Color Atlas of Pharmacology (Part 8): Adverse Drug Effects

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Adverse Drug Effects 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,...

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70 Adverse Drug Effects Adverse Drug Effects premature breakdown of red blood cells (hemolysis) in subjects with a glucose- The desired (or intended) principal ef- 6-phosphate dehydrogenase deficiency. fect of any drug is to modify body func- The discipline of pharmacogenetics deals tion in such a manner as to alleviate with the importance of the genotype for symptoms caused by the patient’s ill- reactions to drugs. ness. In addition, a drug may also cause The above forms of hypersensitivity unwanted effects that can be grouped must be distinguished from allergies in- into minor or “side” effects and major or volving the immune system (p. 72). adverse effects. These, in turn, may give Lack of selectivity (C). Despite ap- rise to complaints or illness, or may propriate dosing and normal sensitivity, even cause death. undesired effects can occur because the Causes of adverse effects: over- drug does not specifically act on the tar- dosage (A). The drug is administered in geted (diseased) tissue or organ. For in- a higher dose than is required for the stance, the anticholinergic, atropine, is principal effect; this directly or indirect- bound only to acetylcholine receptors of ly affects other body functions. For in- the muscarinic type; however, these are stances, morphine (p. 210), given in the present in many different organs. appropriate dose, affords excellent pain Moreover, the neuroleptic, chlor- relief by influencing nociceptive path- promazine, formerly used as a neuro- ways in the CNS. In excessive doses, it leptic, is able to interact with several inhibits the respiratory center and different receptor types. Thus, its action makes apnea imminent. The dose de- is neither organ-specific nor receptor- pendence of both effects can be graphed specific. in the form of dose-response curves The consequences of lack of selec- (DRC). The distance between both DRCs tivity can often be avoided if the drug indicates the difference between the does not require the blood route to therapeutic and toxic doses. This margin reach the target organ, but is, instead, of safety indicates the risk of toxicity applied locally, as in the administration when standard doses are exceeded. of parasympatholytics in the form of eye “The dose alone makes the poison” drops or in an aerosol for inhalation. (Paracelsus). This holds true for both With every drug use, unwanted ef- medicines and environmental poisons. fects must be taken into account. Before No substance as such is toxic! In order to prescribing a drug, the physician should assess the risk of toxicity, knowledge is therefore assess the risk: benefit ratio. required of: 1) the effective dose during In this, knowledge of principal and ad- exposure; 2) the dose level at which verse effects is a prerequisite. damage is likely to occur; 3) the dura- tion of exposure. Increased Sensitivity (B). If certain body functions develop hyperreactivity, unwanted effects can occur even at nor- mal dose levels. Increased sensitivity of the respiratory center to morphine is found in patients with chronic lung dis- ease, in neonates, or during concurrent exposure to other respiratory depress- ant agents. The DRC is shifted to the left and a smaller dose of morphine is suffi- cient to paralyze respiration. Genetic anomalies of metabolism may also lead to hypersensitivity. Thus, several drugs (aspirin, antimalarials, etc.) can provoke Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Adverse Drug Effects 71 Decrease in Effect Respiratory depression pain perception Decrease in (nociception) Nociception Respira- Morphine tory overdose activity Morphine Safety margin Dose A. Adverse drug effect: overdosing Increased Effect sensitivity of respiratory Safety margin center Normal dose Dose B. Adverse drug effect: increased sensitivity e. g., Chlor- Atropine promazine mACh- mACh- receptor receptor Receptor specificity but lacking organ !-adreno- selectivity ceptor 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.
