A Textbook of Clinical Pharmacology and Therapeutics

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EPO Erythroid precursors Erythrocytes SCF IL-1 IL-3 IL-6 Megakaryocyte precursors Platelets MCSF GM-CSF Tpo Megakaryocytes Stem cell factor Pluripotent stem cell Myeloid stem cell Uncommitted myeloid precursor Granulocyte macrophage precursors Monocyte precursors Monocytes produced by interstitial cells of the renal cortex adjacent to the proximal tubules and 10% by the liver. Biosynthesis is stimulated by anaemia/tissue hypoxia which increases levels of the active form of a transcription factor called ‘hypoxia-inducible factor-1’ (HIF), which enhances transcription of the erythropoietin gene. Endogenous erythropoietin homeostasis is further controlled by a negative feedback loop that maintains red-cell mass at an optimal level for oxygen transport. Uses Epoetin, the recombinant form of erythropoietin and darbepoetin (an analogue with a longer plasma half-life) are used to stimulate red cell growth. These agents are given by subcutaneous injection. Haemoglobin is monitored to titrate dosing. Iron supplementation should be used routinely. Recent studies in cancer patients showed that when compared to placebo, erythropoietic agents used to treat patients with weaknesss, malaise and fatigue, but whose Hb was not �12 g/dL and who were not currently receiving cytotoxic chemotherapy, reduced patient survival. This suggests the need to more critically evaluate and use erythropoietic agents in such patients and in cancer patients generally, as many tumours express erythropoietin receptors. Granulocyte precursors Granulocyte precursors Lymphoid stem cell Eosinophil precursors Erythropoietin is used in: HAEMATOPOIETIC GROWTH FACTORS 393 Eosinophils Basophils G-CSF GM-CSF Lymphocytes (for influence of interleukins see Figure 50.1) MCSF GM-CSF Basophils precursors Macrophages Neutrophils Figure 49.3: Haematopoiesis and haematopoietic growth factors. EPO, erythropoietin; IL, interleukin; G-CSF, granulocyte colonystimulating factor; MCSF, macrophage colony-stimulating factor; GM-CSF, granulocyte macrophage colony-stimulating factor; SCF, stem-cell factor; Tpo, thrombopoietin. T cell B cell • anaemia of chronic renal failure; • anaemia of drug-induced bone marrow suppression (e.g. cancer chemotherapy or ZDV therapy); • anaemia with myeloma; • anaemia of rheumatoid arthritis; • autologous blood harvesting for transfusion during elective surgery; • prevention of anaemia in premature babies of low birth weight. Mechanism of action Erythropoietin binds to a membrane receptor on erythroid cell precursors. Signal transduction is through a tyrosine kinase, that increases transcription of the genes for key haem biosynthetic enzymes. Thus, erythropoietin increases haem biosynthesis and causes differentiation of erythroid precursors into mature erythroid cells. Pharmacokinetics Elimination occurs by catabolism in the erythroid cells in the marrow following internalization, by hepatic metabolism and to a lesser extent urinary excretion.
394 ANAEMIA AND OTHER HAEMATOLOGICAL DISORDERS Adverse effects These include the following: • hypertension which can be severe; • thrombosis, for example of shunts, or causing a cardiovascular/cerebrovascular accident; • influenza-like symptoms; • iron deficiency may be unmasked; • pure red cell aplasia associated with antibodies to erythropoietin has been reported during treatment with epoetin alfa. HUMAN GRANULOCYTE COLONY-STIMULATING FACTOR (FILGRASTIM, LENOGRASTIM, PEG-FILGRASTIM). Granulocyte colony-stimulating factor (G-CSF) is a 174 amino acid glycoprotein. Filgrastim is unglycosylated rhG-CSF and lenograstim is glycosylated rhG-CSF. Pegylated G-CSF (PEGfilgrastim) has a protracted half-life and can be given much less frequently. Uses Indications for G-CSF include: • to prevent and treat the neutropenia induced by cytotoxic cancer chemotherapy (main use); • congenital neutropenia; • human immunodeficiency virus (HIV)-related AZT-induced neutropenia (chronic therapy); • aplastic anaemia; • mobilization of peripheral blood-cell progenitors and subsequent harvesting for transplant; • following bone marrow transplantation. G-CSF is usually administered by subcutaneous injection. Therapy is monitored by regular neutrophil counts. After stopping treatment, neutrophil counts return to baseline after four to seven days. Mechanism of action G-CSF stimulates the proliferation and differentiation of progenitor cells of the myelogranulocyte lineage. It binds to the G-CSF receptor on myelogranulocyte precursors, enhancing cell replication and differentation. Once bound to its receptor, G-CSF is internalized and signal transduction involves a number of tyrosine kinase proteins which induce the synthesis of proteins that upregulate cell-cycle and differentiation processes. Adverse effects These include the following: • bone pain; • injection site reactions; • myalgia and fevers; • splenomegaly; • thrombocytopenia; • abnormal liver enzymes. Contraindications G-CSF should not be given to patients with myeloid or myelomonocytic leukaemia, because it increases proliferation of the malignant clone. Pharmacokinetics The bioavailability of subcutaneously administered G-CSF is 54%. The G-CSF plasma t1/2 ranges from two to six hours. Clearance of G-CSF is complex and it increases as the granulocyte count rises. In addition, G-CSF is metabolized in the kidney and liver to its component amino acids, with little or no G-CSF found in the urine. INTERLEUKIN-11 AND THROMBOPOIETIN Interleukin-11 is a recombinant protein which enhances megakaryocyte maturation and is used to prevent thrombocytopenia in patients who developed platelet counts �20 000/μL with prior cycles of cytotoxic chemotherapy. Interleukin-11 (oprelvekin, not yet available in the UK) is given daily via subcutaneous injection until the platelet count �10 000/μL. Major side effects include fluid retention and associated cardiac symptoms, injection site reactions, paraesthesias and blurred vision. Thrombopoietin is a recombinant protein which binds to the mpl-proto-oncogene, stimulates megakaryocyte proliferation and differentiation in humans. It synergizes with stem cell factor and G-CSF in promoting bone marrow production of granulocytes. Thrombopoietin may be useful in drug-induced thrombocytopenia and in bone marrow transplantation. Key points Haematopoietic growth factors • The clinically used haematopoietic growth factors are recombinant DNA products of the endogenous glycoprotein. • Erythropoietin (Epo)/darbepoetin: – stimulate proliferation of erythroid (red cell) precursors; – are used in the treatment of the anaemia of renal failure (myelodysplasia); – are given parenterally; its toxicities include hypertension and thrombotic episodes. • Granulocyte colony-stimulating factor (G-CSF): – stimulates proliferation of myeloid precursors; – is used to treat neutropenia of chemotherapy, aplastic anaemia and bone marrow transplant; – is given parenterally and its toxicities include myalgias, bone pain, fever, thrombocytopenia and hepatitis. COAGULATION FACTORS AND HAEMOPHILIAS A AND B Pathophysiology In haemophilia A there is a deficiency of factor VIII. In haemophilia B there is a deficiency of factor IX. Both types present with excessive bleeding in response to trauma, e.g. muscle haematoma, haemarthrosis, haemorrhage after minor (e.g. dental) or major surgery, and intracranial bleeding following minor head injury.
