A.5 Flashcards
CYP450 inhibitors
sodium valproate
isoniazid
cimetidine
ketoconazole
fluconazole
alcohol
chloramphenicol
erythromycin
sulfonamides
ciprofloxacin
omeprazole
metronidazole
CYP450 inducers
carbamazepine
rifampin
alcohol
phenytoin
griseofulvin
phenobarbital
sulfonylurea
Characterize the dosing regimen and its goal
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.
What does the time to reach steady state depend on?
Elimination half-life of a drug
Drug-drug interaction (pharmacokinetics)
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
Drug interactions (pharmacodynamics)
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)
calculate dosing rate
dosing rate=CL*desired plasma concentration/ bioavailability
calculate loading dose
loading dose=Vd*desired plasma concentration/bioavailability
first-order elimination
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
Zero-order elimination
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
Phase 1 biotransformation reactions
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
Hydrolysis
addition of water molecules to break bonds -> includes esterases and amidases. Genetic polymorphism exist with pseudocholinsterase -> deficiency in PC -> increase ACh levels (muscle relaxant)
MAO (monoamide oxidases)
Metabolizes: dopamin, NE, seratonin, tyramine (cheese effect if MAO block)
Alcohol metabolims
Metabolized to aldehydes and then to acids by dehydrogenase
Phase 2 biotransforamtion reactions
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
loading dose
- 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
Maintenance dose
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
Elimination
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
excretion
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
clearance
Rate of elimination to the plasma concentration
CL = Rate of elimination/plasma drug concentration (unit = volume per time)
clearance for a drug eliminated with 1st order kinetics
By area under the curve (AUC) -> Clearance = Dose/AUC
Half-life
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
T1/2 calculated
t1/2=0.693*Vd/CL
biotransformation
Metabolic conversion of drug molecules to more water-soluble metabolites that are more readily excreted
function and key organ or biotransformation
Get rid of toxic molecules after they are absorbed, as well as excreting undesirable substances produced within the body -> Liver is the key organ
Possible outcomes of metabolites of biotransformation
- Metabolism -> metabolite with no pharmacological activity
- Metabolism -> metabolite with pharamcological actions (e.g. morphine)
- Prodrugs -> metabolized -> action (e.g. levodopa)
Which drugs can we see shift from 1st order kinetics at low doses to zero order kinetics at moderate to high doses?
Phenytoin and Ethanol
