- •Preface to the 3rd edition
- •General Pharmacology
- •Systems Pharmacology
- •Therapy of Selected Diseases
- •Subject Index
- •Abbreviations
- •General Pharmacology
- •History of Pharmacology
- •Drug and Active Principle
- •The Aims of Isolating Active Principles
- •European Plants as Sources of Effective Medicines
- •Drug Development
- •Congeneric Drugs and Name Diversity
- •Oral Dosage Forms
- •Drug Administration by Inhalation
- •Dermatological Agents
- •From Application to Distribution in the Body
- •Potential Targets of Drug Action
- •External Barriers of the Body
- •Blood–Tissue Barriers
- •Membrane Permeation
- •Binding to Plasma Proteins
- •The Liver as an Excretory Organ
- •Biotransformation of Drugs
- •Drug Metabolism by Cytochrome P450
- •The Kidney as an Excretory Organ
- •Presystemic Elimination
- •Drug Concentration in the Body as a Function of Time—First Order (Exponential) Rate Processes
- •Time Course of Drug Concentration in Plasma
- •Time Course of Drug Plasma Levels during Repeated Dosing (A)
- •Time Course of Drug Plasma Levels during Irregular Intake (B)
- •Accumulation: Dose, Dose Interval, and Plasma Level Fluctuation (A)
- •Dose–Response Relationship
- •Concentration–Effect Curves (B)
- •Concentration–Binding Curves
- •Types of Binding Forces
- •Agonists—Antagonists
- •Other Forms of Antagonism
- •Enantioselectivity of Drug Action
- •Receptor Types
- •Undesirable Drug Effects, Side Effects
- •Drug Allergy
- •Cutaneous Reactions
- •Drug Toxicity in Pregnancy and Lactation
- •Pharmacogenetics
- •Placebo (A)
- •Systems Pharmacology
- •Sympathetic Nervous System
- •Structure of the Sympathetic Nervous System
- •Adrenergic Synapse
- •Adrenoceptor Subtypes and Catecholamine Actions
- •Smooth Muscle Effects
- •Cardiostimulation
- •Metabolic Effects
- •Structure–Activity Relationships of Sympathomimetics
- •Indirect Sympathomimetics
- •Types of
- •Antiadrenergics
- •Parasympathetic Nervous System
- •Cholinergic Synapse
- •Parasympathomimetics
- •Parasympatholytics
- •Actions of Nicotine
- •Localization of Nicotinic ACh Receptors
- •Effects of Nicotine on Body Function
- •Aids for Smoking Cessation
- •Consequences of Tobacco Smoking
- •Dopamine
- •Histamine Effects and Their Pharmacological Properties
- •Serotonin
- •Vasodilators—Overview
- •Organic Nitrates
- •Calcium Antagonists
- •ACE Inhibitors
- •Drugs Used to Influence Smooth Muscle Organs
- •Cardiac Drugs
- •Cardiac Glycosides
- •Antiarrhythmic Drugs
- •Iron Compounds
- •Prophylaxis and Therapy of Thromboses
- •Possibilities for Interference (B)
- •Heparin (A)
- •Hirudin and Derivatives (B)
- •Fibrinolytics
- •Intra-arterial Thrombus Formation (A)
- •Formation, Activation, and Aggregation of Platelets (B)
- •Inhibitors of Platelet Aggregation (A)
- •Presystemic Effect of ASA
- •Plasma Volume Expanders
- •Lipid-lowering Agents
- •Diuretics—An Overview
- •NaCl Reabsorption in the Kidney (A)
- •Aquaporins (AQP)
- •Osmotic Diuretics (B)
- •Diuretics of the Sulfonamide Type
- •Potassium-sparing Diuretics (A)
- •Vasopressin and Derivatives (B)
- •Drugs for Gastric and Duodenal Ulcers
- •Laxatives
- •Antidiarrheal Agents
- •Drugs Affecting Motor Function
- •Muscle Relaxants
- •Nondepolarizing Muscle Relaxants
- •Depolarizing Muscle Relaxants
- •Antiparkinsonian Drugs
- •Antiepileptics
- •Pain Mechanisms and Pathways
- •Eicosanoids
- •Antipyretic Analgesics
- •Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
- •Cyclooxygenase (COX) Inhibitors
- •Local Anesthetics
- •Opioid Analgesics—Morphine Type
- •General Anesthesia and General Anesthetic Drugs
- •Inhalational Anesthetics
- •Injectable Anesthetics
- •Sedatives, Hypnotics
- •Benzodiazepines
- •Pharmacokinetics of Benzodiazepines
- •Therapy of Depressive Illness
- •Mania
- •Therapy of Schizophrenia
- •Psychotomimetics (Psychedelics, Hallucinogens)
- •Hypothalamic and Hypophyseal Hormones
- •Thyroid Hormone Therapy
- •Glucocorticoid Therapy
- •Follicular Growth and Ovulation, Estrogen and Progestin Production
- •Oral Contraceptives
- •Antiestrogen and Antiprogestin Active Principles
- •Aromatase Inhibitors
- •Insulin Formulations
- •Treatment of Insulin-dependent Diabetes Mellitus
- •Treatment of Maturity-Onset (Type II) Diabetes Mellitus
- •Oral Antidiabetics
