Déjà Review ﹣ [1.1] Pharmacokinetics

Front 1

Q:

Define the following terms:

PHARMACOKINETICS

Back 1

PHARMACOKINETICS is the study of how a medication is:

• ABSORBED ≈ through the skin, intestine, oral mucosa
• DISTRIBUTED ⇔ spread throughout the body
• METABOLIZED ⇔ converted inside the body
• EXCRETED ⇔ removed from the body through bile

Front 2

Volume of distribution(Vd)

Back 2

The apparent volume in the body available to contain the drug.

Vd = Dose/Plasma Drug Concentration

Front 3

Is Vd a physiologic value?

Back 3

No

Front 4

Is Vd an absolute value for any given drug?

Back 4

No

Front 5

Define the following term:

Clearance (CI)

Back 5

Volume of blood cleared of the drug per unit time;
Total Body Cl = Clhepatic + Clrenal + Clpulmonary + Clother

Front 6

Define the following terms:

Half-life (t₁/₂)

Back 6

Time required for plasma concentration of drug to decrease by one-half after absorption and distribution are complete;
t₁/₂ = (0.693 × Vd)/(Cl)

Front 7

Define the following terms:

Bioavailability (F)

Back 7

The fraction of (active) drug that reaches the systemic circulation/site of action after administration by any route; F = (AUCpo)/(AUCiv), where AUCpo and AUCiv are the extravascular and intravenous areas under the plasma concentration versus time curves, respectively

Front 8

Define the following terms:

Steady state (Css)

Back 8

Steady state is reached when the rate of drug influx into the body = the rate of drug elimination out of the body; Css = plasma concentration of drug at steady state

Front 9

How much drug is left after two half-lives?

Back 9

25%

Front 10

How much drug is left after three half-lives?

Back 10

12.5%

Front 11

During constant infusion, what percent of steady state is reached after one half-life?

Back 11

50%

Front 12

During constant infusion, what percent of steady state is reached after two half-lives?

Back 12

75%

Front 13

During constant infusion, what percent of steady state is reached after three half-lives?

Back 13

87.5%

Front 14

During constant infusion, what percent of steady state is reached after four half-lives?

Back 14

94%

Front 15

Give the equation for the following term:

Infusion rate (K₀)

Back 15

K₀= Cl × Css

Front 16

Give the equation for the:

Loading dose (LD)

Back 16

LD = (Vd × CSS)/(F); for examination purposes, F is usually 1

Front 17

Give the equation for the following term:

Maintenance dose (MD)

Back 17

(Cl × Css × τ)/(F), where τ (tao) is the dosing interval

Front 18

Give the equation for:

Clearance (Cl)

Back 18

Front 19

Give the equation for the following term:

Volume of distribution (Vd)

Back 19

Vd = (LD)/(CSS)

Front 20

Give the equation for the following term:

Half-life (t₁/₂)

Back 20

t₁/₂ = (0.693)/(K) or (0.693 × Vd)/(Cl)

Front 21

What happens to the steady state concentration of a drug if the infusion rate is doubled?

Back 21

Steady state concentration is also doubled; remember that dose and concentration are directly proportional (linear kinetics); Css × K₀/Cl

Front 22

If there is no active secretion or reabsorption, then renal clearance (Clrenal) is equal to what?

Back 22

Glomerular filtration rate (GFR)

Front 23

If a drug is protein bound, then Clrenal is equal to what?

Back 23

GFR × free fraction (of drug)

Front 24

What happens to the LD in patients with impaired renal or hepatic function?

Back 24

Stays the same

Front 25

What happens to the MD in patients with impaired renal or hepatic function?

Back 25

Decreases

Front 26

For each of the following statements, state whether it refers to zero-order elimination or first-order elimination?

Rate of elimination is constant, regardless of concentration

Back 26

Zero-order elimination

Front 27

For each of the following statements, state whether it refers to zero-order elimination or first-order elimination?

Plasma concentration decreases exponentially with time

Back 27

First-order elimination

Front 28

For each of the following statements, state whether it refers to zero-order elimination or first-order elimination?

Rate of elimination is proportional to the drug concentration

Back 28

First-order elimination

Front 29

For each of the following statements, state whether it refers to zero-order elimination or first-order elimination?

Plasma concentration decreases linearly with time

Back 29

Zero-order elimination

Front 30

For each of the following statements, state whether it refers to zero-order elimination or first-order elimination?

