Intro to Pharmacokinetics

Question 1

Define pharmacology

Answer 1

The study of the effects of drugs on the function of living systems

Question 2

Pharmacokinetics

Answer 2

What body does to drug

Question 3

Pharmacodynamics

Answer 3

What the drug does to the body

Question 4

What are the pharmacokinetic parameters that influence the amount of drug in the blood?

Answer 4

Absorption Distribution Metabolism Excretion

Question 5

Define absorption

Answer 5

Drug is absorbed from site of administration into blood stream

Question 6

Define distribution

Answer 6

Drug leaves bloodstream and distributes to interstitial and intracellular fluids

Question 7

Define metabolism (in context of ADME)

Answer 7

Drug may be biotransformed by metabolism in liver and other tissues b/c body wants to break down compound for excretion once it enters body

Question 8

Define excretion

Answer 8

Drug and metabolites are excreted from the body in urine, bile or feces

Question 9

What is meant by volume of distribution?

Answer 9

That a high enough dose needs to be given to account for the fact that the drug will distribute through whole body not just end organ of interest

Question 10

What is the onset of action?

Answer 10

Time it takes for drug to reach plasma following oral administration

Question 11

What two things determine how fast a drug will work?

Answer 11

Pharmaceutic phase (formulation of drug, liquid, powder, etc.) Pharmacodynamic phase (ADME)

Question 12

How is the volume of distribution calculated? (Vd)

Answer 12

Vd = Dose / initial concentration, Co

Question 13

What does a lower Vd mean?

Lower initial concentration has what effect on Vd (if dose kept constant)?

Answer 13

The drug tends to stay in the plasma and not distrubute to other tissues

Lower Co = Higher Vd

Question 14

What does it mean if the Vd exceeds the total body water amount for a person?

Answer 14

That the drug has distributed into the body’s tissues. Fat can act as a drug depot and store drug within its tissue. Drugs can also distrubtue into muscle.

Question 15

Some drugs can bind to albumin (plasma protein in the blood). What effect does this have on ADME?

Answer 15

Proteins bound to plasma proteins have a predictable and restricted volume of distribution and the binding allows them to exert their effects over a longer period of time (increased half life) because they aren’t being metabolized by the body right away. When the concentration of the drug in the body decreases, this concentration gradient will drive more drug to dissociate from albumin and absorb into the body.

Question 16

Imagine that drug A is administered to a person and is bound to albumin in the plasma. Now imagine that drug B is given to that person and drug B competes with drug A to bind to albumin. What effect will this have on the Vd of drug A?

Answer 16

If Drug B competes with Drug A for albumin binding, then the concentration of Drug A in the plasma will increase. An increase in concentration leads to a subsequent decrease in Vd for that drug. Thus, this drug will be more confined to the plasma.

Question 17

What two bodily factors can contribute to changes in the pattern of drug distribution?

Answer 17

Accumulation of fat (drug depot for lipophilic drugs)

Accumulation of fluids (drug depot for water soluble drugs)

Question 18

Describe how the polarity of drugs changes during metabolism and elimination.

Answer 18

Drugs go from more lipophilic –> slightly more soluble in water –> very soluble in water

Question 19

What are Phase I and Phase II reactions wrt metabolism and elimination?

Answer 19

Phase I: oxidation reactions typically, not much change in drug’s solubility but large change in biological properties which inactivates drug

Phase II: Increase in water solubility via attachment of polar groups or conjugation with another molecule, mass of drug is also increased to facilitate elimination

Question 20

What effect does conjugation have on the Vd and half life of a drug?

Answer 20

Conjugation leads to a decrease in Vd and thus makes a drug have higher clearance in the urine or stool and as a result shorter half life.

Question 21

____ substances are not eliminated efficiently by the kidneys.

A) Hydrophilic

B) Neutral

C) High Molecular Weight

D) Lipophilic

Answer 21

D

Question 22

What is enterohepatic recycling?

Answer 22

When drugs are taken orally, they first enter the gut. Once absorbed in the gut, they travel via the portal system to the liver where they can be processed (First Pass Metabolism, Phase 1 reaction) or left unchanged. The liver then secretes the drugs into the bile, which empties back into the gut where they can be reabsorbed.

Question 23

What is a Phase 1 reaction with respect to drug metabolism? Give 1 example.

