Interactions

Question 1

what are pharmacokinetic interactions

Answer 1

interactions which can affect the process by which drugs are absorbed, distributed, metabolised or excreted

(ADME INTERACTIONS)

Question 2

what are pharmacodynamic itneractions

Answer 2

interactions that occur when the effect of drug A is altered by the presence of drug B without affecting its pharmacokinetics

Question 3

what are CYP450 enzymes and how do they work?

Answer 3

haemoprotein metabolising enzymes

they are major enzymes involved in drug metabolism
they are primarily involved in phase 1 monooxygenase reactions
the source of oxygen is the oxygen joined to the heme co-factor

Question 4

please draw the mechanism of CYP oxidation

Answer 4

aliphatic hydroxylation

Question 5

what will happen if drug A is a CYP substrate and drug B is a CYP inhibititor?

Answer 5

drug a concentration will increase

risk of toxicity

Question 6

what will happen if drug A is a CYP substrate and drug B is a CYP inducer?

Answer 6

drug A concentration will decrease
reduced substrate A efficacy
risk of therapeutic failure

Question 7

what is the rate of onset of effect for CYP inducers? and why?

Answer 7

gradual onset and offset

this is because the process is slow and involves increased DNA transcription and synthesis of new CYP enzymes

Question 8

what affects the length of effect of the CYP inducer?

Answer 8

half life of the inducer
time to make new CYP proteins
rate of degeneration of new CYP proteins

Question 9

what is the rate of onset of effect for CYP inhibitors? and why?

Answer 9

rapid onset of action

Question 10

how long does the effect of CYP inhibiting enzymes last

Answer 10

may be a long lasting effect (depends on the exact MOA)

may be long lasting depending on how long it takes to make new enzymes

Question 11

what are the two methods of inhibiting CYP enzymes

o

Answer 11

oxidative metabolism

n-oxidation

Question 12

how does oxidative metabolism act to inhibit CYP enzymes?

Answer 12

capable of alkylating either the protein or the prosthetic heme group

blocks the enzyme action
prevents its return to function until a new CYP enzyme is produced

Question 13

how does n-oxidation act to inhibit CYP enzymes?

Answer 13

if the inhibitor contains an amine functional group
can lead to formation of an irreversible metabolic intermediate between a nitrogen group and the heme iron (prevents complete function)

Question 14

Inhibitor or inducer?

rifampicin

Answer 14

inducer

Question 15

Inhibitor or inducer?

carbemazapine

Answer 15

inducer

Question 16

Inhibitor or inducer?

phenobarbital

Answer 16

inducer

Question 17

Inhibitor or inducer?

phenytoin?

Answer 17

inducer

Question 18

Inhibitor or inducer?

nevirapine

Answer 18

inducer

Question 19

Inhibitor or inducer?

pioglitazone

Answer 19

inducer

Question 20

Inhibitor or inducer?

st. johns wort

Answer 20

inducer

Question 21

Inhibitor or inducer?

sulfamethazazole

Answer 21

inhibitor

Question 22

Inhibitor or inducer?

amioderone

Answer 22

inhibitor
(not the parent dug amioderone itself but its metabolites
it is the inhibitory metabolites of amioderone that are responsible for causing the drug drug interaction)

Question 23

Inhibitor or inducer?

cimetadine

Answer 23

inihibtor

Question 24

Inhibitor or inducer?

fluoxetine

Answer 24

inhibitor

Question 25

Inhibitor or inducer? | fluxonazole

Answer 25

inhibitor

Question 26

Inhibitor or inducer? | ritonavir

Answer 26

inhibitor

Question 27

what is the role of ritonavir in highly active antiviral therapy?

