THERAPEUTICS

Oral iron

Reference nutrient intake is 8.7 mg for men, 14.8 mg for women.

Indications

Treatment of iron deficiency, prophylaxis in patients with risk factors for iron deficiency, e.g. malabsorption, menorrhagia, pregnancy and post-gastrectomy Adding a 250 mg ascorbic acid tablet at the time of iron administration enhances the degree of iron absorption (iron is best absorbed as the ferrous (Fe2+) ion in a mildly acidic environment). Iron and folic acid combination preparations are used in pregnancy for women who are at risk of developing iron and folic acid deficiency.

Preparations and dose

Ferrous sulphate Tablets: 200 mg (65 mg iron).

Treatment: 1 tablet three times daily - continue for 3 months following normal haemoglobin result (the total duration of therapy should be for 6 months); prophylactic: 1 tablet daily.

Ferrous gluconate Tablets 300 g (35 mg iron).

Treatment: 2-6 tablets daily in divided doses.

Side-effects

Constipation and diarrhoea. Nausea and epigastric pain are related to the amount of elemental iron ingested and are lower with preparations containing a low elemental iron content, e.g. ferrous gluconate.

Cautions/contraindications

Avoid long-term use unless indicated; excretion of iron is fixed at 1-2 mg of iron per day through gastrointestinal loss, and prolonged use may result in iron overload.

Folic acid

Reference nutrient intake is 200 μg/day.

Indications

Folate-deficient megaloblastic anaemia, prevention of folic acid deficiency in chronic haemolytic states, renal dialysis and pregnancy, prevention of neural tube defects.

Preparations and dose

Folic acid Tablets: 400 μg, 5 mg; Syrup: 400 μg/mL, 2.5 mg/mL; Injection: 15 mg/mL.

Folate deficiency: 5 mg daily for 4 months, maintenance 5 mg daily.

To prevent first neural tube defect: 400 μg daily before conception and during pregnancy.

To prevent recurrence of neural tube defect: 5 mg daily before conception and during pregnancy.

Side-effects

Very rarely allergic reactions.

Cautions/contraindications

Folic acid should not be used in undiagnosed megaloblastic anaemia unless vitamin B12 is administered concurrently, otherwise neuropathy may be precipitated.

Vitamin B12

Reference nutrient intake is 1.5 μg/day.

Indications

Vitamin B12 deficiency.

Preparations and dose

Hydroxocobalamin Injection: 1 mg/mL.

Vitamin B12 deficiency without neurological involvement: 1 mg intra-muscularly three times a week for 2 weeks then 1 mg every 3 months lifelong.

Vitamin B12 deficiency with neurological involvement: 1 mg intra-muscularly daily for 6 days then 1 mg every 2 months.

Cyanocobalamin Tablets: 50 μg; Liquid: 35 μg/5 mL.

Vitamin B12 deficiency of dietary origin: 50-150 μg or more daily taken between meals.

Side-effects

Itching, fever, nausea, dizziness, anaphylaxis after injection. Hypokalaemia,sometimes fatal, is due to intracellular potassium shift on anaemia resolution after treatment of severe vitamin B12 deficiency.

Cautions/contraindications

Contraindicated if hypersensitivity to hydroxocobalamin or any component of preparation.

Vitamin K

Mechanism of action

Fat-soluble vitamin necessary for the production of blood clotting factors and proteins necessary for the normal calcification of bone; reference nutrient intake 1 μg/kg bodyweight.

Indications

Water-soluble form used to prevent deficiency in patients with fat malabsorp-tion (especially biliary obstruction or hepatic disease); intravenous form for excessive anticoagulation with warfarin and in patients with prolonged INR (due to fat malabsorption) prior to invasive procedures (e.g. endoscopic retrograde cholangiopancreatography (ERCP) or liver biopsy) or in whom there is bleeding.

Preparations and dose

Phytomenadione Vitamin K1 tablets: 10 mg; Injection: 10 mg/mL.

Oral Excessive anticoagulation (INR >8.0): 0.5-2.5 mg.

IV Excessive anticoagulation and major bleeding (any INR value): 5 mg over 10 minutes together with prothrombin complex concentrate or FFP (15 mL/kg).

Menadiol sodium phosphate Water-soluble tablets: 10 mg. For prevention of vitamin K deficiency in patients with fat malabsorption: 10 mg daily.

Side-effects

Anaphylaxis with i.v. preparation.

Cautions/contraindications

Caution with menadiol in G6PD deficiency and vitamin E deficiency (risk of haemolysis).

