This document discusses diuretics, with a special focus on hydrochlorothiazide. It provides details on renal physiology and pharmacology. It describes the main types of diuretics and their mechanisms of action. It discusses thiazide diuretics in depth, including common examples like hydrochlorothiazide, their effects, kinetics, side effects, and clinical uses, especially for hypertension.

1. Diuretics
Special focus on
hydrochlorthiazide

2. Topics for discussion
 Renal pathology
 Diuretics
 Thiazides

3. Renal pathology
& pharmocology

4. Renal Pathology
 Kidneys: Represent 0.5%
of total body weight, but
receive ~25% of the total
arterial blood pumped by
the heart
 Each contains from 1-2
million nephrons:
 Glomerulus
 Proximal convoluted
tubule
 Loop of Henle
 Distal convoluted tubule

5. Renal Pharmacology
 Renal processes
 Functions  Filtration - glomerulus
 Clean extracellular  Reabsorption
fluid and maintain ECF  Tubular secretion
volume and
composition  In 24 hours the kidneys
reclaim:
 Acid-base balance  ~ 1,300 g of NaCl
 Excretion of wastes  ~ 400 g NaHCO3
 ~ 180 g glucose
and toxic substances  almost all of the 180 L of water
that entered the tubules

6. Renal Pharmacology
 Blood enters the glomerulus under pressure
 This causes water, small molecules (but not
macromolecules like proteins) and ions to filter
through the capillary walls into the Bowman's capsule
 This fluid is called nephric filtrate
 Not much different from interstitial fluid
 Nephric filtrate collects within the Bowman's capsule
and flows into the proximal tubule:
 Here all of the glucose and amino acids, >90% of the
uric acid, and ~60% of inorganic salts are reabsorbed by active transport
 The active transport of Na+ out of the proximal tubule is controlled by angiotensin II.
 The active transport of phosphate (PO4)3- is regulated (suppressed by) the parathyroid hormone.
 As these solutes are removed from the nephric filtrate, a large volume of the water follows
them by osmosis:
 80–85% of the 180 liters deposited in the Bowman's capsules in 24 hours
 As the fluid flows into the descending segment of the loop of Henle, water continues to
leave by osmosis because the interstitial fluid is very hypertonic:
 This is caused by the active transport of Na+ out of the tubular fluid as it moves up the ascending
segment of the loop of Henle
 In the distal tubules, more sodium is reclaimed by active transport, and still more water
follows by osmosis.

7. Diuretics

8. Diuretics
 Diuretics are drugs which increase urine
excretion mainly by ↓ reabsorption of salts
and water from kidney tubules
 General clinical uses:
 Hypertension
 Oedema of heart, renal, and liver failure
 Pulmonary oedema
 ↑ intracranial pressure (Mannitol)
 ↑ Intraocular pressure=Glaucoma ( CA inhibitors)

9. Diuretics – main types
 Loop Diuretics
 Frusemide, Torasemide
 Potassium Sparing Diuretics:
 Spiranolactone, Eplerenone, Triamterene,
amiloride
 Osmotic diretics
 Mannitol
 Carbonic anhydrase inhibitors
 Thiazides

10. Diuretic- applications
 Hypercalcemia (Furosemide=Frusemide)
 Idiopathic hypercalciuria (Thiazides)
 Inappropriate ADH secretion (Furosemide)
 Nephrogenic diabetes insipidus
 Basicknowledge of renal physiology
particularly salt and water movements
(absorption, reabsorption and secretion) and
cotransporter systems is mandatory.

11. Diuretics – what are they?
 Diuretics are considered 1st line therapy for
most hypertensive patients
 They are effective, relatively safe and cheap
 Accumulating evidence proves that diuretics,
particularly thiazides decrease the risk of
cardiovascular disease, fatal and nonfatal MI and
stroke.

12. Diuretics - MOA
 Diuretics act simply by increasing urine
output → ↓ plasma and stroke volume →↓
CO → ↓ BP
 The initial ↓ CO leads to an ↑ in peripheral
resistance but with chronic use extra cellular
fluid and plasma volume return to normal
and peripheral resistance ↓ to values lower
than those observed before diuretic therapy
 Thiazide diuretics also are believed to have
direct vasodilating effect

13. Diuretics – Common Thiazides
 Thiazides and Thiazide Like Diuretics = Low
to moderate efficacy diuretics
 Hydrochlorothiazide
 Chlorthiazide
 Chlorthalidone
 Indapamide
 Metolazone

14. Diuretics – Rare Thiazides
 Bendroflumethiazide
 Hydroflumethiazide
 Methyclothiazide
 Polythiazide
 Benzthiazide
 Quinethazone
 Trichlormethiazide
 **All are usually given orally (Chlorthiazide could
be given IV); they differ in potency, DOA and t½

15. Thiazides
Special focus on
hydrochlorthiazide

16. Diuretics –Thiazides
 Inhibition of Thiazide sensitive Na+/Cl-
transporter in distal convoluted tubule, thus
inhibiting Na+ reabsorption → ↑ Na+, K+, Cl-,
HCO3- and H2O excretion
 They lead to about 5-10% loss of filtered
Na+
 ↑ in dose will not lead to further increase in
diuretic effect ( low ceiling )
 Thiazides are ineffective in patients with
impaired renal function or patients with GFR

17. Diuretics –Thiazides
 Thiazides ↑ Ca++ reabsorption
 Thiazides have little carbonic anhydrase
inhibitory effect
 Thiazides have a direct vasodilating effect
 ( Indapamide has been observed for its
pronounced vasodilating effect)
 Thiazides ↓ response of blood vessels to NE

18. Diuretics – Common Thiazides
 Widely used Thiazides are Hydrochlorothiazide and
Chlorthalidone and Thiazide kinetics are as follows:
 Usually given orally
 Strongly bind to plasma albumin
 Excreted via the kidney by a specific secretory
mechanism (not filtered) (small fraction biliary excretion)
 Thiazides are highly effective in lowering BP when
combined with other antihypertensive agents
(synergistic effect )

19. Diuretics –Thiazides
 Side effects of Thiazides:
 Weakness
 Muscle cramps
 Erectile dysfunction
 Hyperglycemia
 Hypercalcemia
 Pancreatitis
 Hyperlipidemia ( ↑ LDL; ↑ TG’s )
 Hypokalemia and hypomagnesemia
 The most frequent and dangerous side effect which could lead to
muscle weakness and serious cardiac arryhthmias

20. Diuretics – Thiazides
 Patients at high risk of hypokalemia are those with:
 LVH
 Previous history of MI
 Previous history of cardiac arrhythmias, or
 Patients who are on digoxin therapy
 Hyperuricemia → could precipitate Gout
 The effect of thiazides on blood uric acid is dose
dependent…Low doses → Hyperuricemia
 Large doses → ↓ uric acid reabsorption →↓ uric acid
blood levels.

21. Diuretics – Thiazide clinical uses
 Hypertention
 Oedema of CHF, Liver cirrhosis, etc
 Nephrogenic diabetes insipidus
 Hypercalciuria
 Available as 12.5 mg. / 25 mg. tablets
 Combined with:
A. Ace Inhibitors / ARBs
B. Beta blockers
C. Calcium channel blockers, if present along with A & B.