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STEP Pharm I > Drugs and the Kidney > Flashcards

Drugs and the Kidney Flashcards

1
Q

What mediates the tubular reabsorption of peptide-like drugs such as β-lactam antibiotics and ACEIs?

A

Peptide transporters (PEPT1, PEPT2) expressed on the apical membrane of renal epithelial cells keep in mind that must drugs enter the PT from the bloodstream on the BL and reabsorption is from the lumenal side is more rare

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2
Q

Describe the relationship between Pcr and GFR.

A

In healthy subjects, large declines in GFR are associated with relatively small increases in serum creatinine. Beyond drop of GFR of ~50%, further decrements are associated with larger increases in serum creatinine, whichmakes the marker more sensitive to change.

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3
Q

Drugs are implicated in up to __% of acute kidney injury in hospitalized patients.

A

25%.

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4
Q

Why do drugs cause so much toxicity in the kidneys?

A

High bloodflow means kidney easily exposed to drugsReabsorption of water along loop of Henlé concentrates drug; this magnifies toxicity

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5
Q

When would creatinine be low even if the kidneys weren’t functioning well?

A

in those (typically females) with low muscle mass, low creatinine levels can exist even in the presence of significant renal insufficiency

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6
Q

How do NSAIDs affect GFR?

A

inhibit prostaglandin induced afferent vasodilation

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7
Q

What does chronic use of NSAIDs lead to?

A

Hyponatremia 2° to increased fluid retention (ADH effect)Hyperkalemia & metabolic acidosisHyporeninemic hypoaldosteronism 2° to decreased RAAS activityHypertension

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8
Q

Why are aminoglycosides very nephrotoxic (10-25% of time)?

A

Their toxicity is directly related to charge (cationic). Proximal tubule accumulation results in cell death

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9
Q

How common is nephrotoxicity due to SMX-TMP?

A

~11%

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10
Q

What is seen in the kidneys with trimethoprim (TMP) administration?

A

increases measured serum creatinine w/o affecting GFR inhibits epithelial N+ channels in DCT resulting in hyperkalemia

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11
Q

What is seen in the kidneys with SMX administration?

A

injury 2° to acute interstitial nephritis (AIN)rarely, crystal nephropathy

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12
Q

How can you avoid the crystal nephropathy seen with SMX?

A

Hydrate and alkalinize urine

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13
Q

What are some other drugs causing AIN?

A

NSAIDs, including COX-2 inhibitors• Penicillins and cephalosporins• Rifampin• Diuretics, including furosemide and bumetanide, and thiazide-type diuretics• Ciprofloxacin • Cimetidine• Allopurinol• PPIs such as omeprazole and lansoprazole• Indinavir• 5-aminosalicylates (e.g., mesalamine)

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14
Q

When would AIN (typically) present after 1st exposure of a drug inducer?

A

10-14 days

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15
Q

When would AIN (typically) present after 1st exposure of a drug inducer?

A

3-5 days

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16
Q

How does AIN present?

A

Fever, rash (~50%), eosinophilia (>75%)• Urinalysis– WBC casts, hematuria, eosinophiluria, mild proteinuria, oliguria

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17
Q

Note on NSAID induced AIN

A

NSAIDs onset 2-3 m; NO eosinophilia/uria, fever or rash; proteinuria >3g/24 h

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18
Q

Are the effects of drug-induced AIN dose-related?

A

No, but definitely discontinue the offending agent

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19
Q

What are the three ‘parts’ of acute tubular necrosis (ATN)?

A

InitiationMaintenanceRecoveryATN is basically tubule damage/cell death result from acute ischemia

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20
Q

Where does the most intense ATN damage occur?

A

Most prominent damage in proximal tubules and in TALH

21
Q

What happens during the ‘initiation’ stage of ATN?

A

– Hypo-perfusion plus casts and debris obstruct tubule lumen, causing back-leak of filtrate through the damaged epithelium– Na+/K+ ATPase pumps and integrins relocate to apicalmembrane– ATP is depleted – pump function fails and cells swell,accumulating Na+ and Ca2+– Lipid peroxidation and free radical damage occurs

22
Q

What happens during the ‘maintanence’ stage of ATN?

A

Low level GFR stabilizes over 1-2 weeks

23
Q

What happens during the ‘recovery’ stage of ATN?

A

Tubular epithelial cells are regeneratedabnormal renal function may lead to salt/H2O loss and volume depletion

24
Q

What drugs can cause ATN?

A

-Contrast media-Aminoglycosides-Vanco-AmphoB-cisplatin-sulfa drugsCAVACS

25
Q

How should ATN be treated?

