- •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
308 Antidotes
Antidotes and Treatment of Poisonings
Drugs used to counteract drug overdosage are considered under the appropriate headings; e.g., physostigmine with atropine; naloxone with opioids; flumazenil with benzodiazepines; antibody (Fab fragments) with digitalis; and N-acetylcysteine with acetaminophen intoxication.
Chelating agents (A) serve as antidotes in poisoning with heavy metals. They act to complex and, thus, “inactivate” heavy metal ions. Chelates (from Greek: chele = pincer [of crayfish]) represent complexes between a metal ion and molecules that carry several binding sites for the metal ion. Because of their high af nity, chelating agents “attract” metal ions present in the organism. The chelates are nontoxic, are excreted predominantly via the kidney, and maintain a tight organometallic bond in the concentrated, usually acidic, milieu of tubular urine and thus promote the elimination of metal ions.
Na2Ca-EDTA is used to treat lead poisoning. This antidote cannot penetrate through cell membranes and must be given parenterally. Because of its high binding af nity, the lead ion displaces Ca2+ from its bond. The lead-containing chelate is eliminated renally. Nephrotoxicity predominates among the unwanted effects. Na3Ca-pentetate is a complex of diethylenetriaminopentaacetic acid (DPTA) and serves as antidote in lead and other metal intoxications.
Dimercaprol (BAL, British Anti-Lewisite) was developed in World War II as an antidote against vesicant organic arsenicals (B). It is able to chelate various metal ions. Dimercaprol forms a liquid, rapidly decomposing substance that is given intramuscularly in an oily vehicle. A related compound, both in terms of structure and activity, is dimercaptopropanesulfonic acid, whose sodium salt is suitable for oral administration. Shivering, fever, and skin reactions are potential adverse effects.
Deferoxamine derives from Streptomyces pilosus. The substance possesses a very high iron-binding capacity butdoes notwithdraw iron from hemoglobin or cytochromes. It is poorly absorbed enterally and must be given parenterally to cause increased excretion of iron. Oral administration is indicated only if enteral absorption of iron is to be curtailed. Unwanted effects include allergic reactions.
It should be noted that bloodletting is the most effective means of removing iron from the body; however, this method is unsuitable for treating conditions of iron overload associated with anemia.
D-Penicillamine can promote the elimination of copper (e.g., in Wilson disease) and of lead ions. It can be given orally. Two additional indications are cystinuria and rheumatoid arthritis. In cystinuria, formation of cystine stones in the urinary tract is prevented because the drug can form a disulfide with cysteine that is readily soluble. In rheumatoid arthritis, penicillamine can be used as a basal regimen (p.332). The therapeutic effect may result in part from a reaction with aldehydes, whereby polymerization of collagen molecules into fibrils is inhibited. Unwanted effects are cutaneous damage (diminished resistance to mechanical stress with a tendency to form blisters; p.74), nephrotoxicity, bone marrow depression, and taste disturbances.
Apart from specific antidotes (if they exist), the treatment of poisonings also calls for symptomatic measures (control of blood pressure and blood electrolytes; monitoring of cardiac and respiratory function; prevention of toxin absorption by activated charcoal). An important step is early emptying of the stomach by gastric lavage and, if necessary, administration of an osmotic laxative. Use of emetics (saturated NaCl solution, ipecac syrup, apomorphine s.c.) is inadvisable.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Antidotes and Treatment of Poisonings |
309 |
A. Chelation of lead ions by EDTA |
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Na2Ca- |
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2Na+ |
Ca2+ |
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EDTA |
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CH2 |
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CH2 |
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O- |
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CH2 |
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EDTA: Ethylenediamine tetra acetate |
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B. Chelators
Dimercaprol (i.m.) |
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Deferoxamine |
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Arsenic, mercury, |
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C O– |
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DMPS |
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Dimercaptopropane sulfonate
D-Penicillamine
CH3
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H3C C CH COOH
HS NH2
β, β -Dimethylcysteine chelation with
Cu2+ and Pb2+
Dissolution of cystine stones: Cysteine-S-S-Cysteine
Inhibition of collagen polymerization
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
310 Antidotes
Reactivators of phosphorylated acetylcholinesterase (AChE). Certain organic phosphoric acid compounds bind with high af n- ity to a serine OH group in the active center of AChE and thus block the hydrolysis of acetylcholine. As a result, the organism is poisoned with its own transmitter substance, acetylcholine. This mechanism operates not only in humans and warm-blooded animals but also in lower animals, ACh having been “invented” early in evolution. Thus, organophosphates enjoy widespread application as insecticides. Time and again, their use has led to human poisoning because these toxicants can enter the body through the intact skin or inhaled air. Depending on the severity, signs of poisoning include excessive parasympathetic tonus, ganglionic blockade, and inhibition of neuromuscular transmission leading to peripheral respiratory paralysis. Specific treatment of the intoxication consists in administration of extremely high doses of atropine and reactivation of acetylcholinesterase with pralidoxime or obidoxime (A).
