THERAPEUTICS

Anti-inflammatories and pain relief

Aspirin (p. 243) is indicated for transient musculoskeletal pain and pyrexia. In inflammatory conditions NSAIDs are usually given. Paracetamol is similar in efficacy to aspirin, but has no demonstrable anti-inflammatory activity. It is first-line treatment in pain relief where anti-inflammatories are not routinely indicated. Codeine may be added when paracetamol alone is insufficient.

Paracetamol (acetaminophen)

Mechanism of action

Inhibits synthesis of prostaglandins in the central nervous system and periph-erally blocks pain impulse generation. Reduces pyrexia by inhibition of the hypothalamic heat-regulating centre.

Indications

Mild to moderate pain, pyrexia. NSAIDs are preferred for pain relief in the inflammatory arthritides.

Preparations and dose

Tablets, capsules, dispersible tablets: 500 mg; Suspension 250 mg/ml; Suppositories 60 mg, 125 mg, 250 mg, 500 mg; Intravenous infusion 10 mg/mL in 50 mL or 100 mL vial.

Oral or rectal: 0.5-1 g every 4-6 hours to a maximum of 4 g daily (3 g if weight <50 kg or liver disease).

IV infusion over 15 minutes: 1 g every 4-6 hours, maximum 4 daily; 15 mg/ kg if body weight <50 kg. Mainly used postoperatively.

Side-effects

Rare unless in overdose (p. 597).

Cautions/contraindications

Dosing interval 6 hours or greater if estimated glomerular filtration rate <30 mL/min. Reduce dose in severe liver disease.

Compound preparations

Paracetamol (500 mg) is also available combined with a low dose of an opioid analgesic e.g. codeine phosphate 8 mg, 15 mg or 30 mg, in tablet, dispers-ible tablet or capsule form. The dose of opioid may be enough to cause opioid side-effects (p. 267).

Non-steroidal anti-inflammatory drugs

Mechanism of action

Inhibition of cyclo-oxygenase (COX), the enzyme which catalyses the synthe-sis of cyclic endoperoxidases from arachidonic acid to form prostaglandins. Inhibition of the COX-1 isoform in the gastrointestinal tract leads to a reduc-tion in protective prostaglandins and predisposes to gastroduodenal damage. COX-2 is the form mainly induced in response to pro-inflammatory cytokines. The selective inhibitors of COX-2 (‘coxibs', etoricoxib and celecoxib) have a lower risk of gastroduodenal damage than the non-selective NSAIDs (e.g. ibuprofen, diclofenac).

Treatment is given in the smallest dose necessary for the shortest time.

■ Pain and inflammation associated with inflammatory arthritides and severe osteoarthritis (paracetamol gives similar pain relief in mild/ moderate).

■ Crystal synovitis

■ Transient musculoskeletal pain.

■ Pain caused by secondary bone tumours.

Preparations and dose

There are many different NSAIDs. They vary in their anti-inflammatory properties and tolerability, e.g. ibuprofen has fewer side-effects than other NSAIDs but anti-inflammatory activity is weaker. Indometacin is more potent with a higher incidence of side-effects. Diclofenac and naproxen lie somewhere between these two in potency and side-effects.
Two examples of non-selective NSAIDs are listed and one coxib.
Ibuprofen Tablets: 200 mg, 400 mg, 600 mg, 800 mg; Syrup: 100 mg/5 mL.
Oral Initially 1.2–1.8 g daily in three to four divided doses after food, increased to a maximum of 2.4 g daily if necessary. Maintenance 0.6– 1.2 g daily in divided doses.
Diclofenac Tablets: 25 mg, 50 mg; Suppositories: 25 mg, 50 mg, 100 mg;
Injection: 75 mg/3 mL.
Oral/rectal 75–150 mg daily in two to three divided doses.
IM 75 mg once or twice daily for up to 2 days.
Celecoxib Capsules 100 mg, 200 mg.
Oral 200 mg in 1–2 divided doses, increased if necessary to maximum 400 mg daily.

