Drugs and the Kidney

Question 1

How are kidneys related to drug excretion?

Answer 1

The kidney is the most important organ for eliminating drugs from body

Question 2

How are drugs metabolised and excreted?

Answer 2

Most are metabolised by the liver to an inactive compound that can be excreted by kidney

Question 3

How does drug polarity effect its excretion by the kidneys?

Answer 3

Kidney excretes polar (charged) drugs more readily than non-polar (uncharged) drugs
Non-polar (uncharged drugs) can be reabsorbed by kidney

Question 4

How does the kidney excrete durgs?

Answer 4

• Glomerular filtration
• Tubular reabsorption
• Tubular secretion

Question 5

How much of the renal plasma flow is filtered by glomerulus?

Answer 5

Approximately 20% renal plasma flow is filtered through the glomerulus

Question 6

How does size of molecules effect glomerular filtration?

Answer 6

Glomerular capillaries allow drugs of MW < 20kDa to be filtered freely, but not when bound on albumin (albumin MW ~ 68kDa)

Question 7

How does the drug Warfarin’s size aid its function?

Answer 7

Anti-coagulant drug warfarin
98% bound to albumin : 2% into filtrate
This results in a long half-life – stays in the body a long time

Question 8

What is the disadvantage of warfarin having a long half life due to their molecular size?

Answer 8

Issues of toxicity with continued dosing – e.g. excess bleeding

Question 9

Where does tubular secretion of drugs occur?

Answer 9

Occurs mainly in proximal tubule

Question 10

How are charged drugs secreted?

Answer 10

Non-specific cation and anion transporters for charged drugs or metabolites, e.g.
Morphine (weak base) – cation transporter
Penicillin (weak acid) – anion transporter

Question 11

What is the polarity of most drugs metabolised and excreted?

Answer 11

Most drugs are weak acids or bases – degree of ionization depends on drug pKa and pH of environment

Question 12

How does the non-specificity of the drug transporters effect their excretion?

Answer 12

Competition can occur between drugs at these transporters (as they are non-specific, no selective binding sites)

Question 13

Explain how competition between penicillin and probenecid affects their half life

Answer 13

e.g. Penicillin (antibiotic) and Probenecid (removes uric acid, treat gout).
If Probenecid is administered with Penicillin, half-life of penicillin is increased – both act at anion transporter

Question 14

What is the effect of diuretics on the kidneys?

Answer 14

Diuretics cause an increase in urine output (diuresis)

Many diuretics also produce increased Na (natriuresis) / and K excretion (hypokalaemia)

Question 15

What are the consequences of over using diuretics?

Answer 15

Can cause hypertension, acute pulmonary oedema, heart failure

Question 16

What are the 2 major groups of diuretics?

Answer 16

1. Osmotic diuretics

2. Electrolyte affecting diuretics

Question 17

What is the effect of osmotic diuretics?

Answer 17

• Mainly affect H₂O excretion
• Water
• Ethanol (↓ADH release)

Question 18

What is the role of Electrolyte affecting/K-sparing diuretics?

Answer 18

• Increase in electrolyte excretion
• Carbonhic anhydrase inhibitors
• Loop diuretics
• Thiazides

Question 19

How do diuretics cause their effects?

Answer 19

Diuretic agents act at specific sites (6 sites along PCT (1+2) and DCT (3-6)) of the nephron and collecting ducts

Question 20

What occurs at site 1 (PCT) due to diuretics?

Answer 20

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

Question 21

What happens at Site 2 on PCT due to diuretics?

Answer 21

Re-absorption of Na in exchange for H - Role of carbonic anhydrase

Question 22

Explain the events of site 3 on the DCT after taking diuretics

Answer 22

Loop of Henle - Site 3:
Transport of NaCl by Na/K/2Cl co- transporter
Thick ascending LoH impermeable to H2O
ICFV in this region becomes hypertonic
Re-absorption of H2O from CD (controlled by ADH)

Question 23

What happens at site 4 along the DCT in response to diuretics?

Answer 23

Site 4:

Re-absorption of Na/Cl (co-transporter), followed by H2O

Question 24

What events occur at site 5 on DCT after taking diuretics?

Answer 24

Site 5:

Na is reabsorbed (through ENaC channels) in exchange for K efflux (through K channels) - stimulated by aldosterone

Question 25

Outline what occurs at site 6 of the DCT in response to diuretics

Answer 25

Site 6: Another Na-H exchanger - also stimulated by aldosterone Sites 5 and 6 can produce K loss (in response to Na reabsorption) and alkalosis (due to increased proton excretion)

Question 26

Outline the features of the osmotic agent Mannitol

Answer 26

e.g. Mannitol - usually administered i.v. Inert substances, freely filtered but not reabsorbed High concentrations → ↑ Osmolarity in tubules → ↓ Reabsorption of H2O Acts at PCT, DCT, and collecting duct Little effect on electrolyte excretion

Question 27

What are the uses of mannitol?

Answer 27

Reduce intracranial and intraocular pressure Prevent acute renal failure Excretion of some types of poisoning

Question 28

How does Mannitol reduce intercranial pressure?