Unfortunately, the organophosphates have been misused as biological weapons. InWorldWarII,theywerestockpiledonboth sides but not deployed. The ef cacy of the poisonswassubsequently“demonstrated”in smaller local armed conflicts in developing countries. In the present global situation, the fear has arisen that organophosphates may be used by terrorist groups. Thus, understanding the signs of poisoning and the principles of treatment are highly important.
Tolonium chloride (toluidine blue). Browncolored methemoglobin, containing trivalent instead of divalent iron, is incapable of carrying O2. Under normal conditions, methemoglobin is produced continuously, but reduced again with the help of glucose- 6-phosphate dehydrogenase. Substances that promote formation of methemoglobin (B) may cause a lethal deficiency of O2. Tolonium chloride is a redox dye that can be given i.v. to reduce methemoglobin.
Antidotes for cyanide poisoning (B). Cyanide ions (CN–) enter the organism in the form of hydrocyanic acid (HCN); the latter can be inhaled, released from cyanide salts in the acidic stomach juice, or enzymatically liberated from bitter almonds in the gastrointestinal tract. The lethal dose of HCN can be as low as 50 mg. CN– binds with high af nity to trivalent iron and thereby arrests utilization of oxygen via mitochondrial cytochrome oxidases of the respiratory chain. Internal asphyxiation (histotoxic hypoxia) ensues while erythrocytes remain charged with O2 (venous blood colored bright red).
In small amounts, cyanide can be converted to the relatively nontoxic thiocyanate (SCN–) by hepatic “rhodanese” or sulfurtransferase. As a therapeutic measure, sodium thiosulfate can be given i.v. to promote formation of thiocyanate, which is eliminated inurine. However, this reaction is slow in onset. A more effective emergency treatment is the i.v. administration of the methemoglobin forming agent 4-dimethylamino- phenol, which rapidly generates trivalent iron from divalent iron in hemoglobin. Competition between methemoglobin and cytochrome oxidase for CN– ions favors the formation of cyanmethemoglobin. Hydroxycobalamin (= vitamin B12a) is an alternative, very effective antidote because its central cobalt atom binds CN– with high af nity to generate cyanocobalamin (= vitamin B12).
Ferric ferrocyanide (“Berlin blue” [B]) is used to treat poisoning with thallium salts (e.g., in rat poison), initial symptoms of which are gastrointestinal disturbances, followed by nerve and brain damage, as well as hair loss. Thallium ions present in the organism are secreted into the gut but undergo reabsorption. The insoluble, nonabsorbable colloidal Berlin blue binds thallium ions. It is given orally to prevent absorption of acutely ingested thallium or to promote clearance from the organism by intercepting thallium that is secreted into the intestines (B).
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Antidotes and Treatment of Poisonings |
311 |
A. Reactivation of ACh-esterase by an oxime |
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Acetylcholine |
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CH3 |
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H3C |
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CH3 |
CH3 |
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CH2 |
CH2 |
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O |
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CH3 |
CH3 |
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Paraoxon residue |
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Aldoxime |
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B. Poisons and antidotes |
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SCN- |
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FeIII-Hb |
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Substances forming |
synthetase |
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Tolonium chloride |
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methemoglobin |
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FeIII4 [FeII(CN)6] 3 |
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e.g., |
NO2 |
Nitrite |
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(toluidine blue) |
H2N |
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Aniline |
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Tl+ = |
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Thallium |
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Nitrobenzene |
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Na2S2O3 |
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DMAP |
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FeII-Hb |
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CN- |
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HCN |
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FeIII-Hb |
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CH3 |
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NH2 |
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H3C |
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Cl– |
Fe3+ |
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CH3 |
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Tolonium chloride |
Arrest of O2 |
Vitamin B12a |
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Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.
Luellmann, Color Atlas of Pharmacology © 2005 Thieme
All rights reserved. Usage subject to terms and conditions of license.