Answer 27

used in combination with other retrovirals ritonavir is rarely used for its own retroviral activity but remains widely used as a "booster" for other protease inhibitors it has these abilities because of its off-target inhibitory action agains CYP3A4 ritonavir is sacrificed to the CYP enzymes it is a potent CYP enzyme inhibitor it reduces the metabolic action of the enzymes therefore it prevents other protease inhibitors being metabolised by the CYP enzymes and so BOOSTS their therapeutic action of the other antiretrovirals !!

Question 28

what is Pglycoprotein

Answer 28

it is a transmembrane molecular pump that acts to protect our cells from toxic molecules it is the most characterised memeber of the ABC-transported subfamily of proteins

Question 29

what is special about the PgP structure that makes it really good

Answer 29

cone shaped intracellular cavity allows it to accept a wide range of structurally diverse substrates

Question 30

explain the process of PgP action

Answer 30

1) PgP sits in the cell membrane and searches for foreign hydrophobic molecules 2) when it finds a foreign hydrophobic molecule it grabs it deep within the protein and then it flips to a new conformation (substrate binding initiates ATP recruitment) 3) the new conformation has an opening towards the outside of the cell and the molecule is ejected out of this opening (the whole process if powered by ATP to ensure the process occurs in a timely manner)

Question 31

what happens in the interaction between anioderone and digoxin

Answer 31

amioderone increases the serum concentration of digoxin but inhibiting the Pgp that facilitates the elimination of digoxin from the body amioderone may also influence the serum concentrations of digoxin bu changing the tissue distribution of digoxin (Vd)

Question 32

name 3 interactions that can occur between a drug molecule and PgP

Answer 32

hydrophobic interaction (weak electrostatic forces, Van Der Waals ) hydrogen bonding aromatic cage formation (align electrons with the drug)

Question 33

what are antacids made of

Answer 33

they are chemically week bases formulated as salts | hydroxides, tricilates, carbonates

Question 34

how can antacids cause drug drug interactions

Answer 34

**because of their effect on pH** they increase gastric pH (make it less acidic and more alkaline) therefore this impacts on pH dependent dissolution as most drug molecules contain an ionisable functional group, changes in pH will have a knock on effect fo the dissolution profiles of any co-administered drugs as dissolution is the rate limiting step of drug administration from a solid dosage form changes in drug dissolution due to changes in stomach pH can therefore lead to enhanced or reduced absorption **chelation** occurs between polyvalent metallic ions (magnesium or aluminium) and organic mocules form an insoluble ring complex in solution that cannot be absorbed

Question 35

what is the problem with using antacids with ketoconazole

Answer 35

ketoconazole is a weak base pH approx 3 it is therefore nearly insoluble at pH 4 but is soluble at acidic pH if the gastric ph is raised >4 for a period longer than gastric emptying (10-20 mins) then the drug may reach the small intestine before dissolution has taken place therefore absorption will be decreased as the drug will not be in solution when it reaches the small intestine therefore it cannot be absorbed

Question 36

what is the problem with using mallow with tetracyclines

Answer 36

reduces the oral bioavailability of the tetracycline and its metabolites bu 80% (the same effect doesnt occur when using omeprazole) this means that tetracycline chelates with the metal ions in the antacids and forms an insoluble complex as the tetracycline has formed the insoluble complex it cannot be absorbed and therefore cannot exert its therapeutic effect.

Question 37

where can pharmacodynamic reactions occur

Answer 37

at the receptor (where it binds) | or the effector (the therapeutic effect that it has)

Question 38

please give an example of a negative interaction at the receptor

Answer 38

salbutamol (beta 2 agonist) | propranolol (non selective beta antagonist)

Question 39

please give an example of a positive interaction at the effector

Answer 39

using a combination of ACE inhibitor and calcium channel blockers to treat hypertension both have different MOA but exert the same final effect of reducing blood pressure

Question 40

please give an example of a negative interaction at the effector

Answer 40

using carvedilol (beta blocker) and verapamil (CCB) both have cardiac suppressant effects can cause serious cardio depression e.g bradycardia, systole, sinus arrest :-(