Basic Pharmacokinetics

Published on 16/06/2015 by admin

Filed under Basic Science

Last modified 22/04/2025

Print this page

rate 1 star rate 2 star rate 3 star rate 4 star rate 5 star
Your rating: none, Average: 2 (2 votes)

This article have been viewed 3046 times

[level-membership-for-basic-science-category]

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
d. All of the above

4. What does “first pass effect” mean?

a. The process by which drug diffuses or is transferred from intravascular space to extravascular space (tissues)
b. The release of the drug from its dosage form
c. The elimination of unchanged drug or metabolite from the body
d. The hepatic metabolism of oral drugs before reaching systemic circulation
e. The movement of drug from the site of administration to the blood circulation

5. True or False: A phenytoin serum level does not have to be adjusted when serum albumin is reduced because it is highly protein bound.

a. True
b. False

6. CYP 450 enzymes are responsible for what type of metabolism reaction?

a. Oxidation
b. Methylation
c. Conjugation
d. Acetylation

7. True or False: Drug metabolism is a mechanism for elimination of drugs from the body.

a. True
b. False

8. Amphetamine is a weak base with a pKa of 9.8. The urine of an overdose victim was found to have a pH of 8.0. What percentage of amphetamine would be ionized at this pH, and should the urine be acidified or alkalinized to increase renal clearance?

a. 1.56%, acidified
b. 98.44%, acidified
c. 1.56%, alkalinized
d. 98.44%, alkalinized

9. A 64-year-old man has been taking phenytoin for 2 years and has come in for routine blood work. What is his adjusted phenytoin level and should he be given a loading dose to reach therapeutic range? (Height = 5′ 10″, weight = 187 lbs, phenytoin = 7.6 mcg/mL, albumin = 3.1 g/dL, SCr = 1.2 mg/dL)

a. 7.6 mcg/mL, requires loading dose
b. 10.56 mcg/mL, requires loading dose
c. 10.56 mcg/mL, does not require loading dose
d. 7.6 mcg/mL, does not require loading dose

10. A patient is given a 300-mg bolus of a drug and the initial concentration is determined to be 4.6 mg/L. What is the apparent volume of distribution of this drug in this patient?

a. 6.52 L
b. 65.2 L
c. 5.43 L
d. 54.3 L

11. If a 58-year-old, 176-lb (Height = 74 inches; IBLO = 81 kg) male patient has a serum creatinine of 2 mg/dL. What is the patient’s estimated creatinine clearance?

a. 46 mg/dL
b. 58 mg/dL
c. 64 mg/dL
d. 66 mg/dL

12. Which statement is true regarding drug-drug interactions?

a. The effect of concomitant use of two separate drugs within the body
b. Not rarely encountered with modern drugs
c. Rarely of a serious nature
d. Only identified in patients with preexisting conditions
e. Almost always avoidable by ingesting drugs at different times during the day

13. Which of the following steady-state serum phenytoin concentrations is within the therapeutic range?

a. 15 mg/mL
b. 15 mcg/mL
c. 25 mg/mL
d. 25 mcg/mL
e. 5 mg/mL

14. Which of the following lithium levels is within the therapeutic range during initiation of therapy?

a. 0.4 meq/L
b. 0.6 meq/L
c. 1.2 meq/L
d. 2.0 meq/L
e. 2.4 meq/L

15. A patient is referred to a psychiatrist for major affective disorder. Which of the following medications will provide the onset of clinical activity?

a. Chlorpromazine
b. Lithium
c. Isocarboxazid
d. Protriptyline
e. None of the above

16. What statement is true regarding first order kinetics?

I. Drug is metabolized at a rate that is constant over time
II. Aspirin is metabolized via first order kinetics
III. V=Vmax[C]/Km
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

17. What drug undergoes phase II methylation?

a. Digoxin
b. Acetaminophen
c. Morphine
d. Diazepam
e. Dopamine

18. What is the correct definition for half-life?

I. Time required for half of the drug to be eliminated from the body
II. Fraction of drug that reaches systemic circulation unchanged
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

19. What factors influence drug bioavailability?

a. First pass effect
b. Solubility
c. Brand vs. Generic formulation
d. a and b
e. a, b, and c

20. Phase I reactions can be categorized into the following?

I. Oxidation
II. Reduction
III. Hydrolysis
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

21. Solubility is LEAST affected by which of the following?

a. Sulfation
b. Hydroxylation
c. Glutathione conjugation
d. Glucuronidation
e. a and d

