A Textbook of Clinical Pharmacology and Therapeutics

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DRUGS THAT ENHANCE IMMUNE SYSTEM FUNCTION ADJUVANTS Adjuvants non-specifically augment the immune response when mixed with antigen or injected into the same site. This is achieved in the following ways: • release of the antigen is slowed and exposure to it is prolonged; • various immune cells are attracted to the site of injection and the interaction between such cells is important in antibody formation. There are a number of such substances, usually given as mixtures and often containing lipids, extracts of inactivated tubercle bacilli and various mineral salts. IMMUNOSTIMULANTS Immunostimulants non-specifically enhance immune responses, examples include bacille Calmette-Guérin (BCG) or killed Corynebacterium parvum. INTERLEUKIN-2 (IL-2) Interleukin-2 is effective treatment for metastatic melanoma and renal cell carcinoma (Chapter 48). VACCINES IMMUNOLOGY AND GENERAL USE Vaccines stimulate an immune response. They may consist of: • an attenuated form of the infectious agent, such as the live vaccines used to prevent rubella, measles or polio, or BCG to prevent tuberculosis; • inactivated preparations of virus (e.g. influenza virus) or bacteria (e.g. typhoid vaccine); • detoxified exotoxins (‘toxoids’), e.g. tetanus vaccine. Live vaccine immunization is generally achieved with a single dose, but three doses are required for oral polio (to cover different strains). Live vaccine replicates while in the body and produces protracted immunity, albeit not as long as that acquired after natural infection. When two live vaccines are required (and are not in a combined preparation) they may be given at different sites simultaneously or at an interval of at least three weeks. Inactivated vaccines usually require sequential doses of vaccine to produce an adequate antibody response. Booster injections are required at intervals. The duration of immunity acquired with the use of inactivated vaccines ranges from months to years. The vaccination programmes recommended by the Department of Health (DH) in the UK are IMMUNOGLOBULINS AS THERAPY 407 described in detail in a memorandum entitled ‘Immunization against infectious disease’, available to doctors from the Department of Health. The British National Formulary summarizes the recommended schedule of vaccinations. Contraindications Postpone vaccination if the patient is suffering from acute illness. Ensure that the patient is not sensitive to antibiotics used in the preparation of the vaccine (e.g. neomycin and polymyxin). Egg sensitivity excludes the administration of several vaccines (e.g. influenza). Live vaccines should not be given to pregnant women, nor should they be given to patients who are immunosuppressed. Live vaccines should be postponed until at least three months after stopping glucocorticosteroids and six months after chemotherapy. Live vaccines should not be administered to HIV-1-positive individuals. Key points Vaccine therapy • Vaccines generally stimulate the production of protective antibodies or activated T cells. • Vaccines consist of: – attenuated infectious agents – antiviral vaccines (e.g. mumps, rubella, etc.). – inactivated viral/bacterial preparations (e.g. influenza virus or typhoid vaccine). – extracts of detoxified toxins (e.g. tetanus toxin). • Live vaccines produce protracted immunity and some (e.g. measles and mumps vaccines) have a low risk of causing a mild form of the disease. • Different countries have different vaccination schedules based on the prevalence of the disease in the population and the level of herd (‘population’) immunity. IMMUNOGLOBULINS AS THERAPY Immunoglobulin injection gives immediate passive protection for four to six weeks. Recombinant technology will yield antibodies of consistent quality in the future, but it is a challenge to replicate the diversity present in polyclonal human normal immunoglobulin. Currently, there are two types of immunoglobulin, namely normal and specific. HUMAN NORMAL IMMUNOGLOBULIN Human normal immunoglobulin (HNIG) is prepared from pooled donations of human plasma. It contains antibodies to measles, mumps, varicella, hepatitis A and other viruses. Uses HNIG is used to protect susceptible subjects from infection with hepatitis A and measles and, to a lesser extent, to protect the fetus against rubella in pregnancy when termination is not an option. Special formulations for intravenous administration are available for replacement therapy in agammaglobulinaemia,
408 CLINICAL IMMUNOPHARMACOLOGY hypogammaglobulinaemia and IgG subclass deficiency (e.g. Bruton’s agammaglobulinaemia, Wiskott–Aldrich syndrome), idiopathic thrombocytopenic purpura and for prophylaxis of infection in bone marrow transplant patients. Adverse effects The most common adverse effects occur during the first infusion and are dependent on the antigenic load (dose) given. They include the following: • fever, chills and rarely anaphylaxis – most commonly seen with the first dose, and reduced by slow administration and premedication with antihistamines and glucocorticosteroids; • increased plasma viscosity – caution is needed in patients with ischaemic heart disease; • aseptic meningitis (high dose). Contraindications Normal immunoglobulin is contraindicated in patients with known class-specific antibody to IgA. Interactions Live virus vaccinations may be rendered less effective. SPECIFIC IMMUNOGLOBULINS These antibodies are prepared by pooling the plasma of selected donors with high levels of the specific antibody required. The following are currently available and effective: rabies immunoglobulin, tetanus immunoglobulin (human origin-HTIG), varicella zoster immunoglobulin (VZIG) (limited supply); anti-CMV immunoglobulin (on a