Answer 23

The drug is modified slightly to make it more hydrophilic, but really this type of reaction just sets the drug up for further modification later in Phase 2 reaction.

Example: Hydroxylation

Question 24

What is a Phase 2 reaction with respect to drug metabolism?

Answer 24

A reaction that makes drugs much more hydrophilic and often increases their molecular weight by attaching bulky hydrophilic groups.

Example: Glucuronidation

Question 25

In what organ do phase 1 reactions take place (mostly)? Where in the cell do these reactions occur?

Answer 25

Liver ER, mitochondria, cytosol, plasma membrane, lysosomes

Question 26

The Cytochrome P450 family of enzymes are monooxygenases that catalyze phase 1 reactions. What are the types of reactions they produce?

Answer 26

Oxidation Hydroxylation Dealkylation Deamination Hydrolysis

Question 27

Where in the cell do phase 2 reactions occur?

Answer 27

Cytosol

Question 28

What is the equation for clearance?

Answer 28

CL = (Metabolism + Excretion) / Plasma drug concentration

Question 29

Describe how you would know that a drug is eliminated by first order kinetics.

Answer 29

First order kinetics is a process by which a constant fraction or percentage of drug is metabolized per unit time.

Question 30

Describe how you would know that a drug is metabolized by saturation kinetics.

Answer 30

Saturation kinetics is a process by which a constant amount of drug is metabolized per unit time regardless of the concentration.

Question 31

The half life of a reaction that follows first order kinetics is variable. A) True B) False

Answer 31

B) False - it is constant

Question 32

The half life of a reaction that follows saturation kinetics is variable. A) True B) False

Answer 32

A) True - half life depends on starting plasma concentration

Question 33

Clearance is defined as the rate of elimination / plasma concentration. However, it is also affected by the amount of blood flow to each organ that is responsible for excretion. The extent to which an organ contributes to clearance is determined by the extraction ratio. What is the extraction ratio?

Answer 33

C_in - C_out / C_in

Question 34

What is the equation for the elimination rate? How does this equation simplify in clinical situations? How would this equation simplify if the drug was given at a very high dose?

Answer 34

* Most drug dosages are administered at concentrations that are much smaller than the Km of the enzymes that eliminate the drugs. As such, the drug plasma concentration does not need to be considered in the denominator only. * If given at a very high dose, the [C] drug in plasma is likely to be much higher than the Km, so the opposite would be true and the denominator would simplify simply [C]

Question 35

What is the equation to determine half life?

Answer 35

t_1/2 = (0.693 \* V_D) / CL \*\*make sure units of V_D and CL match\*\*

Question 36

What is steady state concentration (Css)?

Answer 36

When drug doses are given repeatedly, the drug will accumulate in the body until Css occurs or dosing stops

Question 37

50% of Css is achieved in __ half life 75% of Css is achieved in __ half life 90% of Css is achieved in __ half life 100% of Css is achieved in __ half life

Answer 37

1 2 3.3 4-5

Question 38

What is a maintenance dose of drug? How is this calculated?

Answer 38

* Administration of a drug to maintain a steady state concentration within the therapeutic window and is given to replace the drug that was eliminated since the previous dose * Dosing rate \* dosing interval --\> ((C_ss \* CL) / F)\*dosing interval

Question 39

What is the dosing rate?

Answer 39

(C_ss \* CL) / F

Question 40

What is a loading dose? How is this parameter calculated?

Answer 40

* A larger dose injected initially to achieve plasma concentration within therapeutic window more quickly. Without loading dose, would require 4-5 half lives for drug to reach Css. * (C_ss \* V_D) / F

Question 41

Drugs that are highly absorbed generally require a __ dose than pooly absorbed drugs. A) Higher B) Lower C) Longer D) Shorter

Answer 41

B) Lower

Question 42

Poorly distributed drugs require a ___ dose; highly distributed drugs require a ___ dose. A) Higher, higher B) Lower, higher C) Lower, Lower D) Higher, Lower

Answer 42

B) Lower, higher

Question 43

Drugs with high elimination rates have shorter half lives and require ___ frequent dosing to maintain therapeutic windows. Drugs with low elimination rates have longer half lives and require ___ frequent dosing to maintain therapeutic windows. A) Less, more B) Less, less C) More, less D) More, more

Answer 43

C) More, less