Pharmacology - Kidney & Diuretics

Question 1

Kidney Function - 5

Answer 1

1. Renal pelvis: Collects urine, which is excreted via the ureter to the urinary bladder & out of the body.
2. Regulates body fluid volume & balance.
3. Maintains ion balance (e.g. sodium, chloride) & pH.
4. Excretes foreign substances, including waste products like urea.
5. Secretes renin, which activates the renin-angiotensin-aldosterone system (RAAS) for BP regulation.

Question 2

Ultrafiltration: Normal & Opposing forces

Answer 2

Blood is filtered from the Glomerular Capillaries into the Bowman’s Capsule
Driving force:
PGC - Glomerular Capillary hydrostatic pressure
πBS - oncotic pressure in the Bowman’s Space (negligible in normal kidney)

Opposing forces:
πGC - oncotic pressure of blood plasma
PBS - Pressure in the Bowman’s Space

Question 3

Tubular reabsorption, secretion & excretion - 5

Answer 3

1. Reabsorption or absorption: movement of solutes & water from tubular filtrate into interstitial fluid & plasma.
2. Secretion: movement of solutes & water from plasma & interstitial fluid into tubular filtrate.
   Reabsorption / absorption or secretion can be:
3. Transcellular (through epithelial cell & across luminal & the basolateral membrane)
4. Paracellular (through tight junctions between epithelial cells)
5. Excretion: extrusion of solutes & water in the tubular filtrate by the kidneys

Question 4

Major sites for Tubular Sodium Reabsorption
- 4

Answer 4

1. The Proximal Convoluted Tubule (PCT)
2. The Thick Ascending Limb (TAL) of the loop of Henle
3. The Distal Tubule (DT)
4. The Collecting Tubule (CT)
   & the Collecting Duct (CD)

Question 5

Diuretics: Ranked by ability to produce natriuresis and diuresis:
- 5

Answer 5

1. Loop Diuretics:
   Act on Thick Ascending Limb (TAL) of Loop of Henle
2. Thiazides & Thiazide-like diuretics:
   Act on Distal Tubule
3. Potassium Sparing Diuretics:
   Act on: Collecting Tubule & Collecting Duct
4. Osmotic Diuretics
   Act on: Proximal Convoluted Tubule & Thin Descending Limb of the loop of Henle
5. Carbonic Anhydrase Inhibitors:
   Act on Proximal Convoluted Tubule

Question 6

Tubular Sodium Reabsorption in the PCT - 9

Answer 6

On the Luminal membrane:
1. Na+/H+ exchanger (H+ secretion)
2. Na/H exchanger activity enhanced by Ang II via AT-1 receptors increasing Na+ reabsorption in the PCT
3. Na+-coupled co-transporters (X = glucose, amino acids)
4. Uses these mechanisms to enter PCT from Tubular lumen
On the Basolateral membrane:
5. Driving force is activity of the basolateral Na+-K+ ATPase (Creates Na+ [gradient] between the tubular lumen & interstitial space)
6. Renal K+ channels
7. Moves from PCT to Interstitial fluid
Tight Junctions: (gaps in Basolateral membrane)
8. Water permeable
9. Reabsorption of Ca2+, Mg2+, K+, Cl-

Question 7

Tubular Sodium Reabsorption in the PCT: - 8

Answer 7

On the Luminal membrane:
1. Na+/H+ exchanger (H+ secretion) – maintains pH balance
2. Na+-coupled co-transporters (X = glucose, amino acids)
On basolateral membrane:
3. Na+-K+ ATPase on basal membrane pumps out sodium, & creates Sodium [gradient], drives reabsorption of ions, glucose, amino acids, & other substances.
4. Potassium is recycled via potassium channels.
5. Tight junctions (not very tight): allow Ca, Mg, K, Cl, & H20 to pass through.
6. Increased osmolarity in interstitial space by drugs can pull ions along, aiding in reabsorption
7. 99% of glucose reabsorbed via sodium-glucose transporters (important in diabetes treatment).
8. Drugs can interact with organic anion & cation transporters, influencing each other’s excretion pathways & potentially causing DI.

Question 8

Carbonic Anhydrase Inhibitors: Acetazolamide - 6

Answer 8

1. Inhibition of carbonic anhydrase in the PCT
2. The enzyme reversibly converts carbonic acid into H2O & CO2 in the lumen, & CO2 &+ H2O to bicarbonate (HCO3-) & protons (H+) inside the epithelial cell.
3. Protons excreted via luminal Na+/H+ exchanger on the proximal tubule
   Renal effects of acetazolamide:
4. Moderate decrease in Na+ reabsorption
5. Mild plasma acidosis (due to H+ retention)
6. Urine alkalosis (due to increased bicarbonate secretion)

Question 9

Carbonic Anhydrase Inhibitors: Acetazolamide: Uses -

Answer 9

Urine alkalisation
1. Reduces formation of uric acid & cystine stones
2. Increases excretion of weak acids (e.g. salicylates, barbiturates)
3. Decreases crystallisation of weak acids in the urine (e.g. anti-bacterial sulphonamides)
4. Altitude sickness (reduces respiratory plasma alkalosis by making plasma more acidic)
5. In glaucoma

Question 10

Urine alkalisation: Drugs which can increase urine pH - 2

Answer 10

1. Sodium bicarbonate (to treat aspirin overdose)
2. Citrate (metabolised to bicarbonate increasing levels and its secretion)

