- •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
322 Therapy of Selected Diseases
Congestive Heart Failure
In chronic congestive heart failure, cardiac pump performance falls below a level required by the body’s organs for maintaining function and metabolism. The most common primary causes of heart failure are coronary disease, hypertension, volume overload, or cardiomyopathies. Diminished cardiac performance leads to a precardial congestion of venous blood. Congestion in front of the left ventricle causes dyspnea and pulmonary edema. Ankle edemas, enlarged liver, and ascites signal congestion in front of the right ventricle.
The degree of severity of myocardial failure is categorized according to the New York Heart Association (NYHA) Functional Classification System. Stages I—IV reflect an increasing level of disability.
The decrease in cardiac function activates several compensatory mechanisms that operate to maintain perfusion of organs. These include activation of the sympathetic nerve system and of the renin–angiotensin system. Increased release of norepinephrine raises cardiac rate and evokes peripheral vasoconstriction. Increased production of angiotensin II promotes both vasoconstriction and release of aldosterone from the adrenals. These compensations increase cardiac afterload and plasma volume is expanded because the kidney retains water and sodium. Although such “auxiliary” countermeasures afford transient help in maintaining cardiac output, (nor)epinephrine, aldosterone, and angiotensin II promote the progression of myocardial insuf ciency: hypertrophy and fibrosis are the outcome. Successful therapy of chronic congestive failure is therefore contingent on inhibition of compensation mechanisms.
Although β-blockers were formerly held to be contraindicated, this drug class has been used successfully since the mid-1990s in the management of heart failure. A prerequisite is to begin therapy with very small daily doses. Every 2–3 weeks, the daily dose
can be increased in small increments, as long as the patient does not develop bradycardia. Since bisoprolol, metoprolol, and carvedilol have proved effective in large clinical trials, these β-blockers would be the preferred choice for this indication.
ACE inhibitors are the appropriate agents for inhibiting the renin–angiotensin II system; they prevent the production of angiotensin II. The effect of angiotensin II receptor antagonists is equivalent to that of ACE inhibitors. Both interventions for attenuating compensatory mechanisms improve the clinical state of patients (less hospitalization) and increase life expectancy.
In edemas, dyspnea, and advanced myocardial insuf ciency, diuretics are indispensable.
Digitalis glycosides augment contractile force and are likewise used in severe forms of insuf ciency, specifically in the presence of concomitant atrial fibrillation. Because of the narrow margin of safety, the digoxin dose must be adjusted individually in each patient.
Drugs with an acute positive inotropic action (e.g., catecholamines or phosphodiesterase inhibitors) may be of transient help in sudden decompensation but must not be given in chronic congestive failure.
Congestive Heart Failure |
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A. Congestive heart failure |
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Performance |
Heart failure |
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decrease |
Congestion |
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Cardiac output |
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Dyspnea |
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Edemas |
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Diuretics |
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Na+, H2O retention |
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Vasoconstriction |
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preload |
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Tachycardia |
Afterload |
Spironolactone |
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Inotropism |
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Aldosterone |
Fibrosis |
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Hypertrophy |
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AT1-blockers |
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β -Blocker |
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Angiotensin II |
Digitalis |
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ACE inhibitors |
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Positive |
ACE inhibitors |
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inotropic |
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Renin–Angiotensin System |
Sympathetic System |
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Compensatory mechanisms |
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B. Classification and drug therapy of congestive heart failure
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Impairment of cardiac function |
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NYHA |
I |
II |
III |
IV |
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Functional Class |
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Clinical symptoms |
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slight |
marked |
at rest |
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ACE inhibitors |
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AT1 blocker |
when ACE inhibitors cause adverse effects, e.g., cough |
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β -Blocker |
Infarction |
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Hypertension |
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Diuretics |
Hypertension |
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Edemas |
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Aldosterone |
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Hypokalemia |
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antagonists |
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Digitalis |
Atrial fibrillation |
Atrial fibrillation |
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324 Therapy of Selected Diseases
Hypotension
The venous side of the circulation accommodates ~ 85% of the total blood volume; because of the low venous pressure (mean ~ 15 mmHg), it is referred to as the low-pres- sure system. The arterial vascular beds, representing the high-pressure system (mean pressure ~ 100 mmHg), contain ~ 15%. The arterial pressure generates the driving force for perfusion of tissues and organs. Blood draining from these collects in the low-pres- sure system and is pumped back by the heart into the high-pressure system.