Rate of elimination is independent of concentration

Back 30

Zero-order elimination

Front 31

For each of the following statements, state whether it refers to zero-order elimination or first-order elimination?

Rate of elimination is dependent on concentration

Back 31

First-order elimination

Front 32

What are some examples of drugs/substances that undergo zero-order elimination?

Back 32

Acetylsalicylic acid (Aspirin, ASA) at high/toxic concentrations;
phenytoin;
ethanol

Front 33

Describe the following types of metabolism:

Phase I metabolism

Back 33

Metabolism that generally yields more polar, water-soluble metabolites (may still be active); enzyme activity decreases with patient’s age

Front 34

Describe the following types of metabolism:

Phase II metabolism

Back 34

Metabolism that generally yields very polar, inactive metabolites (renally excreted); enzyme activity does not decrease with patient’s age

Front 35

Phase I (microsomal) metabolism involves what types of reactions?

Back 35

Oxidation; reduction; hydrolysis (carried out by cytochrome P-450 enzymes)

Front 36

Phase II (nonmicrosomal) metabolism involves what types of reactions?

Back 36

• Glucuronidation
• acetylation
• sulfation
• amidation
• glutathione conjugation

Front 37

Give examples of drugs that undergo phase II metabolism:

Back 37

Isoniazid (INH), morphine, 6-mercaptopurine, acetaminophen

Front 38

What are the potential consequences of phase I oxidation reactions with regard to drug activity and elimination?

Back 38

Drug activity may or may not change (no rule, ie, potentially dangerous outcome). Drug elimination is usually increased due to greater water solubility.

Front 39

What are the potential consequences of phase II reactions with regard to drug activity and elimination?

Back 39

Drug products of phase II reactions are usually inactive and their renal elimination is enhanced.

Front 40

Where are cytochrome P-450 enzymes found?

Back 40

Smooth endoplasmic reticulum of cells in mainly the liver, but also found in the gastrointestinal (GI) tract, kidney, and lungs

Front 41

Explain what each type of the following clinical phases in drug development is trying to accomplish?

Phase I

Back 41

Safety in healthy individuals; drug pharmacokinetics

Front 42

Explain what each type of the following clinical phases in drug development is trying to accomplish?

Phase II

Back 42

Efficacy in diseased individuals (small scale trials, single- double-blind)

Front 43

Explain what each type of the following clinical phases in drug development is trying to accomplish?

Phase III

Back 43

Efficacy in diseased individuals (small scale trials, single- or double-blind)

Front 44

Explain what each type of the following clinical phases in drug development is trying to accomplish?

Phase IV

Back 44

Postmarketing surveillance (monitored release)

Front 45

At what point during drug development is an investigational new drug (IND) application filed?

Back 45

Before phase I

Front 46

At what point during drug development is a new drug application (NDA) filed?

Back 46

After phase III (and before phase IV)

Front 47

What does the term bioequivalence mean?

Back 47

When comparing two formulations of the same compound, they are said to be bioequivalent to each other if they have the same bioavailability and the same rate of absorption.

Front 48

What is the first-pass effect?

Back 48

After oral administration, many drugs are absorbed intact from the small intestine and transported first via the portal system to the liver, where they undergo extensive metabolism, therefore usually decreasing the bioavailability of certain oral medications.

Front 49

How many liters are in each of the following compartments of an average adult human?

Blood

Back 49

5L

Front 50

How many liters are in each of the following compartments of an average adult human?

Plasma

Back 50

3L

Front 51

How many liters are in each of the following compartments of an average adult human?

Total body water (TBW)

Back 51

42 L (avg. 70 kg man × 60%. For women 50% of mass [body weight] in kg is body water due to lower lean muscle mass and higher fat content [adipose tissue]).

Front 52

What is the most common plasma protein that drugs bind to?

Back 52

Albumin

Front 53

Displacing a drug that is bound to plasma protein(s), for example, albumin, will increase its what?

Back 53

Its free fraction (therefore may possibly increase the risk of toxicity because the plasma concentration of active drug has been increased, yet depending on the drug, an increase in free fraction may actually increase its metabolism because more drug is available to metabolizing enzymes)

Front 54

For each of the following mechanisms of membrane transport, state if energy is required, if a carrier is required, and if the system is saturable?

