FoM:L3 - Pharmacokinetics 2, distribution and metabolism

Question 1

What is drug distribution?

Answer 1

postabsorptive reversible transfer of a drug from the systemic circulation to other compartments of the body

Question 2

What are extravascular fluids?

Answer 2

intracellular and interstitial fluid

Question 3

What is perfusion rate?

Answer 3

the volume of blood that flows per unit time per unit volume of the tissue

Question 4

What are free and bound drugs?

Answer 4

free - not bound to plasma proteins
bound - bounds to plasma protein (reversible)
drug/protein complex temporary storage, cant cross membranes

Question 5

How is the extent of drug distribution defined?

Answer 5

By its apparent Volume of Distribution (Vd) estimated by the dilution principle

Question 6

What is drug metabolism?

Answer 6

the biotransformation of drugs in the body in preparation for excretion

Question 7

How do you measure plasma conc.?

Answer 7

drug dose / Vd

Question 8

What are Vd values?

Answer 8

• volume of body fluids into which a drug appears to have been distributed
• fixed characteristic (independent of dose)
• often L/Kg

Question 9

What do different Vd values (in litres) mean? for a typical 70kg man

Answer 9

less than 5 = confined to plasma water
5-15 = extracellular water
40-45 = total body water
60-100 = adipose tissue where it has been absorbed and sequestered

Question 10

Why can Vd be deceptive?

Answer 10

• some drugs are not evenly distributed
• if plasma conc. doesnt reflect local tissue conc. -> impossibly large

Question 11

What is the blood brain barrier?

Answer 11

• tight junctions and astrocytes
• brain made privileged space that excludes large and/or water soluble drugs
• allows small, lipid-soluble drugs

Question 12

Why is rate of elimination important?

Answer 12

determines the rate of drug administration needed to maintain drug concentrations in the body

Question 13

Outline the pathway of drugs through the liver

Answer 13

• enter through hepatic artery or hepatic portal vein
• diffuse into hepatocytes
• exit via central vein

Question 14

What are the phases of metabolism?

Answer 14

phase 1: inactivation
phase 2: solubilisation

Question 15

What enzymes are involved in phase 1 metabolism?

Answer 15

• CYP450 isoenzymes
• hepatocyte SER
• membrane bound haemoproteins (inactivation: oxidation, reduction, hydrolysis)

Question 16

How do CYP enzymes impact drug interactions?

Answer 16

• limited capacity of induction of CYP synthesis
• 2 or more drugs catalysed by the same CYP

Question 17

What enzymes are involved in phase II metabolism?

Answer 17

secondary enzymes in SER and cytoplasm of hepatocytes

Question 18

What are the consequences of drug metabolism?

Answer 18

• can generate active or longer lived metabolites, most are made less active
• inactive/pro-drugs converted to active drugs
• may generate toxic metabolites