The mechanism of action of thiazides in lowering blood pressure in the long term is not fully understood. When administered acutely thiazides lower blood pressure by causing diuresis, a fall in plasma volume and a reduction in cardiac output. However, after chronic use thiazides cause a reduction in blood pressure by lowering peripheral resistance (i.e. vasodilation). The mechanism of this effect is uncertain but it may involve effects on 'whole body' or renal autoregulation, or direct vasodilator actions either through inhibition of carbonic anhydrase^[12] or by desensitizing the vascular smooth muscle cells to the rise in intracellular calcium induced by norepinephrine.^[13]

Thiazides also lower urinary calcium excretion, making them useful in preventing calcium-containing kidney stones. This effect is associated with positive calcium balance and is associated with an increase in bone mineral density and reductions in fracture rates attributable to osteoporosis.^[14] By a lesser understood mechanism, thiazides directly stimulate osteoblastdifferentiation and bone mineral formation, further slowing the course of osteoporosis.^[15]

Because of their promotion of calcium retention, thiazides are used in the treatment of

• Dent's Disease
• Hypocalcemia
• Nephrolithiasis (idiopathic hypercalciuria)
• Bromide intoxication
• Nephrogenic diabetes insipidus

Mechanisms of action

The members of this class of diuretics are derived from benzothiadiazine. They control hypertension in part by inhibiting reabsorption of sodium (Na⁺) and chloride (Cl⁻) ions from the distal convoluted tubules in the kidneys by blocking the thiazide-sensitive Na⁺-Cl⁻ symporter.^[16] The term "thiazide" is also often used for drugs with a similar action that do not have the thiazide chemical structure, such as chlorthalidone and metolazone. These agents are more properly termed thiazide-like diuretics.

Thiazide diuretics also increase calcium reabsorption at the distal tubule. By lowering the sodium concentration in the tubule epithelial cells, thiazides indirectly increase the activity of the basolateral Na⁺/Ca²⁺ antiporter. This facilitates the transport of Ca²⁺ from the epithelial cells into the renal interstitium. This movement of Ca²⁺, in turn, decreases the intracellular Ca²⁺concentration, which allows more Ca²⁺ to diffuse from the lumen of the tubules into epithelial cells via apical Ca²⁺-selective channels (TRPV5). In other words, less Ca²⁺ in the cell increases the driving force for reabsorption from the lumen.^[17]

Thiazides are also thought to increase the reabsorption of Ca²⁺ by a mechanism involving the reabsorption of sodium and calcium in the proximal tubule in response to sodium depletion. Some of this response is due to augmentation of the action of parathyroid hormone.^{[18](from Internet)}

One of the common causes of kidney stones, aside from hyperparathyroidism, is

idiopathic hypercalciuria, which requires 24 hour urine collection for diagnosis.

After a diagnosis of kidney stone is established, ruling out hyperparathyroidism and

idiopathic hypercalciuria should be a routine part of the diagnostic work up.

Unfortunately urologists and many internists neglect to do 24 hour urine collection

to rule out the hpercalciuria so that the patient would come back with the recurrence of kidney stones.

I have a personal experience on this subject. I had kidney stone twice one year apart some 20 years ago

and self diagnosed myself to have had the idiopathic hypercalciuria for which I put myself on

hydrochlorthiazide 12.5 mg q d and confirmed the correction of the hypercalciuria by repeating the 24 hr urine test.

I've had no recurrence since so far.

Obviously taking thiazides for any reason helps retain calcium which in turn strengthening our bones to prevent fractures.

I take hydrochlorothiazide 25mg/day for my borderline high BP.

It didn't really help in lowering my borderline BP.

Only when I take double dose (50mg), I feel diuresis. No side effects.

I did not realize that it does help to strengthen my skeletal structures.

In that case, I may continue my HCTZ which cost $4 for 30 pills.

Funny thing...

If I buy 30 pills, it cost $4 but if I buy 31 pills (as you know, some month has 31 days),

it cost $8 as my insurance considers it as two months supply,

meaning that 31 or 60 pills cost the same.

In this study they used chlorthalidone 25mg q d which has longer duration than that of hydrochlorthiazide

so that perhaps it has more diuresis and more antihypertensive effect.

In America, most practitioners choose hydrochlorthiazide for fear of the greater chance of hypokalemia

which rarely can occur in spite of bananas and oranges to supplement potassium.

Sometimes I take 25mg as well when I eat Korean food. Taking 25mg q d can rarely bring on hypokalemia.

Taking 50mg q d will have a greater chance of bringing on hypokalemia.

As you know, hypokalemia can bring on arrhythmia.

Most cardiologists would prescribe dyazide capsule one q d if his patient needs to take hydrochlorthiazide 25 mg q d.

Dyazide has hctz 25 mg plus potassium saving med, Triamterene.

Or simply add another Rx for KCL 10meq q d.

The reason for this is that 10 meq of KCL is equal to about 6 bananas so that eating one or two bananas a day is not enough.

If hydrochlorthiazide 25mg q d does not control your BP satisfactorily, you would consider adding angiotensin receptor blockers

such as losartan, candesartan, etc at the lowest dosage.

Actually, I talked to my family doctor (who is my daughter's partner) to give me HCTZ

because I read somewhere that it works well for "Kim-Chee"-eating Koreans.

My serum potassium level is always normal.

My young family doctor always do whatever I say but I won't know what he's going to say

if I ask him for one of the angiotensin receptor blockers.

Well, live like a snappy young man in the way I am now,

or take the new pills and then live like a withered old man??

You were correct, and I am proud of your selecting HCTZ.

HCTZ works well not only for Asiatics but for the elderly.

It is good to know that Potassium level was normal with 25mg q d,

which is usually the case.

However, as I said, rarely hypokalemia can develop especially when 

you are doing a high level exertion and sweating in hot weather, etc.,

so that you need to take precaution by supplementing potassium.

On the contrary to what you stated, keeping the BP at the ideal level,

would increase cardiac output by lowering vascular resistance(cardiac output equal to BP divided by

vascular resistance) and will make you snappier, in my opinion.

Forgive me for this boring lecture, which as you know is elementary stuff.

Major factors influencing stroke volume – Multiple factors impact preload, afterload, and contractility, and are the major considerations influencing SV.^{[7]Cardiac output equals stroke volume times heart rate. Aterload is blood pressure so that decreasing BP to normal decreases the afterload and increases the stroke volume and cardiac output giving you more energy.}

http://www.nejm.org/doi/pdf/10.1056/NEJM199406303302603

This was an important study which became one of guidelines

for practicing internists until now as far as using thiazides diuretics on long term basis.

My statements earlier are based on this particular study besides my personal observations

as a medical practitioner.