A.5

Question 1

CYP450 inhibitors

Answer 1

sodium valproate
isoniazid
cimetidine
ketoconazole
fluconazole
alcohol
chloramphenicol
erythromycin
sulfonamides
ciprofloxacin
omeprazole
metronidazole

Question 2

CYP450 inducers

Answer 2

carbamazepine
rifampin
alcohol
phenytoin
griseofulvin
phenobarbital
sulfonylurea

Question 3

Characterize the dosing regimen and its goal

Answer 3

A plan for drug administration over a period of time -> optimal dosage regimen is to achieve therapeutical levels of drug in the plasma without exceeding the minimum toxic concentration

Its goal is to reach a steady state of drug concentration in plasma, in which the rate of input of drug = elimination.

Question 4

What does the time to reach steady state depend on?

Answer 4

Elimination half-life of a drug

Question 5

Drug-drug interaction (pharmacokinetics)

Answer 5

1 medication alters the absorption/distribution/metabolism/excretion of another drugs (i.e. changing the amount available to produced desired effect), for example ritonavir inhibits CYP3A4 required for metabolism of many drugs like cyclosporinA
e.g. 2 meds metabolized by the same enzymes (i.e. compete for same enzyme sites), for example succinylcholine and mivacurium are both metabolized by pseudocholinesterase

Question 6

Drug interactions (pharmacodynamics)

Answer 6

Meds influence each other’s effects directly
e.g. 2 meds ↑ each others effect (Trimetoprim-sulfamethoxazole → synergistic effect)
e.g. Medications having 2 opposite effects (antagnistic effect)

Question 7

calculate dosing rate

Answer 7

dosing rate=CL*desired plasma concentration/ bioavailability

Question 8

calculate loading dose

Answer 8

loading dose=Vd*desired plasma concentration/bioavailability

Question 9

first-order elimination

Answer 9

Rate of elimination is proportional to the drug concentration (the higher concentration -> the greater amount of drug eliminated)
- Drug concentration in plasma decreases exponentially with time
- Half-life of elimination is constant regardless of the amount of drug in the body

Question 10

Zero-order elimination

Answer 10

Rate of elimination is independent of the concentration
- Occurs with drugs that saturate their elimination mechansims at concetrations of therapeutic value (e.g. ethanol)
- Drug concentration in plasma decreases in a linear fashion with time
- Half-life of elimination is NOT constant
- Slower elimination than 1st order kinetics

Question 11

Phase 1 biotransformation reactions

Answer 11

Reaction that converts parent drug to a more polar (Water-soluble) or more reactive product by oxidation, reduction and hydrolysis -> mediated by CYP450 isoenzymes
Non-microsomal metabolims: Hydrolysis, Monoamine oxidase, Alcohol metabolism

Question 12

Hydrolysis

Answer 12

addition of water molecules to break bonds -> includes esterases and amidases. Genetic polymorphism exist with pseudocholinsterase -> deficiency in PC -> increase ACh levels (muscle relaxant)

Question 13

MAO (monoamide oxidases)

Answer 13

Metabolizes: dopamin, NE, seratonin, tyramine (cheese effect if MAO block)

Question 14

Alcohol metabolims

Answer 14

Metabolized to aldehydes and then to acids by dehydrogenase

Question 15

Phase 2 biotransforamtion reactions

Answer 15

Reactions that involve addition (conjugation) of subgroup -> glucuronidation is most common. (but also acetate, glutathione, glycine, sulphate, methyl groups) to the drug -> catalyzed by transferases
- Most of these groups are relatively polar and make the product less lipid soluble than the original molecule -> easilier excreted

Question 16

loading dose

Answer 16

• Initial higher dose of a drug that may be given -> before dropping down to a lower maintenance dose
• Single dose for saturating the drug
• Most useful for drugs with relatively slow elimination -> long systemic T1/2
• Such drugs need only a low maintenance dose to keep the amount of the drug in the body at the appropriate therapeutic level, but this also means that without an initial higher dose, it would take a long time for the drug to reach that level

Question 17

Maintenance dose

Answer 17

keep the amount of the drug in the body at the appropriate therapautic level.
Administration rate = rate of elimination in steady state
- Maintenance dose = Dosing rate x Dosing interval

Question 18

Elimination

Answer 18

Process involved in the elimination of drugs from the body (mainly by kidney, bile, lungs) and their kinetic characteristics. a chemical change to the drug that renders it inactive

Question 19

excretion

Answer 19

Drug elimination is not the same as drug excretion - a drug may be eliminated by metabolism long before excreted from the body. expulsion of the drug from the body

Question 20

clearance

Answer 20

Rate of elimination to the plasma concentration
CL = Rate of elimination/plasma drug concentration (unit = volume per time)

Question 21

clearance for a drug eliminated with 1st order kinetics

Answer 21

By area under the curve (AUC) -> Clearance = Dose/AUC

Question 22

Half-life

Answer 22

Time required for a drug concenctration to reduce to 50% of its initial value
- Directly proportional to volume of distribution
- Inversly proportional to clearance and eliination coefficient

Question 23

T1/2 calculated

Answer 23

t1/2=0.693*Vd/CL

Question 24

biotransformation

Answer 24

Metabolic conversion of drug molecules to more water-soluble metabolites that are more readily excreted

Question 25

function and key organ or biotransformation

Answer 25

Get rid of toxic molecules after they are absorbed, as well as excreting undesirable substances produced within the body -> Liver is the key organ

Question 26

Possible outcomes of metabolites of biotransformation

Answer 26

1. Metabolism -> metabolite with no pharmacological activity
2. Metabolism -> metabolite with pharamcological actions (e.g. morphine)
3. Prodrugs -> metabolized -> action (e.g. levodopa)

Question 27

Which drugs can we see shift from 1st order kinetics at low doses to zero order kinetics at moderate to high doses?

Answer 27

Phenytoin and Ethanol