Hydrochlorothiazide and its Mechanism of Action
Hydrochlorothiazide is a thiazide diuretic used to treat edema associated with a number of conditions, and hypertension. Hydrochlorothiazide is the most commonly prescribed thiazide diuretic.
The drug has been widely used to treat hypertension globally and is relatively very safe. Hydrochlorothiazide acts on the distal convoluted tubules and inhibits the sodium chloride co-transporter system. This action leads to a diuretic action and loss of potassium in the urine. The half-life of hydrochlorothiazide varies from 6 to 12 hours. Of the thiazide diuretics, hydrochlorothiazide is the most frequently used for the treatment of hypertension. Unfortunately, over the past decade, the use of hydrochlorothiazide has been declining, and it is being replaced by angiotensin-converting enzyme inhibitors, which overall are far more effective and have fewer adverse effects.
There have been countless studies showing that when hydrochlorothiazide is prescribed at doses of 12.5 mg to 25 mg per day, it can lower the systolic blood pressure by 5 mmHg to 7 mmHg and the diastolic blood pressure by 4 mmHg to 5 mmHg over a 24 hour period. While this magnitude of blood pressure lowering is small compared to the angiotensin-converting enzyme inhibitors, calcium channel blockers, or beta-blockers, the effects of hydrochlorothiazide are more consistent and reliable in almost all populations.
Hydrochlorothiazide prevents the reabsorption of sodium and water from the distal convoluted tubule, allowing for the increased elimination of water in the urine. Hydrochlorothiazide has a wide therapeutic window as dosing is individualized and can range from 25-100mg. Hydrochlorothiazide should be used with caution in patients with reduced kidney or liver function.
Mechanism of action
Hydrochlorothiazide inhibits sodium chloride transport in the distal convoluted tubule. More sodium is then excreted in the kidney with accompanying fluid. Pharmacological effects begin about 2 hours after an oral dose, peak in 4 hours, and last for about 6 to 12 hours. Hydrochlorothiazide is not metabolized, and a majority is excreted in the urine unchanged. It also causes a loss of potassium and bicarbonate.
The long-term actions of hydrochlorothiazide when it comes to reduction in blood pressure are not well understood. When administered acutely, the drug lower blood pressure by promoting diuresis and decreasing plasma volume. However, following chronic use, hydrochlorothiazide appears to be reducing blood pressure by decreasing peripheral resistance. How the drug causes vasodilation is not known, but laboratory evidence suggests that it may be inhibiting the enzyme carbonic anhydrase, desensitizing the smooth muscle receptors to the rise in calcium, or preventing autoregulation in the kidneys.
Hydrochlorothiazide is not metabolized
Route of elimination
Hydrochlorothiazide is eliminated in the urine as unchanged hydrochlorothiazide.
The oral LD50 of hydrochlorothiazide is >10g/kg in mice and rats.
Patients experiencing an overdose may present with hypokalemia, hypochloremia, and hyponatremia. Treat patients with symptomatic and supportive treatment including fluids and electrolytes. Vasopressors may be administered to treat hypotension and oxygen may be given for respiratory impairment.
Before taking hydrochlorothiazide,
- tell your doctor and pharmacist if you are allergic to hydrochlorothiazide, ‘sulfa drugs’, penicillin, or any other drugs.
- tell your doctor and pharmacist what other prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention any of the following: barbiturates such as phenobarbital and secobarbital (Seconal); corticosteroids such as betamethasone (Celestone), budesonide (Entocort), cortisone (Cortone), dexamethasone (Decadron, Dexpak, Dexasone, others), fludrocortisone (Florinef), hydrocortisone (Cortef, Hydrocortone), methylprednisolone (Medrol, Meprolone, others), prednisolone (Prelone, others), prednisone (Deltasone, Meticorten, Sterapred, others), and triamcinolone (Aristocort, Azmacort); corticotropin (ACTH, H.P., Acthar Gel); insulin and oral medications for diabetes; lithium (Eskalith, Lithobid); medications for high blood pressure or pain; nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin, others) and naproxen (Aleve, Naprosyn, others). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
- if you are taking cholestyramine or colestipol, take them 1 hour before or 4 hours after taking hydrochlorothiazide.
- tell your doctor if you have kidney disease. Your doctor may tell you not to take hydrochlorothiazide.
- tell your doctor if you have or have ever had diabetes, asthma, gout, systemic lupus erythematosus (SLE, a chronic inflammatory condition), high cholesterol, or kidney or liver disease.
- tell your doctor if you are pregnant, plan to become pregnant, or are breastfeeding. If you become pregnant while taking hydrochlorothiazide, call your doctor immediately.
- plan to avoid unnecessary or prolonged exposure to sunlight and to wear protective clothing, sunglasses, and sunscreen. Hydrochlorothiazide may make your skin sensitive to sunlight and increase your risk of a certain types of skin cancer. Your doctor will check your skin for skin cancers during your treatment with hydrochlorothiazide. Call your doctor if you notice any new skin changes or growths.
- you should know that hydrochlorothiazide may cause dizziness, lightheadedness, and fainting when you get up too quickly from a lying position. This is more common when you first start taking hydrochlorothiazide. To avoid this problem, get out of bed slowly, resting your feet on the floor for a few minutes before standing up. Alcohol can add to these side effects.
What should I do if I forget a dose?
Take the missed dose as soon as you remember it. However, if it is almost time for your next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.
Tell your doctor if any of these symptoms are severe or do not go away:
- frequent urination
- loss of appetite
- hair loss
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