- •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
166 Diuretics
Diuretics of the Sulfonamide Type
These drugs contain the sulfonamide group –SO2NH2 and are suitable for oral administration. In addition to being filtered at the glomerulus, they are subject to tubular secretion. Their concentration in urine is higher than in blood. They act on the tubule cells from the luminal side. Loop diuretics have the highest ef cacy. Thiazides are most frequently used. The carbonic anhydrase inhibitors no longer serve as diuretics but have important other therapeutic uses; accordingly,theirmodeofactionisconsideredhere.
Acetazolamide is a carbonic anhydrase
(CAH) inhibitor that acts predominantly in the proximal convoluted tubules. Its mechanismofaction canbe summarizedasfollows. Reabsorption of Na+ is decreased because fewer H+ ions are available for the Na+/H+ antiporter. As a result, excretion of Na+ and H2O increases. CAH accelerates attainment of equilibrium of CO2 hydration/dehydration reactions:
(1)(2)
H+ + HCO3– H2CO3 H2O + CO2 Cytoplasmic enzyme is used in tubulus cells to generate H+ (reaction 1), which issecreted into the tubular fluid in exchange for Na+. There, H+ captures HCO3−. CAH localized in the luminal membrane catalyzes reaction 2 (dehydration) to yield again H2O and CO2, which can easily permeate through the cell membrane. In the tubulus cell, H+ and HCO3− are regenerated. When the enzyme is inhibited, these reactions occur too slowly, so that less Na+, HCO3– and water are reabsorbed from the fast-flowing tubular fluid. Loss of HCO3– leads to acidosis. The diuretic effectiveness of CAH inhibitors decreases with prolonged use. CAH is also involved in the production of ocular aqueous humor. Present indications for drugs in this class include: acute glaucoma, acute mountain sickness, and epilepsy.
Dorzolamide can be applied topically to the eye tolower intraocular pressurein glaucoma (p.346).
Loop diuretics include furosemide (frusemide), piretanide, and others. After oral administration of furosemide, a strong diuresis occurs within 1 hour but persists for only about 4 hours. The site of action of these agents is the thick ascending limb of Henle’s loop, where they inhibit Na+/K+/2Cl− cotransport. As a result, these electrolytes, together with water, are excreted in larger amounts. Excretion of Ca2+ and Mg2+ also increases. Special adverse effects include (reversible) hearing loss and enhanced sensitivitytonephrotoxicagents. Indications:pulmonary edema (added advantage of i.v. injection in left ventricular failure: immediate dilation of venous capacitance vessels, † preload reduction); refractoriness to thiazide diuretics; e.g., in renal failure with creatinine clearance reduction (< 30 ml/min); prophylaxis of acute renal hypovolemic failure. Ethacrynic acid is classed in this group although it is not a sulfonamide.
Thiazide diuretics (benzothiadiazines) include hydrochlorothiazide, trichlormethiazide and butizide. Chlorthalidone is a longacting analogue. These drugsaffect the distal convoluted tubules, where they inhibit Na+/ Cl− cotransport in the luminal membrane of tubulus cells. Thus, reabsorption of NaCl and water is inhibited. Renal excretion of Ca2+ decreases, that of Mg2+ increases. Indications are hypertension, congestive heart failure, and mobilization of edema. Frequently, they are combined with the K+ sparing diuretics triamterene or amiloride (p.168)
Unwanted effects of sulfonamide-type diuretics: (a) hypokalemia is a consequence of an increased secretion of K+ in the connecting tubule and the collecting duct because more Na+ becomes available for exchange against K+; (b) hyperglycemia; (c) increase in serum urate levels (hyperuricemia), which may precipitate gout in predisposed patients. Sulfonamide diuretics compete with urate for the tubular organic anion secretory system.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Diuretics of the Sulfonamide Type |
167 |
A. Diuretics of the sulfonamide type |
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Na+ |
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Sulfonamide |
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K+ |
Normal |
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state |
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diuretics |
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Na+ |
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Anion |
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secretory |
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Na+ |
K+loss |
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system |
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K+ |
induced |
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Na+ |
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by |
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diuretic |
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Uric acid |
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Collecting |
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duct |
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Thiazides |
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Gout |
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Na+ |
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Cl- |
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e.g., hydrochlorothiazide |
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H |
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Cl |
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N |
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HN S |
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O |
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S NH2 |
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O |
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Carbonic anhydrase inhibitors |
Loop diuretics |
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Na+ |
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Na+ |
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H+ |
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HCO-3 |
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HCO-3 |
Na+ |
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HCO-3 |
CAH |
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K+ |
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H2O |
CO2 H2O |
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CO2 |
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e.g., acetazolamide |
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e.g., furosemide |
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CH3 |
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NH |
Cl |
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NH2 |
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Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
168 Diuretics
Potassium-sparing Diuretics (A)
These agents act in the connecting tubules and the proximal part of the collecting ducts where Na+ is reabsorbed and K+ is secreted. Their diuretic effectiveness is relatively minor. In contrast to sulfonamide diuretics (p.166), there is no increase in K+ secretion; rather, there is a risk of hyperkalemia. These drugs are suitable for oral administration.