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A Textbook of Clinical Pharmacology
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A Textbook of Clinical Pharmacology
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This fifth edition is dedicated to
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FOREWORD viii PREFACE ix ACKNOWLEDG
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PREFACE Clinical pharmacology is th
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PART I GENERAL PRINCIPLES
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● Use of drugs 3 ● Adverse effe
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and acquired factors, notably disea
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100 Effect (%) 0 0 5 10 1 10 100 (a
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Dose ratio -1 100 50 The relationsh
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● Introduction 11 ● Constant-ra
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In reality, processes of eliminatio
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lood (from which samples are taken
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● Introduction 17 ● Bioavailabi
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ROUTES OF ADMINISTRATION ORAL ROUTE
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Transdermal absorption is sufficien
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FURTHER READING Fix JA. Strategies
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and thromboxanes are CYP450 enzymes
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and lorazepam. Some patients inheri
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Orally administered drug Parenteral
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● Introduction 31 ● Glomerular
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ACTIVE TUBULAR REABSORPTION This is
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DISTRIBUTION Drug distribution is a
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Detailed recommendations on dosage
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DIGOXIN Myxoedematous patients are
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● Introduction 41 ● Role of dru
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25 20 10 Life-threatening toxicity
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● Introduction 45 ● Harmful eff
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vagina in girls in their late teens
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an anti-analgesic effect when combi
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Case history A 20-year-old female m
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METABOLISM At birth, the hepatic mi
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lifelong effects as a result of tox
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DISTRIBUTION Ageing is associated w
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DIGOXIN Digoxin toxicity is common
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FURTHER READING Dhesi JK, Allain TJ
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Factors involved in the aetiology o
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analgesic. Following its release, t
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antibiotics, such as penicillin or
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predisposes to non-immune haemolysi
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● Introduction 71 ● Useful inte
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Response Therapeutic range Toxic ra
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Table 13.1: Interactions outside th
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Table 13.5: Competitive interaction
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● Introduction: ‘personalized m
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Table 14.2: Variations in drug resp
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lipoprotein (LDL) is impaired. LDL
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Key points • Genetic differences
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• Discovery • • Screening Pre
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Too many statistical comparisons pe
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ETHICS COMMITTEES Protocols for all
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Table 16.1: Recombinant proteins/en
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duration and benefit. Adenoviral ve
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● Introduction 97 ● Garlic 97
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A case report has suggested a possi
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including hypericin and pseudohyper
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PART II THE NERVOUS SYSTEM
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● Introduction 105 ● Sleep diff
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and daytime sleeping should be disc
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Key points • Insomnia and anxiety
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Box 19.1: Dopamine theory of schizo
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The Boston Collaborative Survey ind
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Oral medication, especially in liqu
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e.g. interpersonal difficulties or
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Partial response to first-line trea
