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70 Adverse Drug Effects Adverse Drug Effects The desired (or intended) principal effect of any drug is to modify body function in such a manner as to alleviate symptoms caused by the patient’s illness. In addition, a drug may also cause unwanted effects that can be grouped into minor or “side” effects and major or adverse effects. These, in turn, may give rise to complaints or illness, or may even cause death. Causes of adverse effects: overdosage (A). The drug is administered in a higher dose than is required for the principal effect; this directly or indirectly affects other body functions. For instances, morphine (p. 210), given in the appropriate dose, affords excellent pain relief by influencing nociceptive pathways in the CNS. In excessive doses, it inhibits the respiratory center and makes apnea imminent. The dose dependence of both effects can be graphed in the form of dose-response curves (DRC). The distance between both DRCs indicates the difference between the therapeutic and toxic doses. This margin of safety indicates the risk of toxicity when standard doses are exceeded. “The dose alone makes the poison” (Paracelsus). This holds true for both medicines and environmental poisons. No substance as such is toxic! In order to assess the risk of toxicity, knowledge is required of: 1) the effective dose during exposure; 2) the dose level at which damage is likely to occur; 3) the duration of exposure. Increased Sensitivity (B). If certain body functions develop hyperreactivity, unwanted effects can occur even at normal dose levels. Increased sensitivity of the respiratory center to morphine is found in patients with chronic lung disease, in neonates, or during concurrent exposure to other respiratory depressant agents. The DRC is shifted to the left and a smaller dose of morphine is sufficient to paralyze respiration. Genetic anomalies of metabolism may also lead to hypersensitivity. Thus, several drugs (aspirin, antimalarials, etc.) can provoke premature breakdown of red blood cells (hemolysis) in subjects with a glucose6-phosphate dehydrogenase deficiency. The discipline of pharmacogenetics deals with the importance of the genotype for reactions to drugs. The above forms of hypersensitivity must be distinguished from allergies involving the immune system (p. 72). Lack of selectivity (C). Despite appropriate dosing and normal sensitivity, undesired effects can occur because the drug does not specifically act on the targeted (diseased) tissue or organ. For instance, the anticholinergic, atropine, is bound only to acetylcholine receptors of the muscarinic type; however, these are present in many different organs. Moreover, the neuroleptic, chlorpromazine, formerly used as a neuroleptic, is able to interact with several different receptor types. Thus, its action is neither organ-specific nor receptorspecific. The consequences of lack of selectivity can often be avoided if the drug does not require the blood route to reach the target organ, but is, instead, applied locally, as in the administration of parasympatholytics in the form of eye drops or in an aerosol for inhalation. With every drug use, unwanted effects must be taken into account. Before prescribing a drug, the physician should therefore assess the risk: benefit ratio. In this, knowledge of principal and adverse effects is a prerequisite. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Adverse Drug Effects Decrease in pain perception (nociception) Respiratory depression Effect Decrease in Nociception Respiratory activity Safety margin Morphine Morphine overdose Dose A. Adverse drug effect: overdosing Increased sensitivity of respiratory center Effect Safety margin Normal dose Dose B. Adverse drug effect: increased sensitivity e. g., Chlorpromazine Atropine mAChreceptor mAChreceptor Receptor specificity but lacking organ selectivity !-adrenoceptor Atropine Dopamine receptor Histamine receptor Lacking receptor specificity C. Adverse drug effect: lacking selectivity Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 71 72 Adverse Drug Effects Drug Allergy The immune system normally functions to rid the organism of invading foreign particles, such as bacteria. Immune responses can occur without appropriate cause or with exaggerated intensity and may harm the organism, for instance, when allergic reactions are caused by drugs (active ingredient or pharmaceutical excipients). Only a few drugs, e.g. (heterologous) proteins, have a molecular mass (> 10,000) large enough to act as effective antigens or immunogens, capable by themselves of initiating an immune response. Most drugs or their metabolites (so-called haptens) must first be converted to an antigen by linkage to a body protein. In the case of penicillin G, a cleavage product (penicilloyl residue) probably undergoes covalent binding to protein. During initial contact with the drug, the immune system is sensitized: antigen-specific lymphocytes of the T-type and B-type (antibody formation) proliferate in lymphatic tissue and some of them remain as socalled memory cells. Usually, these processes remain clinically silent. During the second contact, antibodies are already present and memory cells proliferate rapidly. A detectable immune response, the allergic reaction, occurs. This can be of severe intensity, even at a low dose of the antigen. Four types of