of the immune system. Moreover, these small drugs are unable to positively interact with immune receptors to activate T (or B) cells. Therefore, a drug may cause an allergic reaction only if: a) it has a MW higher of 6000 or b) 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. The Gell and Coombs classification of allergic reactions is based upon the mechanism by which the antigen evokes the immunologic response. It subdivides the reactions into the following 4 basic types: 1) Type I (immediate reactions) The first exposure to the antigen provokes the production of antibodies (IgE) that are bound to membranes of tissue mast cells and blood basophils. On the second exposure, the antigenantibody reaction on the surface of the sensitized cells causes the release of potent vasoactive and inflammatory mediators (histamine, heparin, kinins, leukotrienes, platelet activating factor, slow reacting substance, etc.) either preformed or newly generated from membrane lipids. These mediators trigger the allergic inflammatory response. Allergic diseases of this group include anaphylaxis, some types of angioneurotic edema, allergic asthma, atopic dermatitis, allergic rhinitis and conjunctivitis, some types of urticaria, and some types of intestinal disorders. 2) Type II (antibody-dependent cytotoxicity) The drug binds to or reacts with surface component of a cell, such as an erythrocyte, causing it to appear to be foreign. This evokes the production of antibodies (IgG or IgM) that can react with the cell-bound drug (autoimmune reaction). This antigen-antibody reaction may trigger the activation of the complement system or permit attack by mononuclear killer cells. In both cases the ultimate result is the death of the target cell. Allergic diseases of this group include the lupoid syndrome, some types of hemolytic anemia, thrombocytopenia, granulocytopenia or agranulocytosis, some types of hepatitis and of tubulointerstitial nephritis. Some examples of drugs causing Type II reactions include (discussed in other lectures):  Hemolytic anemia: cephalosporins, penicillins, nonsteroidal anti-inflammatory drugs (NSAIDs) 6 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine  Thrombocytopenia: heparin, sulfonamides, beta-lactam antibiotics, carbamazepine, NSAIDs  Severe neutropenia or agranulocytosis: propylthiouracil (PTUP, the antimalarial drug amodiaquine, and flecainide 3) Type III (immune complex-mediated reaction) This occurs when antibodies (IgG or IgM) are formed against soluble antigens. The antigenantibody complex usually precipitates very quickly and, being phagocytized by macrophages, elicits no reaction. If the antigen is in excess of the antibody however, the immune complex may remain soluble in the blood and continue to circulate. Eventually it may deposit on the walls of blood vessels, at basement membranes, causing complement activation and local inflammation. Although IgE antibodies may play some role, complement-fixing antibodies of the IgG or IgM class are usually involved. Allergic diseases of this group include serum sickness, systemic lupus erythematosus, some forms of hepatitis, nephritis, arthritis and vasculitis, some cases of drug fever. 4) Type IV (delayed or cell-mediated reaction) Unlike Types I, II and III, Type IV reactions are not mediated by antibodies. The antigen sensitizes T lymphocytes which produce T cell receptors appropriate for reacting with the antigen. On the second exposure T lymphocytes recognize the antigen and release lymphokines which produce local edema and inflammation. The reaction is called delayed because hours or days elapse for the reaction to occur after the administration of an eliciting dose of antigen to a sensitized subject. In this type of drug reaction, the skin is the chief site of allergic response. Contact dermatitis is the most common manifestation of cell-mediated allergic reaction. Other reactions include some types of eczema, erythema multiforme and Stevens-Johnson syndrome. In some cases, drug administration provokes a type I-like allergic reaction but circulating antibodies cannot be detected. Therefore, the reaction is called pseudoallergic. In such cases the clinical symptoms are due, most likely, to a direct release of histamine and other mediators, caused by the drug. In the most serious cases the clinical picture is similar to that of anaphylaxis and the reaction is called "anaphylactoid". Drugs such as opioids, some antibiotics (vancomycin), curare-like drugs, some plasma expanders (dextran) and some contrast media are among drugs able to directly release histamine from mast cells and basophils. Unlike the true anaphylaxis, these pseudoallergic reactions are dose-dependent in most cases. Furthermore, because pseudoallergic reactions are not true drug allergies, the medications are not contraindicated for future use by the patient. 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. When a drug is administered to a pregnant woman it reaches, except very rare cases, the fetal circulation since the placenta is generally a quite permeable barrier to chemicals of low molecular weight (MW). In fact, drugs with MW less than 800-1000 can cross the placenta 7 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine easily (depending upon their lipid solubility and the degree of ionization) while those with MW exceeding 1000 cross very poorly. Drugs given during pregnancy may have direct as well as indirect effects on the fetus. Direct effects can be: 1) Toxic: they are the same effects that a drug causes also in adults if given in too high of doses. Since fetal tissues are usually more sensitive than adults' a toxic effect will show even for plasma concentrations that do not cause trouble to the mother. For instance, a therapeutic dose of diazepam given to the mother a few hours before delivery can cause muscle flaccidity, apnea attacks, sucking difficulty etc. in the newborn (the "floppy baby" syndrome). Exceedingly high doses of a drug administered during pregnancy can have lethal effects on the fetus (abortion). Toxic effects on the fetus are generally reversible (as well as in adults) once the drug is withdrawn. 2) Teratogenic: these effects are provoked by the drug in the fetus only. In fact, 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." Accordingly, a teratogenic effect may lead to morphological damage (appearance of one or more malformations) or functional damage (alteration of one or more physiological functions). A teratogenic effect is usually irreversible. Hence, to be considered a teratogen, the candidate drug must: a) cause a characteristic set of malformations; b) exert its effect at a particular stage of development; c) show a dose-dependent incidence. Examples of teratogens are several chemical agents (e.g. alcohol), ionizing radiations, intrauterine infections, RH incompatibility, etc. Indirect effects on the fetus can be caused by: 1) 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). 