named patient basis). ANTI-D (RHO) IMMUNOGLOBULIN This immunoglobulin is used to prevent a rhesus-negative mother from forming antibodies to fetal rhesus-positive cells that enter the maternal circulation during childbirth or abortion. An intramuscular injection is given to rhesus-negative mothers up to 72 hours after the birth/abortion. This prevents a subsequent child from developing haemolytic disease of the newborn. Case history A 35-year-old woman had a cadaveric renal transplant for polycystic kidneys two years previously and was stable on her immunosuppressive regimen of ciclosporin, 300 mg twice a day, and mycophenolate mofetil, 1 g twice a day. Her usual trough ciclosporin concentrations were 200–250 μg/L and her hepatic and liver function was normal. She went on holiday to southern California for ten days, where she was well, but drank plenty of fluids (but no alcohol) as she was warned about the dangers of dehydration. By the end of her visit, she noted some nausea and a mild tremor. Following a long return flight, she went to her local hospital and sustained a brief spontaneously remitting epileptic fit in the outpatient department where she was having her blood ciclosporin concentration checked. The fit lasted about one minute and she was taken to the Accident and Emergency Department. Examination revealed no abnormalities apart from slight tremor which she said she had noted for the last 48 hours. Her ciclosporin concentration was 650 μg/L. All other medical biochemistry tests were normal. She was not taking any other prescribed medications or over-the-counter drugs. Questions What caused this patient’s seizures? How can you explain the markedly elevated trough ciclosporin concentration? Answer In this patient, the development of an acute epileptic seizure in the context of a very high ciclosporin trough concentration indicates ciclosporin toxicity; epilepsy is a well-recognized toxic effect of high ciclosporin concentrations. The difficult issue in the case is why she developed high ciclosporin blood concentrations (in the face of normal renal and hepatic function) when she was adamant that there had been no alteration in the daily dose of ciclosporin she was taking, nor had she started any other drugs (prescribed or over-the-counter agents). Further questioning defined that she was drinking about 1 L/day of grapefruit juice – a taste she had acquired while on holiday in California. Grapefruit juice contains psoralens and flavonoids which inhibit CYP3A (gastrointestinal and hepatic) and flavonoids which inhibit P-gp in the gut wall, increasing the bioavailability of ciclosporin by 19–60%, the combined effect leading to higher concentrations without a change in dose. The patient had her ciclosporin dosing stopped until the concentration was �300 μg/L. She had no further fits, her nausea and tremor subsided, and she was then restarted on her normal dose with clear instructions not to drink grapefruit juice. Examples of other drugs whose oral bioavailability is increased in humans with co-ingestion of grapefruit juice include midazolam, oestrogens, atorvastatin (and most statins except pravastatin), testosterone, felodipine, nifedipine (but not diltiazem), some anti-HIV protease inhibitors, other calcinerin inhibitors. Patients who are taking these agents or other drugs metabolized by CYP3A/P-gp should be warned not to ingest even single cupfuls of grapefruit juice, as this may precipitate toxic drug concentrations. FURTHER READING Golightly LK, Greos LS. Second-generation antihistamines: actions and efficacy in the management of allergic disorders. Drugs 2005; 65: 341–84. Lindenfeld J, Miller GG, Shakar SF et al. Drug therapy in the heart transplant recipient: part II: immunosuppressive drugs. Circulation 2004; 110: 3858–65. Lipsky JJ. Drug profile. Mycophenolate mofetil. Lancet 1996; 348: 1357–9. Plaut M, Valentine MD. Clinical practice. Allergic rhinitis. New England Journal of Medicine 2005; 353: 1934–44. Simons ERF, Simons KJ. Drug therapy:the pharmacology and use of H1-receptor antagonist drugs. New England Journal of Medicine 1994; 330: 1663–70. Waldman TA. Immunotherapy: past, present and future. Nature Medicine 2003; 9: 269–77.
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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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therapy is adequate though more fre
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NUCLEOSIDE ANALOGUES ACICLOVIR Uses
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Table 45.3: Summary of available ac
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Uses Interferon-α when combined wi
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● Introduction 351 ● Immunopath
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Table 46.1: Examples of combination
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NON-NUCLEOSIDE ANALOGUE REVERSE TRA
Page 368 and 369: FUSION INHIBITORS Uses Currently, e
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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 404 and 405: EPO Erythroid precursors Erythrocyt
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 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
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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
Page 454 and 455: FURTHER READING Goldman D, Oroszi G
Page 456 and 457: Table 54.2: Common indications for
Page 458 and 459: Table 54.5: Antidotes and other spe
Page 460 and 461: Commission on Human Medicines (CHM)
Page 462 and 463: Note: Page numbers in italics refer
Page 464 and 465: atrial fibrillation 217, 221 digoxi
Page 466 and 467: 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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