Passive diffusion

Back 54

No energy required; no carrier; not saturable (proportional to concentration gradient)

Front 55

For each of the following mechanisms of membrane transport, state if energy is required, if a carrier is required, and if the system is saturable?

Facilitated diffusion

Back 55

No energy required; carrier required; saturable

Front 56

For each of the following mechanisms of membrane transport, state if energy is required, if a carrier is required, and if the system is saturable?

Active transport

Back 56

Against concentration/electrical gradient, therefore energy required; carrier required; saturable

Front 57

The permeation of drugs across cellular membranes is dependent on what drug properties and (local) circumstances?

Back 57

• Drug solubility
• drug concentration gradient
• drug ionization
• surface area
• vascularity

Front 58

Acidification of urine will increase renal elimination of what types of drugs?

Back 58

Weak bases (ionized form of drug, BH⁺) will be trapped in the renal tubules and thus excreted in the urine.

Front 59

Acidification of urine will decrease renal elimination of what types of drugs?

Back 59

Weak acids (nonionized, HA, form of a drug) can cross membranes.

Front 60

Alkalinization of urine will increase renal elimination of what types of drugs?

Back 60

Weak acids (ionized, A⁻, form of a drug) will be trapped in the renal tubules and thus excreted in the urine.

Front 61

Alkalinization of urine will decrease renal elimination of what types of drugs?

Back 61

Weak bases (nonionized, B, form of a drug) can cross membranes.

Front 62

What agents are used to acidify urine?

Back 62

NH₄Cl; high dose of vitamin C

Front 63

What agents are used to alkalinize urine?

Back 63

NaHCO₃; acetazolamide

Front 64

Give an example of a weakly acidic drug:

Back 64

Acetylsalicylic acid (ASA); barbiturates

Front 65

Give an example of a weakly basic drug:

Back 65

Amphetamines

Front 66

Give examples of drugs metabolized by each of the following cytochrome P-450 enzymes metabolizes:

CYP 1A2

Back 66

• Caffeine
• ciprofloxacin
• theophylline
• R-warfarin

Front 67

Give examples of drugs metabolized by each of the following cytochrome P-450 enzymes metabolizes:

CYP 2C9

Back 67

• Ibuprofen
• naproxen
• phenytoin
• S-warfarin

Front 68

Give examples of drugs metabolized by each of the following cytochrome P-450 enzymes metabolizes:

CYP 2C19

Back 68

Diazepam; omeprazole

Front 69

Give examples of drugs metabolized by each of the following cytochrome P-450 enzymes metabolizes:

CYP 2D6

Back 69

• Codeine
• dextromethorphan
• fluoxetine
• haloperidol
• loratadine
• metoprolol
• paroxetine
• risperidone
• thioridazine
• venlafaxine

Front 70

Give examples of drugs metabolized by each of the following cytochrome P-450 enzymes metabolizes:

CYP 2E1

Back 70

Ethanol; INH; acetaminophen (at high doses)

Front 71

Give examples of drugs metabolized by each of the following cytochrome P-450 enzymes metabolizes:

CYP 3A4 (50%-60% of all therapeutically used drugs are metabolized via CYP 3A4)

Back 71

• Alprazolam
• carbamazepine
• cyclosporine
• diltiazem
• erythromycin
• fluconazole
• itraconazole
• ketoconazole
• lidocaine
• lovastatin
• Midazolam
• nifedipine
• quinidine
• simvastatin
• tacrolimus
• verapamil

Front 72

Give examples of drugs and herbal extracts that generally induce cytochrome P-450 enzymes:

Back 72

• Phenobarbital
• nicotine
• rifampin
• phenytoin
• carbamazepine
• St. John’s wort
• chronic ethanol consumption

Front 73

Give examples of drugs and foods that generally inhibit cytochrome P-450 enzymes:

Back 73

• Erythromycin
• ketoconazole
• ciprofloxacin
• quinidine
• cimetidine
• omeprazole
• ritonavir
• chloramphenicol
• acute alcohol intoxication, grapefruit juice

Front 74

The following graph depicts what type of elimination?

Back 74

Front 75

The following graph depicts what type of elimination?

Back 75

Front 76

Intracellular volume (ICV) makes up what fraction of TBW?

Back 76

⅔
(ICV = ⅔TBW)

Front 77

Extracellular volume (ECV) makes up what fraction of TBW?