aTriamterene and amiloride, in addition to glomerular filtration, undergo secretion in the proximal tubule. They act on cortical collecting tubule cells from the luminal side. Both inhibit the entry of Na+ into the cell, whereby K+ secretion is diminished. They are mostly used in combination with thiazide diuretics, e.g., hydrochlorothiazide, because the opposing effects on K+ excretion cancel each other, while the effects on secretion of NaCl and water complement each other.
bAldosterone antagonists. The mineralocorticoid aldosterone increases synthesis of Na-channel proteins and Na+/K+-ATPases in principal cells of the connecting tubules and the cortical collecting ducts, thereby promoting the reabsorption of Na+ (Cl–
and H2O follow), and simultaneously enhancing secretion of K+. Spironolactone, as well as its metabolite canrenone, are antagonists at the aldosterone receptor and attenuate the effect of the hormone. The diuretic effect of spironolactone develops fully only with continuous administration for several days. Two possible explanations are: (1) the conversion of spironolactone into and accumulation of the more slowly eliminated metabolite canrenone;
(2)an inhibition of aldosterone-stimu- lated protein synthesis would become noticeable only if existing proteins had become nonfunctional and needed to be re-
placed by de-novo synthesis.
A particular adverse effect results from interference with gonadal hormones, as evidenced by the development of gynecomastia. Clinical uses include conditions of
increased aldosterone secretion (e.g., liver cirrhosis with ascites) and congestive heart failure.
Vasopressin and Derivatives (B)
Vasopressin (ADH), a nonapeptide, is released from the posterior pituitary gland and promotes reabsorption of water in the kidney. This response is mediated by vasopressin receptors of the V2 subtype. AVP enhances the permeability of connecting tubules and medullary collecting duct epithelium for H2O (but not electrolytes) in the following manner: H2O-channel proteins (type 2 aquaporins) are stored in tubulus cells within vesicles. When AVP binds to V2 receptors, these vesicles fuse with the luminal cell membrane, allowing influx of H2O along its osmotic gradient (the medullary zone is hyperosmolar). AVP thus causes urine volume to shrink from 15 l/day at this point of the nephron to the final 1.5 l/day. This aquaporin type can be reutilized after internalization into the cell. Nicotine augments (p.112) and ethanol decreases release of AVP. At concentrations above those required for antidiuresis, AVP stimulates smooth musculature, including that of blood vessels (“vasopressin”). The latter response is mediated by V1 receptors. Blood pressure rises; coronary vasoconstriction can precipitate angina pectoris.
Lypressin (8-L-lysine-vasopressin) acts like AVP. Other derivatives may display only one of the two actions.
Desmopressin is used for the therapy of diabetes insipidus (AVP deficiency), primary nocturnal enuresis and von Willebrand disease (p.152); it is given by injection or via the nasal mucosa (as “snuff”).
Felypressin and ornipressin serve as adjunctive vasoconstrictors in infiltration local anesthesia (p.204).
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Potassium-sparing Diuretics and Vasopressin |
169 |
A. Potassium-sparing diuretics |
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Na+ |
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H2N N N NH2 |
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CH2OH |
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HO |
HC |
C O |
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K+ |
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NH2 |
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Triamterene |
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Aldosterone |
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Na+ |
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Aldosterone |
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antagonists |
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K+ or |
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H+ |
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Canrenone |
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Protein synthesis |
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Transport capacity |
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O |
Amiloride |
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Spironolactone |
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HN2 H |
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H2N |
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NH2 |
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B. Antidiuretic hormone (ADH) and derivatives |
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Nicotine |
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Neuro- |
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hypophysis |
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Ethanol |
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V2 |
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Adiuretin = Vasopressin |
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H2O |
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permeability |
Cys |
Tyr |
Phe |
Gln |
Asn |
Cys |
Pro |
Arg |
Gly |
NH2 |
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of collecting |
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duct |
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Desmopressin |
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Ornipressin |
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Orn |
CH2 |
C |
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D-Arg |
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Felypressin |
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CH2 |
O |
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S |
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Phe |
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Lys |
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.