Renal Pharmacology - Imig Flashcards Preview

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Flashcards in Renal Pharmacology - Imig Deck (60):

What is the mechanism of action of Mycophenolate Mofetil (MMF)?

Is it natively active?

Mechanism: competitive, reversible inhibitor of IMPDH, a critical enzyme in de-novo purine synthesis. Inhibits proliferation of B and T lymphocytes

Prodrug: MMF is activated to Mycophenolic Acid (MPA), its active form


Mycophenolate Mofetil:

  1. Method of administration?
  2. Route of metabolism?
  3. Half-life?
  4. Adverse effects?

  1. oral or IV
  2. liver metabolism
  3. long half-life (18 hours)
  4. Adverse effects:
    • hypertension, edema, tachycardia
    • dyspnea, cough
    • dizziness, insomnia, tremor, seizures
    • leucopenia, thrombocytopenia, anemia
    • opportunistic infections (CMV, bacterial UTI, etc)
    • lympoproliferative disease, cancer


Name some drugs that decrease MPA levels in the administration of mycophenolate mofetil (MMF)?

Is MMF affected by the administation of tacrolimus or sirolimus?

Decrease MPA levels: antacids, cholestyramine, sevelamer, FeSO, phenytoin, phenobarbital, corticosteroids, cyclosporine

No change in MPA levels with tacrolimus or sirolimus


Describe the mechanism of action of azathioprine

Purine analogue. Metabolized by the liver to 6-MP, then TIMP. Decreases synthesis of DNA and also incorporates into DNA. Also blocks CD28 co-stimulation of T-cells.


What are some similar alternatives to azathioprine?





  1. Route of administration?
  2. Half life?
  3. Unwanted side effects?

  1. oral
  2. short (3-5 hours)
  3. Unwanted side effects:
    • bone marrow suppression (leukopenia, thrombocytopenia)
    • hypersensitivity reactions (malaise, dizziness, fever, rash, GI issue, hypotension)
    • opportunistic infections
    • alopecia
    • small lymphoma risk


Why should you use caution when administering allopurinol with azathioprine?

Allopurinol decreases 6-MP metabolism -> reduce azathioprine dose by 75% if used together


Discuss the clinical monitoring implications of azathioprine and MMF

Both: monitor CBC regularly for hematologic side effects

MMF: monitor for GI effects and consider lower dose / more frequenct administration to relieve this side effect


Name (3) IL-2 receptor antibody drugs used in renal transplant

Basiliximab - anti-CD25 chimeric

Daclizumab - anti-CD25 humanized

Alemtuzumab - anti-CD52 humanized



  1. Route of administration?
  2. half life?
  3. Use?
  4. Adverse effects

  1. IV
  2. very long (1 week)
  3. inductive transplant agent given immediatly prior to surgery and 4 days following surgery
  4. (rare) hypersensitivity reaction



  1. route of administration
  2. mechanism of action
  3. therapeutic use
  4. half life
  5. unwanted side effects

  1. IV
  2. Binds CD80/86 -> blocks co-stimulatory step of T-cell activation
  3. Renal transplant for EBV-seropositive patients
  4. very long (8-10 days)
  5. unwanted side effects:
    • (rare) hypersensitivity reaction
    • lymphoproliferative disorder in patients w/ no prior EBV exposure


Discuss the therapeutic effects of prednisolone administration in renal transplant

Are its effects fast of slow?

  • inhibits NF-kB (pro-inflammatory transcription factor)
  • Activates anti-inflammatory genes
  • Reduce T-cell proliferation and increase T-cell apoptosis

These effects are slow: >8 hours (transcription and protein synthesis.


What is an important interaction to consider when using corticosteroids with other typical transplant drugs?

Interactions with calcineurin inhibitors (CNIs) - may potentiate adverse effects


Name some possible side effects of corticosteroid use


cushingoid facies


mood disorders


glucose intolerance



growth retardation (children)


Due to advances in immunosuppression, what is the typical longevity in renal allografts?

10-15 years. Sometimes 20.


What are the two general categories of agents used in an overall transplant rejection suppression strategy?