Back 77

⅓
(ECV = ⅓ TBW)

Front 78

Interstitial volume makes up what fraction of ECV?

Back 78

⅔
(interstitial volume = ⅔ ECV)

Front 79

Plasma volume makes up what fraction of ECV?

Back 79

⅓ (plasma volume = ⅓ ECV)

Front 80

What type of elimination involves a constant fraction of drug eliminated per unit time?

Back 80

First-order elimination

Front 81

What type of elimination involves a constant amount of drug eliminated per unit time?

Back 81

Zero-order elimination

Front 82

PHARMACODYNAMICS

Back 82

PHARMACODYNAMICS

Front 83

Define the following terms:

Pharmacodynamics (PD)

Back 83

Field of study that deals with the relationship between plasma concentration of a drug and the body response obtained to that drug; in short, the drug’s effect on the body

Front 84

Define the following terms:

Affinity

Back 84

Ability of a drug to bind to a receptor; on a graded dose-response curve, the nearer the curve is to the y axis, the greater the affinity (affinity deals with drugs acting on the same receptor)

Front 85

Define the following terms:

Efficacy

Back 85

How well a drug produces a pharmacological response; on a graded dose-response curve, the height of the curve represents the efficacy

Front 86

Define the following terms:

Potency

Back 86

The amount of drug required to obtain a desired effect; on a graded dose-response curve, the nearer the curve is to the y axis, the greater the potency

Front 87

Will the curves for two drugs acting on the same receptor be parallel or nonparallel to each other on a graded dose-response curve?

Back 87

Parallel

Front 88

Will the curves for two drugs acting on different receptors be parallel or nonparallel to each other on a graded dose-response curve?

Back 88

Nonparallel

Front 89

For the graph below, which drug has greater potency?

Back 89

Drug A

Front 90

For the graph below, which drug has greater efficacy?

Back 90

Drug A

Front 91

Define the following term:

Agonist

Back 91

A drug that binds to a receptor, alters its conformation, and activates that receptor’s function

Front 92

Define the following term:

Full agonist

Back 92

An agonist capable of producing a maximal response

Front 93

Define the following term:

Partial agonist

Back 93

An agonist incapable of producing a maximal response; less efficacious than a full agonist

Front 94

Define the following term:

Antagonist

Back 94

A drug that binds to a receptor and prevents activation of a receptor

Front 95

Define the following term:

Competitive antagonist

Back 95

An antagonist that competes with an agonist for the same receptor site; graded dose-response curve will be shifted to the right (parallel) thus decreasing the agonist’s potency (and affinity); maximal response will not be affected

Front 96

Define the following term:

Noncompetitive antagonist

Back 96

• An antagonist that acts at a different site from the agonist, yet still prevents the agonist from activating its receptor
• potency not affected
• maximal response will be decreased
• causes a nonparallel shift to the right on a graded dose-response curve

Front 97

What happens when a partial agonist is added in the presence of a full agonist?

Back 97

The response of the full agonist is reduced; partial agonist is acting as an antagonist.

Front 98

How does a competitive antagonist affect the following?

Affinity (1/Km) of agonist

Back 98

Decreased (thus Km will increase as it is inversely proportional to affinity)

Front 99

How does a competitive antagonist affect the following?

Maximal response (Vmax) of agonist

Back 99

No change

Front 100

How does a noncompetitive antagonist affect the following?

Affinity (1/Km) of agonist

Back 100

No change

Front 101

How does a noncompetitive antagonist affect the following?

Maximal response (Vmax) of agonist

Back 101

Decreased

Front 102

What type of antagonism does the following graph represent?

Back 102

Competitive antagonism

Front 103

What type of antagonism does the following graph represent?

Back 103

Non-competitive inhibitor

Front 104

What type of antagonism does the following graph represent?

Back 104

Non-competitive inhibitor

Front 105

What type of antagonism does the following graph represent?

Back 105

Competitive antagonism

Front 106

Will increasing the dose of an agonist Yes completely reverse the effect of a competitive antagonist?

Back 106

Yes

Front 107

Will increasing the dose of an agonist No completely reverse the effect of a noncompetitive antagonist?

Back 107

No

Front 108

Define the following terms:

Pharmacologic antagonism

Back 108

Antagonist and agonist compete for the same receptor site.

