Drugs And The Kidneys

Question 1

A large proportion of acute kidney injury (AKI) is drug/chemical induced. This is because the kidneys are susceptible to 4 things. What are they?

Answer 1

1. Vascularity
2. Large SA for binding + transport
3. Reabsorption of water from kidneys which concentrates some drugs in the nephron
4. Main route of excretion for most drugs

Question 2

What should you consider when prescribing for patients with renal disease?

Answer 2

• How the renal impairment affects handling/effective of drug: drugs may accumulate to toxic levels if excreted through kidneys in renal impairment
• Could the drug worsen the renal impairment: i.e. avoid nephrotoxic drugs (e.g. aminoglycosides like gentamicin can be directly toxic to tubular cells)

Question 3

Why do problems occur with medications in patients with impaired renal function?

Answer 3

Reduced renal excretion of drug
Side-effects poorly tolerated (e.g. increased K+)
Increased sensitivity to some drugs
Some drugs less effective (e.g. diuretics like furosemide)

Question 4

How can you avoid/minimise problems when prescribing drugs to patients with renal impairment?

Answer 4

Reducing dose/frequency

Considering alternative drugs (e.g. different antibiotic to aminoglycoside)

Question 5

What are dose adjustments of drugs based on?

Answer 5

Severity of renal impairment
Proportion of drug eliminated by renal excretion (some may be more liver dependent)
Toxicity of drug/’safety margin’ (therapeutic window)

Question 6

In what 3 patient groups must more accurate measures of GFR be used than eGFR?

Answer 6

Elderly patients (>75 yrs)
Toxic drugs
Patients at extremes of weight

Question 7

What 3 pieces of practical advice can be given for prescribing drugs?

Answer 7

Check BNF for individual drug advice
Be aware that renal function normally declines with age when prescribing to elderly
Understand limitations of eGFR (+ other measures) + how this can be misleading

Question 8

What are the prescribing considerations for patients on dialysis?

Answer 8

Need specialist advice
Some drugs will be removed by dialysis + may lead to loss of therapeutic effect
No longer have to worry about nephrotoxic effects (advantage as machine has taken over kidney function)

Question 9

How does urine pH affect speed of drug excretion?

Answer 9

Most drugs weak acids or bases:
Alkaline urine will more readily ionise acidic drugs (+ vice versa) -> ionised substances (polar) are more water soluble -> easier to excrete via kidneys (urine pH can be manipulated for treatment e.g. aspirin is a weak acid so infuse sodium bicarbonate to increase excretion in poisoning)

Question 10

What are diuretics and what are they commonly used for?

Answer 10

Substance that promotes formation (excretion) of urine most commonly by promoting renal excretion of Na+ (natriuresis)
Commonly used for conditions associated with oedema + hypertension

Question 11

What are the 6 types of diuretic (in decreasing number of importance from top to bottom)?

Answer 11

Loop
Thiazide (+ related)
K+ sparing
Carbonic anhydrase inhibitors
Osmotic
ADH antagonists

Question 12

Where is Na+ reabsorbed in the nephron?

Answer 12

100% filtered ->
~65% in PT
~25% in ascending loop of henle
~8% in DT + collecting duct

Question 13

Where is water reabsorbed in the nephron?

Answer 13

~65% in PT
~20% in descending loop of henle
~15% in cortical + medullary collecting ducts

Question 14

Why are diuretics that act on the more proximal area of the nephron more powerful?

Answer 14

More Na+ is still in the tubule fluid at this stage as less has been reabsorbed so there is more to play with (if Na+ is affected, water will follow as a general rule)

Question 15

How do carbonic anhydrase inhibitors work?

Answer 15

Inhibit carbonic anhydrase in PT but have weak diuretic action as only small amount of Na+ normally reabsorbed in this way
Also prevents secretion of H+ (side effect could be metabolic acidosis)
E.G. acetazolamide

Question 16

Why is carbonic anhydrase needed in the reabsorption of Na+/water?

Answer 16

HCO3- ions from tubular lumen cannot be directly transported into tubular cells. Secreted H+ is needed to covert HCO3- -> H2CO3. H2CO3 is broken down to CO2 + H20 via CA action which can now go into tubular cells. In tubular cells, H2CO3 is reformed and then so is HCO3- and H+. HCO3- is co-transported into blood with Na+/water. Therefore, with CA blocked, HCO3-, Na+ and water cannot be reabsorbed via this route.