The arterial blood pressure (ABP) depends on: (1) the volume of blood per unit of time that is forced by the heart into the highpressure system—cardiac output corresponding to the product of stroke volume and heart rate (beats/min), stroke volume being determined by, inter alia, venous filling pressure; (2) the counterforce opposing the flow of blood, i.e., peripheral resistance, which is a function of arteriolar caliber.
Chronic hypotension (recumbent systolic BP
< 105 mmHg). Primary idiopathic hypotension generally has no clinical importance. If symptoms such as lassitude and dizziness occur, a program of physical exercise instead of drugs is advisable.
Secondary hypotension is a sign of an underlying disease that should be treated first. If stroke volume is too low, as in heart failure, a cardiac glycoside can be given to increase myocardial contractility and stroke volume. When stroke volume is decreased owing to insuf cient blood volume, plasma substitutes will be helpful in treating blood loss, whereas aldosterone deficiency requires administration of a mineralocorticoid (e. g., fludrocortisone). The latter is the drug of choice for orthostatic hypotension due to autonomic failure. A parasympatholytic (or electrical pacemaker) can restore cardiac rate in bradycardia.
Acute hypotension. Failure of orthostatic regulation. A change from the recumbent to the erect position (orthostasis) will cause blood within the low-pressure system to sink toward the feet because the veins in body parts below the heart will be distended, despite a reflex venoconstriction, by the weight of the column of blood in the blood vessels. The fall in stroke volume is partly compensated by a rise in heart rate. The remaining reduction of cardiac output can be countered by elevating the peripheral resistance, enabling blood pressure and organ perfusion to be maintained. An orthostatic malfunction is present when counterregulation fails and cerebral blood flow falls, with resultant symptoms, such as dizziness, “black-out,” or even loss of consciousness. In the sympathotonic form, sympatheticallymediated circulatory reflexes are intensified (more pronounced tachycardia and rise in peripheral resistance, i.e., diastolic pressure); however, there is failure to compensate for the reduction in venous return. Prophylactic treatment with sympathomimetics would therefore hold little promise. Instead, cardiovascular fitness training would appear more important. An increase in venous return may be achieved in two ways. Increasing NaCl intake augments salt and fluid reserves and, hence, the blood volume (contraindications: hypertension, heart failure). Constriction of venous capacitance vessels might be produced by dihydroergotamine. Whether this effect could also be achieved by an α-sympathomimetic, remains debatable. In the very rare asympathotonic form, use of sympathomimetics would certainly be reasonable.
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Hypotension |
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A. Treatment of hypotension |
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Low-pressure |
High-pressure |
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system |
system |
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Brain |
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Lung |
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β -Sympathomimetics |
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Cardiac |
Parasym- |
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glycosides |
patholytics |
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Venous |
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return |
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Stroke vol. x rate |
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Heart |
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Blood pressure (BP) |
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Kidney |
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Peripheral resistance |
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Intestines |
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Arteriolar |
α -Sympatho- |
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caliber |
mimetics |
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Skeletal muscle |
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Initial condition |
Increase of blood volume |
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0.9% |
SALT |
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NaCl |
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BP |
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NaCl + H2O |
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BP |
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Redistribution of blood volume |
NaCl |
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BP |
+ H2O |
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Constriction of venous capacitance |
Mineralo- |
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vessels, e.g., dihydroergotamine if |
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appropriate, α -sympathomimetics |
corticoid |
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