Drugs affecting haemostasis

Antiplatelet agents

■ Aspirin, dipyridamole

■ Clopidogrel

■ Glycoprotein GP11b/111a inhibitor.

Mechanism of action

Decrease platelet aggregation and inhibit thrombus formation in the arterial circulation, where anticoagulants have little effect. Aspirin irreversibly inhibits the enzyme cyclo-oxygenase, reducing production of thromboxane A2, a stimulator of platelet aggregation. Dipyridamole inhibits phosphodiesterase-mediated breakdown of cyclic AMP, which leads to impaired platelet activa-tion by multiple mechanisms. Clopidogrel is a pro-drug that is metabolized by the liver, partly by cytochrome P450 2C19, before it is biologically active. It blocks binding of ADP to platelet receptors and thus inhibits activation of the GpNb/NIa complex and platelet activation. Glycoprotein GpIIb/IIIa inhibitors (e.g. abciximab, eptifibatide, tirofiban) prevent platelet aggregation by block-ing the binding of fibrinogen to receptors on platelets. They are used as an adjunct to percutaneous coronary intervention in selected patients with acute coronary syndromes.

Preparations and dose

Aspirin Tablets: 75 mg, 300 mg, also as a dispersible form.

Secondary prevention of thrombotic cerebrovascular or cardiovascular disease: 300 mg chewed followed by maintenance dose of 75 mg daily.

Primary prevention when estimated 10-year cardiovascular risk is > 20% (p. 446), provided that blood pressure is controlled.

After coronary artery bypass gratting: 75 mg daily.

In combination with clopidogrel - see below.

Atrial fibrillation (selected cases, p. 429): 75 mg daily.

Transient musculoskeletal pain and pyrexia (see Chapter 7).

Dipyridamole Tablets: 25 mg, 100 mg; Oral suspension: 50 mg/mL; modi-fied release capsules: 200 mg.

Secondary prevention of ischaemic stroke and transient ischaemic attacks: 300-600 mg daily in three to four divided doses before food. MR preparation, 200 mg twice daily.

Clopidogrel Tablets: 75 mg, 300 mg.

Where aspirin is contraindicated for the prevention of atherosclerotic events in patients with history of ischaemic stroke, myocardial infarc-tion, or established peripheral artery disease: 75 mg daily.

Following coronary artery stent insertion: 300 mg daily, then 75 mg daily with aspirin 75 mg daily. Continue clopidogrel for 6 weeks; 12 months if a drug-eluting stent. Continue aspirin indefinitely.

Acute coronary syndrome: 300 mg, then 75 mg daily in addition to aspirin and other treatments. Continue clopidogrel for 12 months.

Side-effects

An increased risk of bleeding is the main risk with all antiplatelet agents. Aspirin causes peptic ulceration. Patients with a past history of ulceration must be co-prescribed a proton pump inhibitor (PPI) with aspirin, to prevent recurrent ulceration. In patients with a history of peptic ulcer bleeding while taking aspirin, co-administration of a PPI is associated with a reduced rate of rebleeding compared with administration of clopidogrel alone.

The effects of aspirin and clopidogrel lasts for the duration of the platelet life i.e. 7-10 days. For surgical interventions: stop aspirin if indicated for primary prevention and continue if indicated for secondary prevention. Clopi-dogrel is likely to have been given for a high-risk indication e.g. to prevent coronary stent thrombosis and should not be stopped perioperatively without prior discussion with the cardiology team. However, the risk of bleeding perioperatively is high if clopidogrel is continued and non-urgent surgery should be delayed until such time that clopidogrel can be stopped. For urgent surgery, excessive and uncontrolled bleeding is treated with platelet transfusion.

Cautions/contraindications

Active bleeding, haemophilia and other bleeding disorders are contraindica-tions. Aspirin also causes bronchospasm and must be prescribed with caution to patients with asthma. Aspirin interacts with a number of other drugs, and its interaction with warfarin is a special hazard (refer to National Formulary for details). Drugs that inhibit CYP2C19 (fluoxetine, moclobemide, voricona-zole, fluconazole, ticlopidine, ciprofloxacin, cimetidine, carbamazepine. oxcarbazepine and chloramphenicol) reduce the efficacy of clopidogrel and should be avoided.

Thrombin inhibitors

■ Heparin

■ Fondaparinux

■ Bivalirudin.

Mechanism of action

Heparin binds to and activates antithrombin (AT), which inactivates thrombin and other proteases involved in blood clotting, particularly factor Xa. Fonda-parinux binds to AT and inhibits only factor Xa. Bivalirudin is a direct thrombin inhibitor. Heparin is the most widely used, usually the low molecular weight form.

