Pharm Flashcards
1
Q
What are the common sites for metastasis growth for renal cancer?
A
- Lymph nodes (most common)
- Lung, liver, bone (destructive lesions)
- Adrenal gland, brain
- Opposite kidney
- Subcu skin nodules
2
Q
What is the principal means of curing renal cancer? Alternatives?
A
- Principal means of producing a cure -> sx excision
- More advanced stage/grade, or if metastasis, chemo, targeted tx, immunotx, radiotx employed
- Drugs are also employed as adjunctive therapy with surgery/radiation
- Drugs employed as primary therapy where medical circumstances preclude surgery
3
Q
What is the main renal childhood tumor?
A
- Nephroblastoma (Wilm’s tumor): most common renal tumor in children (usually kids 3-4 y/o)
- Curable in majority of affected children: 5 year survival rate consistently above 90%
4
Q
What is the standard tx for nephroblastoma? Recurrent disease?
A
-
Standard chemo post nephrectomy:
1. Vincristine, dactinomycin x 18 weeks
2. Vincristine, dactinomycin, doxorubicin 24 wks
3. Vincristine, doxorubicin, cyclophosphamide, etoposide x 24 weeks -
Recurrent disease involves alternating courses of:
1. Vincristine, Doxorubicin, Cyclophosphamide
2. Etoposide and Cyclophosphamide
5
Q
What is the standard chemo for childhood clear cell sarcoma? Recurrent disease?
A
-
Standard chemo involves one of the following:
1. Vincristine, dactinomycin and doxorubicin for 15 months and radiation therapy
2. Vincristine, doxorubicin, cyclophosphamide and etoposide and radiation therapy -
Recurrent disease
1. Cyclophosphamide and carboplatin should be considered if not used initially
2. If involving the brain, kids have responded to tx with ifosfamide carboplatin and etoposide (ICE) coupled with local control consisting of either surgical resection and/or radiation
6
Q
What is the therapy for childhood rhabdoid and neuroepithelial tumors?
A
No satisfactory therapy has been discovered
7
Q
Carboplatin toxicity
A
Myelosuppression, infection susceptibility
8
Q
Cyclophosphamide toxicity
A
Myelosuppression, hemorrhagic cystitis (MESNA antidote)
9
Q
Doxorubicin toxicity
A
Bone marrow suppression, acute and chronic cardiotoxicity
10
Q
Dactinomycin toxicity
A
- Myelosuppression
- Hepatic dysdunction
- Infection susceptibility
11
Q
Etoposide toxicity
A
- Hematologic toxicity
- BP instability
12
Q
Ifosfamide toxicity
A
- Bone marrow suppression
- Hemorrhagic cystitis (MESNA antidote)
13
Q
Vincristine toxicity
A
- Neurotoxicity
- Bilateral sensory stocking-glove pattern
14
Q
What genetic alteration is associated with clear cell renal cell carcinoma? Describe the pathway.
A
- Von Hippel Lindau (VHL)
- VHL-HIF-EPO pathway
1. Functional VHL gene produces pVHL, which forms a pVHL-E3 ligase complex and mediates poly ubiquitination (Ub) and proteasomal degradation (PD) of HIF. As a result, the translocation (TR) of HIF to the nucleus and the subsequent transactivation of HIF regulated molecules, including EPO is prevented
2. When VHL gene mutated, pVHL and formation of the pVHL-E3 ligase are impaired -> HIF stabilized, up-regulated, and translocated to nucleus, where it dimerizes with o/HIF subunits, transactivates HIF responsive genes incl EPO -> EPO binds to its receptor EPOR and mediates some of the bio aspects of cancer progression, like INC in angiogenesis, inflammation and DEC in intrinsic and drug-induced apoptosis - Apart from VHL mutations, hypoxia is the major factor regulating production of EPO. In normoxic conditions, HIF is degraded, whereas in hypoxia, HIF is stabilized and lead leads to the activation of EPO
15
Q
What are the primary molecular targets in the tx of metastatic clear cell renal cell carcinoma? Via which drugs?
