lecture 4 (pharmacokinetics) Flashcards
Describe the relationship between pKa and pH
- if pKa is GREATER then the pH, then the drug will exist predominantly in the pronated form
- If pKa is LESS than the pH, then the drug will exist predominantly in the unpronated form
describe the ionized/non-ionized forms
- Non-ionized forms more readily cross membranes
–> pronated form of WEAK ACID is non-ionized
–> unprotonated form of a WEAK BASE is non-ionized
describe the factors that affect distribution of a drug in the body
- Proportion of cardiac output (greater the CO the greater the distribution)
- regional blood flow (more blood flowing to the tissue then the greater the distribution of the drug to the tissue)
- Capillary permeability
- binding to plasma proteins (the more drug that sticks to proteins, the LESS of it is distributed to tissues)
- lipid solubility (lipid soluble drugs can move across lipid membranes and therefore can access targets more readily)
what are the sites of biotransformation
- GI, lungs, skin, kidney, brain and LIVER
- liver is main metabolizing organ due to vascular architecture
describe the phase 1 of biotransforamtion
- generate a more polar molecule by EXPOSING a functional group on parent compound
–> rate limiting step is mediated by cytochrome P450s (CYP) enzymes in the NEDOPLASMI RETICULUM of cells
describe the phase 2 of biotransformation
- Yeilds a more WATER SOLUBLE conjugated product
–> transported to bile cuniculi –> bile duct –> excreted with feces
–> transported back into the blood to be excreted by kidneys
describe the first-pass effect
- Large percentage of oral drug absorbed by the stomach or intestine will be initially carried to the LIVER via portal vein
–> most of the orally administered drug will be exposed to metabolizing enzymes in the liver before distributing to the entire body.
–> results in LARGE amount of drug inactivation prior to reaching the inteded target
- C = concentration of drug in blood
- V = volume of distribution
- The larger the volume of distribution, the GREATER the extent to which the drug distributes to extravascular tissue (e.g. FAT)
- V is an apparent volume and can exceed actual body volume
- Clearance = rate of elimination in relation to drug concentration
- Clearance is additive
define zero-order elimination
- Specific amount of drug is eliminated over a period of time
- Elimination process is AT CAPACITY or SATURATED. Independent of drug conc.
- 100mg –2hr–> 80mg –2hr–> 60mg –2hr–> 40mg etc (amount of drug is constant)
define first-order elimination
- Clearance is constant over the range of drug concentration in the body
- The FRACTION of drug eliminated is constant and not dependent upon the drug conc
- 65mg –2hr–> 32.5mg –2hr–> 16.25mg etc
Define Capacity-limited elimination
- Concentration of a drug has SATURATED the elimination capacity or capabilities of our system
- -> MIMICS ZERO-ORDER KINETICS
- -> If dosing rate is greater than the elimination rate, the drug concentration will CONTINUE TO INCREASE in the blood (lead to TOXIC EFFECTS)
Define Flow-dependent elimination
- Organ has HIGH capacity or is NOT SATURATED by the drug concentration
- -> Kinetic would mimic FIRST-ORDER
- -> Limiting factor for elimination of a drug is the blood flow to the metabolizing organ (Greater the blood flow the greater the extend of elimination)
–> Half-life is dependent upon the volume of distribution and clearance when considering a drug eliminated by first-order kinetics
–> Half-life is variable if the drug is eliminated by zero-order kinetics
- As volume increases, so does the half life
- As CL increases, the half-life decreases
–> At about 4-5 half-life, we consider 1 dose of the drug to be gone
- Accumulation of drugs in the body will be detectable if the dosing interval is shorter than four half-lives
- Accumulation is inversely proportional to the fraction of drug lost with each dosing interval
- -> If a drug is given once every half life: AF = 1/0.5 = 2 (drug will accumulate to a concentration twice as much as was seen following the first dose)
- -> If a drug is given once eveyr 3 half lifes: AF = 1/.875 = 1.143
describe bioavailability
- Bioavailability = amount of drug that reaches the systemic circulation
–> what happens if hepatic blood flow decreases?
–> what if absorption of gut increaes?
define therapeutic window
–> The range between concentration of drug that produces desired response and concentration that will produce adverse effects = THERAPEUTIC WINDOW
–> MEC = minimum concentration for the toxic or unwanted drug effect
- Steady state concentration (Css) = the point during a dosing regimenw hen elimination of a drug is equal to the bioavailability of the drug
–> Only obtained after 4-5 half-lives (dependent upon the half-life)
- If CL of a drug decreases then the Css will increase; CL is constant and the dosing rate increases then the Css will increase
describe the maintenance dose
- Maintenance dose = dose needed to maintain steady state conc.
1) Dosing Ratess = CL x TC
2) Dosing Rateoral = (Dosing Ratess)/(Foral)
3) Maintenance Dose = dosing rate x Dosing interval - Increase dosing interval (decreasing frequency) –> decreases the amount of drug –> greater variation from peak to lowest conc
- decreasing doseing interval (increasing frequency) –> less variation in the peaks and lowest conc.
Describing loading dose
- Loading dose = initial dose that can be given in order to achieve the target concentration rapidly
describe the advantage/disadvantage of loading dose
Advantage:
- -> Useful when time to steady state is long but need to rapidly reach TC
- -> This can occur with drugs that have a long half-life
Disadvantage
- -> Abrupt high concentrations may be toxic
- -> Calculation takes into account final volume of distribution but drug is initially restricted to central compartment (blood)
- -> Due to disadvantages, LD is typically divided into multiple smaller dose or infused over a period