2) a disease of the mother that compromises fetal growth and development. Susceptibility to teratogenic agents varies during gestation and hence depends on the stage of development of the fetus. During the 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. Thus, the effect of teratogenic agents at this stage is all or none: either the embryo is destroyed or so few cells are damaged that the embryo can recover. 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. The fetal stage (weeks 9-38) is the most sensitive to functional teratogenic effects. These effects may become evident only after many years. For instance, it is well known that 8 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine alcohol, consumed by a pregnant woman, can alter the development of the central nervous system of the fetus, but such a teratogenic effect may show up only during school age (difficulty in learning, low IQ etc.) Abortion and gross malformations are much rarer in the fetal stage, as the organs are already formed. Describe the main features of drug carcinogenesis. Give examples of drugs proven or highly suspected to be carcinogenic in humans. More than 5 million chemical compounds are known today, about 50,000 of them are widely used and for about 1000 a carcinogenic activity has been demonstrated in laboratory animals. However, the number of drugs with known or suspected carcinogenic activity in humans is very small. Anticancer drugs and alcohol have known carcinogenic activity. The features and mechanisms of drug carcinogenesis are similar to those of carcinogenesis caused by other chemicals. The effects of carcinogens are in general dosedependent, 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.). Define the terms "drug misuse", "drug abuse", “drug addiction” and "physical dependence". Describe the main features of drug addiction and physical dependence. Drug misuse is the use of a substance for a purpose not consistent with legal or medical guidelines. 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. Drug addiction refers to the drug craving and compulsive drug seeking behavior. Substance use disorder is a diagnosis that is made based on several criteria described by the Diagnostic and Statistical Manual of Mental Disorders (DSM). People use psychoactive drugs for many different reasons, but all these motives have one thing in common: the use of the drug is rewarding to the user, whether by producing pleasure, by relieving anxiety or other rewards. When these rewarding properties make the user take the drug repeatedly and the drug-seeking behavior becomes compulsive, the drug use is described as an addiction or a substance use disorder. Since addiction is related to the rewarding properties of the drug, addiction occurs only with drugs that have those properties, either because of direct positive effects, or because of negative effects associated with the absence of the drug. It is worth noting that the positive effect is pharmacological; and this positive effect (e.g. euphoria or anxiolysis) is in the central nervous system. Main variables that affect addiction to a given drug are: a) The dose of the drug. Since the rewarding effect of the drug is pharmacological, it is dose-dependent b) 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. 9 Adverse Effects of Drugs Pharmacology, Ross University School of Medicine c) 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. d) The frequency of administration. Addiction is the consequence of frequent and strongly reinforced drug-taking behavior. As a general rule, addictive drugs (including nicotine, cocaine, amphetamine, ethanol, and opioids) reliably activate the mesolimbic dopamine pathway in the brain. This pathway is also called the “reward pathway”. Euphoric effects of drugs (and therefore their addiction liability) are mediated by increased extracellular dopamine levels in the nucleus accumbens, a brain region important in the reward pathway. Physical dependence is an altered physiological state produced by the repeated administration of a drug, which necessitates the continued administration of the drug to prevent the appearance of intense unpleasant symptoms called withdrawal (or abstinence) syndrome. Therefore, the appearance of a withdrawal syndrome when the administration of the drug is terminated is the evidence of physical dependence. Tolerance is another component to physical dependence; it is defined as needing more drug to get the same effect (or alternatively, observing reduced effect with the same dose). Physical dependence can also occur with many drugs that do not cause addiction, including sympathomimetic vasoconstrictors, nitrate vasodilators, antiepileptic drugs, and some antidepressants. Physical dependence is evident only with certain drugs and only after repeated administrations. Its intensity is related to the dose used as well as to the route of administration and frequency of administration. Although physical dependence invariably occurs with chronic use of certain drugs, not all subjects develop a habit, lose control and develop a substance use disorder or addiction. The exact mechanisms that account for physical dependence have not been fully elucidated. However, it can be appreciated that drugs can disrupt body systems that previously were in equilibrium. With chronic drug use, these systems find a new balance (tolerance) in the presence of the drug-induced stimulation or inhibition. Therefore, a person requires continued administration of the drug to maintain the newly restored balance. If the drug is not present in the system, an imbalance results and the system must go through a process of readjusting to a new equilibrium (withdrawal syndrome). Some examples of the processes that reset homeostatic mechanisms include increased/decreased receptor numbers, increased/decreased activity of enzymes, and increased/decreased expression of specific genes. These mechanisms also explain why the withdrawal syndrome from a given drug is often characterized by symptoms opposite to those produced by the drug itself. Thus, the withdrawal syndrome from heroin, ethanol, and benzodiazepines is mainly an excitatory one, whereas the withdrawal syndrome from cocaine and amphetamines is characterized by profound fatigue and depression. 10