Pharmacokinetics DSA

Question 1

pharmacokinetics

Answer 1

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

Question 2

Systemic absorption

Answer 2

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

Question 3

Distribution

Answer 3

process of reversible transfer of a drug to and from the site of measurement and the peripheral tissues.

Question 4

Metabolism

Answer 4

conversion of one chemical species to another (usually mediated by enzymes).

Question 5

Elimination

Answer 5

combination of excretion and metabolism. Excretion – irreversible loss of chemically unchanged compound.

Question 6

Compartmental model:

Answer 6

(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.

Question 7

First-order kinetics

Answer 7

(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.

Question 8

Rate constant k

Answer 8

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.

Question 9

How many half-lives to steady state?

Answer 9

4-5

Question 10

Zero-order kinetics

Answer 10

(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.

Question 11

Examples of drugs following zero-order kinetics

Answer 11

Examples: ethanol, aspirin at high does, and phenytoin (antiepileptic drug).

Question 12

Mass-law kinetics (saturation, dose-dependent, Michaelis-Menton kinetics)

Answer 12

(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.

Question 13

Volume of Distribution- equation and description

Answer 13

= 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.

Question 14

equation of loading dose

Answer 14

X0 = Vd x Initial Plasma Cancentration of Drug (Co)

Question 15

Clearance (definition)

Answer 15

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.

Question 16

Clearance (equation

Answer 16

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

Question 17

Key notes on Half-Life

Answer 17

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.

Question 18

The one-compartment model

Answer 18

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.

Question 19

Assumptions of the one compartment model

Answer 19

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.

Question 20

Principles of Single Dose, Oral Administration

Answer 20

(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.

Question 21

Varied Absorption

Answer 21

(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.

Question 22

Bioavailability (F)

Answer 22

= 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).

Question 23

Plateau state

Answer 23

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).

Question 24

Steady-state

Answer 24

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

Question 25

Options to increase steady-state concentrations:

Answer 25

(i) Increase the drug dose but maintain dosing interval (τ)
(ii) Keep the same dose but give it more frequently
1. ½ τ = more frequent dosing interval, or half of the original dosing interval
(iii) NOTE: repeated doses of drug require 4-5 half-lives to reach new steady-state.

Question 26

Fluctuations

Answer 26

, during a given plateau/steady-state, are a function of the ratio of dose interval to elimination half-life.

(i) Example: if the patient wishes to take a medication half as often, they must take twice the dose to achieve the same steady-state concentration (this doubles the extent of fluctuations).
1. Doubling fluctuations may not be desirable if the drug has a narrow therapeutic window because the excessive fluctuations may produce excursions of blood concentration into toxic range or below the therapeutic window.
2. Normally for such drugs, giving a smaller dose at more frequent intervals is desirable to minimize fluctuations.

Question 27

Varied Absorption

Answer 27

(i) Slowed absorption (e.g., controlled-release formulation) results in a blunting of the fluctuations characteristic of intermittent medication.
(ii) Importance of absorption rate depends on type of illness. For treatment of pain, it would be desirable to use an analgesic with rapid absorption; versus treatment of a chronic disease, which may require a lower absorption rate for more consistent concentrations.

Question 28

Varied Clearance (Elimination)

Answer 28

(i) If drug dose, dosing interval, and volume of distribution remain the same but clearance increases, drug concentrations will decrease (drug removed at faster rate).
(ii) If drug clearance increases by a factor of two, the steady-state plasma concentration will decrease by half.
(iii) If drug clearance decreases by half, the steady-state plasma concentration will increase by a factor of two.
(iv) Critical: changes in clearance necessitate adjustment of dosage schedules.

Question 29

Adjustment for impaired elimination

Answer 29

(i) Impaired elimination may be a consequence of altered cardiovascular function, but is usually caused by impaired renal or hepatic function. If possible, avoid drugs that might cause additional renal or hepatic damage.
(ii) Time for attainment of steady-state is a function of the impaired elimination half-life (4-5 times the elimination half-life).
(iii) Maintenance dose may be adjusted by increasing the dosing interval and/or reducing the dose.

(iv) Initial dose, if full loading dose, may or may not need to be reduced. Reduction required if concurrent reduction in volume of distribution (reduced plasma protein concentration, debilitated patient, etc.) and/or concurrent increase in reactivity to drug effects. Frequently, do not need adjustment.

Question 30

Renal impairment of elimination

Answer 30

1. Creatinine clearance is a useful indicator of renal function.
2. Monitor function and adjust doses as necessary.
3. At times, drug clearance may be a good predictor of organ function (e.g., when renal function is rapidly changing, estimation of drug clearance may elucidate organ performance faster than laboratory tests).

Question 31

Hepatic impairment of elimination

Answer 31

1. No reliable indicator of hepatic function to use as a marker of hepatic drug-metabolizing function (in a manner similar to creatinine clearance in renal impairment).

Recommendations: avoid all unnecessary drugs, special caution with CNS depressants, diuretics, and other drugs that can precipitate encephalopathy; increase clinical monitoring.

Question 32

The Target Concentration Strategy

Answer 32

i) Pharmacodynamics helps predict target concentration required for therapeutic effect.
ii) Pharmacokinetics is the means to target concentration achievement through design of a suitable dosing regimen.
(1) Choose target concentration
(2) Predict Vd and CL based on population values
(a) Adjust based on weight and renal function as necessary
(3) Give LD or MD calculated from target concentration, Vd, and CL
(4) Measure patient’s response and drug concentration
(5) Revise Vd and/or CL based on measured concentration
(6) Repeat steps 3-5, adjusting predicted dose to achieve target concentration