Phamacology of the kidney

Question 1

Mechanism of Carbonic anhydrase inhibitors

Answer 1

Reduces HCO3- reabsorption in the PCT.

Inhibits carbonic anhydrase type IV on the apical membrane of the tubule which prevents conversion of carbonic acid into CO2 and water. CO2 and water from the reaction is normally reabsorbed into tubular cells and converted into HCO3- and H+ by CA type II in the cell. H+ produced is used to drive Na+ reabsorption by a Na+/H+ exchanger. Therefore inhibiting carbonic anhydrase blocks reabsorption of of H2O, Na+ and HCO3-. H+ secretion into the tubular fluid is prevented, which can cause acidosis.

Question 2

Non-renal use of carbonic anhydrase inhibitors

Answer 2

Can be used in glaucoma to reduce intraocular pressure by reducing production of aqueous humour

Preventing HCO3- synthesis reduces Na+ transport and therefore H2O.

Also used as a prophylactic for altitude sickness (reverses alkalosis)

Question 3

Action of osmotic diuretics

Answer 3

E.g. Mannitol, glucose

Increase the osmolality of the filtrate, and therefore prevent water reabsorption. Act best where osmotic reabsorption occurs.

Mannitol reduces intracranial and intraocular pressure

Glucose is a natural diuretic. If transporter capacity is exceeded, it remains in the lumen and prevents water reabsorption. Causes polydipsia

Question 4

Uses of loop diuretics

Answer 4

Usually given orally to reduce peripheral and pulmonary oedema in heart failure. Given IV to paitents with pulmonary oedema in acute ventricular failure.

Effective in patients with diminished renal function because it is not filtered by the glomerulus. Bind to plasma proteins and secreted directly into the PT.

Non-renal uses:
Treat hypercalemia - promotes Ca2+ excretion by inhibiting tubular absorption and increasing filtrate flow rate

Ascites

Question 5

Mechanism of action of loop diuretics

Answer 5

Inhibit Na+/Cl-/K+ reabsorption in the ascending loop of Henle by competing for the Cl- binding site.

Na+ is actively transported out of the cells into the intersitium to maintain the osmotic gradient.

This means more water remains in the nephron, causing diuresis.

Increased NaCl passes to the collecting duct and is reabsorbed, leading to a loss of H+ and K+ ions

Question 6

Adverse effects of loop diuretics

Answer 6

May cause low Na+, low K+, hypovolemia and low bp.

At high doses electrolyte disturbance may cause deafness.

Increase uric acid retention (gout)

Question 7

Mechanism of action of thiazides

Answer 7

Acts on the proximal and distal tubules

Inhibit NaCl reabsorption by binding to the symporter. This reduces the reabsorption of water and NaCl.

Weak diuretic because increased delivery of NaCl to the distal nephron and decrease blood volume. This activates ENac in principal cells in the collecting duct and RAAS. Therefore Na+ and water reabsorption increases. K+ is lost from the cells as Na+ is reabsorbed.

Longer acting than loop diuretics

Question 8

Adverse effects of thiazide diuretics

Answer 8

Hypokalemia: can cause cardiac arrhythmias.

Hyperuricaemia: thiazides are secreted by the organic acid secretory system in the tubules and compete with uric acid for secretion.

Glucose tolerance: may be reduced, contraindicated in patients with DiabetesM

weakness, impotence, rashes, increased frequency of urination

Not useful in patients with renal impairment. Drug is filtered and secreted

Question 9

Uses of thiazides

Answer 9

Treat oedema in mild/moderate heart failure

hypertension

Prevent kidney stones and hypercalcuria (thiazides stimulate Ca2+ reabsorption ans extrusion. Results in lower Ca2+ in the urine)

Question 10

Potassium sparing diuretics

Answer 10

Act on the aldosterone-responsive parts of the nephron.

Reduce Na+ reabsorption by either antagonising aldosterone or blocking ENac Na+ channels. Less Na+ enters the cell meaning less K+ is secreted.

Question 11

Mechanism of action of spironolactone

Answer 11

Mineralocorticoid receptor antagonist.

Competitively blocks the binding of aldosterone to its receptor. Increases the excretion of Na+ (Cl- and H2O) which means less K+ is secreted.

Weak diuretic because only small amount of Na+ reabsorption is under the control of aldosterone.

Used in liver disease with ascites, Conn’s syndrome and severe heart failure

Question 12

Mechanism of action of Amiloride

Answer 12

Blocks ENac by competing for the Na+ binding site, and therefore reduces permeability to Na+.

This increases Na+ excretion and decreases K+ excretion.

Question 13

Uses of K+ sparing diuretics

Answer 13

Hypertension

Heart failure

Primary hyperaldosteronism (Conn’s)

in conjuction with other diuretics to prevent K+ loss

Question 14

Side effects of K+ sparing diuretics

Answer 14

Hyperkalaemia

Gynaecomastia (similar structure to oestrogens. Blocking receptor increases levels)

Don’t use with ACEi. Increases hyperkalemia

Question 15

Why do loop diuretics cause low Ca2+ levels

Answer 15

Loop diuretics block the Na+/K+/Cl co-transporter.

This increases excretion of Na+ and Cl-.

The amount of Na+ reaching the collecting duct increases, so more K+ and H+ is excreted from tubular cells.

Loss of K+ alters the potential difference acros the tubule cells, reduces diffusion of Ca2+ out of the lumen into the blood. More is excreted.

Question 16

How are drug affected by kidney function

Answer 16

Many drugs areexcreted through the kidenys may accumulate to toxic levels if renal function is impaired.

Nephrotoxic drugs further compromise function in patients with renal disease. Either cause underperfusion e.g through excessive GI loss or direct renal damage

Question 17

How does urine pH influence drug excretion

Answer 17

Most drugs are weak acids or bases.

In alkaline uine, acidic drugs are more rapidly ionised. Alkaline drugs readily ionised in acidic urine.

Ionised subtances are more polar, therefore more soluble in water and easier fo excrete via the kidneys.

Question 18

Name three classes of diuretics and give an example of each

Answer 18

Loop diureics: furosemide

Thiazides: bendroflumthiazide

Aldosterone antagonist: spironolactone

Na+ channel blockers: amiloride

Carbonic anhydrase inhibitors: azetazolamide

Question 19

Why can diuretics cause metabolic alkalosis?

Answer 19

Diuretics (loop and thiazides) decrease Na+ and water reabsorption from the lumen, causing diuresis.

Increased excretion of Na+ also causes a loss of H+ and K+ ions because the increase in Na+ in the distal tubule stimulates ENac to increase sodium reabsorption in exchange for K+ and H+.

Loss of H+ ions causes the pH of the blood to rise, producing metabolic alkalosis