Question 11

Mechanism of diuretic action: e.g. Mannitol - 8

Answer 11

1. Freely filtered in the glomerulus
2. Pharmacologically inert and not reabsorbed
3. Increases osmolarity of the tubular filtrate
4. Decreases water reabsorption
5. Increases sodium excretion (by retaining sodium ions in diluted filtrate – secondary effect)
6. Act on areas freely permeable to water: PCT & Descending Limb of the loop of Henle
7. Collecting tubule and Collecting duct in the presence of ADH

Question 12

Osmotic Diuretics: Therapeutic applications. E.g. Mannitol - 5

Answer 12

1. Weak diuretics, rarely used in the kidney
2. May be used in acute renal failure
3. Non-renal uses (increase osmolarity of blood plasma):
4. Cerebral oedema (to reduce intracranial pressure)
5. Glaucoma (to reduce intraocular pressure)

Question 13

Effects of Loop Diuretics (e.g., Furosemide and Bumetanide) - 5

Answer 13

1. Inhibit the NKCC2 cotransporter (Ion reabsorption), leading to:
2. Reduced Na, Cl, Ca, & Mg (decreased reabsorption, secretion).
3. Hypocalcaemia & hypomagnesemia in some patients due to disrupted absorption.
4. Increased K excretion as K channels remain open.
5. Diuretics reduce Na absorption, can result in low plasma Na levels, requiring supplementation.

Question 14

Pharmacokinetics of Loop Diuretics (e.g. Furosemide, Bumetanide) - 4

Answer 14

1. Absorbed in gut & secreted into filtrate by organic anionic transporters.
2. Share these transporters with other drugs (e.g., uric acid), possible DIs affecting their excretion.
3. Delivered to the site of action as filtrate flows to the Loop of Henle.
4. Excreted in the urine

Question 15

LOOP DIURETICS e.g. Furosemide, Bumetanide: Therapeutic uses
- 5

Answer 15

1. Acute pulmonary oedema
2. Diuretic resistant oedemas
3. Resistant hypertension
4. Patients with impaired kidney function or with CHF
5. Liver cirrhosis with ascites

Question 16

Thiazides & Thiazide-like diuretics: Effects of Diuretics on the Distal Tubule - 4

Answer 16

1. Inhibits NCC, reducing Na & Cl reabsorption, causing Na loss & moderate increase in K excretion.
2. Ca reabsorption increased because Na gradient for Ca transport is reduced.
3. Basolateral Na+Ca” exchanger (NCX1) and the basolateral Ca-ATPase (Ca-pump) moves Ca into interstitial space and then into blood.
4. Tight junctions in distal tubule are water-impermeable, so water does not follow the ions in this section.

Question 17

Thiazides & Thiazide-like diuretics: Renal Effects of Diuretics in the Distal Tubule - 3

Answer 17

1. Sodium (Na+) & chloride (Cl-) reabsorption are reduced.
2. Increase in Potassium (K+) excretion.
3. Calcium (Ca2+) reabsorption is increased, leading to decreased calcium excretion.

Question 18

THIAZIDES & THIAZIDE-RELATED DIRETICS - 5

Answer 18

Thiazides:
1. Hydrochlorothiazide
2. Bendroflumethiazide

Thiazide-like:
1. Chlortalidone
2. Indapamide
3. Metolazone

Question 19

THIAZIDES vs LOOP DIURETICS: Comparison - 4

Answer 19

1. are less powerful, but better tolerated than loop diuretics
2. have more prolonged action
3. have vasodilating properties
4. a greater risk of hypercalcemia

Question 20

THIAZIDES & THIAZIDE-RELATED DIRETICS (e.g. Hydrochlorothiazide, Indapamide): Therapeutic Uses - 4

Answer 20

1. Hypertension
2. Severe resistant oedema
3. Prevention of kidney stone formation in idiopathic hypercalciuria (reduced Ca accumulation)
4. Nephrogenic diabetes insipidus

Question 21

Loop and thiazide/thiazide-like diuretics (Hydrochlorothiazide, Indapamide): Common Adverse Effects
- 5

Answer 21

1. Hypotension
2. Gout due to hyperuricaemia (high levels of uric acid)
3. Erectile dysfunction
4. Tachyarrhythmias: cause: hypokalaemia can reduce rate of repolarisation, promote abnormal depolarizations
5. Hyperglycaemia: cause:: dose-related glucose intolerance due to depletion of intracellular K+ in pancreatic beta-cells.
   Depletion of intracellular K (hypokalaemia) interferes with normal activation of insulin release, can cause hyperglycaemia & may lead to T2D Mellitus

Question 22

Potassium Regulation & Hyperkalaemia - 6

Answer 22

1. Primary mechanism for K excretion involves a coupling of Na reabsorption & K excretion. The more sodium is reabsorbed, the more potassium is lost.
2. Hyperkalaemia occurs when large amounts of Na reach the distal tubule, leading to excessive K loss via this coupling.
3. Aldosterone regulates K levels by increasing K excretion when plasma K levels are high. It acts on three components:
4. Increased Enac expression (renal Na channels for Na reabsorption).
5. Increased ROMK (K channels for K excretion)
6. Increased activity of Na-K ATPase.

Question 23

Potassium-Sparing Diuretics MoA - 4

Answer 23

1. These diuretics aim to reduce potassium loss, counteracting the effects of aldosterone.
   Two main classes:
2. Mineralocorticoid Receptor Antagonists (e.g., spironolactone): Block aldosterone’s action, reducing Na reabsorption & K excretion.
3. Sodium-Potassium Channel Blockers (e.g., amiloride, triamterene): Inhibit Na reabsorption & prevent K loss by blocking sodium channels.
4. Amiloride and triamterene are weaker diuretics but are used to preserve potassium levels