Pharmacology
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Cardiovascular
A 42 year old women presents to ED complaining of swollen ankles. She has recently been started on furosemide by her GP. What is the mechanism of action of furosemide:
Answer:
Loop diuretics inhibit the Na+/K+/2Cl- symporter on the luminal membrane in the thick ascending limb of the loop of Henle, thus preventing reabsorption of NaCl and water. These agents reduce reabsorption of Cl- and Na+ and increase Ca2+ excretion and loss of K+ and Mg2+.Loop Diuretics
Pharmacology / Cardiovascular
Last Updated: 17th April 2019
Indications
Loop diuretics are powerful diuretics used in acute pulmonary oedema due to left ventricular failure; intravenous administration produces relief of breathlessness and reduces preload sooner than would be expected from the time of onset of diuresis.
They are also used in oedema in patients with chronic heart failure; diuretic-resistant oedema can be treated with a loop diuretic combined with a thiazide or related diuretic.
If necessary, a loop diuretic can be added to antihypertensive treatment to achieve better control of blood pressure in those with resistant hypertension, or in patients with impaired renal function or heart failure.
Mechanism of Action
Loop diuretics inhibit the Na+/K+/2Cl- symporter on the luminal membrane in the thick ascending limb of the loop of Henle, thus preventing reabsorption of NaCl and water. These agents reduce reabsorption of Cl- and Na+ and increase Ca2+ excretion and loss of K+ and Mg2+.
Furosemide and bumetanide are similar in activity; both act within 1 hour of oral administration and diuresis is complete within 6 hours so that, if necessary, they can be given twice in one day without interfering with sleep. Following intravenous administration furosemide has a peak effect within 30 minutes. The diuresis associated with these drugs is dose related.
Contraindications
Loop diuretics are contraindicated in:
- Hypovolaemia and dehydration
- Severe hypokalaemia or severe hyponatraemia
- Anuria, acute kidney injury or chronic kidney disease due to nephrotoxic drugs
- Comatose and pre-comatose states associated with liver cirrhosis
Cautions
Loop diuretics can exacerbate diabetes (but hyperglycaemia is less likely than with thiazides) and gout.
If there is an enlarged prostate, urinary retention can occur, although this is less likely if small doses and less potent diuretics are used initially.
Hypotension, hypovolaemia and electrolyte disturbance should be corrected before initiation of treatment.
Hepatorenal syndrome; hypoproteinaemia may reduce diuretic effect and increase risk of side-effects.
Lower initial doses of diuretics should be used in the elderly because they are particularly susceptible to the side effects.
Side Effects
Adverse effects of loop diuretics include:
- Mild gastrointestinal disturbances, pancreatitis and hepatic encephalopathy
- Hyperglycaemia
- Acute urinary retention
- Water and electrolyte imbalance
- Hyponatraemia, hypocalcaemia, hypokalaemia, hypomagnesaemia, hypochloraemia
- Hypotension, hypovolaemia, dehydration, and venous thromboembolism
- Metabolic alkalosis
- Hyperuricaemia
- Blood disorders (bone marrow suppression, thrombocytopenia, and leucopenia)
- Visual disturbance, tinnitus and deafness
- Hypersensitivity reactions
Hypokalaemia
Hypokalaemia can occur with both thiazide and loop diuretics. The risk of hypokalaemia depends on the duration of action as well as the potency and is thus greater with thiazides than with an equipotent dose of a loop diuretic.
Hypokalaemia is dangerous in severe cardiovascular disease and in patients also being treated with cardiac glycosides. Often the use of potassium-sparing diuretics avoids the need to take potassium supplements. In hepatic failure, hypokalaemia caused by diuretics can precipitate encephalopathy, particularly in alcoholic cirrhosis.
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- Biochemistry
- Blood Gases
- Haematology
| Biochemistry | Normal Value |
|---|---|
| Sodium | 135 – 145 mmol/l |
| Potassium | 3.0 – 4.5 mmol/l |
| Urea | 2.5 – 7.5 mmol/l |
| Glucose | 3.5 – 5.0 mmol/l |
| Creatinine | 35 – 135 μmol/l |
| Alanine Aminotransferase (ALT) | 5 – 35 U/l |
| Gamma-glutamyl Transferase (GGT) | < 65 U/l |
| Alkaline Phosphatase (ALP) | 30 – 135 U/l |
| Aspartate Aminotransferase (AST) | < 40 U/l |
| Total Protein | 60 – 80 g/l |
| Albumin | 35 – 50 g/l |
| Globulin | 2.4 – 3.5 g/dl |
| Amylase | < 70 U/l |
| Total Bilirubin | 3 – 17 μmol/l |
| Calcium | 2.1 – 2.5 mmol/l |
| Chloride | 95 – 105 mmol/l |
| Phosphate | 0.8 – 1.4 mmol/l |
| Haematology | Normal Value |
|---|---|
| Haemoglobin | 11.5 – 16.6 g/dl |
| White Blood Cells | 4.0 – 11.0 x 109/l |
| Platelets | 150 – 450 x 109/l |
| MCV | 80 – 96 fl |
| MCHC | 32 – 36 g/dl |
| Neutrophils | 2.0 – 7.5 x 109/l |
| Lymphocytes | 1.5 – 4.0 x 109/l |
| Monocytes | 0.3 – 1.0 x 109/l |
| Eosinophils | 0.1 – 0.5 x 109/l |
| Basophils | < 0.2 x 109/l |
| Reticulocytes | < 2% |
| Haematocrit | 0.35 – 0.49 |
| Red Cell Distribution Width | 11 – 15% |
| Blood Gases | Normal Value |
|---|---|
| pH | 7.35 – 7.45 |
| pO2 | 11 – 14 kPa |
| pCO2 | 4.5 – 6.0 kPa |
| Base Excess | -2 – +2 mmol/l |
| Bicarbonate | 24 – 30 mmol/l |
| Lactate | < 2 mmol/l |
