Pharmacology

Question 1

Mechanism of Action of NSAIDs

Answer 1

Inhibit COX (cyclooxygenase) to inhibit prostaglandins
- COX1 and COX 2
Examples: aspirin (COX 1 > 2), ibuprofen, diclofenac, naproxen
COX2 selective inhibitors: celecoxib, meloxicam

COX1: regulation of homeostatic functions throughout the body
COX2: regulate prostaglandins that mediate pain and inflammation

Cyclooxygenase is required to convert arachidonic acid into thromboxanes, prostaglandins, and prostacyclins.

Question 2

Triple Whammy

Question 3

Mechanism of Action of Frusemide

Answer 3

• Acts on the Na/K/Cl co-transporter
• Causes contraction alkalosis
• RAAS: increased sodium/water, decreased K/hydrogen
• Hypokalaemia independently associated with metabolic alkalosis (transcellular shift)
• HCT causes low Na+, frusemide tends to not affect NA

Question 4

What happens to the afferent/efferent arterioles with:
SGLT2 inhibitors
NSAIDs
ACEi

Answer 4

SGLTs inhibitors: VASOCONSTRICTION of AFFERENT arterioles
NSAIDS: VASOCONTRICTION of AFFERENT arterioles
ACEI: VASODILATION of EFFERENT arterioles

Question 5

MOA and SE of tolvaptan

Answer 5

MOA: Tolvaptan is a competitive antagonist at vasopressin V2 receptors - reduce aquaporin 2 channels in collecting duct. Its major action is in the renal collecting ducts to reduce water reabsorption and produce aquaresis without sodium loss, thus increasing free water clearance and correcting dilutional hyponatraemia.

SE:
- Profound polyuria + polydypsia- patients need to be able to drink at least 5-6L of water or can cause pre-renal AKI, stop other diuretics
- Abnormal LFTs - monitoring monthly for 18 months
- Decrease in EGFR (not true AKI) - similar effect with RAASi and SGLT2i
- Increase gout
- Hypernatremia

Question 6

When is renin secreted?

Answer 6

Renin is only secreted when there is renal hypoperfusion in the setting of reduced circulating volume

Question 7

MOA of belatacept and abatacept

Answer 7

• Belatacept and Abatacept
  MOA: selective T cell co-stimulation blocker. Binds to Cd80/86 on antigen presenting cells, thereby blocking CD28 mediated costimulation of T lymphocytes
  Fusion protein composed of Fc fragment of IgG1 linked to the extracellular domain of CTLA-4 which inhibits T cell activation

Question 8

MOA of tacrolimus and cyclosporin

Answer 8

Calcineurin inhibitor
IL-2 inhibitor

• TAC>CYC: ↑ NODAT/DM, ↑ CVS dx, ↑ tremor, ↑ alopecia, NO gum hypertrophy
• Both: nephrotoxicity (biopsy: striped fibrosis), ↑ HTN, ↑K, ↓Mg, TMA/aHUS, PRES, NODAT, CVS dx, tremor/neurotoxicity, alopecia

Question 9

MOA of anti-proliferatives: mycophenolate, azathioprine

Answer 9

• inhibits IMPDH(II), preferential action lymphocytes, involved in purine synthesis
  IMPDH: Inosine-5′-monophosphate dehydrogenase
• blocks de novo purine synthesis - G1 ARREST

Mycophenolates more potent in first 12 months and relatively leukocyte specific:

Dose controlled
- Mycophenolate sodium absorbed more distally, less GI tox
- Synergies with other Immunosuppressives
- Interactions – mycophenolate levels lower with CSA

Bone marrow suppression

• additive to sirolimus, everolimus, valgancyclovir
• azathioprine accumulation with allopurinol (4-fold)

Mycophenolate

• MMF>AZA: ↓ Rejection
• Side Effects: ↓ BM suppression, GIT upset (diarrhoea)
• NOT for pregnancy

AZA

• Side Effects: ↓ BM suppression, GIT upset, ↑LFT, ↑Cx, ↑pneumonitis, pancreatitis
• SAFE in pregnancy
• ↑ levels: allopurinol, febuxostat