Drugs & The Kidney

Question 1

Describe the role of the kidney in drug excretion

Answer 1

• The kidney is the most important organ for eliminating drugs from the body
• Most are metabolised by the liver to an inactive compound that can be excreted by the kidney
• Polar drugs or metabolites (water soluble and partially ionised) are excreted via specialised transporters

Question 2

Where does tubular secretion of drugs occur? Give an example of a weak acid and weak base drug

Answer 2

Occurs mainly in the proximal tubule -
- Most drugs are weak acids or bases - the degree of ionisation depends on the drugs pKa and pH of the environment e.g.

• Penicillin is a weak acid = HA -> H+ + A- = A- is an anion transporter
• Morphine is a weak base = B + H2O -> BH+ + OH- = BH+ is a cation transporter

Question 3

What do diuretics do?

Answer 3

• Increase urine output (diuresis)
• May also increase electrolyte excretion (Na, natriuresis, k kaliuresis)
• Very important drugs e.g. used in acute pulmonary oedema, heart failure, hypertension

Question 4

Describe the classes of diuretics

Answer 4

(Class, site of action, mechanism, notes (in order))

CA inhibitors
Proximal tubule
Inhibits CA
Weak - increased HCO3- excretion

Loop
Ascending loop of Henle
Blocks NaK2Cl
Most powerful - increased K+ excretion

Thiazide
Distal tubule
Blocks NaCl cotransporter
Moderate - increased K+ excretion

K sparing
Collecting duct
Blocks ENaC
Weak - decreased K+ excretion

Osmotic
Whole nephron
Osmotic shift of water
Mannitol - used to treat cerebral oedema

Question 5

Describe how osmotic diuretics like mannitol work and what they are used to treat

Answer 5

E.g. mannitol
- Freely filtered but not reabsorbed
- Dilution of DT fluid is impaired
- Decreased gradient for water reabsorption as mannitol increases the osmolarity

Commonly used to treat cerebral oedema
- Does not cross the blood brain barrier
- Creates an osmotic gradient for withdrawal of water from cerebrospinal fluid to plasma

Question 6

Describe how carbonic anhydrase inhibitors like acetazolamide work

Answer 6

• Mild diuretics
• Inhibit carbonic anhydrase activity so there is a net result of decreased NaHCO3 reabsorption
• There is less formation of carbonic acid from H2O and CO2 so less formation of H+ and HCO3- ions so less HCO3- and Na+ is reabsorbed into the tubule lumen
• HCO3- and H+ form and then Na+ enters epithelial cells via antiporter that pumps H+ ions into the ECF
• The Na+ then enters the tubular lumen via the Na+/K+ ATPase and HCO3- enter tubule via its own transporter

Question 7

Describe what loop diuretics like frusemide do and the side effects

Answer 7

E.g. frusemide
- Powerful diuretics
- Inhibit the Na/K/2Cl cotransporter in the thick ascending limb of loop of Henle
- Impedes concentration of medullary interstitial fluid
- Reduced osmotic drive for ADH mediated water reabsorption

Side effects:
- Significant loss of K+ so hypokalaemia

Question 8

Describe what thiazide diuretics are and what the side effects are

Answer 8

Thiazide diuretics -
- 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 - there is less Na+ entering epithelial cells from Na+/Cl- symporter so there is less Na+ gradient so less Na+/K+ ATPase activity so K+ is not entering epithelial cells
- Hypercalcaemia - increased Ca/Na exchanger - Ca2+/Na+ exchanger is more active so more calcium enters the epithelial cells

Question 9

Describe what K sparing diuretics do and some examples

Answer 9

K sparing diuretics:
- Weak diuretic action
- Important as they cause K retention countering the powerful electrolyte secretions of loops diuretics
- Acts at the end of the DCT and collecting duct

• Amiloride - blocks ENaC - less Na+ reabsorption so less K+ excretion
• Spironolactone - aldosterone antagonist - used to treat volume overload in heart failure - less aldosterone so less ENaC expression so less K+ excretion

Question 10

Describe thiazide diuretics

Answer 10

• Have been first line hypertension treatment for decades
• It is no longer the first used one - is now second or third
• Low doses effective for hypertension
• Higher doses may be used for volume overload
• Severe volume overload e.g. pulmonary oedema due to LV failure

Question 11

What are the uses of K+ sparing diuretics?

Answer 11

• May supplement thiazide or loop to counter hypokalaemia
• Heart failure
• Aldosterone antagonists may be used to control hyperaldosteronism

Question 12

Describe how SGLT2 inhibitors are used as mild diuretics

Answer 12

Sodium glucose cotransporters (SGLTs)
- Secondary active transport
- SGLUT1 - glucose absorption from the gut
- SGLT1 and SGLT2 - glucose reabsorption from kidney - 90% reabsorbed in PCT in SGLT2 and 10% reabsorbed in descending limo loop of Henle by SGLT1

SGLT 2 inhibitors used to treat hyperglycemia
- Impairs glucose reabsorption
- More remains in tubular fluid, lowers plasma concentration
- Mild osmotic diuresis