Pharmacokinetics DSA Flashcards
pharmacokinetics
the absorption, distribution, metabolism (biotransformation), and elimination (ADME) of drugs
= the quantitative description of the time course of a drug.
i) Therapeutic applications include:
(1) Guide for drug choice and dosage adjustment
(2) Interpretation of plasma drug concentrations
(3) Insight into drug interactions
Systemic absorption
process by which unchanged drug proceeds from site of administration (oral, intramuscular, subcutaneous, and other extravascular sites) to site of measurement within the body.
Consider the First-Pass Effect
Distribution
process of reversible transfer of a drug to and from the site of measurement and the peripheral tissues.
Metabolism
conversion of one chemical species to another (usually mediated by enzymes).
Elimination
combination of excretion and metabolism. Excretion – irreversible loss of chemically unchanged compound.
Compartmental model:
(1) Categorized by the number of compartments needed to describe drug movement in the body.
(2) In the simplest case, just one compartment is used with one input and one output.
(3) There are also two-compartment and multicompartment models.
(4) Example compartments:
(a) Central – heart, liver, lungs, kidney, blood.
(b) Peripheral – adipose tissue, muscle tissue, cerebrospinal fluid.
First-order kinetics
(1) The amount of drug absorbed or eliminated in a set amount of time is directly proportional to the drug concentration. (Rate = k[C]; [C] = drug concentration). Examples:
(a) Rate of elimination decreases as drug concentration decreases.
(b) Rate of absorption increases as concentration at site of administration (e.g., GI tract with oral dose administered) increases.
Rate constant k
In first-order kinetics, the fractional change per unit of time,
k and t1/2 are simply related; given one, the other is easily obtainable.
Thus, ke is the elimination rate constant; a value of 0.1 hr-1 might indicate that 10% of remaining drug is eliminated per hour; t1/2 = almost 7 hours.
k and t1/2 do not change with drug concentration, but the rate does. k and t1/2 are constants.
How many half-lives to steady state?
4-5
Zero-order kinetics
(1) Amount of drug eliminated does not change with amount or concentration within the body.
(2) Rate process is independent of drug concentration.
(3) Zero-order kinetics are typically encountered because the mechanism of absorption or elimination becomes saturated. Thus, if an enzyme or transporter protein is completely saturated with substrate it will be operating at its maximal capacity (i.e., it cannot go faster, even if concentration was increased). The rate is constant and independent of drug concentration.
Examples of drugs following zero-order kinetics
Examples: ethanol, aspirin at high does, and phenytoin (antiepileptic drug).
Mass-law kinetics (saturation, dose-dependent, Michaelis-Menton kinetics)
(1) A mixed-order system: at drug concentrations far below saturation of the particular enzyme or transport system, first-order kinetics prevail; at drug concentrations that exceed saturation of the system, zero-order kinetics prevail; in between, a mixed order prevails.
(2) Example: renal tubular secretion of drugs for which there is maximum tubular transport capacity. If plasma concentration exceeds transport limit, zero-order kinetics prevail, when the concentration falls, first-order kinetics take over.
Volume of Distribution- equation and description
= Amount of drug in the body/ C (concentration of drug in the plasma)
The volume of distribution is the apparent volume of fluid in which drug would be distributed assuming it existed throughout that volume at the same concentration as in plasma.
Or, in other words, the volume required to account for all the drug in the body if the concentration in all tissues was uniform.
A large volume of distribution generally means the drug distributes extensively into body tissues and fluids; while a small volume of distribution indicates limited distribution.
equation of loading dose
X0 = Vd x Initial Plasma Cancentration of Drug (Co)
Clearance (definition)
i) Measure of the removal of drug from the body.
ii) This is one of the key pharmacokinetic principles. Ideally, clinicians maintain a patient’s drug concentration within a specific therapeutic range to achieve efficacy while minimizing toxicity. Plasma drug concentrations are affected by the rate at which the drug is administered, the volume in which it distributes, and drug clearance.
iii) Clearance describes drug removal from a volume in a given unit of time (volume/time).