A
- VEGF, VEGF receptor, mTOR
1. Bevacizumab: anti-VEGF Ab
2. Axitinib: blocks VEGFR, PDGFR tyrosine kin
a. Pazopanib: blocks VEGFR, PDGFR, FFGFR, c-kit, others
b. Sunitinib: blocks VEGFR tyrosine kinase
3. Sorafenib: blocks VEGFR, PDGFR, KIT, and RAF tyrosine kinases
4. Everolimus, Temsorolimus: block mTOR - These rx primarily inhibit angiogenesis and tumor growth; cytotoxic therapy ineffective (<10% response)
- Aldesleukin (IL-2), IFN-alpha also used
16
Q
Clear cell renal carcinoma sequence of tx. Are these txs curative?
A
- Common clinical practice: TKI first, then mTOR agent gives rise to better outcome that administering the mTOR inhibitor as first-line therapy
- Recently approved Axitinib only approved as follow up therapy, after failure of the initial drug
- None of the treatments is curative -> typically they produce a median progression-free survival in the order of 9-12 months
17
Q
Rapamycins summary
A
-
Bind to FKBP12 and inhibit mTORC1
1. Immunosuppressant effects
2. INH cell-cycle progression, angiogenesis
3. Promotion of apoptosis - Resistance incompletely understood, but may arise through action of a 2nd (unaffected) mTOR complex, which regulates AKT kinase
1. May be responsible for incomplete responses or resistance of rapamycins -> dual mTORC1 and mTORC2 inhibitors are in clinical development
18
Q
What is the activity of the rapamycins?
A
- Temsirolimus prolongs survival and delays disease progression in pts w/adv and poor, intermediate-risk renal cancer, as compared to standard interferon-alpha treatment
- Everolimus, as compared to placebo, prolongs survival in patients who had failed initial treatment with anti-angiogenic drugs
19
Q
Rapamycin important issues
A
- Temsirolimus: weekly IV (metabolized to sirolimus, likely the more important agent)
- Everolimus: daily oral drug
- Both CYP 3A4 substrates: drug-drug interactions
- Prominent side effects: mild maculopapular rash, mucositis, anemia, and fatigue -> 30-50% of pts
- Reversible leukopenia, thrombocytopenia with progressive drug cycles (minority)
-
Pulmonary infiltrates in 8% of patients receiving everolimus and in a smaller percentage of those treated with temsirolimus
1. If cough or shortness of breath sxs devo or radiological changes progress, drug should be discontinued -> prednisone may hasten the resolution of radiological changes and sxs
20
Q
TKI’s summary
A
- Primarily INH VEGFR tyrosine kinases, although some have activity at o/receptor systems that contributes to clinical activity and AE’s
- Small molecular weight orally administered drugs metabolized in liver by CYPs incl, CYP3A4 (potential for drug-drug interactions -> diminished bioavail and clinical effectiveness)
- Common but non life-threatening adverse effects, including N/V, fatigue, weakness, rash, etc.
- Several SIGNIFICANT adverse effects common to these drugs. CV problems are predictable, given the action of these drugs on VEGFR, and its involvement in vascular form and function
21
Q
TKI adverse effects
A
-
CV: thromboembolism, hemorrhagic events
1. HTN: rapid onset -> mgmt. For pts already receiving rx tx for this condition, need for dose adjustment when starting/stopping TKI tx
2. QT prolongation: most prominently with pazopanib and sorafenib
3. Blood dyscrasias: lympho-, neutro-, leuko- & thromobocytopenias - Hepatic (elevated enzymes): hepatic failure (black box warning for pazopanib and sunitinib)
- Renal: proteinuria
- Endocrine: monitor thyroid, adrenal func, blood glu
- Hypersensitivity: Stevens Johnson syndrome (sorafenib, sunitinib)
22
Q
Bevacizumab summary and AE’s
A
- Monoclonal Ab: IV infusion (no CYP3A4 interactions)
- Pattern of AE”s mirrors that of TKIs -> in addition to N/V, fatigue, weakness, dizziness, also assoc with:
1. Thromboembolic events
2. Hypertension
3. CHF
4. Proteinuria
5. Blood dyscrasias - Black box warnings: hemorrhage, GI perforation, wound healing complications
- Usually admin on 2-wk cycle, alone, or in combo w/INF -> combo has been shown to be superior to INF alone, but even the combo provides only a limited duration of clinical effect
1. Significant improvement in progression-free survival (10.2 months), compared with interferon alfa alone (5.4 months)
23
Q
What two immunotherapeutic drugs are used to treat renal cell carcinoma? Are they efficacious?