reactions can be distinguished: Type 1, anaphylactic reaction. Drug-specific antibodies of the IgE type combine via their Fc moiety with receptors on the surface of mast cells. Binding of the drug provides the stimulus for the release of histamine and other mediators. In the most severe form, a lifethreatening anaphylactic shock develops, accompanied by hypotension, bronchospasm (asthma attack), laryngeal edema, urticaria, stimulation of gut musculature, and spontaneous bowel movements (p. 326). Type 2, cytotoxic reaction. Drugantibody (IgG) complexes adhere to the surface of blood cells, where either circulating drug molecules or complexes al- ready formed in blood accumulate. These complexes mediate the activation of complement, a family of proteins that circulate in the blood in an inactive form, but can be activated in a cascadelike succession by an appropriate stimulus. “Activated complement” normally directed against microorganisms, can destroy the cell membranes and thereby cause cell death; it also promotes phagocytosis, attracts neutrophil granulocytes (chemotaxis), and stimulates other inflammatory responses. Activation of complement on blood cells results in their destruction, evidenced by hemolytic anemia, agranulocytosis, and thrombocytopenia. Type 3, immune complex vasculitis (serum sickness, Arthus reaction). Drug-antibody complexes precipitate on vascular walls, complement is activated, and an inflammatory reaction is triggered. Attracted neutrophils, in a futile attempt to phagocytose the complexes, liberate lysosomal enzymes that damage the vascular walls (inflammation, vasculitis). Symptoms may include fever, exanthema, swelling of lymph nodes, arthritis, nephritis, and neuropathy. Type 4, contact dermatitis. A cutaneously applied drug is bound to the surface of T-lymphocytes directed specifically against it. The lymphocytes release signal molecules (lymphokines) into their vicinity that activate macrophages and provoke an inflammatory reaction. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Adverse Drug Effects Reaction of immune system to first drug exposure Drug (= hapten) Immune system (^ = lymphatic tissue) recognizes: Protein "Non-self" Production of antibodies (Immunoglobulins) e.g. IgE IgG etc. Proliferation of antigen-specific lymphocytes Macromolecule MW > 10 000 Distribution in body Antigen Immune reaction with repeated drug exposure e.g., Neutrophilic granulocyte IgE Mast cell (tissue) basophilic granulocyte (blood) Receptor for IgE Histamine and other mediators IgG Complement activation Urticaria, asthma, shock Type 1 reaction: acute anaphylactic reaction Formation of immune complexes Deposition on vessel wall Type 2 reaction: cytotoxic reaction Contact dermatitis Activation of: complement Cell destruction Membrane injury Antigenspecific T-lymphocyte Inflammatory reaction and neutrophils Lymphokines Type 3 reaction: Immune complex Inflammatory reaction Type 4 reaction: lymphocytic delayed reaction A. Adverse drug effect: allergic reaction Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 73 74 Adverse Drug Effects Drug Toxicity in Pregnancy and Lactation Drugs taken by the mother can be passed on transplacentally or via breast milk and adversely affect the unborn or the neonate. Pregnancy (A) Limb malformations induced by the hypnotic, thalidomide, first focused attention on the potential of drugs to cause malformations (teratogenicity). Drug effects on the unborn fall into two basic categories: 1. Predictable effects that derive from the known pharmacological drug properties. Examples are: masculinization of the female fetus by androgenic hormones; brain hemorrhage due to oral anticoagulants; bradycardia due to !-blockers. 2. Effects that specifically affect the developing organism and that cannot be predicted on the basis of the known pharmacological activity profile. In assessing the risks attending drug use during pregnancy, the following points have to be considered: a) Time of drug use. The possible sequelae of exposure to a drug depend on the stage of fetal development, as shown in A. Thus, the hazard posed by a drug with a specific action is limited in time, as illustrated by the tetracyclines, which produce effects on teeth and bones only after the third month of gestation, when mineralization begins. b) Transplacental passage. Most drugs can pass in the placenta from the maternal into the fetal circulation. The fused cells of the syncytiotrophoblast form the major diffusion barrier. They possess a higher permeability to drugs than is suggested by the term “placental barrier”. c) Teratogenicity. Statistical risk estimates are available for familiar, frequently used drugs. For many drugs, teratogenic potency cannot be demonstrated; however, in the case of novel drugs it is usually not yet possible to define their teratogenic hazard. Drugs with established human teratogenicity include derivatives of vitamin A (etretinate, isotretinoin [used internally in skin diseases]), and oral anticoagulants. A peculiar type of damage results from the synthetic estrogenic agent, diethylstilbestrol, following its use during pregnancy; daughters of treated mothers have an increased incidence of cervical and vaginal carcinoma at the age of approx. 