Pharmacokinetics I & II

Question 1

Define pharmacokinetic phase of drug action and four factors that determine it. What is it often referred to as?

Answer 1

determines the concentration of a drug and its time course of action

1. absorption 2. distribution 3. metabolism 4. excretion (ADME)

“what the body does to the drug”

Question 2

Define pharmacodynamic phase of drug action. What is it often referred to as?

Answer 2

concentration of a drug and its interaction with receptors in target tissues determines the magnitude o fits effect (dose-response relationship)

“what the drug does to the body”

Question 3

What are the important factors to determine the dose and dosing regimen of a drug?

Answer 3

pharmacokinetic and pharmacodynamic features

Question 4

What are the goals of dose and dosing regimen?

Answer 4

to maintain the concentrations of a drug in plasma (or target tissue) at the therapeutic ranges

Question 5

What are physiochemical properties of the following types of small molecule drugs vs biologics?

Answer 5

small molecule drugs:

1. molecular size < 500 daltons
2. weak acid or base
3. low water solubility, lipophilic
4. mostly orally active

biologics:

1. molecular size > 1000 daltons
2. peptides, peptidomimetics, proteins, nucleotides
3. administered by IV, IM, SC
4. orally inactive

Question 6

What are the 4 routes of drug administration?

Answer 6

1. enteral - drug placed directly into the GI tract; oral; sublingual; rectal
2. parenteral - routes that bypass the GI tract (iv, I’m, sc, intrathecal)
3. inhalation
4. topical - eye, intranasal, skin

Question 7

What are two general ways drugs cross the cell membrane?

Answer 7

1. passive transport

2. specialized transport

Question 8

What 5 factors affect drug absorption via passive diffusion?

Answer 8

1. size of drug
2. lipoid solubility
3. polar
4. degree of ionization
5. pH of the local fluid of body

Question 9

In terms of membrane polarity, do non-ionized or ionized drugs diffuse more effectively?
Acidic drugs are more permeable at an ____ pH. Opposite for basic.

Answer 9

Non-ionized

acid drugs are more permeable at an acid pH. (will be non-ionized here)

Question 10

What is the Henderson-Hasselbalch equation?

Answer 10

log ([A-]/[AH]) = pH - pKa

where AH is non-ionized drug, A- is ionized drug

Question 11

Absorption of acid drugs is greater at _______. (opposite for bases)

Answer 11

lower pH

Question 12

Describe the “first-pass effect” (metabolism) and how it affects the bioavailability of orally-administered drugs.

Answer 12

enteral administration of drugs undergoes partial inactive or elimination during their ‘first past’ through GI tract to liver; decreases the amount of drug that can reach systemic circulation

Question 13

How can you avoid the “first pass effect”?

Answer 13

using alternative routes of drug administration

Question 14

FDA required bioavailability of a drug to be greater than __.

Answer 14

5%

Question 15

Define drug distribution. What 6 factors affect it?

Answer 15

• movement of a drug from systemic circulation into various tissues and body fluids

1. tissue perfusion rate (organ blood flow)
2. capillary/tissue membrane permeability
3. tissue mass
4. regional differences in pH
5. transport mechanisms
6. binding of drug to plasma or tissue proteins

Question 16

What is the ultimate outcome of a plasma protein-bound drug?

Answer 16

eliminated through excretion (binding is usually reversible and nonselective)

Question 17

Only ___ drug can exert a pharmacologic effect and undergo ____ clearance.

Answer 17

Free

passive clearance

Question 18

Why does the brain have a limited drug distribution?

Answer 18

due to the blood-brain barrier

Question 19

Define volume of distribution (Vd).
What is the formula to determine Vd?
What does it indicate?

Answer 19

an apparent volume of fluid in which a drug seems to be distributed in the body

Vd = dose of drug/peak plasma concentration

indicates the relative size of the body compartment containing the drug

Question 20

What is Vd influenced by?

Answer 20

protein binding, lipid solubility of drug, body composition (varies with age, sex, etc)

Question 21

What can happen if there is a pH difference across a membrane?

Answer 21

the ionized fraction of a drug may be greater on one side than on the other; acidic drugs accumulate on the more basic side –> ionic trapping in body fluids whose pH differs from blood

Question 22

What is important for drug diffusion across brain capillaries?

Answer 22

lipid solubility

Question 23

What two things affect permeability of BBB?

Answer 23

1. age

2. inflammation

Question 24

What is placental exchanged related to? What type of drugs cross more readily?

Answer 24

1. concentration gradients
2. rate of drug delivery

lipid-soluble drugs cross readily

Question 25

How can a drugs's effects be terminated?

Answer 25

1. biotransformation (metabolism) in the liver | 2. excretion in the kidney

Question 26

Define Phase I reaction

Answer 26

aka functionalization; Phase I - alter and creates functional groups (through oxidation and reduction) to make the drug more receptive to conjugation; drugs become less lipophilic (all cases) and less active (in most cases)

Question 27

What is a pro drug?

Answer 27

inactive compounds that are converted to pharmacologically active moieties by metabolic processes. metabolic transformation may result in detoxification or generation of more toxic forms of the drug

Question 28

What cytochrome P450 isozyme is responsible for 50% of drug metabolism?

Answer 28

CYP3A4/5

Question 29

What are the 3 reaction class mechanisms to make a drug hydrophilic in Phase I reactions of metabolism? (Remember the goal o Phase I)

Answer 29

goal of phase I is to make/alter functional groups oxidation reduction hydrolysis

Question 30

When does microsomal enzyme induction occur?