A
- INF-alpha, IL-2: more durable response in some pts and in a small number, a clinical cure
- Pt performance, # of metastatic sites and where (liver), prior nephrectomy, time from nephrectomy to systemic tx some factors that may impact outcome
- Overall chance of partial or complete remission with immunotherapy is 12.9%, compared to 2.5% for non-immunotherapy, and 4.3% with no treatment
1. Median survival averaged 13.3 months - Reduced dose IV or SC interleukin-2 provides equivalent survival to high dose with less toxicity
- Optimal dose, duration of INF-alfa unclear; modest survival benefit compared to o/commonly used txs and should be considered for control arm of future studies of systemic agents. In fit patients with metastases at diagnosis and minimal symptoms, nephrectomy followed by interferon-alfa gives the best survival strategy for fully validated therapies
24
Q
IL-2 summary and AE’s
A
- T-cell growth factor: involved in imm system control
- Admin of high dose IL- 2 akin to the induction of controlled state of septic shock
- Administered IV to hospitalized pts 3 x weekly; max # of doses usually tolerated is 14
- IL-2 produces CAPILLARY LEAK SYNDROME:
1. Hypotension
2. Low systemic vascular resistance
3. Tachycardia
4. Heme toxicity (grade 3⁄4)
5. Pulmonary edema
6. Renal toxicity - 126 AE’s listed
25
Q
Why do pts on IL-2 need to be carefully monitored?
A
- Careful mgmt b/c potential for sepsis; w/o anti-microbial tx, can occur in as many as 70% of pts
- Pharmacologic support required to maintain renal perfusion (e.g., dopamine), provide BP support (e.g., phenylephrine) + acetaminophen for fever and chills and a proton pump inhibitor for gastric hyperacidity
- NOTE: there has been interest in low dose with intermittent pulse doses of this rx due to report that low dose leads to selective expansion of subset of NK cells that overexpress a high affinity IL-2 receptor, but trials have been disappointing
26
Q
INF-alpha-2b summary and AE’s
A
- MOA: binding of endogenous Type I: IFN-α, β, and ω to cell surface IFNAR1/IFNAR2 receptors activates cyto JAK/STAT to produce ISGF3 complex (IFN- stimulated gene factor 3 complex of STAT1, STAT2, and IRF-9) that translocates to nucleus & binds IFN-stimulated response element (ISRE) -> transcriptional up-regulation of genes responsible for antiviral, anti-proliferative, antitumor activities
- Used off label in tx of clear cell renal carcinoma, and also used for other medical conditions including malignant melanoma and hepatitis B & C
- Administration is SC 3 x weekly
- Black box warnings: neuropsychiatric, autoimmune, ischemic, and infectious disorders
-
Most common AE’s:
1. ≤ 95% fatigue, fever, flu-like symptoms
2. Leukopenia (72%), neutropenia (92%) -
Less common AE’s:
1. Xerostomia, dysguesia (distortion of taste)
2. Diaphoresis, dizziness, cough, somnolence
27
Q
How do NSAIDs affect renal function?