Question 17

When are carbonic anhydrase inhibitors used?

Answer 17

Not usually for diuretic effect but used:

• To reduce intraocular pressure e.g. in glaucoma (aqueous humour production requires HCO3- secretion/isoform of enzyme in eye)
• Mountain sickness prophylaxis (although unlicensed)

Question 18

How do osmotic diuretics work?

Answer 18

Increase osmolality of filtrate preventing water reabsorption; act best where most osmotic reabsorption occurs i.e. PT + descending LOH
E.G. mannitol

Question 19

What are the main uses of osmotic diuretics?

Answer 19

Not used for diuretic effect but used to:
Decrease intracranial pressure
Decrease intraocular pressure e.g. in glaucoma

Question 20

How can glucose act as an osmotic diuretics and what can happen in disease states as a result of this?

Answer 20

Glucose is usually filtered + reabsorbed by SGLT
If Tm is exceeded (e.g. uncontrolled DM), glucose is excreted in urine + prevents water reabsorption
-> diuresis + polyuria

Question 21

How is the mechanism of action of loop diuretics?

Answer 21

Act on thick ascending LOH by inhibiting the Na+K+Cl- co-transporter by competing with Cl- binding decreasing NaCl reabsorption decreasing osmotic concentration in medulla + ADH mediated H20 absorption -> increased NaCl delivery to distal tubules will increase Na+ uptake by principal cells + so loss of K+ and H+ (Ca2+ & Mg2+ reabsorption reduced too)
E.G. furosemide

Question 22

Why are loop diuretics so powerful?

Answer 22

Potentially can excrete ~25% of the filtered load of Na+

Question 23

Why are loop diuretics not filtered but secreted directly into the PT? What does this mean for them?

Answer 23

Because they bind to plasma proteins so:

• Effective in renal impairment
• May be less effective in nephrotic syndrome where is a large amount of albumin (leakage of plasma proteins due to impaired filtration barrier) in the tubular lumen so the drug will bind to that rather than the NaKCl transporter it should bind too

Question 24

What are the main uses of loop diuretics and their selected side effects?

Answer 24

Peripheral oedema (e.g. CHF)
Acute pulmonary oedema (due to vasodilator effect)
Resistant hypertension
Side effects: hypovolaemia/hypotension, hyponatraemia/hypokalaemia + ototoxicity (hearing loss in high doses)

Question 25

What is the thiazide diuretics mechanism of action on the nephron?

Answer 25

Act on early DT + inhibit Na+Cl- co-transporter by competing with Cl- for binding -> block Na+ reabsorption via this route so more is delivered to late DT + more water stays in tubular fluid and is secreted -> weak/moderate diuresis (well tolerated) + slower but longer lasting action than loop diuretics
E.G. Bendroflumethiazide, hydrochlorothiazide, indapamide + chlortalidone

Question 26

What are the uses + problems with using thiazide diuretics?

Answer 26

Peripheral oedema (CHF)
Hypertension
Not so good in renal impairment (filtered + secreted) + can cause:
- Hyponatraemia/hypokalaemia
- Plasma uric acid (gout)
- Erectile dysfunction
- Hyperglycaemia
(later ones are better)

Question 27

How do loop + thiazide diuretics cause hypokalaemia?

Answer 27

Increased NaCl delivery to distal nephron + decreased blood volume which increases K+ secretion via increased tubular flow rate + increased activity of Na/K ATPase (via increased I[Na+] & increased aldosterone activating RAAS). Intercalated cells also stimulated to secrete H+ hence alkalosis may occur.

Question 28

What is the K+ sparing diuretics mechanism of action overall?

Answer 28

Act on principal cells in late DT + CCT to inhibit ENaC OR the mineralocorticoid (MR) receptor -> Na+ reabsorption blocked in principal cell meaning in turn K+ will not be secreted either

Question 29

What are the ENaC antagonists (K+ sparing diuretics) mechanism of action?

