- •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
- •Drugs for the Treatment of Anemias
- •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
- •Atopy and Antiallergic Therapy
- •Bronchial Asthma
- •Emesis
- •Alcohol Abuse
- •Local Treatment of Glaucoma
- •Further Reading
- •Further Reading
- •Picture Credits
- •Drug Indexes
240 Hormones
Thyroid Hormone Therapy
Thyroid hormones accelerate metabolism. Their release (A) is regulated by the hypophyseal glycoprotein TSH, whose release, in turn, is controlled by the hypothalamic tripeptide TRH. Secretion of TSH declines as the blood level of thyroid hormones rises; by means of this negative feedback mechanism, hormone production is “automatically” adjusted to demand.
The thyroid releases predominantly thyroxine (T4). However, the active form appears to be triiodothyronine (T3); T4 is converted in part toT3, receptor af nity in target organs being 10-fold higher for T3. The effect of T3 develops more rapidly and has a shorter duration than does that of T4. Plasma elimination t½ for T4 is about 7 days; that for T3, however, is only 1.5 days. Conversion of T4 toT3 releases iodide; 150 µg T4 contains 100 µg of iodine.
For therapeutic purposes, T4 is chosen, although T3 is the active form and better absorbed from the gut. With T4 administration, more constant blood levels can be achieved because T4 degradation is so slow. Since T4 absorption is maximal from an empty stomach, T4 is taken about half an hour before breakfast.
Replacement therapy of hypothyroidism.
Whether primary, i.e., caused by thyroid disease, or secondary, i.e., resulting from TSH deficiency, hypothyroidism is treated by oral administration of T4. Since too rapid activation of metabolism entails the hazard of cardiac overload (angina pectoris, myocardial infarction), therapy is usually started with low doses and gradually increased. The final maintenance dose required to restore a euthyroid state depends on individual needs (~ 150 µg/day).
Thyroid suppression therapy of euthyroid goiter (B). The cause of goiter (struma) is usually a dietary deficiency of iodine. Owing to increased TSH action, the thyroid is acti-
vated to raise utilization of the little iodine available to a level at which hypothyroidism is averted. Accordingly, the thyroid increases in size. In addition, intrathyroid depletion of iodine stimulates growth.
Because of the negative feedback regulation of thyroid function, thyroid activation can be inhibited by administration of T4 doses equivalent to the endogenous daily output (~ 150 µg/day). Deprived of stimulation, the inactive thyroid regresses in size.
If a euthyroid goiter has not persisted for too long, increasing iodine supply (with potassium iodide tablets) can also be effective in reversing overgrowth of the gland.
In older patients with goiter due to iodine deficiency, there is arisk of provoking hyperthyroidism by increasing iodine intake (p.243B). During chronic maximal stimulation, thyroid follicles can become independent of TSH stimulation (“autonomic tissue” containing TSH receptor mutants with spontaneous “constitutive activity”). If the iodine supply is increased, thyroid hormone production increases while TSH secretion decreases owing to feedback inhibition. The activity of autonomic tissue, however, persists at a high level; thyroxine is released in excess, resulting in iodine-induced hyperthyroidism.
Iodized salt prophylaxis. Goiter is endemic in regions where soils are deficient in iodine. Use of iodized table salt allows iodine requirements (150–300 µg/day) to be met and effectively prevents goiter.
