Drugs and the Kidney

Question 1

What are the roles of the liver and kidneys in drug excretion?

Answer 1

he kidney is the most important organ for eliminating drugs from body
Most are metabolised by the liver to an inactive compound that can be excreted by kidney
Polar drugs or metabolites (water soluble, partially ionized) are excreted via specialized transporters (mainly PT)

Question 2

How are drugs tubularly secreted?

Answer 2

Occurs mainly in PT
Most drugs are weak acids or bases – degree of ionization depends on drug pKa and pH of the environment, e.g.,
Penicillin is a weak acid:
HA ↔ H+ + A- (

Question 3

What do diuretics do?

Answer 3

Increase urine output (diuresis)
May also increase electrolyte excretion (Na, natriuresis; K, kaliuresis)
Very important drugs, especially where there is volume overload e.g.,
Acute pulmonary oedema, heart failure (reduce ECF volume), hypertension

Question 4

What are the classes of diuretics?

Answer 4

Class, Site of action, Mechanism, Notes
CA inhibitors- Proximal tubule, inhibits CA, Weak with increased HCO3- excretion
Loop- Ascending loop of Henle, blocks NaK2Cl, most powerful with increased K+ excretion
Thiazide- Distal tubule, blocks NaCl cotransporter, moderate with reduced K+ excretion
K sparing- Collecting duct, blocks ENaC, weak with reduced K+ excretion
Osmotic- Everywhere, osmotic shift of water, e.g. mannitol- used in cerebral oedema

Question 5

How do osmotic diuretics work?

Answer 5

Example: mannitol
Freely filtered but not reabsorbed
Dilution of DT fluid impaired
Decreased gradient for water reabsorption
Commonly used to treat cerebral oedema
Does not cross the blood-brain barrier
Creates osmotic gradient for withdrawal of water from cerebrospinal fluid to plasma

Question 6

What do carbonic anhydrase inhibitors work as diuretics?

Answer 6

Example: acetazolamide
Mild diuretics
Inhibit carbonic anhydrase activity
Net result is decreased NaHCO3 reabsorption
Present in the lumen and cells lining the PT
Reabsorption of bicarbonate in the PT is coupled to sodium reabsorption
At this stage the tubular fluid is similar in composition to plasma
So there is a high concentration gradient of Na in the lumen which uses a sodium hydrogen antiporter to enter the cell
Protons are produced by the carbonic anhydrase reaction in the cell (from water and CO2)
The hydrogen ions will be extruded into the lumen where they will combine with bicarbonate molecules already present and carbonic anhydrase will catalyse it to form water and CO2 once again which will diffuse back into the cell
If you inhibit the carbonic anhydrase here ultimately inhibits water reabsorption

Question 7

How do loop diuretics work?

Answer 7

Example: frusemide
Powerful diuretics
Inhibit Na/K/2Cl cotransporter in the thick ascending limb
Impedes concentration of medullary interstitial fluid
Reduced osmotic drive for ADH-mediated water reabsorption
Side effects
Significant loss of K: hypokalaemia

Question 8

How do thiazide diuretics work?

Answer 8

Moderately powerful
Inhibit Na/Cl cotransporter in distal tubule
Impedes dilution of tubular fluid
Reduced osmotic drive for ADH-mediated water reabsorption
Side effects
Significant loss of K: hypokalaemia
Hypercalcemia (Increased Ca/Na exchanger)

Question 9

How do K sparing diuretics work?

Answer 9

Weak diuretic action 
Important as they cause K retention, countering the powerful electrolyte   secretions of loop diuretics
Act at end of DCT and collecting duct 
Amiloride 
Blocks ENaC 
Spironolactone 
Aldosterone antagonist
Used to treat volume overload in heart failure

Question 10

What are the diuretic uses of thiazide and loop diuretics?

Answer 10

Thiazide:
Have been first-line hypertension treatment for decades
No longer first line in NHS (see NICE guidelines) but may be 2nd or 3rd
Low doses effective for hypertension
Higher doses may be used for volume overload (e.g. mild to moderate HF)
Loop:
Severe volume overload (e.g. pulmonary oedema due to LV failure)
Potassium-sparing:
May supplement thiazide or loop to counter hypokalaemia
Heart failure
Aldosterone antagonists may be used to control hyperaldosteronism

Question 11

What are some recent drugs with mild diuretic action?

Answer 11

Sodium-glucose cotransporters (SGLTs)
Secondary active transport
SGLT1: glucose absorption from gut
SGLT1, SGLT2: glucose reabsorption from kidney (PCT)
SGLT-2 inhibitors used to treat hyperglycaemia
Impair glucose reabsorption
More remains in tubular fluid, lower plasma concentration
Mild osmotic diuresis