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Key points Drug treatment of depres
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Case history A 45-year-old man with
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Levodopa PRINCIPLES OF TREATMENT IN
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• pulmonary, retroperitoneal and
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CHOREA The γ-aminobutyric acid con
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Cholinergic crisis Treatment of mya
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● Introduction 133 ● Mechanisms
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absolute arbiter. The availability
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Table 22.2: Metabolic interactions
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FURTHER ANTI-EPILEPTICS Other drugs
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Case history A 24-year-old woman wh
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Assessment of migraine severity and
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● General anaesthetics 145 ● In
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is the theoretical concern of a ‘
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• Respiratory system - apnoea fol
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Competitive antagonists (vecuronium
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have also proved useful in combinat
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● Introduction 155 ● Pathophysi
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ASPIRIN (ACETYLSALICYLATE) Use Anti
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Key points Drugs for mild pain •
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increases, correlating with the hig
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• If possible, use oral medicatio
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PART III THE MUSCULOSKELETAL SYSTEM
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● Introduction: inflammation 167
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Chapter 33). All NSAIDs cause wheez
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• Stomatitis suggests the possibi
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Pharmacokinetics Allopurinol is wel
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PART IV THE CARDIOVASCULAR SYSTEM
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esponsible for the strong predilect
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Ezetimibe Fat Muscle Dietary fat In
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educed). The risk of muscle damage
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Each of these classes of drug reduc
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AT 1 receptor) produce good 24-hour
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Table 28.2: Examples of calcium-cha
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Key points Drugs used in essential
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Case history A 72-year-old woman se
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Assess risk factors Investigations:
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Persistent ST segment elevation Thr
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Mechanism of action GTN works by re
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Because of the risks of haemorrhage
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Intrinsic pathway XIIa XIa the acti
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that the pharmacodynamic response i
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used with apparent benefit in acute
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The drugs that are most effective i
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therapeutic plasma concentration ca
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● Common dysrhythmias 217 ● Gen
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BASIC LIFE SUPPORT CARDIOPULMONARY
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arrest. The electrocardiogram is li
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should be given to insertion of an
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Drug interactions Amiodarone potent
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effect when treating sinus bradycar
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Case history A 24-year-old medical
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PART V THE RESPIRATORY SYSTEM
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CHAPTER 33 THERAPY OF ASTHMA, CHRON
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STEP 5: CONTINUOUS OR FREQUENT USE
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Adenylyl cyclase Table 33.1: Compar
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Drug interactions Although synergis
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use in asthma has declined consider
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α 1-antitrypsin deficiency, neutro
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PART VI THE ALIMENTARY SYSTEM
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● Peptic ulceration 247 ● Oesop
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PEPTIC ULCERATION 249 • With rega
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Ranitidine has a similar profile of
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Vestibular stimulation ? via cerebe
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cortical centres affecting vomiting
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• in hepatocellular failure to re
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Ciprofloxacin is occasionally used
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withdrawal), small doses of benzodi
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Table 34.7: Dose-independent hepato
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● Introduction 265 ● General ph
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dinucleotide (NAD) and nicotinamide
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Table 35.1: Common trace element de
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PART VII FLUIDS AND ELECTROLYTES
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● Introduction 273 ● Volume ove
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Key points Diuretics Diuretics are
