Lecture 9 Drugs and the Kidney

Question 1

1. Describe the pharmacokinetics of penicillins
2. What happens to the elimination half life in renal impairment?
3. What actions are taken in renal impairment?

Answer 1

1. • Oral absorption available
     - Widely distributed in body fluids
     - Mainly renal excretion
     - Short plasma half-life
2. Increases because there is removal of the penicillin elimination pathway.
3. Adjustment of dose may be necessary e.g. decreasing tazocin (piperacillin/tazobactam) from 4.5g 8-hourly to 4.5g 12-hourly

Question 2

1. Give the names of two drugs which are less effective in renal impairment.
2. Name alternatives to these drugs.

Answer 2

1. Thiazide diuretics
   Nitrofurantoin (concentrates in the urine and so is ineffective in renal impairment).
2. Loop diuretics (caution because you need higher dose to work on LoH in renal impairment but also toxicity associated)
   Trimethoprim

Question 3

Name two drug categories in which drug effect is increased in renal impairment.

Answer 3

(1) Opioids

(2) Sedatives

Question 4

Name 5 drugs in which toxicity is increased with renal impairment.

Answer 4

(1) Digoxin (arrhythmias/ nausea, narrow therapeutic range and only one elimination pathway)
(2) K+ sparing diuretics (hyperkalaemia, problem esp when there is underachieve RAAS system)
(3) Nitrofurantoin (neuropathy)
(4) Tetracyclines (increased protein breakdown)
(5) Metformin (lactic acidosis)

Question 5

1. What causes pre-renal kidney impairment?

2. What actions do you take in this case?

Answer 5

1. Caused by decreased renal perfusion or altered auto regulation (blood through flow microvasculature). Especially if sudden changes in volume state e.g. vomiting, diarrhoea, bleeding, cardiac failure, cirrhosis.
2. Discontinue potentially nephrotoxic drugs +/- support blood pressure.

Question 6

Name 5 classes of drugs which are associated with pre-renal impairment.

Answer 6

(1) Diuretics (esp with diarrhoea and vomiting)
(2) Antihypertensives, especially ACEis, ARBs and other vasodilators (CCBs, nitrates etc)
(3) NSAIDs (hidden problem because of OTC purchase)
(4) Ciclosporin (DMARD)
(5) Radio contrast media.

Question 7

Name 9 drugs which cause acute kidney injury i.e. intrinsic renal impairment.

Answer 7

(1) Aminoglycosides (Gentamicin)
(2) Amphotericin B
(3) Other antimicrobials (Quinolones, macrolide)
(4) Anti-platelets (clopidogrel)
(5) Anti-convulsants (Phenytoin/ carbamazepine)
(6) DMARDs
(7) Lithium
(8) NDSAIDs / COX-2 inhibitors
(9) Radio contrast media

Question 8

Post-renal impairment:

1. Name two drugs that cause crystal/stone formation
2. Name two drugs that cause retroperitoneal fibrosis (rare)

Answer 8

1. Aciclovir and methotrexate
2. Ergot derivatives
   Methyldopa/ Hydralazine/ atenolol

Question 9

Name the 6 specific drugs to use with caution:

Answer 9

(1) NSAIDs
(2) ACEis/ ARBS
(3) Diuretics
(4) Lithium
(5) Digoxin
(6) Gentamicin

Question 10

How are NSAIDs nephrotoxic?

What is the issue with NSAID availability?

Answer 10

They can cause:

• Acute tubular necrosis
• Interstitial Nephritis (!!!)
• Glomerulonephritis
• Renal papillary necrosis.

Available OTC and so you need to ask about use because can often be hidden!

Question 11

1. How do ACE inhibitors and ARBs cause renal impairment?

2. When are they contraindicated?

Answer 11

1. They reduce intra-glomerular pressure and reduce proteinuria which is why they are used to cause a decrease in blood pressure. However this may be associated with a deterioration in renal function
2. Renal Artery Stenosis (and held when patient is acutely unwell).

Question 12

What drugs do diuretics interact with? (5)

Answer 12

(1) DIURETICS - increased electrolyte disturbances when combined
(2) AMINOGLYCOSIDE ANTIBIOTICS - Increased ototoxicity and nephrotoxicity with loop diuretics
(3) NSAIDs - Impaired diuresis
(4) ACE INHIBITORS and VASODILATORS - Hypotension
(5) LITHIUM - Cause lithium toxicity when co-prescribed with thiazide diuretics (coprescribed because patients which psychosis have a high cardiovascular risk)

Question 13

1. What is the route of elimination of lithium?
2. When should lithium be avoided?
3. How do they interact with the effect of ADH?
4. What does long-term use cause?
5. What does lithium interact with to increase the chance of lithium toxicity?