A
- Inhibit PGs, which play important role in: maintaining adequate renal perfusion (COX-1) and natriuretic & diuretic effects (COX-2)
-
Chronic use can produce:
1. Hyponatremia 2° to INC fluid retention (ADH)
2. Hyperkalemia & metabolic acidosis
a. Hyporeninemic hypoaldosteronism 2° to DEC RAAS activity
3. Hypertension - Group to remember in regards to PRE-RENAL injury; also have effect in other parts of the tubule
- Thinking about pts that have inflammatory disease, e.g., rheumatoid arthritis
28
Q
How do ACEI’s and ARB’s affect renal function?
A
- Inhibit renal auto-regulation of GFR
- Usually well tolerated, BUT can cause acute injury:
1. Bilateral renal artery stenosis
2. Renal artery stenosis in solitary kidney
3. Volume depletion
4. With NSAIDs, cyclosporine, tacrolimus - Hold drugs if pt has/is at risk of, volume depletion
- Combining ACEIs and ARBs increases risk of AE’s, incl hyperkalemia and acute renal injury
29
Q
How do aminoglycosides damage the kidney?
A
- 10-25% incidence of nephrotoxicity
- Toxicity directly related to (+) charge
- Proximal tubule accumulation results in cell death
- Func change mem transporters (Fanconi) possible: hypokalemia, hypomagnesemia, hypocalcaemia
- Accumulation in distal tubule & collecting duct can impair concentrating ability and cause polyuria
- Loading & maintenance doses based upon estimated CrCl
- Monitoring: 1) Measure peak & trough levels, 2) Expand volume, 3) Limit dosing to once daily
30
Q
How does SMX-TMP damage the kidney?
A
-
TMP: INC measured serum creatinine w/o affecting GFR (disconnect b/t serum creatinine and GFR)
1. Inhibits ENaC in DCT –> hyperkalemia -
SMX: injury 2° to AIN
1. Rarely, crystal nephropathy
2. Freq urinalysis w/micro exam recommended in pts receiving all sulfonamides
3. Hydrate and alkalinize urine
31
Q
Is AIN immune-based?
A
Yes -> there will be inflammation if you do a renal biopsy
32
Q
What are some common drugs that produce AIN?
A
- NSAID’s, incl COX-2 inhibitors
- Penicillins and cephalosporins
- Rifampin
- Diuretics, incl loops and thiazide-type diuretics
- Ciprofloxacin and other quinolones
- Cimetidine
- Allopurinol
- PPI’s: omeprazole, lansoprazole
- Indinavir
- 5-aminosalicylates (e.g., mesalamine)
33
Q
How does Amphotericin-B damage the kidney?
A
- Can create pores in cell membrane -> allows back flux of H+ into cell, inhibiting urinary H+ excretion and, therefore, results in distal RTA, urinary conc defects and electrolyte disturbances
- Also produces renal vasoconstriction
- Volume expansion is standard of care
34
Q
How do VEGF inhibitors damage the kidney?
A
- VEGF plays important role in homeostatic maintenance of fenestrated glomerular epi
- Disruption by drug therapy may result in HTN, proteinuria, and thrombotic microangiopathy
35
Q
How do EGFR drugs damage the kidney?
A
- Drugs like cetuximab [Erbitux] can cause renal Mg wasting and hypomagnesemia
- May also bind to and inhibit P-gp activity
- Because of proximity of DCT and proximal tubule, EGF generated by DCT may activate EGFRs at the proximal tubule and therefore affect Mg2+ handling by this nephron segment, which reabsorbs 25% of filtered Mg2+
36
Q
How does lithium damage the kidney?
A
- Accumulation of cytotoxic levels of lithium, via the ENaC -> inhibition of glycogen synthase kinase type 3β signaling pathways, causing dysregulation of aquaraporin-2 and development of NDI
- ENaC inhibitor amiloride used for the treatment of lithium-induced NDI -> whether this agent can prevent the long-term adverse effects of lithium is not yet known
37
Q
How do calcineurin inhibitors damage the kidney?
