CKD Pharamacology

Question 1

What are the drugs for CKD? (4 main)

Answer 1

Statins
aspirin
trimethoprim
gentamicin

previously mentioned…
calcium channel blockers
ACEi
angiotensin receptor blockers
dapagliflozin
NSAIDs

Question 2

What are examples of statins?

Answer 2

Simvastatin, artorvastatin

Question 3

What are the drug targets of statins?

Answer 3

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase

Question 4

What is the mechanism of action of statins?

Answer 4

Statins are a selective, competitive inhibitor of hydroxymethylglutaryl-CoA (HMG-CoA) reductase, which is the enzyme responsible for converting HMG-CoA to mevalonate in the cholesterol synthesis pathway. By reducing hepatic cholesterol synthesis, an upregulation of LDL-receptors and increased hepatic uptake of LDL-cholesterol from the circulation occurs.

Question 5

What are the side effects of statins?

Answer 5

Muscle toxicity
- can occur with all statins, however the likelihood increases with higher doses and in certain patients at increased risk of muscle toxicity.

Constipation or diarrhoea. Other gastrointestinal symptoms

Question 6

What adverse effect are statins good at reducing?

Answer 6

cardiac events

Question 7

Should patients be followed up if using statins?

Answer 7

All patients should be regularly followed up to monitor for hyperkalaemia and acute renal failure.

Question 8

Statins co-administered with what may increase statin serum conc?

Answer 8

potent 3A4 inhibitors

Question 9

What is the drug target of aspirin?

Answer 9

Cyclo-oxygenase

Question 10

What is the mechanism of aspirin?

Answer 10

Irreversible inactivation of COX enzyme. Prevents oxidation of arachidonic acid to produce prostaglandins.
Reduction of thromboxane A2 in platelets reduces aggregation.
Reduction of PGE2 (i) at sensory pain neurones reduces pain and sensation and (ii) in the brain decreases fever.

Question 11

What are the main side effects of aspirin?

Answer 11

Dyspepsia
Haemorrhage
In the elderly, avoid doses greater than 160mg daily (increased risk of bleeding) and co-administer PPI if past history of peptic ulcer.

Question 12

What is the most cost effective medicine for the prevention of secondary events of thrombosis?

Answer 12

Low dose aspirin

Question 13

How can aspirin expose the stomach lining to acid?

Answer 13

Blockade of COX1 in gastric mucosal cells reduces mucus/bicarbonate production which can expose the stomach lining to acid.

Question 14

What is the drug target of trimethroprim?

Answer 14

Dihydrofolate reductase

Question 15

What is the mechanism of trimethoprim?

Answer 15

Direct competitor of the enzyme dihydrofolate reductase. Inhibits the reduction of dihydrofolic acid to tetrahydrofolic acid (active form) – a necessary component for synthesising purines required for DNA and protein production in bacteria (it is an antibiotic)

Question 16

What are the side effects of trimethoprim?

Answer 16

Diarrhoea
Skin reactions

Question 17

What is trimethoprim often administered with?

Answer 17

sulfamethoxazole – known as co-trimoxazole.

In combination, they block two steps in bacterial biosynthesis of essential nucleic acids and proteins.

Question 18

What do you need to monitor if prescribing trimethoprim?

Answer 18

Need to monitor blood counts with long term use or in those at risk of folate deficiency. Also monitor serum electrolytes in patients at risk of developing hyperkalaemia.

Question 19

What are the drug targets of gentamicin?

Answer 19

30s ribosomal subunit

Question 20

What is the mechanism of action for gentamicin?

Answer 20

Binds to the bacterial 30s ribosomal subunit disturbing the translation of mRNA leading to the formation of dysfunctional proteins.

Question 21

What are the side effects of gentamicin?

Answer 21

Ototoxicity and nephrotoxicity are important side effects to consider.

Question 22

What is gentamicin?

Answer 22

Gentamicin is an aminoglycoside antibiotic. Can pass through gram negative cell membrane in an oxygen dependent manner (why they are ineffective against anaerobic bacteria).

Question 23

How is gentamicin more likely to be administered?

Answer 23

More likely to be administered intravenously (in hospital) for endocarditis, septicaemia, meningitis, pneumonia or surgical prophylaxis.

Question 24

Answer 24

Question 25

What treatment would the GP initiate at this point?

Answer 25

For HTN:
Aged > 55 = Amlodipine (L-type calcium channel blocker) Target should be lower than normal due to CKD (eg 130/70)

For CKD:
Tight blood pressure control (to slow CKD progression – regardless of cause)

For cardiovascular risk:
Conservative measures (smoking, salt, exercise) Atorvastatin as risk >10% (13%-31% depending on ethnicity)
Statins reduce cholesterol – you will learn about them later

Question 26

The patient is referred to nephrology services and diagnosed with chronic kidney disease secondary to hypertension, with no other causes identified. The amlodipine is controlling his BP well (125/70) but he now has significant proteinuria (ACR >30).

What treatments should the nephrologist initiate for the proteinuria and what treatment might need to be stopped?

Answer 26

• Proteinuria is a marker of glomerular dysfunction AND damaging in its own right
• Drugs/interventions which improve proteinuria:
  Ø Angiotensin converting enzyme inhibitors (ACEi)
  or angiotensin receptor blockers (ARB)
  Ø Sodium-glucose co-transporter-2 (SGLT-2) inhibitors (e.g. dapagliflozin)
  Ø Salt restriction (to normal recommended levels!)
• Stop Amlodipine if the ACEi reduces his BP too low

Question 27

His use of trimethoprim invalidates the GFR calculators. Why is this, and do you think his GFR has in fact changed?

Answer 27

GFR probably hasn’t changed (but impossible to say without formally measuring it)

Trimethoprim inhibits the active secretion of creatinine so the equation to calculate GFR is now invalid.

Trimethoprim breaks the link between creatinine and GFR

Question 28

The patient is referred to nephrology services and diagnosed with chronic kidney disease secondary to hypertension, with no other causes identified. The amlodipine is controlling his BP well (125/70) but he now has significant proteinuria (ACR >30).
Would you treat this patient with aspirin?

Answer 28

Both answers are justified
NICE guidelines in CKD:
* Consider prescribing aspirin in people with a high risk of stroke or myocardial
infarction
* There is limited evidence of benefit even in people with multiple risk factors and there is a risk of harm

In general, we tend to avoid aspirin for primary prevention

Question 29

What is his GFR now and which of his drugs are contributing to the worsening GFR and how?

Answer 29

GFR – 12mls/min (15mls/min if black)

Ibuprofen
Inhibits PG synthesis and reduces renal blood flow

ACEi
Reduces perfusion pressure in glomerulus, exacerbated by sepsis

Note sepsis will also be contributing to his acute injury

Question 30

You are the admitting doctor on the medical ward and making a plan for his medication. What would you do about the ibuprofen, ACEi, and gentamicin?

Answer 30

Ibuprofen
STOP. Use alternatives (e.g., paracetamol)

ACEi
Pause whilst he is acutely unwell.

Gentamicin
Can continue but reduce frequency and be guided by blood gentamicin levels. (Or choose alternative!)

Question 31

What are 2 things to consider when prescribing for a patient with reduced renal function?

Answer 31

1) Might the drug damage the kidney and hence worsen the kidney injury (eg ibuprofen)

2) Is the drug eliminated by the kidney, and hence will it accumulate in the blood if kidney function is impaired, and hence lead to side effects?
(eg morphine, metformin)