Answer 13

1. Lithium is excreted by the kidney.
2. In severe renal impairment. Also reduce dose during episodes of illness as lithium renal excretion is reduced.
3. Can block the effect of ADH on the kidney - can cause diabetes insipidis.
4. Long term use can cause tubulo-interstitial damage.
5. Diuretics, ACE Inhibitors and ARBs.

Question 14

1. How is Digoxin excreted?
2. Comment on digoxin’s therapeutic range.
3. What happens to digoxin’s half-life and time to reach steady state in renal impairment?
4. What ion imbalance increases the risk of toxicity? And what drug combination should be avoided due to this?

Answer 14

1. By the kidney.
2. Narrow therapeutic range
3. Half-life increases and time to steady state increases also.
4. Hypokalaemia.
   Therefore you should take caution in co-prescription with diuretics (heart failure common Rx)

Question 15

1. What is the route of administration of gentamicin and why?
2. What is the route of elimination of gentamicin? Rate?
3. What is its half life?
4. How is gentamicin prescription adjusted in renal impairment?
5. What do you need to measure more often?

Answer 15

1. IV because the molecules are highly polar. Therefore variable penetration into body fluids.
2. Via the kidney. The elimination rate mirrors the eGFR.
3. Half life is 2-3 hours
4. Adjust the DOSE and the FREQUENCY to prevent dose-dependent side effects.
5. Trough levels and U&E

Question 16

Give 4 main points about drug induced acute kidney injury.

Answer 16

(1) Usually irreversible if detected early.
(2) Detection of this is done by looking at the serum creatinine and eGFR along with urinary sediment.
(3) Stop potentially nephrotoxic drugs
(4) Ensure appropriate supportive treatment e.g. IV fluids

Question 17

Chronic Kidney Disease Staging. 
Stage 1 - eGFR? Description? Qualifier
Stage 2 - eGFR? Description? Qualifier? 
Stage 3 - A eGFR? B eGFR? Description? Qualifier? 
Stage 4 - eGFR? Description? Qualifier?
Stage 5 - eGFR? Description? Qualifier?

Answer 17

Stage 1 - > or equal to 90 ml/min/1.73m2
Kidney damage, normal or increased GFR, Qualifier kidney damage for 3 months or more

Stage 2 - 60-89ml/min/1.73m2
Kidney damage, mildly reduced eGFR, qualifier kidney damage for 3 months or more.

Stage 3 - A eGFR = 45-59
B eGFR = 30-44 ml/min/1.73m2
Moderately reduced eGFR +/- other evidence of kidney damage, qualified by FR 60 ml/min for 3 months or more +/- kidney damage.

Stae 5 -

Question 18

1. How does renal impairment affect the loading dose and volume of distribution of a drug?
2. How is maintenance dose affected by renal impairment?
3. How do you change the maintenance dose? For drugs with what characteristics?
4. What guides these decisions?

Answer 18

1. No change in the loading dose as volume of distribution is unaltered.
2. Decreased (for drugs eliminated by the kidney).
3. Reduce individual doses
   Lengthen the dosage interval. Narrow therapeutic window and primarily eliminated by the kidney.
4. eGFR and (less accurately) the serum creatinine.

Question 19

Describe the principles for prescribing in renal failure?

Answer 19

• For many drugs with only minor and no dose-related side effects a simple scheme for dose reduction is sufficient.
• Reduce the dose of drugs eliminated by the kidney
• The time taken to reach steady state will be increased
• Avoid drugs which are nephrotoxic if possible
• Adjustment of the maintenance dose should be made using the GFR and where appropriate plasma drug levels.

Question 20

Give two other functions of the kidney (other than as an elimination organ).

Answer 20

(1) Release of erythropoietin which stimulates RBC production
(2) Parathyroid hormone stimulates Ca++ uptake in kidneys and release of active Vitamin D.

Question 21

What treatments are given in severe Chronic Kidney Disease?

Answer 21

(1) Phosphate binding agents - Calcium carbonate taken with meals
(2) Vitamin D (calcitrol) daily tablet for secondary hyperPTH/ renal osteodystrophy
(3) Erythropoeitins for symptomatic anaemia.
(4) Dialysis/ replacement therapy

Question 22

1. Which drugs are removed more readily in dialysis treatment?
2. What drugs may require a supplementary dose?
3. Dialysis can be used in acute poisoning for which drugs?

Answer 22

1. Small molecules with low protein binding will be removed more readily.
2. • Theophylline
     - Metronidazole
     - Gentamicin/ Tobramicin
     - Anti-virals
3. • Aspirin
     - Lithium
     - Ethylene glycol
     - Methanol
     - Sodium Valproate
     Depending on how readily the drug molecule can diffuse across.