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A Textbook of Clinical Pharmacology and Therapeutics

A Textbook of Clinical Pharmacology and Therapeutics

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effective in life-threatening hyperkalaemia-induced cardiac dysrhythmias (Chapter 32). Calcium and vitamin D supplements are used in patients at risk of osteoporosis if intake is below 1 g of elemental calcium daily. Effervescent or chewable preparations are available and easy to take. TREATMENT OF HYPERCALCAEMIA Hypercalcaemia may be a life-threatening emergency. Causes include hyperparathyroidism, malignancy with bone metastases or ectopic PTH synthesis, sarcoidosis and vitamin D intoxication. Treating the underlying cause is crucial. Management of hypercalcaemia per se buys time for this and can be divided into general and specific measures. GENERAL MEASURES The following general measures apply: 1. rehydration; 2. avoid thiazide diuretics (cause Ca 2� retention, see Chapter 36); 3. avoid excessive vitamin D; 4. avoid immobilization if possible. Specific measures to: 1. increase calcium excretion: • intravenous saline increases calcium excretion; • once extravascular volume has been restored, furosemide further increases urinary calcium excretion. 2. decrease bone resorption: • bisphosphonates (see below); • calcitonin (see below); 3. glucocorticosteroids: • glucocorticosteroids are useful for treating the hypercalcaemia associated with sarcoidosis. Key points Management of acute hypercalcaemia • Avoid thiazides, vitamin D (milk), any calcium preparations and, if possible, immobilization. • Vigorously replace fluid losses with intravenous 0.9% sodium chloride. Once replete, furosemide administration further increases urinary calcium loss. • Give parenteral bisphosphonates (e.g. disodium etidronate or disodium pamidronate). • Calcitonin lowers calcium levels more rapidly than bisphosphonates, and may be used concomitantly in severe cases. • Glucocorticosteroids are used for the hypercalcaemia of sarcoidosis. BISPHOSPHONATES BISPHOSPHONATES 299 Bisphosphonates resemble pyrophosphate structurally, except that the two phosphorus atoms are linked by carbon rather than by oxygen. The P-C-P backbone structure renders such compounds very stable – no enzyme is known that degrades them. Uses Alendronic acid or risedronate (by mouth) are first-choice bisphosphonates for the prevention and treatment of osteoporosis; etidronate is an alternative if these are not tolerated. Bisphosphonates are also used to treat Paget’s disease of bone, in the treatment of hypercalcaemia of malignancy (e.g. pamidronate i.v.) and to reduce skeletal complications in breast cancer metastatic to bone and multiple myeloma (e.g. clodronate p.o. or i.v.). They are effective for glucocorticoidassociated and post-menopausal osteoporosis. In Paget’s disease, risedronate is given for two months and this can be repeated after at least two months off treatment. Etidronate is started at low dosage up to six months when many patients achieve remission; a further course may be given following relapse. Use for longer than six months at a time does not prolong remission. High doses should be used only if lower doses fail or if rapid control of disease is needed. Serum alkaline phosphatase, phosphate and if possible urinary hydroxyproline are monitored during treatment of Paget’s disease. Mechanism of action Bisphosphonates modify the crystal growth of calcium hydroxyapatite by chemical adsorption to the crystal surface, reducing bone remodelling and turnover by osteoclasts. Adverse effects Renal impairment is a caution or contraindication for all bisphosphonates. Oesophagitis and ulceration can be severe. This is minimized by taking alendronic acid or risedronate when sitting upright or standing, on an empty stomach before breakfast, and remaining standing for half an hour before eating. Other adverse effects include the gamut of gastrointestinal symptoms. Etidronate increases the risk of fracture in patients with Paget’s disease. Key points Bisphosphonates and bone disease • Used to treat malignant hypercalcaemia, bone pain from metastatic cancer (breast, prostate) and Paget’s disease, and to prevent and reduce the progression of osteoporosis. • Inhibit bone resorption by osteoclasts; etidronate also inhibits mineralization with chronic use. • Oral absorption is poor; short t 1/2 in plasma and long t 1/2 in bone; renal clearance. • Food and/or calcium-containing antacids further reduce gastrointestinal absorption of bisphosphonates. • The most common side effects are gastro-intestinal disturbances (Note: with regard to oesophagitis and ulceration with alendronic acid, this drug must be taken with water and the patient must be able to stand for 30 minutes post-ingestion).

