Pharmaceutics Ii- Renal Disease

Front 1

mol wt that are not filtered by kidneys

Back 1

Mol. Wt. > 60,000 daltons not filtered.

Front 2

factors that alter ______ also change GFR

Back 2

Factors that alter filtration pressure change GFR

Front 3

most widely used marker of GFR in
clinical practice.

Back 3

SrCr

Front 4

5 things that affect SrCr and thus GFR estimation accuracy

Back 4

muscle mass
Dietary protein intake affects
Tubular secretion (compensates when GFR goes down)
— Variability in laboratory measurement
— Intra-individual variability 7-20%

Front 5

GFR- protein binding influence, % of blood flow

Back 5

• Influenced by protein binding
• GFR is 25% of blood flow

Front 6

drugs that alter renal hemodynamics (4)

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— NSAIDS
— Vasoconstrictors
— ACE inhibitors
— Hepatorenal syndrome (failure of renal and hep)

Front 7

tubular reabsorption- active or passive?
interactions

Back 7

passive

alteration of urine pH

Front 8

Proximal Tubule diseases (4)

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 Ischemia
 Prerenal azotemia
 Crystalluria
 Nephrotoxicity (AGs and such)

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distal tubule toxicity

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nephrotoxins

Front 10

interstitium toxicity (2)

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 Interstitial Nephritis (NSAIDS)
 Fibrosis

Front 11

cllecting tube disease (2)

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 SIADH
 Nephrogenic
diabetes
insipidus

Front 12

tubular secretion- occurs where (2), influenced by protein binding? affected by...

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 Secretion occurs in the PCT & DCT
 Not influenced by protein binding
 May be affected by competition with other drugs

Front 13

Transporters – in renal- where are they, what are they (3)

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organic cations (OCT)
organic anions- (OAT)
OATP- for large anions
Proximal Renal Tubular Cell

Front 14

Reabsorption by non-ionic diffusion (4)- affects what type of drug, effect of pH, importance

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 Most drugs undergo reabsorption back into
blood
 Passive process in distal tubules for lipophilic or
not highly ionized drugs
 Urinary pH affects reabsorption of weak acids
and bases
 Only important if excretion of free drug is major
elimination path

Front 15

examples of drugs affected by reabsorption (4)

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Weak acids Phenobarbital
Weak bases Quinidine

Front 16

Tubular Reabsorption: Effect of Urine pH and pKa on drugs (weak acids/bases) (3)

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 Many drugs are weak acids or weak bases and
therefore urine pH (range 4.5 to 7.5) modulates
rate of reabsorption.
 Acidic conditions suppress ionization of weak
acids and increase fraction unionized, leading to
increased reabsorption and reduced renal
clearance.
 In contrast acidic conditions increase the renal
clearance of weak bases.

Front 17

how to affect baseness/acidity of urine (2)

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 Alkaline urine can be produced by ingesting
sodium bicarbonate (up to 7.5) and acidic urine
from ammonium chloride (down to 4.5).
 Weak bases are pH sensitive for pKa values between 6 and 12.
 Weak acids are pH sensitive for pKa values between 3 and 7.5.

Front 18

glucose active reabsorption

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Glucose is normally 100% reabsorbed in the
distal tubule

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active reabsorption- affects what drugs/things (2)

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 Affects ions
 Is uncommon and is restricted to drugs that imitate endogenous cpds (salicylates,
probenecid, benzoic acids).

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Effect of Renal Disease on Drug
Distribution (2)

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 Binding of acidic drugs (phenytoin, sulfonamides,
warfarin, furosemide) is decreased in uremic
patients.
 Displaced from albumin by organic acids that
accumulate in uremia.

Front 21

effects of ascities from renal/liver disease on distribution (3)

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 Presence of edema and ascites may  V of
hydrophilic and highly protein bound drugs.
 In nephrotic syndrome (with extensive loss of
plasma proteins) the binding of clofibric acid, the
active metabolite of clofibrate, .
 This results in an  V.

Front 22

Effect of Renal Disease on Drug
Metabolism- know for exam

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Tissue peptidase alters insulin- decreases metabolic CL (can lower insulin req)

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Phenytoin in renal disease- metabolic CL effects (2)

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increases due to acidic toxins that displace from protein binding sites

also increase in metabolic CL (compensation for decreased hepatic?)

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procainamide and renal metabolic CL disease (2)

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Procainamide- Acetylation
slowed
CLcr must fall below 25 ml/min before acetylation rate impaired (more parent drug)

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Renal Insufficiency and Acyl-glucuronides- compare normal vs. renal disease pathways**

give drug example (2)

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normal- glucuronidation- acyl glucuronide-->elimintation

disease: glucuronidation-->acyl glucuronidate-->no elimination, so gets hydrolyzed back to parent drug "futile cycle"

ketoprofen/clofibrate

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chronic kidney disease definition (duratoin)

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Kidney damage or abnormal kidney function for
>3 months

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pathophys of chronic renal disease (2)

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Reduction of renal
mass causes
structural and
functional
hypertrophy of the
remaining nephrons.
— This compensatory
response eventually
predispose to
sclerosis of the
residual glomerul

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Stages of Chronic Kidney Disease

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Stage 1-5

stage 1- >=90 GFR
stage 3 <60
severe (4) >30

stage 5 <15

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3 labs that show acute impaired kidney

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Cr increased by >0.5 mg/dL, GFR <10mL/min, or <25% of normal

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ESRD GFR

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GFR <5% of normal

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Metabolic Consequences of ESRD (4)

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“Uremia”
acid/base disorders- acidosis
anemia
Renal Osteodystrophy

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uremic toxins

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 Multiple “toxins” are formed and unable
to be eliminated in patients with CRF

formed in renal disease

Front 33

Erythromycin N-Demethylation and uremic toxin effect (4)

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 Erythromycin (Ery) has reduced nonrenal CL in
patients with ESRD.
 Ery is partially metabolized by CYP3A4 to Ndemethyl-
Ery but primarily excreted unchanged in
bile.
 CMPF (a uremic toxin) inhibits metabolism.
 CMPF inhibits the OATP uptake of Ery & Ndemethyl-
Ery into hepatocyte

Front 34

General Principles of Drug Dosing in Patients
with Renal Insufficiency*** (3)

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 Accumulation sufficient to be of clinical concern
occurs if ≥ 30% of the drug or its active
metabolite is eliminated unchanged in urine of
patients with normal renal function
 In renal insufficiency endogenous organic
acids accumulate in plasma (competes for active secretion or displaces from protein)
Hypoalbuminemia from any cause results in
diminished binding of drugs bound to albumin

Front 35

Dosage adjustment – Dettli method (dosing on dose decrease or interval adjustment)

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 With impaired renal function, can decrease dose or increase dosing interval(longer)
 Once CL has been estimated, the daily dose can be usual maint dose/modified maint dose = usual CL/pt clearance (set up ratio)


can also calc. half life and dose based on that idk how

Front 36

key assumptions of dettli method (2) (non renal CL and renal CL patterns)

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 CLnr remains constant when renal function is
impaired
 CLr declines in linear fashion with CLCR