Basic Pharmacokinetics

CHAPTER 28 Basic Pharmacokinetics


Pharmacokinetics is the study of the rate of movement of drugs within biological systems, or the study of what the body does to the drug, as characterized by drug absorption, distribution, metabolism, and excretion (ADME). It establishes a time course of the drug in the body and helps optimize drug therapy (Figure 28-1).


I. Absorption
A. The rate at which the medication enters the systemic circulation

B. Drug characteristics that affect absorption
1. Formulation (e.g., enteric coating may prevent the drug from dissolving until it reaches small intestine)

2. Solubility (water soluble or lipid soluble)

3. Molecular weight

4. Ionization

C. Patient factors that affect absorption
1. Route of administration (e.g., drug absorption is instantaneous with IV administration)

2. Gastric pH

3. Content of the GI tract

4. Other concurrent medications

D. Bioavailability is the fraction (F) of the dose that reaches systemic circulation
1. Absolute bioavailability is the estimation of F for other routes of administration compared to IV administration (100% bioavailability or F = 1)

2. Relative bioavailability is the estimation of F of a particular drug compared with another formulation of the same drug

E. Loading doses
1. Loading dose refers to the higher concentrations of a drug that may be administered at the initial course of treatment. It allows for a rapid achievement of therapeutic serum levels.

II. Distribution
A. The movement of drug to the body’s tissues

B. Mechanisms
1. Solubility in lipid (lipophilicity) as opposed to water (hydrophilicity)
a) Lipophilic drugs accumulate in adipose tissue.

2. Affinity for various body tissues

3. Blood flow to each of these tissues

4. Plasma protein binding
a) Major plasma protein: albumin
(1) Acidic (anionic) drugs, including phenytoin, warfarin, and ibuprofen, bind to albumin.

(2) Basic drugs, including lidocaine and quinidine, bind to globulins.

b) Factors that determine the degree of binding
(1) Amount of available binding sites

(2) Affinity of drug for plasma protein

C. Volume of distribution is the extent of drug distribution

III. Metabolism
A. The removal of drug from the body by transforming the drug to less-active forms and other compounds

B. Liver is the primary site of metabolism; other sites include blood and lungs

C. Typically, drugs undergo two phases of drug metabolism (phase I and phase II)
1. Phase I
a) Cytochrome P-450 (CYP) is the most important enzyme system of Phase I.
(1) CYP 450 enzymes may be induced or inhibited by other substances and are involved in many drug interactions.

b) Reaction types
(1) Hydrolysis

(2) Oxidation

(3) Reduction

(4) Demethylation

(5) Methylation

(6) Alcohol dehydrogenase metabolism

2. Phase II
a) Conjugation reactions
(1) Acts on parent drug or phase I metabolite

b) Introduces highly polar conjugates

c) Conjugates readily excreted in urine
(1) More water soluble compared with parent compound

d) Reaction types
(1) Glucuronidation most common

(2) Acetylation

(3) Sulfoconjugation

IV. Elimination
A. Removal of drug from the body as excreted into urine, lungs, bile, or sweat
1. Pulmonary, expired in the air

2. Bile, excreted in feces
a) Enterohepatic circulation

3. Renal
a) Glomerular filtration

b) Tubular reabsorption

c) Tubular secretion

V. Clearance
A. The volume of blood or plasma cleared of the drug per unit of time expressed as mL/min.

B. Most drugs are cleared through the kidneys by glomerular filtration, active tubular secretion, and passive tubular reabsorption.

VI. Linear Pharmacokinetics
A. When the area under the curve (AUC) is proportional to the dose, the drug is said to follow linear kinetics. Increases in dosage result in proportional increases in plasma drug levels. Most drugs follow linear pharmacokinetics.

B. At steady state, the rate of drug administered is proportional to the amount of drug eliminated within one dosing interval, and the body reaches an equilibrium or constant serum or blood level.

C. Drugs that have a short half-life, such as gabapentin, reach steady state rapidly; drugs with a longer half-life, such as digoxin, require more time to reach steady state. Half-life is the time required for the body to decrease the amount of drug by half (50%). Generally, it takes 4–5 half-lives for the dosing of the drug to reach steady state.

VII. Nonlinear Pharmacokinetics
A. When drugs do not change proportionally with the dose and the rate of elimination is constant regardless of amount of drug present, the drug is said to follow nonlinear pharmacokinetics (e.g., phenytoin).

B. When enzymes responsible for metabolism and elimination are saturated or occupied and the result is nonproportional increases in drug levels, the occurrence is known as Michaelis-Menten kinetics (e.g., phenytoin).

image

Figure 28-1 Concentration and time of drug action.


(Reprinted by permission from Macmillan Publishers Ltd: International Journal of Impotence Research, 19:253-264, Sept. 21, 2006.)



REVIEW QUESTIONS


(Answers and Rationales on page 382.)


1. What is the correct definition for steady state?
I. Fraction of drug that reaches systemic circulation unchanged

II. Time required for half of the drug to be eliminated from the body

III. The rate of drug entering the body equals the rate of elimination

a. I only

b. III only

c. I and II

d. II and III

e. I, II, and III

2. What is the half-life of a drug with a Vd = 310/L/70 kg, CL = 72 L/h/70 kg, and F = 52?
a. 1.5 hrs

b. 2 hrs

c. 3 hrs

d. 4 hrs

3. Drug absorption in patients with renal failure may be altered due to which of the following?
a. Gastric pH changes in gastrointestinal emptying time

b. Changes in gastrointestinal emptying time

c. Edema of the gastrointestinal tract
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Jun 21, 2016 | Posted by in PHARMACY | Comments Off on Basic Pharmacokinetics

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