Induction agents - monoclonal or polyclonal antibodies administered immediately before/after surgery

Maintenence agents - corticosteroids, CINs, anti-proliferative agents


What drug class forms the 'cornerstone' of immunosuppressive maintenence therapy?

Calcineurin inhibitors (CINs)


What is an important physiological parameter to monitor when using induction agents?

Check fluid volume status


Describe the recent trends in usage of the following in renal transplant:

  • cyclosporin or tacrolimus
  • MMF or AZA
  • mTOR inhibitors
  • corticosteroids

  • tacrolimus used more -> cyclosporine falling out of use
  • MMF used more -> AZA falling out of use
  • mTOR inhibitors generally used less
  • Corticosteroids are generally used less


With respect to RAAIs and corticosteroids/immunosuppressants, give the treatment indication for the following:

  • IgA nephropathy
  • Nephrotic syndrome
  • Membranous nephropathy
  • Focal Segmental Glomerulosclerosis
  • Lupus Nephritis
  • Anti-GBM/Goodpasture's

  • ACE-I, corticosteroids or immunosuppressants
  • ACE-I or ARB
  • ACE-I or ARB, corticosteroids or immunosuppressants
  • ACE-I, corticosteroids or immunosuppressants
  • Corticosteroids (class V)
  • Corticosteroids


Summarize several possible approaches to preventing renal transplant rejection.

Calcineurin inhibition

mTOR inhibition


T-cell depleting mAbs


What is the mechanism of action of cyclosporine?

How is it administered and metabolized?

Binds cyclophilin to inhibit calcineurin, leads to decreased IL-2 and T-cell proliferation.

Oral/IV (+ophthalmic?), concentrates in various tissues (~27hr half-life) and metabolized by CYP3A4 in liver.


What are the side effects associated with cyclosporine? (lol)

Nephrotoxicity (vasoconstriction, TGFb, fibrosis, tubular atrophy)

HTN & fluid retention

Hepatic dysfunction

N/V/D, Headache, Fatigue, Tremor

Hypertrichosis, Gum hypertrophy

Hyperlipidemia, hypomagnesemia, hypokalemia.


What drugs should be avoided with cyclosporine treatment?

Is this drug commonly used?

Anything nephrotoxic (NSAIDs, AMGs), and CYP inhibitors (too many to actually list)

No, it has been largely replaced by tacrolimus because of its poor SE profile and poor compliance.


Compare and contrast Tacrolimus with Cyclosporine's:

Mechanism of action


Side effect profile

Binds FKBP12 which inhibits calcineurin.

More variable half life (requires monitoring), same administration and liver CYP3A4.

Less nephrotoxic (no TGFb), less HTN/lipid disturbance, more neurotoxicity. Beware effusions & cardiomyopathy.


What monitoring should be done when administering calcineurin inhibitors?

Assess liver function, blood pressure, lipid & glucose profiles, neural functions, and drug concentration (Tacrolimus?)


What drugs should be avoided when administering calcineurin inhibitors in general?

Nephrotoxic agents (NSAIDs, many Abx)

Potassium-sparing diuretics (hyperkalemia)

Antacids (affect absorption of CNI)

Statins (rhabdomyloysis, BMS)


Distinguish between the mechanisms of action of tacrolimus and sirolimus.

What are the benefits of sirolimus over calcineurin inhibitors?

Both bind FKBP12, but the complex with sirolimus. Both block proliferation via IL-2, but sirolimus also blocks cell cycle progression.

Provide prophylaxis with less vasoconstriction and less renal insuffiency (less fibrosis, GFR ok)


Describe the pharmacokinetic profile of sirolimus.

What are its side effects?

Orally administered (mind PgP effects), metabolized by intestine & liver. Very long half-life (60hrs)

Edema, tachycardia, hypertension, GI upset, hyperlipidemia, hypokalemia, hypophosphatemia, lymphocele, rash


Between Cyclosporine, Tacrolimus, and Sirolimus, which has:

The worst nephrotoxicity?

The worst neurotoxicity?

The worst hyperlipidemia?