22. Which of the following dosing routes would be chosen for limited first-pass effect and extended duration of action?

I. Transdermal
II. Rectal
III. Inhalation
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

23. Which of the following routes of administration would avoid first-pass metabolism?

a. Oral
b. SC
c. IM
d. IV
e. b, c, and d

24. Clearance of theophylline is decreased by which of the following?

a. Albuterol
b. Atropine
c. Ipratropium
d. Cimetidine
e. Epinephrine

25. What drugs are substrates for cytochrome P-450 3A4 (CYP 3A4)?

I. Verapamil
II. Ethyinyl estradiol
III. Quinidine
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

26. What drug does NOT undergo glucoronidation?

a. Digoxin
b. Acetaminophen
c. Morphine
d. Diazepam
e. Dopamine

27. Which of the following dosing routes could be the most painful and can be administered in a depot preparation?

I. Transdermal
II. Rectal
III. Intramuscular
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

28. Which of the following statements about first-order elimination is/are true?

a. Doubling the rate of administration of a first-order elimination drug will double the steady-state plasma concentration.
b. A constant amount of drug is eliminated per unit of time.
c. The amount of serum protein binding affects the volume of distribution.
d. a and b
e. a and c

29. What is the correct definition for bioavailability?

I. Time required for half of the drug to be eliminated from the body
II. The rate of drug entering the body equals the rate of elimination
III. Fraction of drug that reaches systemic circulation unchanged
a. I only
b. III only
c. I and II
d. II and III
e. I, II, and III

30. Which of the following statements regarding elimination half-life is/are INCORRECT?

a. It always increases with decreasing clearance.
b. It can be used to estimate time required to reach steady state concentration.
c. It is the time required for the total body amount of drug to be decreased by 50%.
d. a and b
e. b and c

31. Which of the following is a phase II reaction?

a. O-methylation
b. N-acetylation
c. Hydrolysis
d. Glucuronidation
e. a, b, and d

32. Rifampin induces CYP 3A4 enzymes.

a. True
b. False

33. Which of the following are alternative routes of administration to avoid first-pass effect?

I. suppository
II. sublingual
III. Intramuscular
a. I only
b. III only
c. I and II only
d. II and III only
e. I, II, and III

34. Phenobarbital induces cytochrome P-450 2C9 (CYP 2C9) enzymes.

a. True
b. False

35. Which does NOT affect the removal of a drug from plasma during hemodialysis?

a. Protein binding
b. Volume of distribution
c. Bioavailability
d. Molecular size

36. Which of the following statements about elimination half-life is true?

a. If total body clearance is doubled, elimination half-life is decreased.
b. If volume of distribution is doubled, elimination half-life is increased.
c. If total body clearance and volume of distribution are both decreased to the same degree, there will be no effect on elimination half-life.
d. All of the above
e. None of the above

37. Of the following, which strategy would best to minimize adverse drug events in patients with impaired renal function is to:

a. Give smaller doses of the drug at the normal dose interval
b. Give the normal doses of the drug but prolong the dose interval
c. Minimize the number of medications given
d. Measure peak and trough drug levels after the third dose

38. Which of the following decreases theophylline clearance?

a. Ranitidine
b. Cimetidine
c. Ciprofloxacin
d. a and c
e. b and c

39. Which of the following does NOT affect theophylline clearance?

a. Ciprofloxacin
b. Warfarin
c. Erythromycin
d. a and c
e. b and c

40. Which of the following does NOT affect maintenance theophylline dosing?

a. Smoking
b. Renal insufficiency
c. Concomitant medications
d. Cor pulmonale
e. Hepatic failure

41. Which of the following increases theophylline clearance?

a. Emesis
b. Oral activated charcoal
c. Nasogastric lavage
d. Induced diuresis
e. All of the above

42. What is the half-life of digitoxin?

a. 12 hours
b. 24 hours
c. 48 hours
d. 5 days
e. 7 days

43. Drug A is given as a rapid, single intravenous (IV) infusion to a 50 kg patient. The volume of distribution (Vd) for drug A is 2 L/kg. What is the predicted initial concentration (Co) in plasma if a 500 mg dose is administered?

a. 1 mcg/mL
b. 3 mcg/mL
c. 5 mcg/mL
d. 12 mcg/mL
e. 15 mcg/mL

44. Which 5-HT1B/1D agonist has the lowest oral bioavailability?

a. Amerge
b. Imitrex
c. Zelnorm
d. Axert
e. Frova

45. When a loading dose is administered, the initial drug concentration is dependent on which of the following?

a. Elimination rate constant
b. Elimination half-life
c. Volume of distribution
d. Clearance
e. None of the above

[/level-membership-for-basic-science-category][not-level-membership-for-basic-science-category]

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
Buy Membership for Basic Science Category to continue reading. Learn more here

[/not-level-membership-for-basic-science-category]