Thyroid Hormone Therapy |
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A. Thyroid hormones – release, effects, degradation |
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TRH |
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Decrease in |
L-Thyroxine, Levothyroxine, |
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TSH |
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Thyroid |
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Liothyronine |
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receptor affinity |
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~ 90 g/day |
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Thyroxine |
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Deiodinase |
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coupling |
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3,3´,5´-Triiodothyronine |
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B. Endemic goiter and its treatment with thyroxine
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Hypophysis |
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TSH |
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Inhibition |
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Hyperthyroidism and Antithyroid |
Antithyroid drugs for long-term therapy |
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(C). Thiourea-derivatives (thioamides) in- |
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Drugs |
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hibit peroxidase and, hence, hormone syn- |
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Thyroid overactivity in Graves disease (A) |
thesis. To restore a euthyroid state, two ther- |
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results from formation of IgG antibodies that |
apeutic principles can be applied in Graves |
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bind to and activate TSH receptors. Conse- |
disease: (a) monotherapy with a thioamide, |
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quently, there is overproduction of hormone |
with gradual dose reduction as the disease |
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with cessation of TSH secretion. Graves dis- |
abates; (b) administration of high doses of a |
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ease can abate spontaneously after 1–2 |
thioamide, with concurrent administration |
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years; therefore, initial therapy consists in |
of thyroxine to offset diminished hormone |
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reversible suppression of thyroid activity by |
synthesis. Adverse effects of thioamides are |
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means of antithyroid drugs. In other forms of |
rare, but the possibility of agranulocytosis |
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hyperthyroidism, such as hormone-produc- |
has to be kept in mind. |
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ing (morphologically benign) thyroid adeno- |
Perchlorate, given orally as the sodium |
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ma, the preferred therapeutic method is re- |
salt, inhibits the iodide pump. Adverse reac- |
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moval of tissue, either by surgery or by ad- |
tions include aplastic anemia. Compared |
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ministration of iodine-131 (131I) in suf cient |
with thioamides, its therapeutic importance |
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dosage. Radioiodine is enriched in thyroid |
is low. |
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cells and destroys tissue within a sphere of |
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a few millimeters by emitting β-particles |
Short-term thyroid suppression (C). Iodine |
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(electrons) during its radioactive decay. |
in high dosage(> 6000 µg/day) exertsatran- |
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Antithyroid drugs inhibit thyroid func- |
sient “thyrostatic” effect in hyperthyroid, but |
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tion. Release of thyroid hormone (C) is pre- |
usually not in euthyroid, individuals. Since |
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ceded bya chain of events. A membrane Na+/ |
release is also blocked, the effect develops |
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I− symporter actively accumulates iodide in |
more rapidly than does that of thioamides. |
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thyroid cells (the required energy comes |
Clinical applications include preoperative |
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from a Na+/K+-ATPase located in the baso- |
suppression of thyroid secretion according |
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lateral membrane region); this is followed |
to Plummer with Lugol’s solution (5% iodine |
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by oxidation to iodine, iodination of tyrosine |
+ 10% potassium iodide, 50–100 mg iodine/ |
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residues in thyroglobulin, conjugationof two |
day for a maximum of 10 days). In thyrotoxic |
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diiodotyrosine groups, and formation of T4 |
crisis, Lugol’s solution is given together with |
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moieties. These reactions are catalyzed by |
thioamides and β-blockers. Adverse effects: |
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thyroid peroxidase, which is localized in |
allergies. Contraindications: iodine-induced |
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the apical border of the follicular cell mem- |
thyrotoxicosis. |
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brane. T4-containing thyroglobulin is stored |
Lithium ions inhibit thyroxine release. |
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inside the thyroid follicles in the form of |
Lithium salts can be used instead of iodine |
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thyrocolloid. Upon endocytotic uptake, col- |
for rapid thyroid suppression in iodine-in- |
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loid undergoes lysosomal enzymatic hydro- |
duced thyrotoxicosis. Regarding administra- |
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lysis, enabling thyroid hormone to be re- |
tion of lithium in manic-depressive illness, |
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leased as required. A “thyrostatic” effect |
see p.230. |
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can result from inhibition of synthesis or |
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release. When synthesis is arrested, the an- |
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tithyroid effect develops after a delay, as |
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stored colloid continues to be utilized. |
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Hyperthyroidism and Antithyroid Drugs |
243 |
A. Graves' disease |
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B. Iodine hyperthyroidosis in endemic goiter |
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Hypophysis |
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TSH |
Autonomous |
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tissue |
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TSH- |
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like |
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anti- |
T4, T3 |
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T4, T3 |
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T4, T3 |
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C. Antithyroid drugs and their modes of action |
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Thioamides |
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Conversion |
CH3 |
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H3C |
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during |
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absorption |
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Thiamazole |
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Propylthiouracil |
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Methimazole |
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Peroxidase |
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ClO - |
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I- |
Tyrosine |
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Synthesis |
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Iodine in |
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Tyrosine |
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T4- |
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Release |
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T4 |
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T4- |
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Storage |
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in colloid |
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Lysosome |
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Lithium |
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ions |
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