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Renal Pharm > NSAIDs and ARF > Flashcards

NSAIDs and ARF Flashcards

1
Q

Where are most drugs and their active metabolites eliminated?

A

thru the kidneys

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2
Q

In what population is drug elimination through the kidneys normally impaired? Why?

A

the elderly; due to both reduced renal blood flow and perturbations in GFR

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3
Q

Dose adjustments for many drugs are commonly indicated according to what?

A

renal function

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4
Q

Dose adjustment of many drugs according to renal function is commonly indicated in order to avoid what? (3)

A
  1. Accumulation of the drugs or their metabolites
  2. Adverse reactions
  3. Aggravation of renal impairment
    (However, it has been shown that clinicians inadequately make these adjustments)
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5
Q

In addition to altering renal excretion of unchanged drugs/active metabolites, renal dysfunction can also lead to what?

A

modifications in distribution, transport, and biotransformation of drug substances

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6
Q

What are three processes in the kidney that can potentially contribute to the renal clearance of a drug?

A
  1. Glomerular Filtration
  2. Tubular Secretion
  3. Tubular Reabsorption
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7
Q

What is typical rate of glomerular filtration?

A

~120mL/min in a 20 y.o. healthy male

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8
Q

What drugs are excreted by glomerular filtration?

A

Only unbound drugs in plasma water are excreted by glomerular filtration

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9
Q

How effective is glomerular filtration at clearing drugs?

A

It is a low clearance process (renal extraction is ~0.11)

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10
Q

Where does tubular secretion primarily occur?

A

primarily in the renal proximal tubule

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11
Q

What types of transport processes are involved in tubular secretion?

A

tubular secretion involves separate organic anion and organic cation transport systems located in the basolateral and luminal membranes of the tubule cells

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12
Q

What potential problem can result from the transportation systems involved in tubular secretion? Why?

A

There is the potential for DRUG-DRUG INTERACTIONS due to overlapping substrate specificities of the different transporters

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13
Q

What two factors can limit the tubular secretion of a substance?

A

Perfusion rate limited

Capacity rate limited

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14
Q

Compare the exctraction ratio limitations of perfusion rate limited and capacity rate limited secretion:

A

PR-limited→the extraction ratio is not limited to the unbound ratio of the drug
CR-limited→the extraction ratio is limited by the reversible binding of drug to plasma proteins or its location in red blood cells

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15
Q

For the majority of drugs and drug metabolites, what type of process is tubular reabsorption? What is the driving force?

A

For the majority of drugs and drug metabolites tubular reabsorption is a PASSIVE process, and the driving force is the extensive reabs of filtered water along the renal tubule.

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16
Q

Why does tubular reabsorption of different drug substances vary from being negligible to virtually complete?

A

reabs depends on the physicochemical characteristics of drug substances

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17
Q

What are the main physicochemical characteristics that cause variable reabsorption of different drugs?

A

lipophilicity, pKa, and molecular weight

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18
Q

How are peptide-like drugs reabsorbed? Examples of peptide drugs?

A

Peptide transporters (PEPT1, PEPT2) expressed on the apical membrane of renal epithelial cells mediate the reabsorption of peptide-like drugs, such as B-lactams and ACE inhibitors.

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19
Q

What gives a reasonably good estimate of overall renal function? Why? (2)

A

GFR; bc it is reduced before the onset of renal impairment and it is related to the severity of structural abnormalities in chronic renal impairment.

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20
Q

Why not measure the important functions the renal tubule (95% of renal mass) controls?

A

It’s impractical to measure this aspect of renal function daily

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21
Q

What is the most convenient method to estimate GFR? Why?

A

calculated creatinine clearance (CLcr) based on serum creatinine concentration; bc it requires only a single blood sample

22
Q

What factors does serum creatinine depend on? How do you account for this in calculating GFR?

A

age, gender, body size→ variable muscle mass; using a formula that corrects for muscle mass: Cockroft-Gault or Modification of Diet in Renal Disease (MDRD)

23
Q

What are the five different levels of renal function? What is the GFR in the different levels?

A
  1. Normal renal function: GFR>80ml/min
  2. Mild renal impairment: GFR= 50-80
  3. Moderate renal impairment: 30-50
  4. Severe renal impairment: <30
  5. End-stage renal disease: requiring dialysis
24
Q

Why are adverse effects of NSAIDs so important? What is their prevalence of use?