A
- Acute, functional, and dose-dependent decrease in RBF and GFR
- Chronic structural changes and dose-independent interstitial fibrosis
1. MOA: INH activity of calcineurin phosphatase, inhibiting transfer of NF-AT to nucleus - Morphologic damage and pathologic lesions result from changes in activity of critical cytokine signal pathways
38
Q
How does Cisplatin damage the kidneys?
A
- Extraordinary accumulation in renal tubular cells
- Ototoxic agent because copper transporter (Ctr1) in the inner ear. Not based on concentration gradient
- Exposure of tubular cells to cisplatin activates signaling pathways that are cell death promoting; also induces TNF-alpha production in tubular cells, triggering a robust inflammatory response, further contributing to tubular cell injury and death
- May induce injury in renal vasculature, and ischemic tubular cell death + DEC GFR -> acute renal failure
- OCT2: organic cation transporter protein
39
Q
For which drugs are you concerned about potassium?
A
- ACEI’s, ARB’s
- Diuretics
40
Q
Which drugs decreased renal K+ excretion?
A
-
Block ENac:
1. K+ -sparing diuretics: amiloride, triamterene
2. Antibiotics: trimethoprim, pentamidine -
Block aldo production:
1. ACE inhibitors, ARB’s
2. NSAIDs and COX-2 inhibitors
3. Heparin
4. Tacrolimus - Block aldo receptors: spironolactone, eplerenone
- Block Na/K-ATPase in distal nephron: cyclosporine
- Worried about co-admin of completely unrelated drugs, all or some of which have capability of causing hyperkalemia. May not be worried about just one
41
Q
What is the most common cause of hyperkalemia?
A
- ACEI’s, ARB’s
42
Q
What drugs inhibit extra-renal K disposal?
A
- Block β2-adrenergic mediated extrarenal K+ disposal: nonselective β-blockers
- Block Na+/K+-ATPase activity in skeletal muscles: digoxin over-dose (not therapeutic doses)
- Inhibit insulin release (e.g., somatostatin)
43
Q
Which drugs increase K release from damaged cells?
A
- Drug-induced rhabdomyolysis, (e.g., lovastatin, cocaine)
- Drug-induced tumor lysis syndrome (chemotherapy agents)
- Depolarizing paralytic agents -> succinylcholine: depolarizing, neuromuscular drug. Produces initial contraction of the muscle (which can produce liberation of potassium into the fluid), then flaccid paralysis
44
Q
How do albuterol and insulin affect the Na/K ATPase?
A
- Albuterol phosphorylates and activates the cAMP-dependent Na+/K+-ATPase causing an increase in the exportation of Na+ to the extracellular compartment. The consequent electrical driving force causes K+ to be taken up from the extracellular compartment.
- Insulin stimulates the Na+/H+ exchanger (NHE), yielding a higher intracellular Na + concentration, which stimulates the Na+/K+ exchanger to increase the intracellular uptake of K+ from the outside.
45
Q
What drugs induce hypokalemia?
A
- INC excretion: diuretics, foscarnet (antiviral), laxatives (can prevent absorption of K from food)
- INC cellular uptake: β2-agonists, Dextrose, Insulin, Levothyroxine, Theophylline (blocked by propranolol)
- Miscellaneous: Amphotericin B, Caspofungin, Corticosteroids (mineralocorticoid activity), Itraconazole
- Secondary to Hypomagnesemia: aminoglycosides, Amphotericin B, Cisplatin, Cyclosporine, Loops
46
Q
How does Mg deficiency cause hypokalemia?
A
- Magnesium physically occludes ROMK channel, acting as a modulator to prevent uninterrupted K excrusion from the cell. If Mg low, there is not longer a regulator in K excrusion, so K leaves, leading to hypokalemia
- Oftentimes hypokalemia with hypomagnesemia is refractory to potassium supplementation
47
Q
What are the most common causes of hypokalemia?
A
- Anti-infective agents
- Diuretics: cause mild to severe hypokalemia and mild to moderate metabolic alkalosis, despite K supplementation
