Pharmacokinetics and Drug Disposition Flashcards
What is pharmacokinetics (PK)?
The study of how the body absorbs, distributes, metabolizes and eliminates (ADME) a drug (what the body does to the drug)
What are the uses of PK?
To determine rates of absorption, metabolism and excretion
To determine bioavailability
To predict plasma (blood) concentrations related to drug dose
To optimize dose regimens
To correlate activity (pharmacodynamics) with circulating drug concentration
To assess factors that may alter drug disposition
What are the different routes of administration?
Oral Intravenous Subcutaneous Intramuscular Transdermal (patch) Rectal Inhalation Sublingual
What are key terms in PK?
Volume of distribution (Vd) Clearance Drug half life (t1/2) Drug accumulation Bioavailability
What is the volume of distribution?
The measure of the apparent space in the body available to contain a drug - how a drug is distributed in the body relative to the plasma
What can we use Vd for?
Needed for determining clearance of a drug from the body
Needed for determining loading dose of a drug
A high Vd means that a drug is not staying in the vascular compartment (i.e., it is extensively distributed)
Mathematically, what is the loading dose?
Loading dose = Vd x desired plasma concentration
Mathematically, what is the volume of distribution?
Amount of drug in the body (mg/kg) divided by the drug plasma concentration (mg/L)
What is the loading dose?
The used to get the dose in the body in the therapeutic window very quickly
What is the maintenance dose?
It follows the loading dose
It’s used to maintain the dose in the body within the therapeutic window
What are factors that influence drug distribution in the body
pKa of cpd and pH of the tissue compartment (acidic drugs are more likely to be concentrated in the blood compartment whereas basic drugs are more likely to be concentrated in the tissue)
Drug binding
Specialized distribution barriers (BBB, placenta)
What is clearance?
The measure of the ability of the body to eliminate the drug.
The volume of plasma that would contain the amount of drug excreted per unit of time (minute).
Volume of plasma that would have to lose all of the drug that it contains within a unit of time (usually 1 minute) to account for an observed rate of drug elimination
What are the major routes of elimination?
Liver
Bile
Urinary excretion
What are the two major sites of elimination?
The kidneys and the liver
What is the importance of clearance?
Provides an index of the efficiency by which a drug is removed from the body
Is subject to changes due to disease state, genetic and environmental factors
Needed for determining dosing rate and maintenance dose
What is dosing rate?
Clearance x target concentration
Mathematically: (vol/time)(amount/vol) = amount/time
What is the maintenance dose, mathematically?
(dosing rate/F)(dosing interval)
Mathematically: (amount/time)(time) = amount
How do the factors affecting Vd affect the half life?
Aging (decreased muscle) decreases the half life
Obesity (increased adipose) increases the half life
Pathologic fluid increases the half life
How do factors affecting clearance affect the half life?
Induction of Cyp450 decreases the half life
Inhibition of Cyp450 increases the half life
Organ failure increases the half life
What is the definition of half life?
The time required to change the amount of drug in the body by one-half during elimination
What are half-lives in PK?
The time it takes for drug concentration in plasma to decline by 50%
Most drug PK is first order - equal proportions of drug are removed per unit of time
What is drug accumulation?
Drug accumulation is inversely proportional to dose lost
What is bioavailability?
The fraction of unchanged drug reaching the systemic circulation following administration by any route
It measures the extent of absorption
How is bioavailability calculated?
(AUCdose (oral, inhalation, etc.) / AUCiv)*100
How is drug absorption determined?
Time to peak concentration (rate)
Peak concentration (rate and extent)
Area under the plasma concentration vs time curve (extent)
What are the limitations for drug absorption?
Tissue perfusion (blood flow) Diffusion-limited absorption (partition coefficient) First pass effect (distribution and metabolism)
What are the factors influencing drug absorption?
Formulation Water solubility Lipid solubility pKa GI motility Gastric pH Posture Other drugs
What are the factors influencing the PK of a drug?
Environmental factors (diet, lifestyle, other medications, dietary supplements, etc.)
Genetics
Physiological/pathophysiological
Mathematically, what is clearance?
(0.693/half life)*Vd
Mathematically, what is half life?
(0.693*Vd)/Cl
What is drug accumulation?
Accumulation factor = 1/dose lost (i.e., elimination fraction)
