Pharmacokinetics week 1 Flashcards
Define therapeutic drug monitoring and under what conditions it is used.
How is therapeutic index calculated?
Clinical testing and evaluation (therapeutic drug monitoring –TDM) is not used with all drugs, only those with a narrow therapeutic index (NTI), i.e. where the dosage for therapeutic effect and toxicity is close together. The main use of PK is predictive. Using PK principles one may predict plasma concentration at any future time and thereby achieve optimal dosing with minimal oversight.
Therapeutic index=TD50/ED50
minimum effective concentration
maximum effective concentration
maximum effect
therapeutic window
The minimum effective concentration is the concentration below which a drug is known to lack sufficient therapeutic benefit. The maximum effective concentration indicates the level above which is toxic or which the drug evokes no further response. This latter dose phenomenon is called a maximum effect; raising the dose beyond this level may not be toxic but there is no greater therapeutic value. The toxic concentration is greater than or equal to the maximum effective concentration. The area between the minimum and maximum effective concentrations is termed the therapeutic window. Levels below this window will result in lack of drug effect. Levels above this window may result in toxicity, but only if the toxic concentration is reached.
Explain how Vd is calculated.
- Volume of distribution Vd
- Size of an imaginary container that is required to account for the total amount of the drug in the body
- Vd does not relate to a physiologic volume
- Vd = amount of drug in the body/initial drug concentration
Vd = Ab/Co = F * dose/Co = mg/(mg/ml) = ml
Co = initial plasma concentration at time 0
Ab: amount of drug absorbed
F: bioavailability
Define the following parameters:
ka
Cmax
Tmax
Absorption rate depends on many factors such as dosage form, drug dissolution and gastric emptying time. The absorption rate constant (ka) is the fraction of the administered dose that leaves the site of administration per unit time. The larger the ka the faster the drug is absorbed. The time required for a drug to reach maximal blood concentration is termed Tmax. The concentration of drug in the blood at this time is termed Cmax.
How is absorption calculated?
Amount of drug absorbed = F * dose
What does it mean for an absorption rate to be zero order?
What are the units for absortion rate?
What type of administration demonstrates zero order absorption kinetics?
What is Ro?
Absorption rate
Zero Order:
- Absorption rate is constant, in independent of amount of drug administered
- ko
- Mg/min or mg/ml/min
- IntraVenous (IV) infusion demonstrates zero order absorption kinetics
- Ro = rate of drug infusion in amount per unit time
What does it mean for absorption rate to be first order?
First Order
- Absorption rate is proportional to the amount of drug present (ka)
- Fraction of drug absorbed per unit of time
- The larger the ka the faster the drug is absorbed
Explain and define zero order elimination rate.
What are the units for elimination of drugs?
What is the half life for drugs eliminated via this route? (constant or variable half life)
Zero Order
- Amount of drug (A) eliminated at a constant rate
- Rate of elimination is independent of plasma concetnration
- Drugs with zero order elimination have no fixed half life (half life is variable) (Kaplan)
- Concentration (C) eliminated at a constant rate
- For example, a decline in serum concentration of 5 mg every hour
- Units of rate of elimination = mg/hr or mg/ml/hr
- examples of drugs with zero order elimination rates are phenytoin (at high thereapeutic doses) ethanol (except low blood levels), and salicylates aka aspirin (toxic doses) (Kaplan), theophylline
- PEA (a pea is round, shaped like the 0 in zero order)
Explain and define first order elimination rate.
How is k (elmination consant) calculated for first order elimination drugs?
What is the half life for drugs eliminated via this route? (constant or variable half life)
First Order
- Amount of drug (A) eliminated at a rate proportional to the amount of drug remaining
- For concentrations, rate of elimination is proportional to concentration of drug (C)
- k is a constant that relates the rate of drug elimination to the amount in the body at any time t
k = (rate of elimination) / (amount of drug in body)
mg/min//mg=1/min=min-1
Explain why some drugs are eliminated according to zero order kinetics and other first order kinetics.
Why drugs eliminate according to first order vs. zero order kinetics
- most drug metabolism takes place in liver
- each molecule binds to and is degraded and/or chemically modified by CYP enzymes
- as more drug molecules are presented to liver, more bind to CYP enzymes and the rate of elimination increases (first order because rate of elimination is proportional to drug concentration)
- rate of elimination increases with drug concentration until the CYP enzymes are all occupied (saturation) => zero order
- molecular burden = # of drug molecules
- Drugs that biotransform slowly cannot tolerate a high molecular burden => zero order
- Drugs with low potency require a high dose => high molecular burden => zero order
- Isoforms of CYP enzymes –> slow and fast metabolizers (isoniazid)
Explain how to calculate rate of elimination when clearance is known.
Rate of elimination (mg/min) = Cl (ml/min) * concentration (mg/ml)
Explain how clearance can be calculated using AUC and why.
Explain the calculations for AUC for IV doses with single compartment systems obeying first order elimination kinetics vs routes other than IV.
Since the total amount eliminated is the dose, total body clearance can also becalculated from the AUC.
Strictly speaking, the amount eliminated is the drug absorbed into systemic circulation, or F*dose. For simplicity, pharmacokinetic equations are often expressed for IV administration, where F=1.)
Cl = Dose/AUC = Mg/[(mg/(ml/min)] = ml/min
Clearance is a primary pharmacokinetic parameter along with the apparent volume
of distribution.
You do not need to know the half-life or Vd to calculate clearance.
AUC: The area under the plot of plasma concentration of drug vs. time after drug administration.
The AUC is of particular use in estimating bioavailability of drugs and in estimating total clearance of drugs (Cl). Following single intravenous doses, AUC = dose/Cl, for single compartment systems obeying first-order elimination kinetics. For routes other than the intravenous, AUC = F*(dose)/Cl where F is the bioavailability of the drug.
AUC = Dose/Cl = Mg / (ml /min)
F = AUCoral/AUCIV for same dose
What are the units of the rate constant for drug elimination?
Rate of drug elimination = k * (amt of drug in the body)
k = rate of drug elimination/ (amt. of drug in the body)
ie, k = the fractional rate of drug removal per unit time.
Units of k = Mg/min//mg = 1/min=min-1
Calculation for half life
Calculation for Ke (also define Ke)
t1/2 = 0.7 / ke = 0.7 *Vd/Cl
Ke=amount of drug eliminated per unit time
Ke= Cl/Vd
Define steady state.
When is steady state assumed to be reached?
How is steady state calculated?
What is the plateu principle?
After the last dose of a drug, how log does it take for a drug to be considered eliminated from the body?
Steady state: a condition of equilibrium in which the rate of administration equals the rate of elimination. We may assume that steady-state is reached after 5 half-lives of the drug have elapsed.
% of steady state achieved = 100 x [( 1-(1/2)n] where n = number of half-lives elapsed.
The time to reach steady state (Css ) is independent of the dose or the route of administration. The plateau principal states the time required to reach steady state is solely dependent on the half-life (t1⁄2). t1⁄2 is important because it determines the time to steady state during the continuous dosing of a drug. The approach to steady state serum concentration is an asymptotic. If a drug is administered on a continuous basis for 3 t 1⁄2, serum concentration are ~90% of Css values; on a continuous basis for 5 t 1⁄2, serum conjugations equal ~95% of Css values. Generally, drug serum concentrations used for PK monitoring can be safely measured after 3 – 5 estimated half lives because most drug assays have 5 – 10% measurement error.
Based on the same principle, after the last dose of the drug, it takes 5 half-lives for the drug to be considered eliminated from the system (in actuality, 1/32 of the initial amount of drug remains at this time.)