Answer 29

Block ENaC by competing for Na+ binding site + therefore, decreasing luminal permeability to Na+ & K+ secretion into lumen is reduced too so K+ is retained
Weak alone but can be used with thiazide or loop diuretics (can balance out K+ effects)
E.G. amiloride, triamterene

Question 30

What are the aldosterone antagonists (K+ sparing diuretics) mechanism of action?

Answer 30

Given orally + metabolised to active form canrenone
Bind to MR receptor preventing aldosterone from having its effects i.e. drug prevents synthesis of ENaC + Na/K ATPase activation reducing Na+ absorption + K+ secretion into lumen so its retained
E.G. spironolactone, eplerenone

Question 31

What are the main uses of K+ sparing diuretics?

Answer 31

CHF
Peripheral oedema/ascites caused by cirrhosis
Resistant hypertension
Primary hyperaldosteronism (Conn’s syndrome/liver failure)
Weak if alone but can be used in combination to prevent K+ loss from loop/thiazide diuretics (main use for ENaC antagonists)

Question 32

What are the selected side effects of K+ sparing diuretics?

Answer 32

Hyperkalaemia so take care if prescribing with other RAAS inhibiting agents
Gynaecomastia (for aldosterone antagonists)

Question 33

What diuretics can be combined together and why?

Answer 33

Loop + thiazide: Loop increase NaCl delivery to distal nephron, increasing efficiency of thiazides = large diuresis (can cause large volume + K+ losses)
Loop/thiazides + K sparing (e.g. co-amilofruse or coamilozide): Good diuretic function w/o K+ loss (beware of K+ retention though)

Question 34

When might diuretics be rendered ineffective?

Answer 34

Need to filtered/secreted into nephron to act on luminal side so if kidney isn’t working properly, effects will be altered rendering diuretic therapy ineffective requiring high doses in renal failure. They can still work on transporters/enzymes in other body areas giving rise to side effects.

Question 35

What are the steps of the RAAS system?

Answer 35

1. Low arterial BP sensed via AAs, sympathetic nerves or low NaCl arriving at macula densa
2. Renin (kidneys) converts angiotensinogen (liver) to angiotensin I
3. ACE (lungs) converts angiotensin I to angiotensin II
4. Angiotensin II has 3 effects:
   Vasoconstriction
   Increased Na/H20 reabsorption in kidneys
   Increased aldosterone in adrenal glands = increased BP (also via increased thirst + ADH release in posterior pituitary)

Question 36

What is the effect of aldosterone secretion in the RAAS system in response to low BP?

Answer 36

Aldosterone acts on MR receptors on principal cells in the collecting duct to cause a secretion/loss of K+ in exchange for Na+

Question 37

What are the 4 classes of drugs that act on the RAAS system? Give examples of each.

Answer 37

1. Renin inhibitor e.g. Aliskiren
2. ACE-inhibitor e.g. Ramipril
3. Angiotensin II receptor blocker (ARB) e.g. Losartan
4. Aldosterone antagonist e.g. spironolactone

Question 38

What can happen if a patient is given a drug that impairs the RAAS system but already has renal impairment?

Answer 38

The system normally will cause secretion/loss of K+ however, these patients will have an issue with K+ secretion due to renal impairment. Drugs will further inhibit patients ability to secrete K+ by inhibiting the RAAS. Blood K+ can go abnormally high (especially if drugs combined) causing severe hyperkalaemia.

Question 39

What do NSAIDs do to the GFR of the kidneys?

Answer 39

Prostaglandins normally cause AA dilation + increased GFR but NSAIDs block prostaglandins so constrict AAs + reduce GFR.

Question 40

What do ACE inhibitors/ARB drugs do to the GFR of the kidneys?

Answer 40

Angiotensin II normally causes EA constriction + increased GFR but these drugs prevent action of angiotensin II causing EA dilation + reduced GFR.

Question 41

Why are ACE inhibitors used for CKD despite the reduction in GFR they cause?

Answer 41

In CKD, there is progressive predictable decline until you need renal replacement therapy. If an ACEi if given, short-term kidneys get worst but in long-term kidneys stabilised for longer. This is because nephrons are not damaged as quickly as there is reduced pressure in the glomerular capillaries so kidney function is actually prolonged long-term with the addition of ACEi.