(1) Clearance is not a measure of amount of drug removed but indicates the volume of plasma or blood from which drug is completely removed in a given time period.
iv) Clearance is usually constant over a range of concentrations for a particular drug. Recall first-order kinetics where a constant fraction of drug is eliminated per unit of time.
Clearance (equation
CL = (Vd)(ke) CL = (Vd)(0.693/t1/2) - in our example
When clearance is constant, rate of drug elimination is directly proportional to drug concentration. CL = Rate of Elimination/ C
Key notes on Half-Life
i) Useful in relation to drug duration of action and may indicate when another dose should be given.
ii) Time course of drug in the body depends on both the volume of distribution and clearance.
iii) Half-life is the time required to change the amount of drug in the body by one-half.
The one-compartment model
i) The body is considered a single kinetic compartment, with a single process for drug absorption and a single process for drug elimination.
ii) Elimination = combined excretion and biotransformation or inactivation.
Assumptions of the one compartment model
i) Distribution of drug throughout its Vd is rapid relative to absorption and elimination. (Thus, can ignore other processes).
ii) Distribution of drug in plasma and various tissues is equal, or of no practical consequence if unequal. (Thus, can ignore other compartments).
iii) Absorption of drug is first-order (exception: IV administration).
iv) Elimination of drug is first-order.
v) Biotransformation, active transport, and binding to macromolecules is not near saturation (eliminates mass-action kinetics).
vi) All kinetic parameters remain constant with time.
Principles of Single Dose, Oral Administration
(1) Lag period before drug concentration exceeds the minimum effective concentration (MEC).
(2) Intensity of effect increases as drug absorption and distribution occurs.
(3) Peak effect reached at maximum concentration (Cmax).
(4) Effect intensity declines as drug is eliminated and effect disappears when concentration MEC.
(6) If a MEC for adverse response exists, toxicity results if concentration > MEC for toxicity.
(7) Goal: maintain concentration within therapeutic window. Subtherapeutic = concentration MEC of adverse response.
(8) Increasing or decreasing drug dose shifts response curve and used to modulate drug effect.
(9) Increasing dose also prolongs drug effect; unless the drug is nontoxic, increasing dose to prolong effect is not recommended as there is increased likelihood of adverse effects. Repeated doses should be given.
Varied Absorption
(1) Most drugs are not completely absorbed when given orally – the full dose does not reach systemic circulation. Varied absorption rates between drugs may have important therapeutic implications.
(a) Concentration correlates with effect; thus, if drug A is absorbed faster than drug B, drug A may produce a higher peak concentration and reach clinical effect sooner.
(b) However, when absorption is delayed (i.e., depot preparations or changes to rate of drug release in a formulation), a prolonged effect may be produced.
Bioavailability (F)
= fractional extent to which unchanged drug reaches site of action following administration by any route. Factors affecting F: route, solubility, first-pass effect, degradation.
(i) = 100% for a dose given intravenously and less than 100% for an oral dose due to: incomplete extent of absorption across the gut wall and the first-pass effect.
(b) Different formulations of drugs may have different absorption characteristics. As bioavailability describes extent of absorption (drug eventually reaching systemic circulation), a drug with lower bioavailability will result in lower systemic concentrations and lower overall drug exposure (as compared to the example of delayed absorption).
Plateau state
As multiple doses are given, drug begins to accumulate. Considering first-order elimination, drug elimination per unit time is proportional to the amount of drug in the body.
Accumulation continues until equilibrium is reached: rate of drug going in = rate of drug going out (plateau state).
Steady-state
is reached when drug administered over a dosing interval equals the amount of drug eliminated over the same period. Steady-state depends on the elimination rate constant.
Reached after 4-5 half lives
