L34. Drugs affecting the Kidney

Question 1

What are the major homeostatic functions of the kidney? [4]

Answer 1

1. Regulation of water and electrolyte balance 2. Endocrine functions 3. Excretion of endogenous waste 4. Excretion of exogenous compounds

Question 2

What is the major site of elimination and excretion in the kidney? What else is it majorly involved in?

Answer 2

The Nephron Regulation of electrolytes and water

Question 3

At what stage is the blood filtered?

Answer 3

The preglomerular capillaries

Question 4

Draw a rough diagram of the kidney nephron from the glomerulus to the collecting ducts. Label the major sites of filtration, secretion and reabsorption.

Answer 4

Question 5

Where is the majority of water and salt reabsorbed (60-70)

Answer 5

The proximal tubule

Question 6

What are the three different types of therapeutic actions on the kidney? [3]

Answer 6

1. Diuretics (affect reabsorption and secretion) 2. Affect urine pH (eg. bicarbonate) 3. Altering secretion of organic molecules (Eg. Probenecid) used in gout but masks secretion of several organic compounds (banned in sports)

Question 7

What are the diuretics?

Answer 7

Drugs that decrease sodium and chloride reabsorption (means an increase in excretion of NaCl and a secondary increased excretion of water)

Question 8

What are the 4 types of diuretics?

Answer 8

1. Loop 2. Thiazide 3. Potassium Sparing 4. Osmotic

Question 9

What do loop diuretics cause? Give an example of a loop diuretic

Answer 9

Frusemide Most powerful and cause a torrential urine flow

Question 10

What is the mechanism of action of loop diuretics?

Answer 10

Thick ascending loop of Henle Inhibit Na/K/2Cl transporter on luminal side Prevents overall flow of ions back into interstitium (no reabsorption)

Question 11

Describe the pharmacokinetics of loop diuretics

Answer 11

Well absorbed (<1hr onset) Plasma protein bound: so it is stopped from being filtered (easily reaches site of action) Duration of action: 3-6 hours

Question 12

What are the adverse effects of loop diuretics?

Answer 12

Excessive K loss H+ excretion (metabolic alkalosis) Hypovolaemia + Hypotension

Question 13

What are some clinical uses of loop diuretics?

Answer 13

Hypertension (decreases blood volume) Decrease salt/water overloads in acute: pulmonary oedema, chronic heart failure and in chronic: liver cirrhosis or kidney failure

Question 14

What do Thiazide Diuretics Do? Give an example

Answer 14

Are moderately powerful drugs that cause increased urine Eg. Bendrofluazide or hydrochlorothiazide (impdapamide - not true thiazide)

Question 15

What is the mechanism of action of the thiazide diuretics?

Answer 15

Acts on the distal convolute tubule and inhibits the Na/Cl co-transporter on the luminal membrane.

Question 16

Describe the pharmacokinetics of the Thiazide Diuretics

Answer 16

Orally active: 4-6 hour onset Excreted in the urine to get to site of action Duration: 8-12 hours

Question 17

What are side effects of the thiazide diuretics?

Answer 17

Excessive K loss (same as loop) Build up of uric acid (can inhibit uric acid secretion) Less with the indapamide

Question 18

What are the clinical uses of the thiazide diuretics?

Answer 18

Hypertension Severe resistant oedema (combination with loop)

Question 19

Both loop and thiazide diuretics cause an excessive loss of potassium. What is done to compensate for this?

Answer 19

Given with a K supplement Or given a K sparing diuretic in combination or instead

Question 20

What are the Potassium Sparing Diuretics?

Answer 20

Used in combination with the K-losing drugs and there are 2 major types with slightly different mechanisms of action They act on the collecting tubule and ducts.

Question 21

Describe the two major types of K-sparing diuretics?

Answer 21

1. Acts on collecting tubule and ducts: aldosterone receptor antagonist - Prevents DNA binding and Na pump expression and thus reduces reabsorption of Na at that point without affecting K EG. Spirinolactone
2. Blocks luminal sodium channels in tubules and ducts EG. Triamterene and amiloride

Question 22

Describe the pharmacokinetics of the K-sparing diuretics

Answer 22

Spirinolactone Orally active Slow onset 2 hours Short half life (minutes) but the metabolite is long (16hrs): duration 12-16 hours Amiloride Poor absorption Slow Onset 24 hr duration

Question 23

What are some adverse effects of the K sparing diruetics

Answer 23

Hyperkalaemia Gastrointestinal upset

Question 24

Give some clinical uses of the K sparing diuretics

Answer 24

Used in combination with loop or thiazide diuretics Heart failure Hyperaldosteronism

Question 25

What are the osmotic drugs, give an example

Answer 25

Pharmacologically inert drugs (no binding) and are filtered without absorption Eg. Mannitol

Question 26

What is the mechanism of action of the osmotic drugs?

Answer 26

Affects all parts that are water permeable (proximal tubule, descending loop of Henle, collecting tubules) Reduces passive water absorption with small reductions caused only (no effect on Na)

Question 27

What are some clinical uses of the osmotic diuretics?

Answer 27

Raised intracranial and intraoccular pressures, prevention of acute renal failure

Question 28

Why is the kidney susceptible to toxicity? [2 reasons]

Answer 28

About 20% of blood flow thus high exposure and concentrated amounts Can carry out metabolism which can generate reactive species

Question 29

What are the mechanisms that kidney damage can occur from its elimination functions?

Answer 29

Direct or metabolite formation of reactive oxygen species Interference with calcium metabolism Protein/enzyme binding can cause inhibition of enzyme function or the initiation of the immune response

Question 30

How does mercury cause toxicity to the kidney?

Answer 30

Directly and vasoconstriction Binds to thiol groups in proteins causing an immune response: immune glomerulonephritis Damage to mainly the proximal tubules (loss of brush border and mitochondrial changed = apoptosis)

Question 31

How does Gentamicin cause toxicity to the kidney?

Answer 31

An antibiotic for gram negatives whose excretion is renal: causes proteinuria, reduced GRD and altered concentrating ability Acts on apical membrane of proximal tubule causing cell death

Question 32

How to antineoplastic drugs cause toxicity to the kidney?

Answer 32

Cytotoxic agents that cause dose-limiting nephrotoxicity (proteinuria, increase blood urea, electrolyte imbalances) Highly reactive species binding to cell components to kill tumour cells and kidney cells (focal tubular necrosis)