72 Adverse Drug Effects Drug Allergy ready formed in blood accumulate. These complexes mediate the activation The immune system normally functions of complement, a family of proteins that to rid the organism of invading foreign circulate in the blood in an inactive particles, such as bacteria. Immune re- form, but can be activated in a cascade- sponses can occur without appropriate like succession by an appropriate stimu- cause or with exaggerated intensity and lus. “Activated complement” normally may harm the organism, for instance, directed against microorganisms, can when allergic reactions are caused by destroy the cell membranes and thereby drugs (active ingredient or pharmaceu- cause cell death; it also promotes pha- tical excipients). Only a few drugs, e.g. gocytosis, attracts neutrophil granulo- (heterologous) proteins, have a molecu- cytes (chemotaxis), and stimulates oth- lar mass (> 10,000) large enough to act er inflammatory responses. Activation as effective antigens or immunogens, of complement on blood cells results in capable by themselves of initiating an their destruction, evidenced by hemo- immune response. Most drugs or their lytic anemia, agranulocytosis, and metabolites (so-called haptens) must thrombocytopenia. first be converted to an antigen by link- Type 3, immune complex vascu- age to a body protein. In the case of pen- litis (serum sickness, Arthus reaction). icillin G, a cleavage product (penicilloyl Drug-antibody complexes precipitate on residue) probably undergoes covalent vascular walls, complement is activated, binding to protein. During initial con- and an inflammatory reaction is trig- tact with the drug, the immune system gered. Attracted neutrophils, in a futile is sensitized: antigen-specific lympho- attempt to phagocytose the complexes, cytes of the T-type and B-type (antibody liberate lysosomal enzymes that dam- formation) proliferate in lymphatic tis- age the vascular walls (inflammation, sue and some of them remain as so- vasculitis). Symptoms may include fe- called memory cells. Usually, these pro- ver, exanthema, swelling of lymph cesses remain clinically silent. During nodes, arthritis, nephritis, and neuropa- the second contact, antibodies are al- thy. ready present and memory cells prolife- Type 4, contact dermatitis. A cuta- rate rapidly. A detectable immune re- neously applied drug is bound to the sponse, the allergic reaction, occurs. surface of T-lymphocytes directed spe- This can be of severe intensity, even at a cifically against it. The lymphocytes re- low dose of the antigen. Four types of lease signal molecules (lymphokines) reactions can be distinguished: into their vicinity that activate macro- Type 1, anaphylactic reaction. phages and provoke an inflammatory Drug-specific antibodies of the IgE type reaction. combine via their Fc moiety with recep- tors on the surface of mast cells. Binding of the drug provides the stimulus for the release of histamine and other media- tors. In the most severe form, a life- threatening anaphylactic shock devel- ops, accompanied by hypotension, bronchospasm (asthma attack), laryn- geal edema, urticaria, stimulation of gut musculature, and spontaneous bowel movements (p. 326). Type 2, cytotoxic reaction. Drug- antibody (IgG) complexes adhere to the surface of blood cells, where either circu- lating drug molecules or complexes al- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Adverse Drug Effects 73 Reaction of immune system to first drug exposure Production of antibodies Drug (Immunoglobulins) (= hapten) Immune system e.g. IgE (^ lymphatic = IgG etc. tissue) recognizes: Proliferation of Protein antigen-specific "Non-self" lymphocytes Macromolecule MW > 10 000 Distribution Antigen in body Immune reaction with repeated drug exposure e.g., Neutrophilic IgE granulocyte IgG Mast cell (tissue) Receptor basophilic for IgE granulocyte (blood) Complement activation Cell Histamine and other mediators destruc- tion Urticaria, asthma, shock Membrane injury Type 1 reaction: Type 2 reaction: acute anaphylactic reaction cytotoxic reaction Formation of Contact immune complexes dermatitis Antigen- specific Deposition on Activation T-lymphocyte vessel wall of: complement Inflammatory reaction and neutrophils Lymphokines Inflammatory reaction Type 4 reaction: Type 3 reaction: Immune complex 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.
74 Adverse Drug Effects Drug Toxicity in Pregnancy and novel drugs it is usually not yet pos- Lactation sible to define their teratogenic haz- ard. Drugs taken by the mother can be Drugs with established human ter- passed on transplacentally or via breast atogenicity include derivatives of vita- milk and adversely affect the unborn or min A (etretinate, isotretinoin [used the neonate. internally in skin diseases]), and oral anticoagulants. A peculiar type of dam- Pregnancy (A) age results from the synthetic estrogen- Limb malformations induced by the ic agent, diethylstilbestrol, following its hypnotic, thalidomide, first focused at- use during pregnancy; daughters of tention on the potential of drugs to treated mothers have an increased inci- cause malformations (teratogenicity). dence of cervical and vaginal carcinoma Drug effects on the unborn fall into two at the age of approx. 20. basic categories: In assessing the risk: benefit ratio, it is 1. Predictable effects that derive from also necessary to consider the benefit the known pharmacological drug for the child resulting from adequate properties. Examples are: masculin- therapeutic treatment of its mother. For ization of the female fetus by andro- instance, therapy with antiepileptic genic hormones; brain hemorrhage drugs is indispensable, because untreat- due to oral anticoagulants; bradycar- ed epilepsy endangers the infant at least dia due to !