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M2 Renal/Respiratory > Renal Pharmacology - Imig > Flashcards

Renal Pharmacology - Imig Flashcards

1
Q

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

Is it natively active?

A

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

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2
Q

Mycophenolate Mofetil:

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

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

Is MMF affected by the administation of tacrolimus or sirolimus?

A

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

No change in MPA levels with tacrolimus or sirolimus

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4
Q

Describe the mechanism of action of azathioprine

A

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.

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5
Q

What are some similar alternatives to azathioprine?

A

methotrexate

cyclophosphamide

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6
Q

Azathioprine:

  1. Route of administration?
  2. Half life?
  3. Unwanted side effects?
A
  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
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7
Q

Why should you use caution when administering allopurinol with azathioprine?

A

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

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8
Q

Discuss the clinical monitoring implications of azathioprine and MMF

A

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

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9
Q

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

A

Basiliximab - anti-CD25 chimeric

Daclizumab - anti-CD25 humanized

Alemtuzumab - anti-CD52 humanized

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10
Q

Basiliximab

  1. Route of administration?
  2. half life?
  3. Use?
  4. Adverse effects
A
  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
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11
Q

Belatacept

  1. route of administration
  2. mechanism of action
  3. therapeutic use
  4. half life
  5. unwanted side effects
A
  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
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12
Q

Discuss the therapeutic effects of prednisolone administration in renal transplant

Are its effects fast of slow?

A
  • 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.

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13
Q

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

A

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

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14
Q

Name some possible side effects of corticosteroid use

A

acne

cushingoid facies

hirsutism

mood disorders

hypertension

glucose intolerance

cataracts

osteoporosis

growth retardation (children)

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15
Q

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

A

10-15 years. Sometimes 20.

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16
Q

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

A

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

Maintenence agents - corticosteroids, CINs, anti-proliferative agents

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17
Q

What drug class forms the ‘cornerstone’ of immunosuppressive maintenence therapy?

A

Calcineurin inhibitors (CINs)

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18
Q

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

A

Check fluid volume status

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19
Q

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

  • cyclosporin or tacrolimus
  • MMF or AZA
  • mTOR inhibitors
  • corticosteroids
A
  • 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
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20
Q

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
A
  • 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
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21
Q

Summarize several possible approaches to preventing renal transplant rejection.

A

Calcineurin inhibition

mTOR inhibition

Anti-proliferatives

T-cell depleting mAbs

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22
Q

What is the mechanism of action of cyclosporine?

How is it administered and metabolized?

A

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.

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23
Q

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

A

Nephrotoxicity (vasoconstriction, TGFb, fibrosis, tubular atrophy)

HTN & fluid retention

Hepatic dysfunction

N/V/D, Headache, Fatigue, Tremor

Hypertrichosis, Gum hypertrophy

Hyperlipidemia, hypomagnesemia, hypokalemia.

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24
Q

What drugs should be avoided with cyclosporine treatment?

Is this drug commonly used?

A

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.

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25
Q

Compare and contrast Tacrolimus with Cyclosporine’s:

Mechanism of action

Kinetics

Side effect profile

A

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.

26
Q

What monitoring should be done when administering calcineurin inhibitors?

A

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

27
Q

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

A

Nephrotoxic agents (NSAIDs, many Abx)

Potassium-sparing diuretics (hyperkalemia)

Antacids (affect absorption of CNI)

Statins (rhabdomyloysis, BMS)

28
Q

Distinguish between the mechanisms of action of tacrolimus and sirolimus.

What are the benefits of sirolimus over calcineurin inhibitors?

A

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)

29
Q

Describe the pharmacokinetic profile of sirolimus.

What are its side effects?

A

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

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

30
Q

Between Cyclosporine, Tacrolimus, and Sirolimus, which has:

The worst nephrotoxicity?

The worst neurotoxicity?

The worst hyperlipidemia?

Which causes hypertrichosis?

A

Cyclosporine worst for kidneys.

Tacrolimus worst for nerves.

Sirolimus +++ for hyperlipidemia.

Cyclosporine causes hirsutism.

31
Q

What is the mechanism of action of MPA?

What is the difference between MPA and MMF?

Why are lymphocytes specifically targeted?

A

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.

32
Q

How is MMF administered & metabolized?

What are its side effects?

A

Oral/IV, metabolized by liver (18hrs)

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

33
Q

What drugs interact with MMF?

A

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.

34
Q

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

A

Antibiotics, chemotherapy, radiocontrast dyes, thoracic surgery

35
Q

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

How is kidney disease treated?

A

20-30%

fluid and BP maintenace, hemodialysis

36
Q

What causes acute renal injury? (very general)

What can cause chronic kidney disease?

A

Renal Ischemia

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

37
Q

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

A

Anti-apoptotic

Anti-inflammatory

Anti-septic

Growth factors

Vasodilators

38
Q

What drugs are being used to treat chronic kidney failure?

A

Renin-Angiotensin inhibitors

39
Q

How is diabetic nephropathy treated?

A

Good glycemic control

BP control

ACEI and ARB

40
Q

When is anemia seen in CKD?

How is it treated?

A

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

Treated with epoetin

41
Q

How does epoetin work?

What are some side effects?

A

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

Nausea, headache, vomitting, diarrhea (of course)

dose-dependent hypertension

Thrombosis

42
Q

Why secondary hyperparathyroidism seen in chronic kidney failure?

A

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

43
Q

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

A

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
44
Q

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

What is the major side effect of these drugs?

A
  • 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

45
Q

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

What analog(s) should be used instead?

A

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

Substitute the hydroxylated active forms alfacalcidol or calcitriol

46
Q

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

A
  1. Fractures (esp. in elderly)
  2. 2° Hyperparathyroidism
47
Q

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

What stages of CKD does this typically occur at?

A

Ca < 9.5 mg/dl

P < 4.6 mg/dl

(Not sure how important these values are)

Stage 3 CKD or greater

48
Q

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

A
  1. Calcium carbonate
  2. Calcium acetate
  3. Lanthanum carbonate
  4. Sevelamer
    • Ca and aluminum free
    • protects from some S/E caused by these compounds (?)
49
Q

Where and how do phosphate-binding drugs act?

What are common side effects?

A

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

S/E: GI effects, hypercalcemia

50
Q

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

How does it occur?

A

Hypercalcemia

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.

51
Q

Name:

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

Which are the most potent?

A
  • 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!)

52
Q

What is the mechanism of action of bisphosphonates?

A

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

53
Q

How often do bisphosphonates need to be administered?

  • Which bisphosphonate is the exception to this?
A

Weekly (relatively short-lived effects)

  • Zoledronate is exception: single dose can suppress bone resorption for up to a year​
54
Q

What are some notable side effects of bisphosphonates?

A
  • GI disturbances / nausea / abdominal pain
  • Osteonecrosis of the jaw when given I.V.
55
Q
  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?
A
  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
56
Q
  • What route(s) is/are used to give synthetic calcitonin?
  • What are some side effects of calcitonin?
A
  • Route: IM or SubQ. Short t1/2: ~20min.
  • S/Es:
    • Facial flushing (most pts)
    • Headache & dizziness
    • GI (N/V, abd pain, diarrhea)
    • Taste disturbances
57
Q

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

A

8-12%

58
Q

Colchicine

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

Colchicine

  • 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
59
Q

Xanthine Oxidase Inhibitors

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

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)
60
Q

Rasburicase

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

Rasburicase

  • 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

M2 Renal/Respiratory (50 decks)

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