20. In assessing the risk: benefit ratio, it is also necessary to consider the benefit for the child resulting from adequate therapeutic treatment of its mother. For instance, therapy with antiepileptic drugs is indispensable, because untreated epilepsy endangers the infant at least as much as does administration of anticonvulsants. Lactation (B) Drugs present in the maternal organism can be secreted in breast milk and thus be ingested by the infant. Evaluation of risk should be based on factors listed in B. In case of doubt, potential danger to the infant can be averted only by weaning. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. 75 Adverse Drug Effects Ovum 1 day Sperm cells ~3 days Endometrium Blastocyst 21 2 Nidation 12 Embryo: organ development Fetal death Malformation Artery Sequelae of damage by drug 38 Fetus: growth and maturation Functional disturbances Uterus wall Transfer of metabolites Capillary Placental transfer of metabolites Vein Mother Development stage 1 Syncytiotrophoblast Placental barrier To umbilical cord A. Pregnancy: fetal damage due to drugs Drug Therapeutic effect in mother ? Unwanted effect in child Extent of transfer of drug into milk Infant dose Distribution of drug in infant Rate of elimination of drug from infant Drug concentration in infant´s blood Sensitivity of site of action Effect B. Lactation: maternal intake of drug Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Fetus Age of fetus (weeks) 76 Drug-independent Effects Placebo (A) A placebo is a dosage form devoid of an active ingredient, a dummy medication. Administration of a placebo may elicit the desired effect (relief of symptoms) or undesired effects that reflect a change in the patient’s psychological situation brought about by the therapeutic setting. Physicians may consciously or unconsciously communicate to the patient whether or not they are concerned about the patient’s problem, or certain about the diagnosis and about the value of prescribed therapeutic measures. In the care of a physician who projects personal warmth, competence, and confidence, the patient in turn feels comfortable and less anxious and optimistically anticipates recovery. The physical condition determines the psychic disposition and vice versa. Consider gravely wounded combatants in war, oblivious to their injuries while fighting to survive, only to experience severe pain in the safety of the field hospital, or the patient with a peptic ulcer caused by emotional stress. Clinical trials. In the individual case, it may be impossible to decide whether therapeutic success is attributable to the drug or to the therapeutic situation. What is therefore required is a comparison of the effects of a drug and of a placebo in matched groups of patients by means of statistical procedures, i.e., a placebo-controlled trial. A prospective trial is planned in advance, a retrospective (case-control) study follows patients backwards in time. Patients are randomly allotted to two groups, namely, the placebo and the active or test drug group. In a double-blind trial, neither the patients nor the treating physicians know which patient is given drug and which placebo. Finally, a switch from drug to placebo and vice versa can be made in a successive phase of treatment, the cross-over trial. In this fashion, drug vs. placebo comparisons can be made not only between two pa- tient groups, but also within either group itself. Homeopathy (B) is an alternative method of therapy, developed in the 1800s by Samuel Hahnemann. His idea was this: when given in normal (allopathic) dosage, a drug (in the sense of medicament) will produce a constellation of symptoms; however, in a patient whose disease symptoms resemble just this mosaic of symptoms, the same drug (simile principle) would effect a cure when given in a very low dosage (“potentiation”). The body’s self-healing powers were to be properly activated only by minimal doses of the medicinal substance. The homeopath’s task is not to diagnose the causes of morbidity, but to find the drug with a “symptom profile” most closely resembling that of the patient’s illness. This drug is then applied in very high dilution. A direct action or effect on body functions cannot be demonstrated for homeopathic medicines. Therapeutic success is due to the suggestive powers of the homeopath and the expectancy of the patient. When an illness is strongly influenced by emotional (psychic) factors and cannot be treated well by allopathic means, a case can be made in favor of exploiting suggestion as a therapeutic tool. Homeopathy is one of several possible methods of doing so. Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license. Drug-independent Effects Conscious and unconscious signals: language, facial expression, gestures Conscious and unconscious expectations 77 Mind Well-being complaints Placebo Effect: - wanted - unwanted Body Physician Patient A. Therapeutic effects resulting from physician´s power of suggestion Homeopath “Similia similibus curentur” Patient “Drug” Normal, allopathic dose symptom profile Dilution “effect reversal” Very low homeopathic dose elimination of disease symptoms corresponding to allopathic symptom “profile” “Potentiation” increase in efficacy with progressive dilution Profile of disease symptoms Symptom “profile” “Drug diagnosis” Homeopathic remedy (“Simile”) Stocksolution Dilution 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 10 1 D9 10 1 1000 000 000 B. Homeopathy: concepts and procedure Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.