Thiazide-Type Diuretics

What are diuretics?

Diuretic drugs work by increasing urinary output, thus reducing extracellular fluid volume, resulting in a fall in blood volume and cardiac output, reducing blood pressure.

There are several classes of diuretics, not all of them expressly recommended for therapeutic treatment of hypertension.

Thiazide and thiazide-like diuretics are the most commonly used diuretics used to treat hypertension.

There are several different thiazide drugs, and a newer class of drugs has been developed that work in a very similar way, known as thiazide-like compounds. For simplicity, this page will refer to the general class of drugs including thiazides and thiazide-like drugs as “thiazide compounds”, because they all exert a similar effect. Although it is important to note that not all of these compounds act in precisely the same way (See “Chronic Effects” section for a discussion of this).
Table 1 shows a list of thiazide compounds. The most widely used drugs in the UK are in bold

Table 1

(Adapted from table 1, Journal of Renin-Angiotensin-Aldosterone System 2004 5: 155 Alun D Hughes, “How do thiazide and thiazide-like diuretics lower blood pressure?”)

Thiazide compounds drugs work in two ways  - via short term and long term mechanisms.

• Short term changes are the result of the action of the drug as a diuretic - it causes diuresis, and a drop in plasma volume, resulting in a lower cardiac output, lowering blood pressure.
• Chronic changes unrelated to diuresis are seen in patients who take thiazides for long periods. More complicated haemodynamic effects have been attributed which are not well understood.
   

They first started being used in the latter half of the 20^th century, and are still in use today as  a First-in-Line drug of choice for treating patients in primary care (patients who visit their GP that are not for referral to specialised practitioners or as inpatients in hospital). 

The Short Term Effects of Thiazides

Short term, transient changes, when first starting use of these drugs seen in patients are the result of diuresis, and a drop in cardiac output where they act by disrupting the transport of salt and water across cells in the kidneys.

They cause the kidneys to reabsorb less fluid back into the body, so producing more urine.

Thiazide compounds block the Sodium/Chloride Co-Transporter in the Distal Convoluted Tubule

• Thiazide compounds target a specific ion channel – the Sodium/Chloride Co-Transporter (NCCT), also known as the Na+/Cl- Symporter.
• This channel is present on the apical membranes of the cells Distal Convoluted Tubule (DCT) in the nephron of the kidneys. This is the main location in which they are found.
• In the DCT, these channels passively reabsorb salt (NaCl) from the tubular fluid into the cell.
• They reabsorb approximately 5% to 10% of the total filtered Na+ in the kidney.
• They can do this because there is a high concentration gradient between the tubular fluid and the cells in the DCT created by the Na+/K+ ATPase pump, present in the basolateral membrane of the tubule.
• This pumps sodium out of the cell into the extracellular fluid using the hydrolysis of ATP.
• This gradient of sodium allows the transporter to co-transport chloride, thus absorbing salt from the tubular fluid.
• Water in the tubular fluid follows the gradient of salt absorption via osmosis, and as such, the NCCT channel contributes to the reabsorption of water from the tubular fluid both in the DCT and later in the collecting ducts.
• As a result, when thiazide compounds block the NCCT channels, less water is absorbed from the tubular fluid, and more is excreted, resulting in a net loss of fluid, and a reduction in plasma volume. This lowers venous return, thus lowering cardiac output, which then lowers blood pressure.

The below diagram summarises some of the channels controlling water and salt transport in the DCT.

Thiazides target the NCCT channel - test your understanding of the above by describing the events that occur by using this diagram!

The

Chronic effects of Thiazide compounds lower BP by lowering the Total Peripheral Resistance (TPR)

Research on the use of thiazide compounds has established that they exert their main effect not by acting as a diuretic, but by lowering the TPR.
The mechanism by which they do this is unclear, even though it remains one of the most widely used antihypertensives. One reason for this is because research is often conflicting.
Several different theories exist, all with varying degrees of supporting evidence.
 

The theories include the following:

• Thiazides act directly as vasodilators by inhibiting carbonic anhydrase.
  •   Carbonic anhydrase is important in renal function and the concentration of urine. It converts the CO2 that passively diffuses into the cell into carbonic acid. This has a variety of downstream of effects which are important in the reuptake of water. Where it is inhibitted, less water is reabsorbed from the distal tubule.
• Thiazides act directly as vasodilators by working on vascular smooth muscle, desensitising their response to calcium. This acts to decrease total peripheral resistance, lowering BP.
• Thiazide compounds increase vasodilation through an indirect mechanism, whereby the change in electrolyte balance they exert causes compensatory mechanisms by the body that result in a decrease in TPR.

Why is the research unclear?

A lot of reason that there are some questions concerning the way that thiazide compounds work is based on the fact that lots of studies have shown conflicting results.

Researchers have proposed a few reasons for this:

• Much of the research was carried out using different thiazide compounds. It is likely that not all these compounds work in the same way to reduce blood pressure. This observation is quite simple, and seems obvious, but it could account for a lot of the conflicting results found by different studies.
• There is evidence to show that this is the case – a notable difference is that hydrochlorothiazide and chlorthalidone, where studies have shown significant pharmacokinetic differences between the two drugs, even though in the past medical professionals have commonly prescribed with an assumed interchangeable effect.
• In addition to this, a lot of the studies were not conducted in the same way. In many cases, where in vitro studies conflict with findings in vivo, the difference in experimental conditions may account differences in findings.
• This is something that a lot of researches take into account when they review literature on the topic, but another problem researchers encounter within the literature on thiazides was done in subtly different ways.
• For example, older findings on thiazides often used doses of experimental compounds much higher than would be given as part of a typical dose.

References

Hughes AD (2004). “How do thiazide and thiazide-like diuretics lower blood pressure?” Journal of Renin-Angiotensin-Aldosterone System Vol 5(155)

NICE Guidelines 2004 "Hypertension (CG34): Management of hypertension in adults in primary care"

 British Hypertension Society "Thiazide Diuretics"