-blockers. as much as does administration of anti- 2. Effects that specifically affect the de- convulsants. veloping organism and that cannot be predicted on the basis of the Lactation (B) known pharmacological activity pro- Drugs present in the maternal organism file. can be secreted in breast milk and thus In assessing the risks attending be ingested by the infant. Evaluation of drug use during pregnancy, the follow- risk should be based on factors listed in ing points have to be considered: B. In case of doubt, potential danger to a) Time of drug use. The possible seque- the infant can be averted only by wean- lae of exposure to a drug depend on ing. the stage of fetal development, as shown in A. Thus, the hazard posed by a drug with a specific action is lim- ited in time, as illustrated by the tet- racyclines, which produce effects on teeth and bones only after the third month of gestation, when mineral- ization begins. b) Transplacental passage. Most drugs can pass in the placenta from the ma- ternal 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 esti- mates are available for familiar, fre- quently used drugs. For many drugs, teratogenic potency cannot be dem- onstrated; however, in the case of Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Adverse Drug Effects 75 Ovum 1 day Sperm cells ~3 days Endometrium Blastocyst Age of fetus 1 21 2 12 38 (weeks) Development Nidation Embryo: organ Fetus: growth stage develop- and ment maturation Fetal death Malformation Functional disturbances Artery Uterus wall Vein Mother Sequelae of Transfer damage of Syncytio- by drug metabolites trophoblast Placental Fetus Capillary barrier Placental transfer of metabolites To umbilical cord A. Pregnancy: fetal damage due to drugs Drug Extent of Distribution transfer of of drug drug into in infant milk Infant dose Therapeutic effect in Rate of mother elimination of drug from infant ? Drug concentration in infant´s blood Unwanted effect in child Sensitivity of Effect site of action B. Lactation: maternal intake of drug Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
76 Drug-independent Effects Placebo (A) tient groups, but also within either group itself. A placebo is a dosage form devoid of an Homeopathy (B) is an alternative active ingredient, a dummy medication. method of therapy, developed in the Administration of a placebo may elicit 1800s by Samuel Hahnemann. His idea the desired effect (relief of symptoms) was this: when given in normal (allo- or undesired effects that reflect a pathic) dosage, a drug (in the sense of change in the patient’s psychological medicament) will produce a constella- situation brought about by the thera- tion of symptoms; however, in a patient peutic setting. whose disease symptoms resemble just Physicians may consciously or un- this mosaic of symptoms, the same drug consciously communicate to the patient (simile principle) would effect a cure whether or not they are concerned when given in a very low dosage (“po- about the patient’s problem, or certain tentiation”). The body’s self-healing about the diagnosis and about the value powers were to be properly activated of prescribed therapeutic measures. In only by minimal doses of the medicinal the care of a physician who projects substance. personal warmth, competence, and con- The homeopath’s task is not to di- fidence, the patient in turn feels com- agnose the causes of morbidity, but to fortable and less anxious and optimisti- find the drug with a “symptom profile” cally anticipates recovery. most closely resembling that of the The physical condition determines patient’s illness. This drug is then ap- the psychic disposition and vice versa. plied in very high dilution. Consider gravely wounded combatants A direct action or effect on body in war, oblivious to their injuries while functions cannot be demonstrated for fighting to survive, only to experience homeopathic medicines. Therapeutic severe pain in the safety of the field hos- success is due to the suggestive powers pital, or the patient with a peptic ulcer of the homeopath and the expectancy of caused by emotional stress. the patient. When an illness is strongly Clinical trials. In the individual influenced by emotional (psychic) fac- case, it may be impossible to decide tors and cannot be treated well by allo- whether therapeutic success is attribu- pathic means, a case can be made in fa- table to the drug or to the therapeutic vor of exploiting suggestion as a thera- situation. What is therefore required is a peutic tool. Homeopathy is one of sever- comparison of the effects of a drug and al possible methods of doing so. of a placebo in matched groups of pa- tients by means of statistical proce- dures, i.e., a placebo-controlled trial. A prospective trial is planned in advance, a retrospective (case-control) study fol- lows patients backwards in time. Pa- tients are randomly allotted to two groups, namely, the placebo and the ac- tive or test drug group. In a double-blind trial, neither the patients nor the treat- ing 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- Lüllmann, Color Atlas of Pharmacology © 2000 Thieme All rights reserved. Usage subject to terms and conditions of license.
Drug-independent Effects 77 Conscious Conscious and and unconscious unconscious signals: expectations Mind language, facial expression, gestures Well-being complaints Placebo Effect: - wanted - unwanted Body Physician Patient A. Therapeutic effects resulting from physician´s power of suggestion Homeopath Patient “Similia similibus curentur” “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 Stock- remedy (“Simile”) solution Dilution 1 1 1 1 1 1 1 1 1 D9 10 10 10 10 10 10 10 10 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.