MW > 10 000 Protein
"Non-self"
Immune system (^ lymphatic tissue) recognizes:
Drug(= hapten)
Antigen
Reaction of immune system to first drug exposure
Proliferation of antigen-specific lymphocytes
Immune reaction with repeated drug exposure
Histamine and other mediators Receptor
for IgE
Type 1 reaction:
acute anaphylactic reaction Mast cell (tissue) basophilic granulocyte (blood) IgE
Urticaria, asthma, shock
IgG
Type 2 reaction:
cytotoxic reaction
Cell destruc-tion Membrane injury e.g., Neutrophilic granulocyte
Complement activation
Deposition on vessel wall
Formation of immune complexes
Activation of:
complement
andneutrophils
Type 3 reaction:
Immune complex
Inflammatory reaction
Contact dermatitis
Type 4 reaction:
lymphocytic delayed reaction Inflammatory
reaction
Lymphokines
Antigen-specific T-lymphocyte Distribution in body
=
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 at-tention 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 andro-genic hormones; brain hemorrhage due to oral anticoagulants; bradycar-dia due to !-blockers.
2. Effects that specifically affect the de-veloping organism and that cannot be predicted on the basis of the known pharmacological activity pro-file.
In assessing the risks attending drug use during pregnancy, the follow-ing points have to be considered:
a) Time of drug use. The possible seque-lae 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 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
novel drugs it is usually not yet pos-sible to define their teratogenic haz-ard.
Drugs with established human ter-atogenicity include derivatives of vita-min A (etretinate, isotretinoin [used internally in skin diseases]), and oral anticoagulants. A peculiar type of dam-age results from the synthetic estrogen-ic agent, diethylstilbestrol, following its use during pregnancy; daughters of treated mothers have an increased inci-dence 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 untreat-ed 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 wean-ing.
74 Adverse Drug Effects
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Adverse Drug Effects 75
Development
stage Nidation Embryo: organ
ment
Fetus: growth and maturation Age of fetus
(weeks)
B. Lactation: maternal intake of drug A. Pregnancy: fetal damage due to drugs
Sequelae ofdamage by drug
Malformation
Fetal death Functional disturbances
38 21 2
1 12
Artery Uterus wall Vein
Transfer ofmetabolites
Capillary
Syncytio-trophoblast Placental barrier
Fetus Mother
To umbilical cord Placental transfer of metabolites
Therapeutic effect in mother
Unwanted effect in child
Drug
?
Extent of transfer of drug into milk Infant dose
Rate of elimination of drug from infant Distribution of drug in infant
Drug concentration in infant´s blood
Effect
Ovum 1 day
Endometrium Blastocyst
Sensitivity of site of action Sperm cells ~3 days
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 thera-peutic setting.
Physicians may consciously or un-consciously 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 con-fidence, the patient in turn feels com-fortable and less anxious and optimisti-cally 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 hos-pital, 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 attribu-table 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 pa-tients by means of statistical proce-dures, i.e., a placebo-controlled trial. A prospective trialis 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-tiveor 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-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 (allo-pathic) dosage, a drug (in the sense of medicament) will produce a constella-tion 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 (“po-tentiation”). 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 di-agnose 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 ap-plied 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) fac-tors and cannot be treated well by allo-pathic means, a case can be made in fa-vor of exploiting suggestion as a thera-peutic tool. Homeopathy is one of sever-al possible methods of doing so.
76 Drug-independent Effects
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Drug-independent Effects 77
“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