Diuretics

Question 1

What are Diuretics?

Answer 1

Drugs which increase the excretion of salts (mainly NaCl) and water by the kidneys.

They act by reducing Na+ and Cl- reabsorption in the nephron; this also reduces reabsorption of water (osmotic)

99% of Na+ and H2O filtered is reabsorbed

Question 2

Clinical uses of diuretics

Answer 2

(has to do with the way these diseases effect the gradients)

Oedematous conditions: Loop (TAL) , K+ sparing (CT)

HTN: Thiazide-type (DCT) (medium efficacy)

Question 3

What causes oedema

osmotic + Hydraulic pressures

Answer 3

Sufficient increase in net H2O filtration (gets back into the venous system via lymph).

1) Hydrostatic: BP inside BV influences how much H2O is pushed out of capillaries into interstitial space. If BV and CO high, BP high!

2) Oncotic: Liver produces less Albumin - higher losses of H2O into INT/
failure of lymphatic system (so H2O accumulates in INT)/
Capillary tissue damage - Albumin molecules leak outside, which shifts oncotic pressure from bloodstream into INT, and sucks more water out with it.
Results in lower BP in cap = lower O2 delivery.

Question 4

Effect of diuretics on blood volume

Answer 4

Decreases. [protein] increase gets rid of oedema

Question 5

Overview of nephron function

Answer 5

PT: ~65% of H2O + salts reabsorbed
Glu + A.A reabsorbed. HCO3- reabsorbed
H+ secreted

Ascending LOH: 25% Na+ reabsorbed. H2O NOT.
Urine becomes dilute. MI becomes hypertonic

DT: Na+ reabsorption and K+ secretion regulated by aldosterone

CD: H2O reabsorbed, or not

Question 6

Loop Diuretics

Answer 6

Furosemide

> Block of the Na+/K+/2Cl- cotransporter in the TAL. Strongly inhibits Na+ reabsorption.
(Diuresis diminishes capacity to create Hypertonic MI to drive ADH-induced H2O reabsorption)

> Also have a vasodilating effect; several mechanisms proposed (opening of K+ channels)

Question 7

Loop Diuretics II

Answer 7

> Also used for oedematous conditions (HF, Hepatic cirrhosis)

• S/E’s
  1. Hypokalaemia,
  2. Metabolic alkalosis
  3. Depletion of plasma Ca and Mg
  4. Ototoxicity (w AG antibodies)
  5. Hypovolaemia
  6. Hyperuricaemia (drugs compete with uric acid for these pumps)

Question 8

History of Thiazide-like diuretics

Answer 8

anti-bacterial drug sulphanilamide found to cause diuresis.
SUL blocks carbonic anhydrase, but this inhibitor caused metabolic acidosis.

Intro of 1st ‘thiazde’, developed by modifying SUL. Isolated the desire property…

Subsequent development of thiadie-like drugs with non-thiazde structure but similar properties.

Question 9

Mechanism of Thiazide-like

Answer 9

Indapamide, bendroflumethiazide.

Block Na+. Cl- co-transport (reabsorption) in the DCT, reduce volume, venus return, cardiac output.

Also reduces TPR by unknown mechanism

Question 10

Adverse reactions of Thiazide-like

(not as serious as Loop diuretics

Answer 10

Hypokalaemia, Hyperglycaemia, hyperuricaemia, erectile dysfunction, hyponatraemia

Question 11

Na transport pathway in DT

Answer 11

Na+/Cl- channel, Na+/K+ ATPase pump

Question 12

Hydrochlorothiazde over time

Answer 12

A fall in BP, due to a transient decrease in CO, and then a fall in TPR.

Question 13

How to prevent hypokalaemia

Answer 13

Increased Na+ uptake and the coupled secretion of K+ and H+ in the CD.
This icreases in K+ and H+ secretion causes hypokalaemia and metabolic alkalosis.

Hypokalaemia can cause cardiac arrhythmias

Can prevent hypokalaemia with a K+ sparing diuretic or a K+ supplement.

Question 14

K+ sparing diuretic

Answer 14

Not ususally used on their own due to limited diuretic effect and tendency to cause hyperkalaemia, resulting from inhibition of K+ secretion.

Mainly used with Loop/ Thiazide-like to enhance diuresis and mainly prevent hypokalaemia.

Question 15

Name K+ sparing diuretic drugs

Answer 15

Also used as anti-HTV if 1st line agents are ineffective

Spironolactone
Competitive aldosterone-r antagonist (MRA’s)
A pro-drug - main active metabolite: 17a-thiomethy
V.slow onset of action - b/c protein expression
Most useful if Aldosterone levels are elevated

Eplerenone - fewer s/e’s

Amiloride & Triamterene:
Block collecting tubule Na+ channels (ENaC), thus decrease Na+ reabsorption and K+ secretion.
Quicker action.

Question 16

Side effects of K+ sparing diuretic drugs

Answer 16

Spironolactone and Eplerenone (MRA’s):
-Hyperkalaemia
- GI upset
- Effects on other steroid-r’s can cause gynecomastia, menstrual disorders, testicular atrophy (less common with Epl)
Eplerenone has less off-target effects on these other steroid-r’s

Triamterene and Amiloride (K+ supplements)

• Hyperkalaemia
• GI upset, but less common than with MRA’s

Co-admin of MRA with K+ supplements is generally contraindicated - b/c v. dangerous.