O

Atropine mACh-receptor

Receptor specificity but lacking organ selectivity

Atropine mACh-receptor

Receptor specificity but lacking organ selectivity

Drug Receptor Specificity

p CHor- Q promazine mACh-receptor a-adreno-ceptor

Dopamine receptor

Histamine receptor

Lacking receptor specificity p CHor- Q promazine mACh-receptor a-adreno-ceptor

Dopamine receptor

Histamine receptor

Lacking receptor specificity

C. Adverse drug effect: lacking selectivity

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 so-called 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 life-threatening anaphylactic shock develops, 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 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 granulo-cytes (chemotaxis), and stimulates other inflammatory responses. Activation of complement on blood cells results in their destruction, evidenced by hemo-lytic anemia, agranulocytosis, and thrombocytopenia.

Type 3, immune complex vascu-litis (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 cuta-neously 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.

Reaction of immune system to first drug exposure

Immune system (= lymphatic ^ tissue) recognizes:

"Non-self"

Reaction of immune system to first drug exposure

Production of antibodies (Immunoglobulins) e.g. IgE

IgG etc.

Proliferation of antigen-specific lymphocytes

Immune system (= lymphatic ^ tissue) recognizes:

"Non-self"

Production of antibodies (Immunoglobulins) e.g. IgE

IgG etc.

Proliferation of antigen-specific lymphocytes

Immune reaction with repeated drug exposure IgE

Receptor for IgE

Receptor for IgE

Mast cell

(tissue)

basophilic granulocyte

(blood)

Histamine and other mediators Urticaria, asthma, shock

Mast cell

(tissue)

basophilic granulocyte

(blood)

Histamine and other mediators Urticaria, asthma, shock

Type 1 reaction:

acute anaphylactic reaction e.g., Neutrophilic granulocyte e.g., Neutrophilic granulocyte

Complement activation

Membrane injury

Complement activation

Type 2 reaction: cytotoxic reaction

Membrane injury

Antigen-specific T-lymphocyte

Type Immune Complex Photo

Antigen-specific T-lymphocyte

Type 3 reaction Immune complex

Type 4 reaction: lymphocytic delayed reaction

Type 3 reaction Immune complex

Type 4 reaction: lymphocytic delayed reaction

A. Adverse drug effect: allergic reaction

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: masculin-ization of the female fetus by androgenic hormones; brain hemorrhage due to oral anticoagulants; bradycardia due to p-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 tet-racyclines, 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 ter-atogenicity include derivatives of vitamin A (etretinate, isotretinoin [used internally in skin diseases]), and oral anticoagulants. A peculiar type of damage results from the synthetic estrogen-ic 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 anti-convulsants.

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.

B. Lactation: maternal intake of drug

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.

A. Therapeutic effects resulting from physicians power of suggestion

"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

Adverse Effect

B. Homeopathy: concepts and procedure

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