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is sometimes caused by drugs, notab
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or with potassium-sparing diuretics
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Greger R, Lang F, Sebekova, Heidlan
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PART VIII THE ENDOCRINE SYSTEM
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in prefilled injection devices (‘
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Metformin should be withdrawn and i
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FURTHER READING American Diabetes A
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deficiency. Potassium iodide (3 mg
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fertility. It is contraindicated du
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● Introduction 297 ● Vitamin D
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effective in life-threatening hyper
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Further reading Block GA, Martin KJ
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Table 40.1: Actions of cortisol and
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injection may be useful, but if don
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CHAPTER 41 REPRODUCTIVE ENDOCRINOLO
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elease by the pituitary via negativ
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Treatment with depot progestogen in
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infusion using an infusion pump to
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significant proportion of men who r
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with symptoms caused by the release
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FURTHER READING Birnbaumer M. Vasop
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PART IX SELECTIVE TOXICITY
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● Principles of antibacterial che
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2. transfer of resistance between o
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Pharmacokinetics Absorption of thes
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Mechanism of action Macrolides bind
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asic quinolone structure dramatical
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Case history A 70-year-old man with
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PRINCIPLES OF MANAGEMENT OF MYCOBAC
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Pharmacokinetics Absorption from th
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MYCOBACTERIUM LEPRAE INFECTION Lepr
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POLYENES AMPHOTERICIN B Uses Amphot
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Page 356 and 357: NUCLEOSIDE ANALOGUES ACICLOVIR Uses
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Page 360 and 361: Uses Interferon-α when combined wi
Page 362 and 363: ● Introduction 351 ● Immunopath
Page 364 and 365: Table 46.1: Examples of combination
Page 366 and 367: NON-NUCLEOSIDE ANALOGUE REVERSE TRA
Page 368 and 369: FUSION INHIBITORS Uses Currently, e
Page 370 and 371: salvage therapy include azithromyci
Page 372 and 373: ● Malaria 361 ● Trypanosomal in
Page 374 and 375: Pharmacokinetics Chloroquine is rap
Page 376 and 377: Table 47.2: Drug therapy of non-mal
Page 378 and 379: ● Introduction 367 ● Pathophysi
Page 380 and 381: Table 48.1: Classification of commo
Page 382 and 383: Polymorph count/mm 3 (a) (b) 10 000
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Page 386 and 387: Adverse effects Methotrexate Inhibi
Page 388 and 389: Table 48.7: Summary of clinical pha
Page 390 and 391: Table 48.9: Summary of the clinical
Page 392 and 393: Plasma membrane Signal transduction
Page 394 and 395: Table 48.10: Monoclonal antibodies
Page 396 and 397: INTERFERON-ALFA 2B Interferon-alfa
Page 398 and 399: PART X HAEMATOLOGY
Page 400 and 401: ● Haematinics - iron, vitamin B 1
Page 402 and 403: one marrow to produce red cells. Th
Page 406 and 407: Therapeutic principles The extent o
Page 408 and 409: PART XI IMMUNOPHARMACOLOGY
Page 410 and 411: ● Introduction 399 ● Immunity a
Page 412 and 413: Key points Antigen recognition Expr
Page 414 and 415: Table 50.1: Novel anti-proliferativ
Page 416 and 417: Key points Treatment of anaphylacti
Page 418 and 419: DRUGS THAT ENHANCE IMMUNE SYSTEM FU
Page 420 and 421: PART XII THE SKIN
Page 422 and 423: ● Introduction 411 ● Acne 411
Page 424 and 425: DERMATITIS (ECZEMA) PRINCIPLES OF T
Page 426 and 427: SPECIALISTS ONLY SPECIALISTS ONLY E
Page 428 and 429: TREATMENT OF OTHER SKIN INFECTIONS
Page 430 and 431: effect of too high a dose of UVB in
Page 432 and 433: PART XIII THE EYE
Page 434 and 435: ● Introduction: ocular anatomy, p
Page 436 and 437: to cause pupillary dilatation, name
Page 438 and 439: Table 52.3: Antibacterial agents us
Page 440 and 441: Table 52.6: Common drug-induced pro
Page 442 and 443: PART XIV CLINICAL TOXICOLOGY
Page 444 and 445: ● Introduction 433 ● Pathophysi
Page 446 and 447: Table 53.2: Central nervous system
Page 448 and 449: which provide anonymized data to th
Page 450 and 451: Peak plasma levels after smoking ci
Page 452 and 453: Key points Acute effects of alcohol
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FURTHER READING Goldman D, Oroszi G
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Table 54.2: Common indications for
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Table 54.5: Antidotes and other spe
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Commission on Human Medicines (CHM)
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Note: Page numbers in italics refer
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atrial fibrillation 217, 221 digoxi
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Cushing’s syndrome 302 cyclic ade
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5-fluorouracil 375-6 fluoxetine, mo
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children 54 diazepam 108 iron prepa
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non-steroidal anti-inflammatory dru
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puberty (male), delay 314 puerperiu
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tolerance 9, 433 benzodiazepines 10
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A Textbook of Clinical Pharmacology and Therapeutics

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