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Flashcards in NSAIDs and AKI Deck (18)
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1

3 processes that can contribute to renal clearance of a drug

Glomerular filtration
tubular secretion
tubular reabsorption

2

glomerular filtration

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

low clearance process (renal extraction is ~.11)

3

Tubular secretion

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

4

Tubular reabsorption

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

5

Normal renal function

>80

6

Mild renal impairment

50-80

7

Moderate renal impairment

30-50

8

Severe renal impairment

<30

9

Conditions exacerbated by NSAIDs

HTN
CHF
Renal insufficiency

10

PG

not a PRIMARY regulator of renal function
(so minimal importance in kidney of healthy individuals w/ normal volume status)

11

PGI2 and PGE2

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

12

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

"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

13

PGs preserve GFR by...

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

14

Risks increase w/...

age
dose and duration of NSAID consumption

15

PGE2 role in LOH and distal nephron

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

16

net effect of chronic NSAID consumption

mild, dose-dependent increase in BP

17

COX-2 ...

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

18

Acute toxicity is manifest in terms of ...

tubular epthelial necrosis secondary to altered renal hemodynamics

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