A

Analgesics are among the most commonly consumed drugs in the world; on any given day,these drugs are used by 20-30% of people over 65

25
Q

What population of people are at increased risk of experiencing adverse effects with NSAIDs? Why? (4)

A

Older adults because:

  1. Higher use
  2. Increased prevalence of of conditions exacerbated by NSAIDs
  3. Larger number of comorbid conditions
  4. High use of concurrent medications
26
Q

What are some conditions that are exacerbated by NSAID use? (3)

A

HTN, CHF, renal insufficiency

27
Q

How does renal function relate to age?

A

Renal function declines with age, irrespective of the use of drug therapy

28
Q

NSAIDs are responsible for what percentage of preventable adverse drug events?

A

15.4%

29
Q

How important is prostaglandin (PG) synthesis in the kidney of healthy individuals with normal volume status? Why?

A

PG synthesis is of minimal importance in these people because it is NOT a primary regulator of renal function

30
Q

What do eicosanoids do?

A

they locally modulate the effects of both systemic and locally produced vasoconstrictor hormones

31
Q

What are the predominant mediators of physiologic activity in the kidney? What do they do?

A

PGI2 (prostacyclin) and PGE2; they induce vasodilation in the interlobular arteries, afferent and efferent arterioles, and glomeruli

32
Q

What is the risk of NSAID-associated acute ARF in a healthy person? Why?

A

Negligible; bc basal PG production is low

33
Q

What are risk factors that render a person’s kidney PG-dependent? How does this affect this person’s risk of NSAID-associated ARF?

A

1.True intravascular volume depletion 2.Effective intravascular volume depletion
3.Kidney disease
4. Certain medications (ACEi’s, ARBs)
5. old age
These patients are at risk for development of ARF when they use NSAIDs

34
Q

When do PG’s have their major role in preservation of kidney function?

A

when pathologic states supervene and compromise physiologic kidney processes

35
Q

What are 2 types of pathologic states that supervene and compromise physiologic kidney processes? (2 categories) How do they affect PG activity/production

A
  1. Development of true intravascular volume depletion as seen with vomiting, diarrhea, and diuretic use→these all stimulate PG synthesis to optimize renal blood flow
  2. Decreases in effective renal blood flow as seen with congestive HF, cirrhosis, and nephrotic syndrome→these also stimulate compensatory PG production
36
Q

What do PGI2 and PGE2 antagonize? Why?

A

They antagonize the local effects of circulating Ang-II, endothelin, vasopressin, and catecholamines because these would normally maintain systemic BP at the expense of the renal circulation (see next question)

37
Q

How do the eicosanoids PGI2 and PGE2 preserve GFR?

A

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

38
Q

Administration of an NSAID to a patient with any of these underluing disease states can result in what?

A

A significant reduction in GFR

39
Q

Risk of reduced GFR and ARF also increases with what two non-disease factors?

A

age and dose and duration of NSAID consumption

40
Q

What also results in increased PG synthesis? By what mechanism does this happen?

A

chronic kidney disease (CKD); upregulation of PG synthesis in CKD is induced by intrarenal mechanisms activated to increase perfusion of remnant nephrons

41
Q

What happens in patients with CKD on an NSAID?

A

impairment of PG production→acute reductions in RBF and GFR

42
Q

Which drugs when given at the same time as an NSAID increase the risk of ARF? What are they commonly used to treat?

A

drugs that antagonize the RAAS→ ACE inhibitors and ARBs; these are commonly used to treat CV and renal conditions

43
Q

Where else do PGs have an important role?

A

in the loop of henle and distal nephron

44
Q

What effect does PGE2 have in TALH and CD cells? What is the direct result of this action of PGE2 on these nephron segments?

A

it decreases cellular transport of NaCl; this results in an increase in renal Na excretion and a decrease in medullary tonicity

45
Q

What other actions do PGE2 and PGI2 have? What do these actions result in?

A
  1. stimulate renin secretion in JG apparatus→increased ANG-II and Aldosterone→enhanced Na retention and K excretion in the distal nephron
  2. inhibit cAMP synthesis→oppose the action of ADH→facilitates increased water excretion
46
Q

Given these effects of PGI2 and PGE2 in the distal nephron, what effect would chronic NSAID use have?

A

A mild dose-dependent increase in BP

47
Q

What patients are at risk to develop severe HTN with NSAID use? (5)

A

elderly patients, those with pre-existing HTN, salt-sensitive pt’s, pt’s with renal failure, and pt’s with renovascular HTN

48
Q

What is to nephrotoxic potential of COX-2 inhibitors?

A

equivalent to that of other NSAIDs

49
Q

An allergic reaction to an individual NSAID chemical structure is associated with what?

A

Interstitial nephritis

50
Q

How does acute renal toxicity to NSAIDs manifest?

A

It manifests in terms of tubular epithelial necrosis secondary to altered renal hemodynamics

Renal Pharm (4 decks)

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