Pharmacokinetics II: Drug Distribution, Metabolism and Elimination

Question 1

What is drug distribution?

Answer 1

• Process by which a drug reversibly leaves blood
  stream and enters the extracellular fluid and/or
  cells of the tissue (intracellular fluid)

Question 2

Describe the pharmacokinetic process of drug
distribution.

Answer 2

• Determines relationship between plasma concentration and total amount of drug in the body.
• Amount of a drug that must be administered to produce a particular plasma concentration.

*Why we use loading doses.

Question 3

Define the term ‘apparent volume of distribution (Vd).

Answer 3

• Theoretical volume of fluid a drug would occupy if
  the total amount of drug in the body was in solution at the same concentration as in the plasma.
• Vd is not a real, physical volume but reflects the ratio of drug in extravascular space relative to plasma space.

Question 4

Why do we calculate Vd?

Answer 4

It gives us a measure of the tendency of a drug to
move out of the plasma to some other site.

Question 5

How do we calculate Vd?

Answer 5

Total amount of drug in the body divided by plasma concentration.

Question 6

Discuss the clinical usefulness of volume distribution.

Answer 6

• Reflects size of distribution space
• Large Vd = need higher dose to fill (load)
• Small Vd = need lower dose to load
• Vd used to calculate loading dose(LD)

Question 7

Discuss the range of Volumes of Distribution.

Answer 7

High range = located mainly in tissue, very little in plasma
Middle range = Similar concentration in both plasma and tissues
Low range = Localised mainly in plasma, little in tissues

Question 8

Why do we give loading doses?

Answer 8

• Given so therapeutic concentrations are achieved quickly.
• LD= Vd x desired plasma concentration.

Question 9

Describe the main routes of drug elimination from the
body.

Answer 9

Irreversible loss of drug from the body; occurs by two processes:
1. Metabolism:
- usually converts lipid soluble chemical to water soluble species.
- Phase 1 (oxidation, reduction, hydrolysis)
- Phase 2 (conjugation)
2. Excretion:
- Fluids (urine, bile, sweat, tears, milk)
- Solids (faeces, hair)
- Gases (expired air)

Question 10

What are the routes of drug excretion?

Answer 10

Major routes:
- Renal
- Biliary/ GI
-Pulmonary
Significant for other reasons
- Mammalian
- Salivary, Skin & Hair

Question 11

Discuss renal excretion.

Answer 11

3 renal processes:
- Glomerular filtration
- Active tubular secretion
- Reabsorption

Question 12

What happens on glomerular filration?

Answer 12

• Molecules less than 20kDa filtered (enter filtrate)
• Protein bound drugs not filtered (plasma albumin 68kDa)

Question 13

What happens in tubular secretion?

Answer 13

• Active carrier mediated elimination
• Secretory mechanisms for both acidic and basic compounds
• Can transport against electrochemical gradient and when drug protein bound

Question 14

What happens in re-absorption in renal excretion?

Answer 14

• Passive diffusion back across tubular epithelium
• Lipid soluble drugs (high tubular permeability), excreted slowly:
• Polar water soluble drugs remain in urine
• pH partitioning relevant

Question 15

Discuss biliary excretion.

Answer 15

• Hepatocyte uptake of lipid soluble drugs, metabolise and excrete into bile.
• But get re-absorbed along with the bulk of the water in small intestine
• Not excreted efficiently
  *Only works effectively if Mol. Wt. high enough (>500Da). Most drugs’ Mol. Wt. too low.

Question 16

When is bile excretion most favourable?

Answer 16

Significant route of excretion for:
1. Glucuronide conjugates (e.g. morphine)
2. Limited number of ionised drugs with very high Mol. Wt

Question 17

Discuss the entero-hepatic circulation.

Answer 17

• Drug conjugates hydrolysed mainly by bacteria in lower intestine
• Active drug released once more; free drug reabsorbed and cycle repeated
• Creates a reservoir of recirculating drug, prolongs drug action

Question 18

Discuss pulmonary excretion.

Answer 18

• Excretion via the lungs and breath
• Significant route of excretion for some volatile molecules:
  – E.g. anaesthetics, ethanol

Question 19

Discuss mammary excretion.

Answer 19

• Concentration in milk generally reflects free concentration in maternal blood.
• Clinical relevance for the effect of a drug on a breastfeeding baby e.g.
  1. Tetracyclines: Incorporated into teeth which become weakened and ‘mottled’
  2. Chloramphenicol: Bone marrow toxicity and ‘grey baby’ syndrome, (baby’s liver cannot metabolise the drug effectively)

Question 20

Explain first order drug elimination kinetics.

Answer 20

• “Elimination of a constant fraction per time unit of the drug quantity present in the organism. The elimination is proportional to the drug concentration
• The fraction of the drug eliminated (not the amount of drug eliminated) is constant.
• Most drugs are eliminated by this process.

Question 21

Explain zero order drug elimination kinetics.

Answer 21

• Elimination of a constant quantity per time unit of the drug quantity present in the organism
• Independent of drug concentration
• e.g. Protein mediated reactions (metabolism of ethanol*).

Question 22

Define the term half-life (t1/2) and its clinical relevance.

Answer 22

• Rates of Drug Elimination usually obey 1st Order Kinetics, and may be summarised by the Plasma Half-Life (t1/2).
• Plasma t1/2 = time for plasma concentration to
  fall by 50%.
• Is independent of dose.

Question 23

What determines plasma half life?

Answer 23

• Activity of metabolising enzymes or excretion mechanisms – clearance.
• Distribution of drug between blood into tissues - high Vd (drug mainly located in tissue) results in prolonged t1/2.

Question 24

What are the general rules of plasma half life t1/2?

Answer 24

• 4 half-lives after stopping drug plasma concentration will have fallen by ~94%
• 4 half-lives after starting drug plasma concentration at steady-state.

Question 25

What is a steady state?

Answer 25

A state of equilibrium where the amount of drug administered during a dosing interval exactly replaces the amount of drug excreted.
- Aim to maintain steady-state conc. of drug within therapeutic range.