Renal: Drugs of the Kidney

Question 1

Why is the kidney the most important organ for eliminating drugs from our body?

Answer 1

Most drugs are metabolised by the liver to an inactive + polar compound.
Kidney excretes polar drugs more readily than non-polar.
This is bc non-polar drugs can be reabsorbed by the kidney back into plasma

A change in kidney function will alter how drugs are eliminated

Question 2

Briefly outline the excretion of drugs by the kidney

Answer 2

Glomerular filtration
Passive tubular reabsorption
Tubular secretion

Question 3

What is important to consider during the glomerular filtration of drugs?

Answer 3

Glomerular capillaries filter drugs of MW < 20kDa, but not when bound on albumin (albumin MW ~ 68kDa)
This is important as some drugs bind to albumin so have a long half life:
98% warfarin bound to albumin, so 2% into filtrate.
This= long half-life, so stays in the body for longer.

So hay toxicity issues w continued dosing – e.g. excess bleeding which u need to monitor

Question 4

What is important to consider during passive tubular reabsorption of drugs?

Answer 4

Uncharged/unionised drugs are lipophilic, so easily cross lipid membrane
Charged/ionised drugs are lipophobic, so need a transporter to cross lipid membrane
Uncharged drugs may diffuse out the kidney and escape elimination. Altering urine pH may alter this process by changing the ionization of the weak acid/base drug

Question 5

Describe the tubular secretion of drugs

Answer 5

Occurs mainly in the PCT
Cation transporter binds weak base, proton acceptor drugs at physiological pH (eg morphine)

Anion transporter binds weak acid, proton donor drugs at physiological pH, eg penicillin

Transporters are non-specific, so bind any cationic/anionic drug

Question 6

What is the clinical significance of the ion transporters during the tubular secretion of drugs?

Answer 6

Competition can occur between drugs at these transporters (as they are non-specific, non-selective binding sites)

e.g. If Probenecid (removes uric acid, treat gout) is administered w Penicillin, half-life of penicillin is increased. This is bc both act at anion transporter but Probenecid has higher affinity

Question 7

What are the major groups of diuretics?

Answer 7

Question 8

What happens in site 1 and 2 of the proximal convuluted tubule?

Answer 8

Site 1:Re-absorption of Na w passive movement of organic molecules (glucose, amino acids) and H2O

Site 2:Re-absorption of Na for H (Na/H exchanger) – catalysed by carbonic anhydrase. This makes sodium bicarbonate which helps acid base balance

Question 9

What happens in the Loop of Henle?

Answer 9

Loop of Henle, Site 3:

• Transport of NaCl by a co- transporter for Na, K and 2Cl
• Thick ascending Loop of Henle is NOT permeable to H2O, so interstitial fluid in this region becomes hypertonic
• This aids re-absorption of H2O from the collecting duct (controlled by ADH)

Question 10

What happens in the DCT?

Answer 10

Distal Convoluted Tubule (DCT)

Site 4: Reabsorption of NaCl (co-transporter) followed by H2O
Site 5: Na is reabsorbed (via ENaC) in exchange for K efflux (via K channels)
Site 6: Na is reabsorbed and H+ lost via Na-H exchanger

Sites 5 and 6 can produce K loss (following Na reabsorption) and alkalosis (due to increased proton excretion). Sites 5 and 6 also are stimulated by aldosterone

Question 11

What is Mannitol? How does it work?

Answer 11

Mannitol - Osmotic diruetic agent, usually administered i.v.

• Inert, freely filtered by the kidney but not reabsorbed
• High concs increase osmolarity in tubules, which thus decreases reabsorption of H2O
• Acts at PCT, DCT, and collecting duct

Question 12

Give the uses for Mannatol

Answer 12

Distal nephron can dry up when filtration is v low. You want more water into your tubule to prevent dryness and increase function.
Mannatol causes less water absoprtion/holds on to more water, so less drying out of the tubules.
Less water absorption in the kidney also prevents drug/poison reabsorption.

Reduces intracranial and intraocular pa: Mannitol does not enter the CNS, so creates an osmotic gradient. This causes water to leave the CSF into plasma).

Question 13

Describe mild diuretics that affect electrolyte excretion

Answer 13

Drugs increase urine flow by increasing Na excretion(natriuresis). Where Na goes, H2O follows
NaCl excretion = less ECFV= less Blood vol= less oedema/CO

Carbonic anhydrase inhibitors (Mild diuretics): decrease water and C02 production, and less H+ and HC03- in the luminal cells of PCT.
Less H+ reduces action of the Na/H+ exchanger
Less NaHCO3, so less H20 is absorbed and more is excreted
Also used in glaucoma bc aqueous humor formation is dependent on CA activity

Question 14

Which strong dirutetics affect electrolyte excretion?

Answer 14

Loop diuretics e.g. Frusemide: strong diuretics with rapid effect (i.v.)

Inhibit Na/K/Cl co-transporter at TAL of Henle: less reabsorption of Na, K, and 2Cl

This makes cortico-medullary interstitial fluid less hypertonic, so reduces effect of ADH on the CD (less osmotic drive). This increases H20 loss

Question 15

Give uses and side effects of loop diuretics

Answer 15

1. Chronic heart failure: less ECFV, blood vol
2. Vasodilatation due to­ increased PCl2 in blood vessels. This is used in: Acute renal failure (more renal blood flow). Acute pulmonary oedema (less capillary pressure)

Side effects: Significant loss of K= hypokalaemia. Metabolic alkalosis (due to compensatory increase in Na/H exchanger, loss of H)

Question 16

Describe Thiazide drugs and what they are used for

Answer 16

Thiazide drugs e.g. Bendrofluazide. Inhibit Na/Cl co-transporter at distal convoluted tubule, reducing NaCl uptake

• Uses: Treatment of hypertension due to less BV and so CO. Major effect is causing vasodilatation due to increased PCl, which lowers TPR
• Mild heart failure: less ECFV= less Oedema

Question 17

What are the side affects for Thiazide drugs?

Answer 17

• Increase Na uptake via ENaC, increase K excretion – hypokalaemia
• Increase Na uptake via Na/H exchanger – H loss, metabolic alkalosis
• Decreases BV, so increases­ aldosterone–> more Na re-absorption causes K/H loss
• Can cause Hypotension (too much vasodilatation)

Question 18

What are K sparing diuretics?

Answer 18

K- sparing diuretics (weak diuretics). Reduce Na reabsorption at end of DCT and collecting duct (Sites 5 + 6)

Spironolactone: Competitive antagonist of aldosterone- less Na reabsorption and K loss. Used in CVD linked to aldosterone overproduction eg heart failure
Amiloride: blocks ENaC at site 5, reduces Na reabsorption and K loss
Captopril (ACEi): less Ang II formation, less aldosterone
Aldosterone stimulates the Na/K pump, so blocking it will stop K loss!