Indications

Heparin is used in the prevention and treatment of deep venous thrombosis and pulmonary embolism, myocardial infarction, acute coronary syndromes.

LMWH, produced by the enzymatic or chemical breakdown of the heparin molecule, is almost always used for these indications. For patients at high risk of bleeding, unfractionated heparin (which requires monitoring by meas-urement of APPT) is more suitable than LMWH because its effect can be terminated rapidly by stopping the infusion. Refer to national formulary for dosing for unfractionated heparin.

Preparations and dose

LMWH Enoxaparin - Injection: 20 mg, 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 150 mg.

Prophylaxis of thromboembolism by subcutaneous injection:

Surgical patients. moderate risk 20 mg daily until the patient is fully mobile with first dose 2 hours before surgery; high risk 40 mg daily until the patient is fully mobile with first dose 12 hours before surgery. Extended treatment (after hospital discharge) for 4-6 weeks is recommended in high-risk patients after major cancer/ gynaecological/orthopaedic surgery.

Medical patients. 40 mg daily.

In all patients reduce dose to 20 mg if body weight <50 kg or creati-nine clearance is <30 mL/min.

Treatment of DVT and pulmonary embolism. 1.5 mg/kg (150 units/kg) by subcutaneous injection every 24 hours, usually for at least 5 days and until oral anticoagulation is established.

Unstable angina and NSTEMI. 1 mg/kg (100 units/kg) by subcutaneous injection every 12 hours usually for 2-8 days.

Side-effects

■ Haemorrhage.

■ Thrombocytopenia, which is immune mediated and does not usually develop until after 6-10 days; it may be complicated by thrombosis. Platelet counts are recommended for patients receiving heparin for more than 5 days. Heparin should be stopped immediately and not repeated in those who develop thrombocytopenia or a 50% reduction of platelet count.

■ Hyperkalaemia due to aldosterone secretion.

■ Osteoporosis after prolonged use.

Cautions/contraindications

Contraindicated with active bleeding, acquired or inherited bleeding dis-orders, thrombocytopenia (platelets <75 X 109/L), recent cerebral haemor-rhage, severe liver disease, severe untreated hypertension (>230/120 mmHg), recent surgery to eye or nervous system, history of heparin-induced thrombocytopenia, lumbar puncture/epidural within the past 4 hours or expected within the next 12 hours, acute stroke (discuss with stroke consultant).

Oral anticoagulants

Mechanism of action

Inhibits vitamin K-dependent Y-carboxylation of coagulation factors II, VII, IX and X, thus leading to biologically inactive forms. Monitoring is by measure-ment of the INR.

Indications

Prophylaxis of embolization in atrial fibrillation, cardioversion and dilated cardiomyopathy (target INR 2.5); prophylaxis of embolization after insertion of mechanical prosthetic aortic (target INR 3.0) or mitral valve (target INR 3.5); prophylaxis and treatment of venous thrombosis and pulmonary embo-lism (target INR 2.5). Warfarin takes at least 48-72 hours for the anticoagu-lant effect to develop fully. All patients starting warfarin should be given an anticoagulant treatment booklet (advice on treatment, recording of INR and dosing) and advised to avoid cranberry juice (increases INR).

Preparations and dose

Warfarin Tablets: 1 mg, 3 mg, 5 mg.

For rapid anticoagulation in venous thromboembolism, starting dose is 10 mg on days 1 and 2 with subsequent doses adjusted according to the INR. A lower dose (5 mg) is used in patients >60 years, body weight <50 kg, baseline INR >1.4 or patients taking interacting drugs which inhibit the metabolism of warfarin. Slow induction of warfarin (1 mg daily for a week) is used for patients in atrial fibrillation with subsequent dosing dependent on the INR.

Maintenance dose - usually 3-9 mg daily by mouth taken at the same time each day. Daily monitoring of the INR in the early days of treat-ment, then at longer intervals depending on response.

Side-effects

Skin necrosis in patients with protein C or protein S deficiency, occurs soon after starting treatment.

Haemorrhage; management is based on the INR and whether there is major or minor bleeding:

■ Major bleeding (intracranial, intraperitoneal, intraocular, muscular com-partment syndrome, or life-threatening from any orifice); stop warfarin, give vitamin phytomenadione (vitamin K1) 5 mg by slow intravenous injection, and prothrombin complex concentrate 30-50 units/kg or FFP (15 mL/kg).

