Pharmacology of CKD

Question 1

What is the mechanism of action of statins?

Answer 1

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 2

What is the primary target of statins?

Answer 2

Hydroxymethylglutaryl-CoA (HMG-CoA) reductase

Question 3

What are the side effects of statins?

Answer 3

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 4

What are statins good at reducing the risk of?

Answer 4

adverse cardiac events

Question 5

Why should patients with statins be followed up?

Answer 5

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





Coadministration with potent 3A4 inhibitors may result in increased statin serum concentrations.

Question 6

What is the mechanism of action of aspirin?

Answer 6

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 7

What is the primary target of aspirin?

Answer 7

Cyclo-oxygenase

Question 8

What are the side effects of aspirin?

Answer 8

Dyspepsia

Haemorrhage

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





Question 9

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

Answer 9

low dose aspirin

Question 10

How can aspirin expose the stomach lining to acid?

Answer 10

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

Question 11

What is the mechanism of action of Trimethoprim?

Answer 11

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

Question 12

What is the primary target of Trimethoprim?

Answer 12

Dihydrofolate reductase

Question 13

What are the side effects of Trimethoprim?

Answer 13

Diarrhoea

Skin reactions



Question 14

What is Trimethoprim often administered with?

Answer 14

Often administered with sulfamethoxazole – known as co-trimoxazole. In combination, they block two steps in bacterial biosynthesis of essential nucleic acids and proteins.



Question 15

What do you need to monitor when using Trimethoprim long term?

Answer 15

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 16

What is the mechanism of action of Gentamicin?

Answer 16

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

Question 17

What is the primary target of Gentamicin?

Answer 17

30s ribosomal subunit

Question 18

What are the side effects of Gentamicin?

Answer 18

Ototoxicity and nephrotoxicity are important side effects to consider.

Question 19

What type of antibiotic is gentamicin?

Answer 19

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 20

How is Gentamicin most likely to be administered?

Answer 20

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



Question 21

What is proteinuria a marker of?

Answer 21

marker of glomerular dysfunction AND damaging in its own right

Question 22

What drugs improve proteinuria?

Answer 22

Angiotensin converting enzyme inhibitors (ACEi)
or angiotensin receptor blockers (ARB)

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors (e.g. dapagliflozin)

Salt restriction (to normal recommended levels!)

Stop Amlodipine if the ACEi reduces his BP too low

Question 23

Why does use of Trimethoprim invalidate the GFR calculator?

Answer 23

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 24

What determines how much creatinine there is in the blood?

Answer 24

If the CREATININE level goes up, it MUST BE because the GFR has decreased

If the CREATININE level goes down, it MUST BE because the GFR has increased

Question 25

What is the effect of ibuprofen on the kidney?

Answer 25

Inhibits PG synthesis and reduces renal blood flow

Question 26

What is the effect of ACE on the kidney?

Answer 26

Reduces perfusion pressure in glomerulus, exacerbated by sepsis

Question 27

What should you consider when prescribing for a patient with reduced renal function?

Answer 27

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)