300 CALCIUM METABOLISM Pharmacokinetics Bisphosphonates are incompletely absorbed (�10%) and food and antacids further reduce absorption. They disappear rapidly from the blood, distributing to bone, where their effects are long lived. Within 24 hours, approximately 50% of the absorbed dose is excreted unchanged in the urine, but the remainder is excreted over many weeks. CALCITONIN This is a 32-amino-acid polypeptide hormone secreted by thyroid parafollicular C-cells. Secretion is determined mainly by the plasma Ca 2� concentration. Uses Synthetic or recombinant salmon calcitonin (salcatonin) is used to lower the plasma calcium concentration in hypercalcaemia, especially from malignancy, and in the treatment of pain and some of the neurological complications (e.g. deafness due to VIII nerve compression) of severe Paget’s disease and for post-menopausal osteoporosis (together with calcium and vitamin D supplements, if diet is inadequate). Calcitonin is given by subcutaneous or intramuscular injection, or as a nasal spray. Plasma calcium, phosphate, alkaline phosphatase and if possible urine hydroxyproline excretion are monitored. Mechanism of action The main action of calcitonin is on bone; it inhibits bone resorption by binding to a specific receptor on osteoclasts inhibiting their action. In the kidney, it decreases the reabsorption of both Ca2� and phosphate in the proximal tubules. Adverse effects Adverse effects include the following: 1. pain at the injection site; 2. nausea and diarrhoea; 3. flushing. STRONTIUM RANELATE Strontium is a bone-seeking element; it was widely used for osteoporosis in the 1950s, but there were concerns that it inhibited calcitriol synthesis and might cause defective bone mineralization. These adverse effects may have reflected a calcium-deficient diet and incorrect dosing. Recent evidence indicates that strontium ranelate reduces bone reabsorption and increases bone formation, and reduces vertebral and hip fractures in women with post-menopausal osteoporosis. It is given by mouth at night to older women with osteoporosis and a history of bone fracture when bisphosphonates are contraindicated or not tolerated. It causes gastro-intestinal adverse effects. TERIPARATIDE Teriparatide is a PTH agonist. It is a recombinant fragment of PTH, used by experts in metabolic bone disease for the treatment of post-menopausal osteoporosis. It is contraindicated in patients with other metabolic bone diseases, including hyperparathyroidism, Paget’s disease or previous radiation therapy to the skeleton and used with caution if there is renal impairment or cardiac disease. It is given daily by subcutaneous injection for periods up to 18 months, monitoring serum calcium, phosphate, alkaline phosphatase, creatinine and electrolytes. CINACALCET Cinacalcet is a calcimimetic drug which enhances signalling through the calcium sensing receptor (CaSR). It is an allosteric activator of CaSR and reduces secretion of PTH. This is accompanied by a modest reduction in plasma calcium and phosphate. It also reduces expression of the PTH gene (and hence the synthesis of PTH) and diminishes parathyroid hyperplasia. It is given by mouth for secondary hyperparathyroidism in patients on dialysis for end-stage renal disease and for hypercalcaemia caused by parathyroid carcinoma, with monitoring of serum calcium and PTH. Case history A 52-year-old woman has had epilepsy since childhood, treated with phenytoin 300 mg/day and her fits have been well controlled. Since the loss of her job and the death of her husband she has become an alcoholic. At the age of 54 years, she is seen by her local GP because of weakness in her legs, difficulty in climbing stairs and getting out of her chair. She has no sensory symptoms in her limbs and no sphincter problems. Neurological examination of her legs is normal apart from signs of thigh and hip muscle weakness and slight wasting. Clinical investigations reveal that haemoglobin, white blood and platelets are normal, but her erythrocyte sedimentation rate is 30 mm per hour, her blood glucose level is 5.4 mM, sodium is 136 mM, K is 4.6 mM, urea is 10 mM and creatinine is 80 μ M. Liver function tests are all normal, except for an elevated alkaline phosphatase of 600 IU/L, and bilirubin is normal. A chest x-ray is normal. Further biochemical investigation reveals a plasma calcium concentration of 1.8 mM and a phosphate concentration of 0.6 mM. Question What is the likely cause of her metabolic disturbance and leg weakness, and how would you treat it ? Answer This patient has hypocalcaemia with hypophosphataemia and a raised alkaline phosphatase, but no evidence of renal dysfunction. This is the clinical picture of a patient with osteomalacia. The aetiology is secondary to her chronic phenytoin therapy. The mechanism of these effects is complex and relates to several actions of the drug. Phenytoin is a potent inducer of hepatic drug metabolizing enzyme systems, including the enzymes involved in vitamin D metabolism, specifically metabolism of calciferol to 25�-hydroxycholecalciferol by the liver, and its further metabolism to inactive products. It also impairs the absorption of vitamin D from the gut. Treatment of this form of drug-induced osteomalacia consists of giving the patient oral Ca 2� supplements together with low-dose 1-α-hydroxy vitamin D (0.5 μg per day), and continuing the phenytoin if necessary.