Side-effects

Gastrointestinal toxicity with highest risk in the elderly. Inflammation and ulceration can occur throughout the gut but clinically most apparent in the stomach and duodenum (dyspepsia, erosions, ulceration, bleeding, perfora-tion). Of the non-selective NSAIDs, ibuprofen is associated with the lowest risk, and piroxicam, indometacin and diclofenac with intermediate risk. NSAIDs associated with the lowest risk are generally preferred, and the lowest NSAID dose compatible with symptom relief should be prescribed. Co-prescribe proton pump inhibitors with non-selective NSAIDs in high-risk patients (>65 years, previous peptic ulceration, serious comorbidity, other medication that increases gastrointestinal risk: warfarin, aspirin, corticos-teroids) to reduce gastroduodenal damage.

Others. hypersensitivity reactions (particularly rashes, bronchospasm, angio-oedema), blood disorders, fluid retention (may precipitate cardiac failure in the elderly), acute kidney injury, hepatitis, pancreatitis and exacer-bation of colitis.

Cautions/contraindications

Contraindicated in patients with a history of hypersensitivity to aspirin or any other NSAID - which includes those in whom attacks of asthma, angio-oedema, urticaria or rhinitis have been precipitated by aspirin or any other NSAID. Contraindicated in severe heart failure. Selective COX-2 inhibitors are contraindicated in ischaemic heart disease, cerebrovascular disease, peripheral arterial disease, and moderate or severe heart failure. Avoid NSAIDs, unless absolutely necessary, in patients with active or previous gastrointestinal ulceration and in patients taking anticoagulants, corticos-teroids or aspirin because of gastrointestinal risk. In patients with renal, cardiac or hepatic impairment, NSAIDs may cause a deterioration in organ function. NSAIDs may cause a flare of inflammatory bowel disease and should be avoided if possible. For interactions of NSAIDs, see a national formulary.

Drugs affecting bone metabolism

Bisphosphonates

Mechanism of action

Adsorbed onto hydroxyapatite crystals in bone and inhibit growth and activity of osteoclasts, thereby reducing the rate of bone turnover.

Indications

Prophylaxis and treatment of osteoporosis in combination with calcium (700-1000 mg daily, 1500 mg post-menopausally) and vitamin D (800 IU/ day) supplements if dietary intake inadequate. Treatment of Paget's disease and hypercalcaemia of malignancy, treatment of osteolytic lesions and bone pain in bone metastases associated with breast cancer or multiple myeloma.

Preparations and dose

Alendronic acid Tablets: daily 10 mg; once weekly: 70 mg.

Treatment and prevention of osteoporosis: 10 mg daily at least 30 minutes before breakfast or 70 mg once weekly.

Because of severe oesophageal reactions (oesophagitis, oesophageal ulcers and strictures), patients should be advised to take the tablets with a full glass of water on rising, to take them on an empty stomach at least 30 minutes before the first food or drink of the day and to stand or sit for at least 30 minutes. Also advise patients to stop the tablets and seek medical attention if symptoms of oesophageal irritation develop.

Risedronate Tablets: 5 mg, 30 mg; once weekly: 35 mg.

Prevention and treatment of osteoporosis: 5 mg daily or 35 mg weekly. Paget's disease: 30 mg daily for 2 months; may be repeated if necessary after at least 2 months.

Precautions for taking risedronate are as for alendronate (above). No food or drink for 2 hours after risedronate.

Disodium pamidronate Injection: 15 mg, 30 mg, 60 mg, 90 mg.

IV Patients should be hydrated first.

Hypercalcaemia of malignancy: Serum calcium <3.0 mmol/L, give 1530 mg; serum calcium >4.0 mmol/L, give 90 mg. Give as single infusion or in multiple infusions over 2-4 consecutive days. Each 60 mg must be diluted with at least 250 mL sodium chloride and given over at least 1 hour.

Osteolytic lesions and bone pain in bone metastases associated with breast cancer or multiple myeloma: 90 mg every 4 weeks (or every 3 weeks to coincide with chemotherapy in breast cancer).

Paget's disease: 30 mg once a week for 6 weeks; may be repeated every 6 months.

