drug interactions

Question 1

what is a pharmaceutical drug-drug interaction?

Answer 1

occurs prior to systemic admin

Question 2

what is a pharmacodynamic drug-drug interaction?

Answer 2

a drug causes change in response to another drug

Question 3

what is a pharmacokinetic drug-drug interaction?

Answer 3

one drug alters rate or extent of ADME of another drug

Question 4

3 drug interaction mechanisms?

Answer 4

• altered absorption
• excretion
• metabolism

Question 5

what is hepatic clearance?

Answer 5

volume of blood from which a drug is completely removed by liver / unit time

Question 6

what is hepatic extraction ratio?

Answer 6

fraction of drug extracted from blood during single pass through liver

Question 7

3 step overview of drug metabolism and clearance?

Answer 7

• enzymatically mediated modification of structure
• make fat soluble chemicals more water soluble
• removal from systemic circulation

Question 8

what happens in metabolism and excretion of lipid soluble molecules?

Answer 8

poorly excreted in urine
stored in adipose and circulate until converted (phase1) to more water soluble or conjugated (phase2) with water soluble molecules

Question 9

what happens in metabolism and excretion of water soluble molecules?

Answer 9

more readily excreted, may be metabolised but not generally by CYP enzymes

Question 10

roles of each phase of metabolism?

Answer 10

phase1 - convert to active molecule (more polar)
phase 2 - conjugation to further increase aqueous solubility
phase 3 - transmembrane transport, efflux into bile or urine

Question 11

exceptions to metabolite products being less pharmacologically active than parent compound?

Answer 11

pro-drugs - metabolite more active
toxic metabolite - paracetamol
carcinogenic metabolite

Question 12

what is hepatic clearance dependent on?

Answer 12

• Fraction of drug not bound to albumin
• Liver blood flow
• Liver intrinsic clearance – Metabolic enzyme activity

Question 13

why do enzymes metabolise drugs?

Answer 13

metabolise drugs only because they resemble natural endogenous compounds

Question 14

what are CYP enzymes?

Answer 14

Haem-containing proteins within the smooth ER responsible for most Phase I biotransformations

Question 15

factors affecting drug metabolism?

Answer 15

• physio-chemical (drug structures)
• biological (age, gender, genetics)
• environmental (diet, enzyme inhibition/induction)

Question 16

principle of enzyme inhibition?

Answer 16

competitive inhibition of CYP450s
drug A reduces clearance of drug B - leads to toxicity

Question 17

principle of enzyme induction?

Answer 17

induces expression of CYP450s
- drug A increases elimination of drug B
- increased production of toxic metabolites of drug B

Question 18

effect of grapefruit juice?

Answer 18

CYP3A4 inhibitor
drugs metabolised by this enzyme will accumulate in plasma

Question 19

importance of CYP3A4?

Answer 19

Responsible for metabolism of 60% of all drugs

Question 20

what inhibits CYP3A4?

Answer 20

macrolide antibiotics (clarithromycin)
antifungal agents (ketoconazole)
HIV protease inhibitors (-vir)
St Johns Wort