- •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
250 Hormones
Follicular Growth and Ovulation, Estrogen and Progestin Production
Follicular maturation and ovulation, as well as the associated production of female gonadal hormones, are controlled by the hypophyseal gonadotropins FSH (follicle-stimu- lating hormone) and LH (luteinizing hormone). In the first half of the menstrual cycle, FSH promotes growth and maturation of ovarian tertiary follicles that respond with accelerating synthesis of estradiol. Estradiol stimulates endometrial growth and increases the permeability of cervical mucus for sperm cells. When the estradiol blood level approaches a predetermined set-point, FSH release is inhibited owing to feedback action on the anterior hypophysis. Since follicle growth and estrogen production are correlated, hypophysis and hypothalamus can “monitor” the follicular phase of the ovarian cycle through their estrogen receptors. Immediately prior to ovulation, when the nearly mature tertiary follicles are producing a high concentration of estradiol, the control loop switches to positive feedback. LH secretion transiently surges to peak levels and triggers ovulation. Within hours after ovulation, the tertiary follicle develops into the corpus luteum, which then also releases progesterone in response to LH. This initiates the secretory phase of the endometrial cycle and lowers the permeability of cervical mucus. Nonruptured follicles continue to release estradiol under the influence of FSH. After two weeks, production of progesterone and estradiol subsides, causing the secretory endometrial layer to be shed (menstruation).
The natural hormones are unsuitable for oral application because they are subject to presystemic hepatic elimination. Estradiol is converted via estrone to estriol; by conjugation, all three can be rendered water-soluble and amenable to renal excretion. The major metabolite of progesterone is pregnanediol, which is also conjugated and eliminated renally.
Estrogen preparations. Depot preparations for i.m. injection are oily solutions of esters of estradiol (3- or 17-OH group). The hydrophobicity of the acyl moiety determines the rate of absorption, hence the duration of effect. Released ester is hydrolyzed to yield free estradiol.
Orally used preparations. Ethinylestradiol
(EE) is more stable metabolically, passes the liver after oral intake and mimics estradiol at estrogen receptors. Mestranol itself is inactive; however, cleavage of the C3 methoxy group again yields EE. In oral contraceptives, one of the two agents forms the estrogen component (p.252). (Sulfate-) Conjugated estrogens (excretory products) can be extracted from equine urine and are used in the therapy of climacteric complaints. Their effectiveness is a matter of debate. Estradiol transdermal delivery systems are available.
Progestin preparations. Depot formulations for i.m. injection are 17-α-hydroxy- progesterone caproate and medroxyprogesterone acetate. Preparations for oral use are derivatives of ethinyltestosterone = ethisterone (e.g., norethisterone, dimethisterone, lynestrenol, desogestrel, gestoden), or of 17α-hydroxyprogesterone acetate (e.g., chlormadinone acetate or cyproterone acetate).
Indications for estrogens and progestins include hormonal contraception (p.252); hormone replacement, as in postmenopausal women for prophylaxis of osteoporosis; bleeding anomalies; menstrual and severe climacteric complaints.
Adverse effects. After long-term intake of estrogen/progestin preparations, increased risks have been reported for breast cancer, coronary heart disease, stroke, and thromboembolism. Although the incidence of bone fractures also decreases, the risk–benefit relationship is unfavorable. Concerning the adverseeffectsoforalcontraceptives,seep.252.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Estrogens and Progestins |
251 |
A. Estradiol, progesterone, and derivatives |
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Hypothalamus |
Hydroxyprogesterone |
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O Estradiol |
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H3C |
caproate |
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GnRH |
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-valerate |
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3 weeks |
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Hypophysis |
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FSH |
LH |
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acetate |
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H3C |
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17 |
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HO |
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Estradiol |
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Progesterone |
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CH3 |
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HC |
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OH |
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OH |
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OH |
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HO |
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Estriol |
Estrone |
Estradiol |
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Conjugation with sulfate, glucuronate |
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Inactivation |
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Inactivation |
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CH |
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CH |
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a gestagen |
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3-Methylether of EE |
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estrogens |
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Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
252 Hormones
Oral Contraceptives
Inhibitors of ovulation. Negative feedback control of gonadotropin release can be utilized to inhibit the ovarian cycle. Administration of exogenous estrogens (ethinylestradiol or mestranol) during the first half of the cycle permits FSH production to be suppressed (as it is by administration of progestins alone). Owing to the reduced FSH stimulation of tertiary follicles, maturation of follicles and hence ovulation are prevented. In effect, the regulatory brain centers are deceived, as it were, by the elevated estrogen blood level, which signals normal follicular growth and a decreased requirement for FSH stimulation. If estrogens alone are given during the first half of the cycle, endometrial and cervical responses, as well as other functional changes, will occur in the normal fashion. By adding a progestin (p.250) during the second half of the cycle, the secretory phase of the endometrium and associated effects can be elicited. Discontinuance of hormone administration would be followed by menstruation.
The physiological time course of estrogenprogesterone release is simulated in the socalled biphasic (sequential) preparations
(A). In monophasic preparations, estrogen and progestin are taken concurrently. Early administration of progestin reinforces the inhibition of CNS regulatory mechanisms, prevents both normal endometrial growth and conditions for ovum implantation, and decreases penetrability of cervical mucus to sperm cells. The two latter effects also act to prevent conception. According to the staging of progestin administration, one distinguishes (A): one-, two-, and three-stage preparations. Even with one-stage preparations, “withdrawal bleeding” occurs when hormone intake is discontinued (if necessary, by substituting dummy tablets).
Unwanted effects. An increased risk of thromboembolism is attributed to the estrogen component in particular but is also associated with certain progestins (gestoden
and desogestrel). The risk of myocardial infarction, stroke, and benign liver tumors is elevated. Nonetheless, the absolute prevalence of these events is low. Predisposing factors (family history, cigarette smoking, obesity, and age) have to be taken into account. The overall risk of malignant tumors does not appear to be increased. In addition, hypertension, fluid retention, cholestasis, nausea, and chest pain, are reported.
Minipill. Continuous low-dose administration of progestin alone can prevent pregnancy. Ovulations are not suppressed regularly; the effect is then due to progestininduced alterations in cervical and endometrial function. Because of the need for constant intake at the same time of day, a lower success rate, and relatively frequent bleeding anomalies, these preparations are now rarely employed.
“Morning-after” pill. This refers to administration of a high dose of estrogen and progestin, preferably within 12–24 hours, but no later than 72 hours after coitus. The mechanism of action is unclear.
Stimulation of ovulation. Gonadotropin secretion can be increased by pulsatile delivery of GnRH (p.238). Regarding clomifene, see p.254; whereas this substance can be given orally, the gonadotropins presented below must be given parenterally. HMG is human menopausal gonadotropin extracted from the urine of postmenopausal women. Owing to the cessation of ovarian function, gonadotropins show elevated blood levels and pass into urine in utilizable quantities. HMG (menotropins) consists of FSH and LH. HCG is human chorionic gonadotropin; it is obtained from the urine of pregnant women and acts like LH. Recombinant FSH (follitropin) and LH are available.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
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Oral Contraceptives |
253 |
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A. Oral contraceptives |
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LH |
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Minipill |
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Ovulation |
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Ovulation |
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Estradiol |
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estradiol |
progestin |
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derivative |
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Penetrability |
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Days of cycle |
7 |
14 |
21 |
28 |
Monophasic preparations
One-stage regimen
Two-stage regimen
Three-stage regimen
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.