Side-effects

Gastrointestinal side-effects (dyspepsia, nausea, vomiting, abdominal pain, diarrhoea, constipation), influenza-like symptoms, oesophageal reactions (see above), musculoskeletal pain. With intravenous disodium pamidronate: biochemical abnormalities (hypophosphataemia, hypocalcaemia, hyper- or hyperkalaemia, hypernatraemia), anaemia, thrombocytopenia, lympho-cytopenia, seizures, acute kidney injury, conjunctivitis. Osteonecrosis of the jaw - greatest risk is in patients receiving intravenous bisphosphonates for cancer indications.

Cautions/contraindications

Correct vitamin D deficiency and hypocalcaemia before starting. Avoid rise-dronate and alendronate in symptomatic oesophageal disorders. Dose adjust-ment in severe renal impairment (see National Formularỳ).

Calcium

Reference nutrient intake 700 mg.

Indications

Hypocalcaemia, osteomalacia, when dietary calcium intake (with or without vitamin D) is deficient in the prevention and treatment of osteoporosis.

Preparations and dose

Calcium carbonate Chewable tablets (calcium 500 mg or Ca2+ 12.6 mmol); Dispersible tablets: 400 (calcium 400 mg or Ca2+ 10 mmol), 1000 (calcium 1 g or Ca2+ 25 mmol); Syrup (calcium 108.3 mg or Ca2+ 2.7 mmol/5 mL).

Osteoporosis and calcium deficiency: 700-1000 mg daily, syrup 55-75 mL daily.

Osteomalacia: 1000-3000 mg daily, syrup 55-155 mL daily.

Calcium gluconate Injection: 10% (calcium 89 mg or Ca2+ 2.2 mmol/10 mL).10-20 mL over 10 minutes for acute hypocalcaemia.

Side-effects

Gastrointestinal disturbances; with injection, peripheral vasodilatation, fall in blood pressure, injection-site reactions.

Cautions/contraindications

Conditions associated with hypercalcaemia and hypercalciuria.

Vitamin D

Mechanism of action

Fat-soluble vitamin whose main action is to promote intestinal absorption of calcium. An oral supplement of 10 μg (400 units) prevents deficiency.

Indications

■ Prevention of vitamin D deficiency in those at risk, e.g. Asians consuming unleavened bread, and in elderly patients, particularly those who are housebound or live in residential or nursing homes.

■ As an adjunct in the prevention and treatment of osteoporosis where dietary intake of vitamin D (and calcium) is suboptimal.

■ Vitamin D deficiency caused by intestinal malabsorption, chronic liver disease and severe renal impairment.

■ Hypocalcaemia of hypoparathyroidism.

Preparations and dose

Ergocalciferol Calciferol (vitamin D;) tablets: 250 μg (10 000 units); Calcium (97 mg) and ergocalciferol (10 μg 400 units) tablets.

Prevention of vitamin D deficiency: calcium and ergocalciferol tablets 1-2 daily.

Adjunct in treatment of osteoporosis: calcium and ergocalciferol tablets 1-2 daily.

Deficiency caused by malabsorption or chronic liver disease: up to 1 mg (40 000 units) calciferol.

Hypocalcaemia of hypoparathyroidism: up to 2.5 mg (100 000 units) calciferol.

Alfacalcidol 1 α-Hydroxycholecalciferol capsules: 250 ng, 500 ng, 1 μg. Vitamin D treatment in patients with chronic kidney disease: 0.25-1 μg daily.

Calcitriol 1,25-Dihydroxycholecalciferol: 250 ng, 500 ng.

Vitamin D treatment in patients with chronic kidney disease: 250-1000 ng daily.

Side-effects

Symptoms of overdosage include anorexia, lassitude, nausea and vomiting, polyuria, thirst, headache and raised concentrations of calcium and phos-phate in plasma and urine. All patients on pharmacological doses of vitamin D should have plasma calcium concentration checked at intervals (initially weekly) and if nausea and vomiting are present.

Cautions/contraindications

Contraindicated in hypercalcaemia and metastatic calcification.

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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