Drug Elimination & Multiple Dosing

Question 1

Define loading dose. How is calculated?

Answer 1

large dose given initially to reach therapeutic levels quickly (followed by lower maintenance dose or infusion to sustain target concentration levels)

LD = TC x Vd/F
(depends on Vd)

Question 2

Define steady-state concept.

Answer 2

steady-state is the maintenance of the target concentration (therapeutic range). Loading doses help reach target concentration faster, BUT it will still take 4-6 half-lives to reach steady state independent of dose)

Question 3

List the primary pharmacokinetic parameters. How are they used to determine loading dose and maintenance dose?

Answer 3

• clearance determines MD

- Vd determines LD

Question 4

Define maintenance dose.

Answer 4

• based on amount of drug cleared from the body since last administration
• maintains steady state after target has been reached

MD = CLxTCxT/F
(depends on CL)

Question 5

Describe the concept of repetitive dosing.

Answer 5

Typically, it takes 4-6 half-lives to reach steady state (maintaining target concentration). With continuous infusion, it takes a long time to reach target concentration and then it plateaus off. By giving repetitive doses, you reach target concentration faster.

Question 6

Compare/Contrast elimination and intercompartmental clearance.

Answer 6

EC: irreversible drug removal from the plasma through an eliminating organ; unidirectional

IC: drug distribution between plasma and tissues (bidirectional)

Question 7

Define first order elimination.

Answer 7

• constant fraction of the drug is being eliminated from the body
• constant half life
• ex: lidocaine

Question 8

Define zero-order elimination.

Answer 8

• drugs eliminated primarily by metabolism
• constant amount of the drug is being eliminated from the body
• elimination does not change with dosage b/c metabolic pathways are saturable
• HALF LIFE DOES NOT APPLY; it is NOT constant
• ex: phenytoin, ethanol, aspirin, heparin, theophylline, warfarin

Question 9

Define dose-dependent elimination.

Answer 9

For drugs that are eliminated primarily by metabolism…

- concentration > Km = zero order; C/t = Vmax

Question 10

Define total clearance.

Answer 10

sum of clearance by all eliminating organs and tissues

Question 11

Define elimination half life.

Answer 11

T1/2 = 0.69xVd/CL ====> k = CL/Vd

time it takes to eliminate 50% of the drug

Question 12

What are the 2 primary pharmacokinetic factors?

Answer 12

• Vd

- CL

Question 13

How do you determine time it takes to reach steady state?

Answer 13

t0.90 = 3.3t0.50

Question 14

Why do you adjust for renal insufficiency? How can you adjust?

Answer 14

• impaired clearance of drugs eliminated by the kidneys
• daily dose must be reduced to prevent buildup of drug and toxic concentration levels
• adjust by reduced dose or increased dose intervals or both

Question 15

Define creatinine clearance rate.

Answer 15

CrCL = volume of blood plasma that is cleared of creatinine/time

• used to approximate GFR
• measures kidney function
• used to adjust dosage for renal failure

Question 16

List determinants of hepatic clearance.

Answer 16

1. hepatic blood flow - rate of drug delivery to liver
2. plasma protein binding - fraction of drug available for clearance
3. intrinsic clearance - hepatocellular metabolism and bile excretion

Question 17

Define restrictive hepatic clearance.

Answer 17

• for drugs that are not extracted by the liver
• blood flow does not matter in the equation (Q&raquo_space; fxCL)
• CLh = fxCLint
• aka capacity-limited
• ex: warfarin, phenytoin

Question 18

Define non-restrictive hepatic clearance.

Answer 18

• drugs are heavily extracted by the liver
• blood flow matters greatly
• aka flow-dependent
• CLh = Q
• conditions that reduce Q (CHF, hypotension) will reduce CL
• ex: lidocaine, propanolol