NSAIDs and AKI

Question 1

3 processes that can contribute to renal clearance of a drug

Answer 1

Glomerular filtration
tubular secretion
tubular reabsorption

Question 2

glomerular filtration

Answer 2

(remember: only unbound drug in plasma is excreted by glomerular filtration)

low clearance process (renal extraction is ~.11)

Question 3

Tubular secretion

Answer 3

primarily in renal proximal tubule

involves separate organic anion and cation transportation systems (OATs, OATPs, MRPs; OCTs, MDR/1, P-gp)

• -overlapping substrate specificities
• *POTENTIAL FOR DRUG-DRUG INTERACTIONS

Can be perfusion rate limited or capacity rate limited

• -Perfusion rate limited: extraction ratio isn’t limited to unbound fraction of drug
• -Capacity rate limited: the extraction ratio is limited by the reversible binding of the drug to plasma proteins or its location in RBCs

Question 4

Tubular reabsorption

Answer 4

passive process for the majority of drugs and drug metabolites

extensive reabsorption of filtered H2O along renal is the driving force

Depending on the physicochemical characteristics of the drug substances, especially lipophilicity, pKa, and molecular weight, tubular reapbsorption may vary from being negligible to being virtually complete

peptide transporters (PEPT1, PEPT2) expressed on apical membrane of renal epthelial cells that mediate tubular reabsorbtion of peptide-like drugs..such as beta-lactam antibiotics and ACEIs

Question 5

Normal renal function

Answer 5

> 80

Question 6

Mild renal impairment

Answer 6

50-80

Question 7

Moderate renal impairment

Answer 7

30-50

Question 8

Severe renal impairment

Answer 8

<30

Question 9

Conditions exacerbated by NSAIDs

Answer 9

HTN
CHF
Renal insufficiency

Question 10

PG

Answer 10

not a PRIMARY regulator of renal function

so minimal importance in kidney of healthy individuals w/ normal volume status

Question 11

PGI2 and PGE2

Answer 11

predominant mediators of physiologic activity in kidney
–induce vasodilation in interlobular arteries, afferent and efferent arterioles, and glomeruli

antagonize effects of circulating angiotensin II, endothelin, vasopressin, and catecholamines

Question 12

Risk factors that make kidney PG dependent (and therefore at risk for AKI)

Answer 12

"true" intravascular volume depletion
--vomiting
--diarrhea
--diuretics
"effective' intravascular volume depletion
--CHF
--Cirrhosis
--Nephrotic syndrome
--Kidney disease
--AKI
--CKD
--medications
--ACEIs and ARBs
--Old age

Question 13

PGs preserve GFR by…

Answer 13

antagonizing arteriolar vasoconstriction and blunting mesangial and podocyte contraction induced by these endogenous vasopressors

Question 14

Risks increase w/…

Answer 14

age

dose and duration of NSAID consumption

Question 15

PGE2 role in LOH and distal nephron

Answer 15

decreases cellular transport of NaCl in TALH and CD cells

increase in renal Na excretion and a decrease in medullary tonicity are direct result of PGE2 action

also (w/ PGI2) stimulates renin secretion in juxtaglomerular apparatus…leads to increased angiotensin II and aldosterone synthesis

(w/ PGI2) inhibits cAMP synthesis and opposes action of ADH, facilitating H2O excretion

Question 16

net effect of chronic NSAID consumption

Answer 16

mild, dose-dependent increase in BP

Question 17

COX-2 …

Answer 17

…equivalent to other classes of NSAIDs w/ respect to nephrotoxic potential

Question 18

Acute toxicity is manifest in terms of …

Answer 18

tubular epthelial necrosis secondary to altered renal hemodynamics

interstitial nephritis (thought to be result of allergic rxn to individual NSAID chemical structures)