Answer 28

Mannitol does not enter the CNS → creates an osmotic gradient → H2O leaves the CNS (into plasma)

Question 29

How does Mannitol administration prevent acute renal failure?

Answer 29

Mannitol can prevent ANURIA | Distal nephron can dry up when filtration is very low

Question 30

How do electrolyte excretion agents work?

Answer 30

Drugs increase urine flow by increasing excretion of Na (natriuresis) – where Na goes → H2O follows (osmosis)

Question 31

Which electrolyte is the major determinant of ECFV ?

Answer 31

NaCl is the major determinant of extracellular fluid (ECF) volume

Question 32

Explain the effects of increased NaCl excretion

Answer 32

↑ NaCl excretion → ↓ ECF vol → ↓ Blood vol → ↓ Cardiac output → ↓ Oedema

Question 33

Name a carbonic anhydrase (CA) inhibitor

Answer 33

Acetazolamide

Question 34

Outline the features and functions of acetazolamide

Answer 34

Mild diuretics Inhibit the activity of CA - decrease formation of protons in the luminal cells of PCT (Site 2) Loss of NaHCO3 into lumen - loss of H2O Also used in non-renal effects - in glaucoma, aqueous humor formation is dependent on CA activity

Question 35

What kind of drug is frusemide?

Answer 35

Powerful loop diuretic that produces rapid effects (i.v)

Question 36

What are the roles of frusemide?

Answer 36

Inhibit Na/K/Cl co-transporter at thick ascending loop of Henle (Site 3) ↓ Reabsorption of Na, K, and 2Cl – marked loss of these electrolytes Prevents concentration of cortico-medullary interstitial fluid and therefore reduces effect of ADH on the collecting duct (less osmotic drive) - ↑ H2O loss

Question 37

What are the clinical uses of frusemide?

Answer 37

Chronic heart failure ↓ ECFV, ↓ CVP, ↓ CO Vasodilatation by increase PGs in blood vessels Acute renal failure ↑ renal blood flow Acute pulmonary oedema ↓ Capillary pressure

Question 38

What are the major side effects of using diuretics?

Answer 38

``` Significant loss of K → hypokalaemia Metabolic alkalosis (compensatory, see thiazides) ```

Question 39

Name a thiazide drug

Answer 39

E.g. Bendrofluazide

Question 40

Outline features of Bendrofluazide

Answer 40

Moderately powerful diuretics | Inhibit Na/Cl uptake via co-transporter at distal convoluted tubule (Site 4)

Question 41

What are the compensatory mechanisms initiated by bendrofluazide?

Answer 41

Site 5: Na uptake via ENaC - K excretion – K loss | Site 6: Na uptake via Na/H exchanger – H loss

Question 42

What is the effects of decreased BV?

Answer 42

↓BV → ↑RAAS, ↑aldosterone → ↑Na re-absorption (sites 5/6) - ↑↑ K/H loss

Question 43

What are the uses of Bendrofluazide?

Answer 43

Treatment of hypertension Diuresis causes ↓ BV → ↓ CO Major effect is causing vasodilatation → ↓ TPR Mild heart failure - ↓ ECFV Oedema

Question 44

What are the major side effects of Bendrofluazide?

Answer 44

Hypokalaemia (loss of K) Metabolic alkalosis (loss of H) Hypercalcemia (Increased Ca/Na exchanger) Hypotension (too much vasodilatation)

Question 45

Describe the diuretic action of K-sparing diuretics

Answer 45

Weak diuretic action

Question 46

Where do K-sparing diuretics act?

Answer 46

Act at end of DCT and collecting duct (Sites 5 + 6)

Question 47

What is the role of K-sparing diuretics?

Answer 47

Important as they cause K retention- counter the powerful electrolyte secretions of diuretics such as frusemide

Question 48

Name a few K-sparing diuretics

Answer 48

Spironolactone Amiloride Captopril

Question 49

Describe the functional features of Spironolactone

Answer 49

Competitive antagonist of aldosterone at sites 5 and 6 CVS diseases linked to overproduction of aldosterone → volume overload, e.g. Heart failure

Question 50

What are the effects of Amiloride?

Answer 50

Blocks ENaC at site 5 | Reduces Na reabsorption and K loss

Question 51

What does the K-sparing diuretic Captopril cause?

Answer 51

Inhibition of angiotensin- converting enzyme - ↓ Ang II formation - ↓ aldosterone

Question 52

What are nephrotoxic drugs?

Answer 52

These are drugs that induce kidney damage

Question 53

List examples of nephrotoxic drugs

Answer 53

``` NSAIDs (commonly prescribed drugs) Radiocontrast agents Aminoglycosides (gentamicin) Lithium (bipolar disorder) Cyclosporine (anti-rejection) Chemotherapy drugs ```

Question 54

How do NSAIDs cause kidney damage?

Answer 54

NSAIDs prevent formation of prostaglandins (PGs) by inhibiting COX PGs are important for vasodilatation in the afferent renal arterioles Hence, COX and PGs formation is important for renal blood flow and GFR