Answer 30

occurs when prior administration of an agent increases the total amount of enzyme due to increased protein synthesis or substrate stabilization

Question 31

Define autoinduction

Answer 31

when a drug induces metabolism of other drugs as well as its own self

Question 32

Which of the following can be induced? 1. Phase I enzymes 2. Phase 2 enzymes 3. non-microsomal enzymes

Answer 32

1. and 2. are microsomal enzymes (enzymes that metabolize drugs and are looked on SER) 3. cannot be induced

Question 33

What is the clinical importance of enzyme induction?

Answer 33

faster rate of metabolism can reduce drug concentrations below their therapeutic levels

Question 34

Describe the two ways that enzyme inhibition can occur.

Answer 34

1. Metabolism-based (reversible) inhibition: addition of a drug with greater affinity for the enzyme inhibits metabolism of the primary drug in a competitive reversible manner 2. Mechanism-based (irreversible) inhibition: inhibitor drug is metabolized by enzyme to form a reactive species that binds irreversibly to the enzyme and prevents further metabolism; this inhibition lasts for the life of the enzyme, inhibitor and enzyme need to be degraded and a new enzyme needs to be produced

Question 35

What is the clinical importance of enzyme inhibition?

Answer 35

because it slows the rate of drug metabolism and can elevate the drug's concentration in the body which can eventually lead to toxicity

Question 36

What are 3 things that inhibit CYP3A4>

Answer 36

erythromycin, ketoconazole, grapefruit juice

Question 37

What may contribute to interindividual variability in drug metabolism & pharmacological response?

Answer 37

genetic polymorphisms

Question 38

What are the clinical consequences of genetic polymorphisms?

Answer 38

may metabolize slower or faster or not at all; affects therapeutic range so need to keep in mind when administering a dose

Question 39

Define Phase II reactions of metabolism

Answer 39

aka conjugations; couple a drug or metabolite to an endogenous substrate (such as an amino acid, acetic acid, glucouronic acid, or sulfate); attachment of these hydrophilic groups usually makes the drug more polar and less active (readily excrete)

Question 40

What are factors that affect drug metabolism?

Answer 40

1. concomitant drug therapy (can lead to enzyme induction or inhibition) 2. social factors (age, gender, nutrition, alcohol) 3. health (liver dz) 4. environmental factors 5. genetics (polymorphisms on drug metabolizing enzymes)

Question 41

Rate of drug excretion in the urine is the net result of which 3 processes?

Answer 41

1. glomerular filtration (passive, only unbound drug) 2. active tubular secretion (via transporters) 3. reabsorption

Question 42

What are the four different mechanisms that may be involved in renal excretion of drugs? What is the formula for drug excretion?

Answer 42

1. glomerular filtration - removes all unbound drugs of low molecular weight (charged are filtered at slower rates) 2. passive reabsorption - depends on lipid solubility, most drugs are passively reabsorbed in the distal renal tubules; non-ionized, lipophilic drugs are extensively resorbed into plasma 3. active tubular secretion - involved in renal excretion of some drugs, actively transport some drugs (like penicillin) into renal tubule 4. active tubular reabsorption drug excretion = filtration - reabsorption + secretion

Question 43

Acidification of a the urine promotes excretion of ______ whereas alkalinization promotes excretion of _____.

Answer 43

weak bases | weak acids

Question 44

What can prolong the duration of action of a drug in the body?

Answer 44

enterohepatic recycling of drugs (conjugates undergo bacterial hydrolysis before reabsorbed into portal circulation (liver))

Question 45

What are the 5 important pharmacokinetic parameters?

Answer 45

``` bioavailability kinetics of elimination volume of distribution half-life clearance ```

Question 46

What is the key parameter to determine the bioavailability of drugs?

Answer 46

area under the curve (AUC) on a conc. vs. time plot

Question 47

The therapeutic range is between which two minimums?

Answer 47

Minimum effective concentration (MEC) and Minimum toxic concentration (MTC)

Question 48

What is bioavailability (BA)?

Answer 48

the fraction/percentage of a drug dose that reaches the systemic circulation unchanged; compares amount of a drug "available" to body after administration by different routes

Question 49

For intravenous drug dose, __% reaches the blood stream.

Answer 49

100%

Question 50

What is the formula of bioavailability (BA) when comparing oral and IV?

Answer 50

F = (AUC)oral / (AUC)iv x (IV dose) / (oral dose) oral dose = (IV dose)/F

Question 51

Kinetics of Elimination Define Zero-order and First-order

Answer 51

zero-order: constant amount of drug in body is eliminated per unit time dA/dt=-k first-order: constant fraction of drug present in the body is eliminated per unit time, regardless of the concentration (most drugs) dA/dt=-kA *where k is the rate of elimination

Question 52

What happens when he capacity for drug elimination becomes saturated?

Answer 52

kinetics may change from first order to zero order where a constant amount (not fraction) of drug is eliminated per unit of time; drugs overdosed (cannot calculate half life)

Question 53

What is volume of distribution (Vd)?

Answer 53

an apparently volume of fluid in which a drug seems to be distributed in the body; indicates the relative size of the body compartment contain the drug; influenced by protein binding and lipid solubility of the drug; useful for calculating the dose of a drug required to achieve an effect plasma concentration

Question 54

What is elimination half-life (t 1/2)?

Answer 54

Time required for the plasma concentration to decrease by one-half (50%); only first order useful for determining the dosing interval and time required to reach steady state after repeated drug administration

Question 55

What is steady state?

Answer 55

when drug is given repeatedly at intervals that are too short to allow complete clearance; plateau will eventually be reached when the amount of drug administered equals the amount eliminated in a given time unit

Question 56

During a continuous infusion or when multiple drug doses are given, the steady state is attained after approximately how many half-lives?

Answer 56

4 to 5 half lives | thus half life is useful in determining dosing frequency

Question 57

How can you promptly raise the plasma drug concentration?

Answer 57

administer a loading dose followed by a maintenance dose