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Pharmacokinetics

The study of the disposition of a drug and/or its metabolites in the body based on time. Pharmacokinetics is an attempt to model how the body acts upon a drug in a systematic manner, by utilizing mathematical correlates adapted to the graphical representation of variables such as time and serum or plasma concentration.

1

Vd

Volume of distribution - the "apparent" volume that relates the amount of the drug in the body to the concentration in the blood. The "imaginary container" that is required to account for the total amount of drug in the body. DOES NOT relate to physiological volumes, only conceptual.
Amount of drug in the body/initial drug concentration
=Ab/Co
=F*dose/Co
Units: L or ml

2

Obese patient alterations

T1/2 increases for lipophilic drugs
Vd: increases for lipophilic drugs, decreases for hydrophilic drugs, CL (clearance) is increased in patients with normal renal fxn
Albumin bound medications are unlikely to be altered in obese patients
CO (cardiac output) increases
Normal W patient - 5% CO goes to adipose tissue
Obese patient - 2% CO goes to adipose tissue

3

Determinants: Protein Binding

Drug properties: pKa, concentration
Protein: Albumin, alpha1-glycoprotein (higher acidic or basic drugs bind more frequently
Protein affinity: Highly protein bound drugs have a lower CL(hepatic), amount of free drug determines clinical effect. Higher protein binding drugs may require more amount to create clinical effect.
Drug interactions: high protein binding, Uremia

4

Protein Binding

Most bind to blood protein (albumin), bound drugs stay in plasma, free drugs cross capillary wall = tissues, unbound and unionized drugs can cross placenta and BBB

5

Bioavailability (F)

Fraction of drug absorbed from a given dose.
Does not consider rate of absorption
Ab (amount absorbed) = F * dose
F is usually given as a percent, which needs to be converted to a decimal.
IV administration is always F=1 (direct)

6

First-Pass Elimination

Consists of the amount of drug transported to the liver after being absorbed by the gut wall, prior to being transported to into circulation
**IV , inhalation, and sublingual administration bypass 1st pass elimination
Concentrates amount of drug at action site

7

Phase I metabolism

Hydrolyses
Oxidation - CYP450 reactions
Reduction
**Patients with liver disease have trouble metabolizing phase I drugs.

8

Phase II Metabolism

Methylation
Acetylation
Glucuronidation
Glutathione conjugation
Glycine conjugation
Sulfation

9

CYP450 Induction

Certain drugs when administered concomitantly can increase the activity of an CYP450 enzyme

10

CYP450 Inhibition

Certain drugs when administered concomitantly can decrease the activity of an CYP450 enzyme

11

Elimination

Metabolism - EX transformation from lipophilic to hydrophilic
Excretion - elimination of the parent drug/metabolite from the body
Clearance - Removal of drug from a given volume in specific time frame (ml/min)

12

Factors effecting CL

Impaired hepatic/renal fxn
Protein binding/ionizing
Blood flow to kidney/liver
Smoking
Concurrent medications (interactions)

13

Clearance (CL)

Renal CL = 100 ml/min
CON = 5 mg/ml so, 500 mg in 100 ml or in 1 min, 500 mg of drug will be eliminated.
=Vd * Ke

14

Zero Order Elimination Rate

Amount of drug eliminated at a constant rate
K is constant that relates amount in body/time
Units=mg/hr
A=Ao-(rate of elimination) * t

15

First Order Elimination Rate

Amount of drug eliminated at a rate proportional to the amount of drug remaining
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 in the body
Units = mg/min
C=Co * e^-kt

16

Rate of elimination

= CL (ml/min) * Concentration (mg/ml)
= CL/Vd

17

Zero Order Absorption Rate

Constant, independent of amount administered
Ko
Ex: IV administration

18

First Order Absorption Rate

Absorption rate is proportional to the amount of drug present (Ka)
Fraction of drug absorbed per unit of time
Larger Ka = faster the drug is absorbed

19

Elimination 1/2 life (T1/2)

Time it takes for 50% drug in the body to be eliminated. Dependent on V and Cl in the same way k is
T1/2= 0.693/Ke
= 0.693 * Vd/Cl

20

Steady State [Css]f

state of equilibrium where the rate of administration = the rate of elimination
**Usually take 5 1/2 life's to reach steady state
** Time to reach Css is independent of dose!! Dependent on T1/2.
** Css value is dependent on dose as well as dosing frequency

21

Maintenance Dosing (MD)

Administration at constant time intervals
time between dosing is denoted with T
MD = (Cl * Css * T) / F

22

Loading Dose (LD)

A higher starting dose used to quickly up concentration of drug in the plasma to a specific target quickly
= Vd * Css , where Css it the target concentration
Since reaching 1/2 life takes time, immediate drug response requires loading doses

23

Creatinine Clearance (CrCl)

Used as a marker for renal function (glomerular filtration rate). Normal CrCl for 70 Kg patient is 120 ml/min
= [(140/age) * IBW] / (72 * Scr)
Multiply this formula by 0.85 for females (smaller CrCl than males).

24

Factors effecting Creatinine

Muscle mass - lower in the elderly
Severe liver disease - interferes with conversion from creatine to creatinine
Directly proportional to BM