45. Clinical Pharmacology II

Question 1

Do disease states usually increase or decrease drug concentrations in the body?

Answer 1

increase

Question 2

F
Vd
CL
T1/2
EC50, ED50
TI

Answer 2

Bioavailability (F)
Volume of distribution (Vd)
Clearance (CL)
Half-life of elimination (T1/2)
Effective dose-50, effective concentration-50 (EC50, ED50)
Therapeutic index (TI)

Question 3

What organ is the principle site of drug metabolism?

Answer 3

liver

Question 4

Total body clearance is highly dependent on what type of clearance?

Answer 4

hepatic

Question 5

What 3 factors is hepatic clearance dependent on?

Answer 5

• hepatic blood flow
• intrinsic clearance
• protein binding

Question 6

What is intrinsic clearance?

Answer 6

ability of metabolic enzymes to metabolize a drug (e.g. in relation to hepatic clearance)

Question 7

Why does protein binding influence hepatic clearance?

Answer 7

only free drugs (not PPB) can cross membranes and bind enzymes to be metabolized

Question 8

ER

Answer 8

extraction ratio

• ability of the liver to metabolize/extract drug
• difference between how much drug enters the liver and how much leaves

Question 9

High ER drug

Answer 9

• ER > 0.7
• “blood flow dependent”
• hepatic clearance changes proportional to changes in blood flow
• examples: morphine, lidocaine, propanolol

Question 10

Low ER drug

Answer 10

• ER > 0.3
• “capacity limited”
• moderate effects on blood flow will have little effect on hepatic clearance, rather clearance is most dependent on the rate of the liver’s metabolic enzymes
• examples: diazepam, prednisolone, phenylbutazone, cimetidine

Question 11

What are 4 changes seen in liver disease likely to affect drug disposition?

Answer 11

• decreased hepatic blood flow
• decreased phase I/II enzymes
• decreased albumin
• ascites

Question 12

How will decreased hepatic blood flow affect absorption and clearance?

Answer 12

• increased absorption - drug-containing blood not reaching functional hepatocytes –> decreased first-pass effect and increased amount of drug reaching systemic circulation
• decreased clearance (especially for high ER drugs that are blood flow dependent)

Question 13

How will decreased phase I/II enzymes affect clearance?

Answer 13

decreased metabolism –> decreased clearance (especially for low ER drugs that are capacity limited)

Question 14

How will decreased albumin affect distribution and clearance?

Answer 14

• drugs that are normally highly PPB may have higher free concentrations –> increased distribution
• clearance may also change, but depends on state of metabolic enzymes

Question 15

How will ascites affect distribution?

Answer 15

depends whether drug is water-soluble or lipid-soluble - if water-soluble, may distribute into free fluid, leading to an increase in Vd that would require a change in dose

Question 16

Which organ is the ultimate route for drug elimination from the body?

Answer 16

kidney - eliminates both parent compounds and metabolites

Question 17

Total renal excretion

Answer 17

rate of glomerular filtration + secretion - reabsorption

Question 18

Glomerular filtration

Answer 18

compounds move via bulk flow –> hydrostatic pressure filters compounds into filtrate –> added to tubular fluid

Question 19

Secretion

Answer 19

movement of compounds via active transport from peritubular capillaries into tubular fluid

Question 20

Reabsorption

Answer 20

movement of drug from tubular fluid back into peritubular capillaries (opposite of secretion)

Question 21

What changes in drug disposition occur with renal disease?

Answer 21

• decreased renal blood flow –> decreased glomerular filtration and secretion
• alterations in GFR independent of renal blood flow (e.g. compromise to renal capsule)
• decreased protein binding (e.g. loss of albumin in the urine)
• altered electrolyte balance
• altered drug disposition secondary to acid-base or fluid balance
• changes in rate of biotransformation (there are some metabolic enzymes in the proximal tubule)

Question 22

What is a good estimate of GFR?

Answer 22

creatinine clearance (usually measure serum creatinine, which is inversely related to urinary creatinine)

Question 23

Alteration in dosing regimen based on serum creatinine

Answer 23

• new dose = old dose x (normal Cr / patient Cr)

- new interval = old interval x (patient Cr / normal Cr)

Question 24

What changes in drug disposition occur with GI disease?

Answer 24

primarily related to absorption:

• changes in pH (ion trapping)
• alterations in gastric emptying
• alterations in intestinal motility

*most of the time, alterations in the bottom two will affect rate rather than extent of absoprtion

Question 25

What changes in drug disposition occur with cardiac disease?

Answer 25

- redistribution of blood flow (blood flow may be directed more toward vital organs such as brain and heart and away from GI tract) - retention of Na/H20 (distribution) - decreased cardiac output, renal and hepatic blood flow (clearance)

Question 26

General recommendations for cardiac disease

Answer 26

- give critical drugs IV - don't administer toxic drugs rapidly (e.g. use slow bolus or infusion instead) - decrease loading doses - decrease maintenance doses - monitor your patient

Question 27

Which occurs first in the progression of kidney disease, isosthenuria or elevated BUN/Cr levels?

Answer 27

isosthenuria - takes loss of 1/2 nephron mass to see isosthenuria, while takes loss of 2/3 nephron mass to see azotemia

Question 28

If we want a drug to maintain high concentrations in the GI tract, should we pick a drug with high or low bioavailability?

Answer 28

low bioavailability