Pharmacology of CKD

Question 1

What is the primary 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 are examples of statins and their drug target?

Answer 2

Drug target: Hydroxymethylglutaryl-CoA (HMG-CoA) reductase.

Examples: Simvastatin, artorvastatin

Question 3

What are the main 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 4 facts about statins?

Answer 4

1. Effective at reducing the risk of adverse cardiac events in people.
2. All patients should be regularly followed up to monitor for hyperkalaemia and acute renal failure.
3. Coadministration with potent 3A4 inhibitors may result in increased statin serum concentrations.
4. In 2020, artorvastatin was the 1st and simvastatin the 11th most commonly prescribed drugs in the West London area

Question 5

What is the primary mechanism of action of aspirin?

Answer 5

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 6

What is the drug target of aspirin?

Answer 6

Cyclo-oxygenase

Question 7

What are the main side effects of aspirin?

Answer 7

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 8

What are 3 facts about aspirin?

Answer 8

1. Low dose aspirin is the most cost effective medicine for the prevention of secondary events of thrombosis.
2. Blockade of COX1 in gastric mucosal cells reduces mucus/bicarbonate production which can expose the stomach lining to acid.
3. In 2020, aspirin was the 8th most commonly prescribed drugs in the West London area

Question 9

What is the primary mechanism of action of trimethoprim?

Answer 9

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 10

What is the drug target of trimethoprim?

Answer 10

Dihydrofolate reductase

Question 11

What are the main side effects of trimethoprim?

Answer 11

Diarrhoea

Skin reactions

Question 12

What are the 2 main facts about trimethoprim?

Answer 12

1. Often administered with sulfamethoxazole – known as co-trimoxazole. In combination, they block two steps in bacterial biosynthesis of essential nucleic acids and proteins.
2. 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 13

What is the primary mechanism of action of gentamicin?

Answer 13

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

Question 14

What is the drug target of gentamicin?

Answer 14

30s ribosomal subunit

Question 15

What are the main side effects of gentamicin?

Answer 15

Ototoxicity and nephrotoxicity are important side effects to consider.

Question 16

What are the two facts about gentamicin?

Answer 16

Gentamicin is an aminoglycoside antibiotic. Can pass through gram negative cell membrane in an oxygen dependent manner (why they are ineffective against anaerobic bacteria).
More likely to be administered intravenously (in hospital) for endocarditis, septicaemia, meningitis, pneumonia or surgical prophylaxis.

Question 17

What is the primary mechanism of action of calcium channel blockers?

Answer 17

Block L-type calcium channels – predominantly on vascular smooth muscle. This results in a decrease in calcium influx, with downstream inhibition of myosin light chain kinase and prevention of cross-bridge formation. The resultant vasodilation reduces peripheral resistance.

Question 18

What is the drug target of calcium channel blockers?

Answer 18

L-type calcium channel

Question 19

What are the main side effects of calcium channel blockers?

Answer 19

Ankle oedema
Constipation
Palpitations
Flushing/Headaches

Question 20

What is a fact about calcium channel blockers?

Answer 20

Dihydropyridine type calcium channel blockers demonstrate a higher degree of vascular selectivity.

Question 21

What is the primary mechanism of action of ACE inhibitors?

Answer 21

Inhibit the angiotensin converting enzyme. Prevent the conversion of angiotensin I to angiotensin II by ACE.

Question 22

What is the drug target of ACE inhibitors?

Answer 22

Angiotensin Converting Enzyme

Question 23

What are the main side effects of ACE inhibitors?

Answer 23

Cough
Hypotension
Hyperkalaemia (care with K+ supplements or K+-sparing diuretics)
Foetal Injury (AVOID IN PREGNANT WOMEN)
Renal failure (in patients with renal artery stenosis)-
Urticaria/Angioedema

Question 24

What are 2 facts about ACE inhibitors?

Answer 24

Most trials indicate that angiotensin receptor blockers are not as effective anti-hypertensive agents as ACE inhibitors.
Losartan and candesartan are pro-drugs. They require hepatic activation to generate the active metabolites required for therapeutic effects.

Question 25

What is the primary mechanism of action of dapaglifozin?

Answer 25

Reversibly inhibits sodium-glucose co-transporter 2 (SGLT2) in the renal proximal convoluted tubule to reduce glucose reabsorption and increase urinary glucose excretion.

Question 26

What is the drug target of dapaglifozin?

Answer 26

SGLT2. The primary site of SGLT2 inhibitor action is the proximal convoluted tubule.

Question 27

What are the main side effects of dapaglifozin?

Answer 27

Uro-genital infections due to increased glucose load (5% of patients). Slight decrease in bone formation. Can worsen diabetic ketoacidosis (stop immediately).

Question 28

What are 2 facts about dapaglifozin?

Answer 28

SGLT2 inhibitors cause weight loss and a reduction in BP.

SGLT2i action depends on normal renal fucntion so they are less effective in patients with renal impairment

Question 29

What is the primary mechanism of action of NSAIDs?

Answer 29

NSAIDS inhibit the enzyme cyclo-oxygenase (COX) which is the rate-limiting step for the production of all prostanoids (prostaglandins & thromboxanes) from the parent arachidonic acid. Prostanoids act through a large number of prostanoid receptors to produce a highly complex array of actions.
It is thought that the anti-inflammatory actions, and probably most of the analgesic & antipyretic actions, of the NSAIDs are related to inhibition of COX-2, while their unwanted effects are largely a result of inhibition of COX-1.

Question 30

What is the primary drug target of NSAIDs?

Answer 30

Cyclo-oxygenase (COX) enzyme

Question 31

What are the most common side effects of NSAIDs?

Answer 31

Common unwanted effects include gastric irritation, ulceration and bleeding and, in extreme cases, perforation; reduced creatinine clearance and possible nephritis; and bronchoconstriction in susceptible individuals (contraindicated in asthma). Skin rashes & other allergies, dizziness, tinnitus.
Adverse cardiovascular effects (hypertension, stroke, MI) may occur following prolonged use or in patients with pre-existing CV risk.
Prolonged analgesic abuse over a period of years is associated with chronic renal failure.
Aspirin has been linked with a rare but serious post-viral encephalitis (Reye’s syndrome) in children.

Question 32

What are the main uses of NSAIDs?

Answer 32

The main uses of NSAIDs are as analgesics for the relief of mild to moderate pain (e.g. musculoskeletal pain, headache, dysmenorrhoea); as antipyretics to reduce fever; as anti-inflammatory drugs for chronic control of inflammatory diseases (e.g. rheumatoid arthritis, osteoarthritis); and (aspirin only) as an anti-aggregatory agent to inhibit platelet aggregation in patients who are at risk of stroke or myocardial infarction.