■ INR >8, no bleeding or minor bleeding, stop warfarin. Give vitamin K, 500 μg by slow intravenous injection or 5 mg by mouth if there are risk factors for bleeding.

■ Any other INR >target range stop warfarin and restart when INR <5.

Contraindications

■ Underlying abnormalities of haemostasis (e.g. haemophilia, thrombo-cytopenia).

■ Hypersensitivity to warfarin or any of the excipients.

■ After an ischaemic stroke for 2-14 days depending on the size of infarct and blood pressure.

■ Surgery - stop warfarin 3 days prior to surgery if there is a risk of severe bleeding. In most instances warfarin can be restarted post-operatively as soon as the patient starts oral intake. Warfarin does not need to be stopped before tooth extraction provided INR <3.

■ Severe uncontrolled hypertension.

■ Active peptic ulceration.

■ Severe liver disease.

■ Pregnancy - teratogenic in first trimester and risk of placental or fetal haemorrhage in third trimester. Warfarin can be used during breast-feeding.

Drug interactions Many drugs interact with warfarin (check national formu-lary for full list) and the patient's INR should be measured frequently when-ever any drug is added to, or withdrawn from, the patient's therapeutic regimen. Warfarin activity is particularly increased by alcohol, allopurinol, amiodarone, aspirin and other NSAIDs, omeprazole, ciprofloxacin, clofibrate, co-trimoxazole, dipyridamole, macrolide antibiotics such as erythromycin, metronidazole, statins, tamoxifen, levothyroxine. Warfarin activity is particu-larly decreased by carbamazepine, rifampicin, rifabutin, griseofulvin, and some herbal remedies, e.g. St John's wort. Warfarin activity may be increased or decreased by phenytoin, corticosteroids, colestyramine. Other drugs co-administered with warfarin increase the risk of bleeding and should be avoided - antiplatelet drugs (p. 242), NSAIDs and the antidepressant drugs serotonin selective reuptake inhibitors.

Fibrinolytic drugs

Mechanism of action

Hydrolyse a peptide bond in plasminogen to yield the active enzyme, plasmin, which promotes clot lysis.

Indications

■ Acute myocardial infarction within 12 hours of symptom onset.

■ Selected cases of venous thromboembolism.

■ Acute ischaemic stroke within 4.5 hours of symptom onset.

Preparations and dose

Alteplase Injection: 10 mg (5.8 million units), 20 mg (11.6 million units) and 50 mg (29 million units)/vial.

Acute myocardial infarction within 12 hours of symptom onset. 15 mg by i.v. injection, followed by i.v. infusion of 50 mg (in patients <65 kg, 0.75 mg/kg) over 30 minutes, then 35 mg (<65 kg, 0.5 mg/kg) over 60 minutes. For acute myocardial infarction 6-12 hours within symptom onset 10 mg by i.v. injection, followed by i.v. infusion of 50 mg over 60 minutes, then 4 infusions each of 10 mg over 30 minutes; maximum total dose 1.5 mg/kg in patients <65 kg.

Massive pulmonary embolism with hypotension. 10 mg by i.v. injection over 1-2 minutes, followed by i.v. infusion of 90 mg over 2 hours; max 1.5 mg/kg in patients <65 kg.

Acute ischaemic stroke, 900 |i/kg (max 90 mg) over 60 minutes by i.v. infusion; initial 10% given by i.v. injection. Start as soon as possible (‘time is brain') and given up to 4.5 hours after symptom onset.

Streptokinase Injection: 1.5 million international units.

Myocardial infarction. 1.5 million units over 60 minutes.

In selected cases of DVT, pulmonary embolism, acute arterial thrombo-embolism, central retinal venous or arterial thrombosis. by i.v. infu-sion 250 000 units over 30 minutes, then according to clinical condition.

Side-effects

The main disadvantage is the indiscriminate activation of plasminogen both in clots and in the circulation, leading to an increased risk of haemorrhage. Other side-effects are cardiac arrhythmias during reperfusion of the myo-cardium, hypotension and allergic reactions (bronchospasm, urticaria) with streptokinase.

Contraindications

Gastrointestinal or genitourinary bleeding (within the previous 21 days), aortic dissection, severe uncontrolled hypertension (systolic blood pressure >180 mmHg, diastolic blood pressure >110 mmHg), intracranial aneurysm, recent major trauma/surgery/head injury (within the previous 14 days) or invasive diagnostic procedure (within last 7-10 days), recent stroke (other than acutely in ischaemic stroke), bleeding disorders, pregnancy or recent obstetric delivery, INR >1.7 if on warfarin.

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology

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