Which causes hypertrichosis?

Cyclosporine worst for kidneys.

Tacrolimus worst for nerves.

Sirolimus +++ for hyperlipidemia.

Cyclosporine causes hirsutism.


What is the mechanism of action of MPA?

What is the difference between MPA and MMF?

Why are lymphocytes specifically targeted?

Competitive, reversible inhibition of IMPDH, to block the de novo pathway of purine synthesis.

MMF (mofetil) is a prodrug.

Lymphocytes apparently are dependent on the de novo pathway, rather than the salvage pathway.


How is MMF administered & metabolized?

What are its side effects?

Oral/IV, metabolized by liver (18hrs)

HTN/Edema, dyspnea/cough, dizziness, tremor, seizures, insomnia. Anemiasopportunistic infections, lymphoproliferative disease and skin cancer.


What drugs interact with MMF?

Seriously? A shitload of drugs interact to decrease MPA: Antacids, cholestyramine, sevelamer, rifampin, blahblah.

Focus on this: Steroids & Cyclosporine decrease MPA, Tacrolimus & Sirolimus do not.


What are some of the most common ways to acute injury the kidney?

Antibiotics, chemotherapy, radiocontrast dyes, thoracic surgery


What percentage of acute kidney injury results in chronic kidney injury?


How is kidney disease treated?



fluid and BP maintenace, hemodialysis


What causes acute renal injury? (very general)  


What can cause chronic kidney disease?

Renal Ischemia


Diabetic nephropathy, hypertension, glomerulonephritis, HIV nephropathy, polycystic kidney disease, kidney infectio


What five classes of drugs are currently being proposed to treat acute kidney failure?




Growth factors



What drugs are being used to treat chronic kidney failure?

Renin-Angiotensin inhibitors


How is diabetic nephropathy treated?

Good glycemic control 

BP control 



When is anemia seen in CKD?


How is it treated?

Can be seen at any stage, but most likely in 3 or 4


Treated with epoetin 


How does epoetin work?  


What are some side effects?

it is a recombinant version of erythropoetin, causes red blood cell production


Nausea, headache, vomitting, diarrhea (of course)

dose-dependent hypertension 



Why secondary hyperparathyroidism seen in chronic kidney failure?

Lower GFR ---> lower phosphate excretion ---> lower free calcium ---> high levels of PTH


How many generations of Vitamin D analogues are there? Describe how each class was produced from a synthetic perspective.

3 Generations

  • 1st Gen: Calcitriol - synthetic form of endogenous Vit D
  • 2nd Gen: Various compounds produced by side-chain modifications to the native molecule
  • 3rd Gen: Various compounds produced by additional modifications to the A-ring of the native molecule


What are the mechanisms of action of Calcitriol and Vit D analogues? Be specific.

What is the major side effect of these drugs?

  • Enchance intestinal absorption of Ca2+ and PO43-
    • Via increased synthesis of Ca channels and the Ca-binding calbindin protein (CaBP)
    • Activation of cytoplasmic Vit D receptor (VDR)
      • Increased mRNA and protein synthesis
      • Promotes endocytic capture and transport of Ca
  • Enchance recruitment and differentiation of osteoclast precursors (resorption of Ca and PO4)
  • Enchances renal tubular reabsorption of Ca

Major S/E: Hypercalcemia from excessive dosing


What Vit D analog can't be used in the setting of kidney failure, and why?

What analog(s) should be used instead?

Ergocalciferol - requires kidney for 1-alpha-hydroxylation to active form

Substitute the hydroxylated active forms alfacalcidol or calcitriol


Name two signs of 1,24-hydroxy- (active) Vitamin D deficiency in CKD?

  1. Fractures (esp. in elderly)
  2. 2° Hyperparathyroidism


What levels of Ca and P indicate the use of Vitamin D anaogs?

What stages of CKD does this typically occur at?

Ca < 9.5 mg/dl

P < 4.6 mg/dl

(Not sure how important these values are)

Stage 3 CKD or greater


Name four Phosphate-binding drugs. Which one's structure is Ca and aluminum free? Why is this important?