- •Drugs for Maintaining Calcium Homeostasis
- •Drugs for Treating Bacterial Infections
- •Inhibitors of Cell Wall Synthesis
- •Inhibitors of Tetrahydrofolate Synthesis
- •Inhibitors of DNA Function
- •Inhibitors of Protein Synthesis
- •Drugs for Treating Mycobacterial Infections
- •Drugs Used in the Treatment of Fungal Infections
- •Chemotherapy of Viral Infections
- •Drugs for the Treatment of AIDS
- •Drugs for Treating Endoparasitic and Ectoparasitic Infestations
- •Antimalarials
- •Other Tropical Diseases
- •Chemotherapy of Malignant Tumors
- •Targeting of Antineoplastic Drug Action (A)
- •Mechanisms of Resistance to Cytostatics (B)
- •Inhibition of Immune Responses
- •Antidotes and Treatment of Poisonings
- •Therapy of Selected Diseases
- •Hypertension
- •Angina Pectoris
- •Antianginal Drugs
- •Acute Coronary Syndrome— Myocardial Infarction
- •Congestive Heart Failure
- •Hypotension
- •Gout
- •Obesity—Sequelae and Therapeutic Approaches
- •Osteoporosis
- •Rheumatoid Arthritis
- •Migraine
- •Common Cold
- •Bronchial Asthma
- •Emesis
- •Alcohol Abuse
- •Local Treatment of Glaucoma
- •Further Reading
- •Further Reading
- •Picture Credits
- •Drug Indexes
254 Hormones
Antiestrogen and Antiprogestin Active Principles
Selective estrogen receptor modulators (SERMs) (A). Estrogen receptors belong to the group of transcription-regulating receptors (p.64). The female gonadal hormone estradiol is an agonist at these receptors. Several drugs are available that can produce estrogen-antagonistic effects. Interestingly, these are associated with estrogen-agonistic effects in certain tissues. A tentative explanation derives from the idea that each ligand induces a specific conformation of the estrogen receptor. The ligand–estrogen receptor complexes combine with co-activators or repressors at specified gene sequences. The pattern of co-regulators differs from tissue to tissue, allowing each SERM to generate a tissue-specific activity. It is of therapeutic significance that the patterns of estrogenic and antiestrogenic effects differ in a sub- stance-specific manner among the drugs of this class.
It is useful to compare the activity profile of a SERM with that of estradiol, particularly in relation to effects seen postmenopausally. During chronic administration of estradiol, the risk of endometrial cancer rises; co-ad- ministration of a progestin prevents this effect. Breast cancers occur more frequently, likewise thromboembolic diseases. Estradiol effectively alleviates climacteric hot flashes and sweating. After chronic treatment it reduces the incidence of osteoporotic bone fractures by preventing the loss of an estro- gen-dependent portion of bone mass. Nonetheless, estrogens can no longer be recommended for this purpose because of the unfavorable benefit–risk constellation (p.330).
Clomifene is a stilbene derivative used orally for the therapy of female infertility. Owing to its antagonistic action at estrogen receptors in the adenohypophysis, feedback inhibition by estradiol of gonadotropin secretion is suppressed. The resulting increase in release of FSH induces augmented maturation of oocyte follicles. For instance, clomi-
fene can be used for the treatment of luteal phase defects associated with disturbances of follicular maturation or the treatment of polycystic ovary syndrome. Since its use is confined to a few selected days during the ovarian cycle, chronic effects need not be considered.
Tamoxifen is a stilbene derivative that is used in metastasizing breast cancer to block the estrogenic stimulus for tumor cell growth. As a mixed estrogenic antagonist/ partial agonist, tamoxifen promotes rather than ameliorates climacteric complaints; at the same time it displays agonistic features that are of concern as a potential risk factor when use of the drug for the prophylaxis of breast cancer is being considered.
Raloxifene is approved for use in the treatment and prophylaxis of osteoporosis. As shown in the table opposite, it has other beneficial as well as adverse effects.
The estrogen receptor antagonist fulvestrant is devoid of agonist activities and, given as a monthly injection may be used to delay progression of breast cancer. It causes downregulation and degradation of the estrogen receptor protein.
