Pharmacology
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Cardiovascular
A 48 year old male patient presents to ED complaining of chest pain. He is currently taking ramipril and bendroflumethiazide for hypertension. Thiazide diuretics act primarily at which of the following sites in the nephron:
Answer:
Thiazides act mainly on the early segments of the distal tubule where they inhibit NaCl reabsorption by binding to the the Na+/Cl- cotransporter. Excretion of Cl-, Na+ and accompanying water is increased. The increased Na+ load in the distal tubule stimulates Na+ exchange with K+ and H+, increasing their excretion and causing hypokalaemia and a metabolic alkalosis. Excretion of Ca2+ is reduced.Thiazide Diuretics
Pharmacology / Cardiovascular
Last Updated: 17th April 2019
Thiazide diuretics are moderately potent diuretics, and are used to relieve oedema in chronic heart failure, and in the management of hypertension. They act within 1 to 2 hours of oral administration and most have a duration of action of 12 to 24 hours.
Mechanism of Action
Thiazides act mainly on the early segments of distal tubule where they inhibit NaCl reabsorption by binding to the the Na+/Cl- cotransporter. Excretion of Cl-, Na+ and accompanying water is increased. The increased Na+ load in the distal tubule stimulates Na+ exchange with K+ and H+, increasing their excretion and causing hypokalaemia and a metabolic alkalosis. Excretion of Ca2+ is reduced.
Indications
Bendroflumethiazide is used for oedema in mild or moderate heart failure. Combination diuretic therapy (with loop and thiazide diuretics) may be effective in patients with oedema resistant to treatment with one diuretic.
Thiazide diuretics are licensed for the treatment of hypertension but are no longer considered the first line diuretic for this indication. In the management of hypertension a low dose of a thiazide produces a maximal or near-maximal blood pressure lowering effect, with very little biochemical disturbance. Higher doses cause more marked changes in plasma potassium, sodium, uric acid, glucose, and lipids, with little advantage in blood pressure control.
Contraindications
Thiazide diuretics are contraindicated in:
- Addison’s disease
- Hypercalcaemia
- Hyponatraemia
- Refractory hypokalaemia
- Symptomatic hyperuricaemia
- Severe hepatic impairment (may precipitate encephalopathy)
Cautions
Thiazide diuretics should be used with caution in:
- Diabetes mellitus (may exacerbate)
- Gout (may exacerbate)
- Systemic lupus erythematosus (may exacerbate)
- Hyperaldosteronism
- Malnourishment
- Nephrotic syndrome
Side Effects
Lower initial doses of diuretics should be used in the elderly because they are particularly susceptible to the side effects. The dose should then be adjusted according to renal function.
Common side effects of thiazide diuretics include:
- Excessive diuresis
- Postural hypotension, dehydration, renal impairment
- Acid-base and electrolyte imbalance
- Hypokalaemia, hyponatraemia, hypomagnesaemia, hypercalcaemia, hypochloraemic alkalosis
- Metabolic imbalance
- Hyperuricaemia and gout
- Impaired glucose tolerance and hyperglycaemia
- Altered plasma-lipid concentrations
- Mild gastrointestinal disturbances
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.
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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 |