Front 109

Define the following terms:

Physiologic antagonism

Back 109

Two different types of agonists acting at different receptors causing opposite responses, therefore, antagonizing each other (acetylcholine [ACh] activating an M receptor to cause bradycardia is antagonized by norepinephrine [NE] acting at a (β-receptor to cause tachycardia)

Front 110

Define the following terms:

Chemical antagonism

Back 110

Response to a drug is antagonized by another compound that binds directly to the effector drug (digoxin is antagonized by digoxin immune Fab[Digibind] which binds directly to digoxin and not its receptor)

Front 111

Define the following terms:

Potentiation

Back 111

When one agonist enhances the action of another compound (benzodiazepines and barbiturates potentiate the effect of gamma-aminobutyric acid (GABA) on its receptor); graded dose-response curve is shifted to the left

Front 112

What is a quantal (cumulative) dose-response curve?

Back 112

Curve showing the percentage of a population responding to a given drug effect versus dose of drug given (or log of dose); allows you to visualize intersubject variability regarding drug response in graph form

Front 113

What is ED₅₀

Back 113

Estimation of the effective dose in 50% of a population; the dose at which 50% of the population will respond to the drug

Front 114

Can you obtain the ED₅₀ from a graded (quantitative) dose-response curve?

Back 114

No (this curve does not represent a population of individuals)

Front 115

Can you obtain the ED₅₀ from a quantal (cumulative) dose-response curve?

Back 115

Yes (this curve represents a population of individuals)

Front 116

What is TD₅₀?

Back 116

Estimation of the toxic dose in 50% of a population; the dose at which 50% of the population will have toxic effects from the drug

Front 117

What is LD₅₀?

Back 117

Estimation of the lethal dose in 50% of a population; the dose at which 50% of the population will die from the drug

Front 118

What is therapeutic index (TI)?

Back 118

The relative safety of a drug by comparing the ED₅₀ to either the TD₅₀ or LD₅₀;

the safer the drug, the 'wider' the TI, meaning the TD₅₀ or LD₅₀ is much greater than the ED₅₀;

drugs with a 'narrow' TI have their TD₅₀ or LD₅₀close to the ED₅₀

Front 119

How do you calculate TI?

Back 119

Front 120

In the following graph, what is the ED₅₀?

Back 120

4 mg/kg

Front 121

In the following graph, what is the TD₅₀?

Back 121

10 mg/kg

Front 122

In the following graph, what is the TI?

Back 122

3

Front 123

What is a narrow therapeutic index (NTI)?

Back 123

Drugs with an NTI usually have a TI less than 2.

Front 124

List some examples of drugs with an NTI:

Back 124

• Carbamazepine
• digoxin
• levothyroxine
• lithium
• phenytoin
• theophylline
• valproic acid
• warfarin

Front 125

CLINICAL VIGNETTES

Back 125

CLINICAL VIGNETTES

Front 126

If the ED₅₀ of a particular drug is 100 mg and the LD₅₀ is 1 g, then what is the drug’s therapeutic index (TI)?

Back 126

TI = 10; TI = LD₅₀/ED₅₀

Front 127

If 100% of a drug is cleared renally, then what would happen to the drug’s half-life if the left kidney was to completely fail?

Back 127

Increase twofold; t₁/₂ - (0.7 × Vd)/(Cl); if only one kidney is 'working' then the clearance has been cut in half thereby doubling the half-life (half-life is inversely proportional to clearance)

Front 128

A 57-year-old man, that recently underwent a liver transplant 2 years ago, is currently being immunosuppressed with cyclosporin A. The patient asks his primary care physician if he can take over-the-counter St. John’s wort for his 'depressed mood.' How should the patient’s physician respond to this question?

Back 128

The physician should advise against the use of over-the-counter medications. St. John’s wort is an inducer of the cytochrome P-450 enzymes that metabolize cyclosporin A, thereby leading to subtherapeutic serum levels and potentially inducing a graft rejection secondary to inadequate immunosuppression.

Front 129

A woman who is a long-time Floridian retiree has enjoyed having red grapefruits for breakfast each morning before taking a beach stroll with her friends. Despite her good physical condition she was recently diagnosed with general anxiety disorder and was prescribed Triazolam before bedtime. Does the physician need to learn this patient’s meal habits before prescribing this medication?

Back 129

Yes, consumption of fresh grapefruits and grapefruit juice will inhibit the metabolism of Triazolam leading to overdosing and increased sedation in an elderly patient.