Progestin receptor antagonist (B). Approximately one week after conception, the embryo implants itself into the endometrium in the form of the blastocyst. By secreting human chorionic gonadotropin (HCG, mainly LH), the trophoblast maintains the corpus luteum and secretion of progesterone and thereby prevents menstrual bleeding. Mifepristone is an antagonist at progestin receptors and prevents maintenance of the endometrium during early pregnancy. Consequently, it acts as an abortifacient in early pregnancy. Its use has provoked medical debates (comparison of adverse reactions to mifepristone vs. surgical intervention) and aroused ethical-ideological conflicts.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
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Antiestrogens and Antiprogestins |
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A. Selective estrogen receptor modulators (SERM) |
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Clomifene |
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Raloxifene |
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O |
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Cl |
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HO |
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CH3 |
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Tamoxifen |
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CH2 |
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CH3 |
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Hypophysis |
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FSH |
Estrogen |
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Ovary |
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Ovulation |
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Advanced breast cancer |
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Estradiol |
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and prophylaxis |
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of osteoporosis in |
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if no gestagen added |
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postmenopause |
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Estradiol |
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Tamoxifen |
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Raloxifene |
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Endometrial |
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cancer risk |
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Breast cancer risk |
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Thromboembolism
Relief of climacteric complaints
Bone mass
B. Gestagen receptor antagonist |
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Mifepristone |
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Corpus |
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Embryo |
luteum |
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N |
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H3C |
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Progesterone |
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OH |
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Maintenance of endometrium |
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Abortion |
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
256 Hormones
Aromatase Inhibitors
Aromatase inhibitors constitute an additional antiestrogenic principle that is based upon inhibition of estrogen formation. They are used chiefly in the therapy of advanced breast cancer when the tumor has become insensitive to estrogen and the patient has completed menopause. However, one agent in this class (anastrozole) was recently licensed for use in early breast cancer.
Aromatase. The enzyme converts androgens such as testosterone and androstenedione into the estrogens estradiol and estrone.This reaction involves cleavage of the methyl group at C10 and aromatization of ring A. Aromatase is a cytochrome P450-containing enzyme (isozyme CYP19). During the female reproductive phase, the major portion of circulating estrogens originates from the ovaries, where estradiol is synthesized in the granulosa cells of the maturing tertiary follicles. Theca cells surrounding the granulosa cells supply androgen precursors. FSH stimulates formation of estrogens by inducing the synthesis of aromatase in granulosa cells. An isoform of the enzyme 17β-hydroxyste- roid dehydrogenase (17β-HSD 1) catalyzes the conversion of androstenedione to testosterone and of estrone to estradiol. After menopause, ovarian function ceases. However, estrogens do not disappear completely from the blood because they continue to enter the circulation from certain other tissues, in particular the subcutaneous adipose tissue, which produces estrone. In hormonedependent breast cancers, tumor growth is thereby promoted. In addition, breast cancer cells themselves may be capable of producing estrogens via aromatase.
Aromatase inhibitors serve to eliminate extraovarian synthesis of estrogens in breast cancer patients. This can be achieved effectively only in postmenopause because, as an FSH-dependent enzyme, ovarian aromatase is subject to feedback regulation of female
gonadal hormones. A drop in blood estradiol concentration would lead to increased release of FSH with a compensatory increase in synthesis of aromatase and estrogens.
Two groups of inhibitors can be distinguished on the basis of chemical structure and mechanism of action. Steroidal inhibitors (formestane, exemestane) attach to the androgen binding site on the enzyme and in the form of intermediary products give rise to an irreversible inhibition of the enzyme.
Nonsteroidal inhibitors (anastrozole, letrozole) attach to a different binding site of the enzyme; via their triazole ring they interact reversibly with the heme iron of cytochrome P450.
Among the adverse effects, climacteric-like complaints predominate, reflecting the decline in estrogen levels. Unlike the SERMs, tamoxifen, which is used for the same indication, aromatase inhibitors do not promote endometrial growth and do not increase the risk of thromboembolic complications.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
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Aromatase Inhibitors |
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A. Aromatase inhibitors |
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Testosterone |
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gonadotropin-dependent |
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expression in granulosa cells |
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CYP 19 |
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Extragonadal |
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tissues; |
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expression also after |
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menopause |
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Androstenedione |
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e.g., |
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stimulated |
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adipose tissue |
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growth |
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I n h i b i t o r s |
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Nonsteroidal |
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Formestane |
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N |
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Anastrozole |
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O |
N |
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C |
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N |
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C |
CH3 |
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i.m. |
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CH3 |
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O |
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H3C |
C |
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OH |
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CH3 |
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Exemestane |
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N |
Letrozole |
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N |
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N |
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p.o. |
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O |
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C |
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C |
N |
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CH2 |
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Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.