A

Discontinue offending agent– Effects sometimes dose-related• Renal function should begin recovery in 1-2 weeks

26
Q

How does AmphoB cause ATN?

A

AmB can create pores in the apical membrane of the PT which allows back flux of H+ into the cell, which inhibits urinary H+ excretion and, therefore, results in distal renal tubular acidosis, urinary concentration defect and electrolyte disturbances

27
Q

What else does AmphoB do to the kidneys?

A

produces renal vasoconstriction

28
Q

What is the standard of care when using AmB?

A

Volume expansion is standard of care

29
Q

What is the role of VEGF in the kidneys?

A

maintenance of fenestrated glomerular epitheliumDisruption (by drug therapy) may result in HTN, proteinuria, and thrombotic microangiopathy

30
Q

What role does EGF play in the kidneys?

A

Activation of EGFR by EGF and its tyrosine phosphorylation may directly activate TRPM6 and/or TRPM7 channel activity ormay regulate insertion or retrieval or TRPM6 present in intracellular vesicularcompartments which stimulates PT Mg++ reabsorption.

31
Q

Where is the EGF made?

A

In the DCT. Because the DCT is so close to the PT, EGF generated by the DCT may activate EGFRs at the proximal tubule and therefore affect Mg2+ handling by this nephron segment, which reabsorbs 25% of filtered Mg2+.

32
Q

What drugs block EGFR?

A

cetuximab, leading to Mg++ wasting

33
Q

What disease does lithium accumulation in the kidneys lead to? How?

A

Accumulation of cytotoxic levels of lithium, via the apical epithelial Na+channel (ENaC) leads to inhibition of glycogen synthase kinase type 3βsignaling pathways, causing dysregulation of AQP-2 and development of NDI.

34
Q

How would lithium toxicity be treated?

A

-stop usage-Enac blockers (amiloride, etc.)

35
Q

What is the result of calcineurin inhibitor toxicity in the kidneys?

A

An acute, functional and dose-dependent decrease in renal blood flow and GFRChronic structural changes and dose-independentinterstitial fibrosis

36
Q

What are the effects of cisplatin on the kidneys?

A

Exposure of tubular cells to cisplatin activatessignaling pathways that are cell death promoting (MAPK, p53, ROS, and so on) orcytoprotective (p21). Meanwhile, cisplatin induces TNF-alpha production in tubular cells

37
Q

What does production of TNF-a stimulate?

A

Triggers a robust inflammatory response, further contributing to tubular cell injury anddeath. Cisplatin may also induce injury in renal vasculature, leading to ischemic tubular cell death and decreased GFR. Together, these events culminate in acute renal failure.

38
Q

What are some diuretics that promote hyperkalemia?

A

K+ -sparing diuretics: amiloride, triamterene

39
Q

What are some antibiotics that promote hyperkalemia?

A

Trimethoprim, Pentamidine

40
Q

Other hyperkalemic inducing drugs by decreasing excretion?

A

-ACEIs/ARBSSpironolactone/Eplerenone-Cycosporine -Tacrolimus

41
Q

How does Cyclosporine cause hyperkalemia?

A

Blocks Na+/K+-ATPase Activity in the Distal Nephron

42
Q

What are some drugs that promote K+ cellular uptake?

A

-insulin-BB agonists

43
Q

Hyperkalemia can also be induced by cell-lysis, where there are massive reservoirs. One place that contains a lot of intracellular K+ is skeletal muscle. What are some drugs that cause rhabdomyolysis induced hyerpkalemia?

A

lovastatincocaine

44
Q

What are some drugs that promote excretion of K+?

A

-Diuretics-Foscarnet-Laxatives

45
Q

What are some drugs that promote intracellular uptake K+?

A

-B2-agonists-dextrose-Insulin-levothyroxine-Theophylline

46
Q

Other drugs that promote hypokalemia?

A

Caspofungin, Corticosteroids(mineralocorticoid activity), Itraconazole

47
Q

What inhibits K+ release into the lumen in the thick ALH?

A

Mg++ binds and prevents its movement into the lumen

48
Q

What are some causes of hypokalemia secondary to hypomagnesia?

A

Aminoglycosides, Ampotericin B, Cisplatin, Cyclosporine,Loop diuretics

49
Q

Notes

A

Keep in mind that there are both BL and lumenal transporters for drugs and so accumulation of a drug in the PT (leading to toxicity) can be the result of increased influx through the BL or decreased efflux throughout the apical membrane

STEP Pharm I (36 decks)

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