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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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    ● Introduction 177 ● Pathophysi

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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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    ● Introduction 185 ● Pathophysi

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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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    ● Introduction 211 ● Pathophysi

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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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  • Page 346 and 347: PRINCIPLES OF MANAGEMENT OF MYCOBAC
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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

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    FUSION INHIBITORS Uses Currently, e

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    salvage therapy include azithromyci

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    ● Malaria 361 ● Trypanosomal in

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    Pharmacokinetics Chloroquine is rap

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    Table 47.2: Drug therapy of non-mal

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    ● Introduction 367 ● Pathophysi

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    Table 48.1: Classification of commo

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    Polymorph count/mm 3 (a) (b) 10 000

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    doses are used to prepare patients

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    Adverse effects Methotrexate Inhibi

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    Table 48.7: Summary of clinical pha

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    Table 48.9: Summary of the clinical

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    Plasma membrane Signal transduction

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    Table 48.10: Monoclonal antibodies

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    INTERFERON-ALFA 2B Interferon-alfa

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    PART X HAEMATOLOGY

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    ● Haematinics - iron, vitamin B 1

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    one marrow to produce red cells. Th

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    EPO Erythroid precursors Erythrocyt

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    Therapeutic principles The extent o

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    PART XI IMMUNOPHARMACOLOGY

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    ● Introduction 399 ● Immunity a

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    Key points Antigen recognition Expr

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    Table 50.1: Novel anti-proliferativ

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    Key points Treatment of anaphylacti

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    DRUGS THAT ENHANCE IMMUNE SYSTEM FU

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    PART XII THE SKIN

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    ● Introduction 411 ● Acne 411

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    DERMATITIS (ECZEMA) PRINCIPLES OF T

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    SPECIALISTS ONLY SPECIALISTS ONLY E

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    TREATMENT OF OTHER SKIN INFECTIONS

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    effect of too high a dose of UVB in

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    PART XIII THE EYE

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    ● Introduction: ocular anatomy, p

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    to cause pupillary dilatation, name

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    Table 52.3: Antibacterial agents us

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    Table 52.6: Common drug-induced pro

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    PART XIV CLINICAL TOXICOLOGY

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    ● Introduction 433 ● Pathophysi

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    Table 53.2: Central nervous system

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    which provide anonymized data to th

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    Peak plasma levels after smoking ci

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    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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