DIURETIC

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.