  1. Calcium carbonate
  2. Calcium acetate
  3. Lanthanum carbonate
  4. Sevelamer
    • Ca and aluminum free
    • protects from some S/E caused by these compounds (?)


Where and how do phosphate-binding drugs act?

What are common side effects?

Reduce phosphate absorption in the GI tract by forming an insoluble compound with phosphate

S/E: GI effects, hypercalcemia


What ion imbalance needs to be watched for after a long-term CKD patient recieves a functioning kidney transplant?

How does it occur?


Parathyroid hyperplasia during CKD causes an increase in base PTH levels.

Restoration of renal function and calcitriol production via the transplant will further increase Ca2+ levels.

Together, these factors can cause excessive calcium levels.



  • Two 1st Gen bisphosphonates
  • Three 2nd Gen bisphosphonates
  • Two 3rd Gen bisphosphonates

Which are the most potent?

  • 1st Gen:
    1. Etidronate
    2. Tiludronate
  • 2nd Gen:
    1. Pamidronate
    2. Aledronate
    3. Ibadronate
  • 3rd Gen:
    1. Risedronate
    2. Zoledronate

(All end in -dronate)

Potency: 3rd > 2nd > 1st (as would be hoped!)


What is the mechanism of action of bisphosphonates?

Pyrophosphate analogs that bind hydroxyapatite crystals in bone matrix to inhibit bone resorption


How often do bisphosphonates need to be administered?

  • Which bisphosphonate is the exception to this?

Weekly (relatively short-lived effects)

  • Zoledronate is exception: single dose can suppress bone resorption for up to a year


What are some notable side effects of bisphosphonates?

  • GI disturbances / nausea / abdominal pain
  • Osteonecrosis of the jaw when given I.V.


  1. What endogenous compound (also synthetically available as a drug) has a similar mechanism of action to bisphosphonates?
  2. What cells produce this compound?
  3. What is this compound released in response to?

  1. Calcitonin - limits bone resorption and increases urinary PO4 excretion
  2. Produced by Parafollicular or C cells of the thyroid gland
  3. In response to increased plasma calcium levels


  • What route(s) is/are used to give synthetic calcitonin?
  • What are some side effects of calcitonin?

  • Route: IM or SubQ. Short t1/2: ~20min.
  • S/Es:
    • Facial flushing (most pts)
    • Headache & dizziness
    • GI (N/V, abd pain, diarrhea)
    • Taste disturbances


What % of the filtered load of uric acid is typically excreted by the kidney?




  • Mechanism of action?
  • Use (that we care about for this unit?)
  • Route
  • Kinetics?
  • S/E?


  • Mech: Reduces inflammation & pain relief
  • Use: Gout
  • Route: Oral
  • Kinetics: 6-12 hour dosing. Effects start in 18 hours, maximal by 48 hours.
  • S/E: GI toxicity, rash


Xanthine Oxidase Inhibitors

  • Name two drugs in this class.
  • Mechanism?
  • Use?
  • Route?
  • Kinetics?
  • S/E?

Xanthine Oxidase Inhibitors

  • Drugs:
    • Allopurinol (purine)
    • Febuxostat (non-purine)
  • Use: Gout
  • Mech: Competitive XO enzyme inhibitors
  • Route: Oral
  • Kinetics: 6-12 hour dosing. Effects start in 18 hours, maximal by 48 hours.
  • S/E
    • GI upset
    • Acute gout flare
    • Hypersensitivity (rashes, esp in renal disease pts)
    • Drug interactions (inhibit azathioprine metabolism)



  • What is it a recombinant form of?
  • Route?
  • Metabolism?
  • Major uses?
  • S/Es?


  • Recombinant: urate oxidase enzyme
  • Route: I.V.
  • Metab: hydrolyzed in the plasma
  • Uses: prophylactic chemo, CKD
  • S/E:
    • Fever
    • N/V, diarrhea
    • Hypersensitivity (rarely anaphylaxis)
    • Hemolysis due to H2O2 production from allantoin, a breakdown byproduct of urate oxidase

Decks in M2 Renal/Respiratory Class (50):