Lecture 5: Pharmacokinetics

Question 1

When treating your patients, a drug may proceed through up to 4 possible stages, what are they?

Answer 1

1) Absorption
2) Distribution
3) Metabolism
4) Elimination

A-D-M-E

Question 2

What are the 2 types of passive (aka simple) absorption used by drugs?

Utilization of each type is determined by what?

Answer 2

1) Filtration: through pores or channels = paracellular transport
- Determined by osmotic/hydrostatic pressure differential
2) Diffusion: through cells membranes
- Determined by concentration gradient

Question 3

What type of passive absorption is most commonly utilized by drugs?

Answer 3

• Diffusion: through cell membranes
• Determined by concentration gradient

Question 4

What are the energy and gradient requirments for passive absorption?

Answer 4

DON’T require energy and CAN’T proceed against gradients

Question 5

What is the ratio of ionizied to unionized when pKa = pH?

Answer 5

50%:50%

Question 6

Why is the active absorption/transport process of facilitated diffusion differ from other forms of active transport?

Answer 6

• Does NOT require energy
• Does NOT proceed against gradients

Question 7

What is the total collective % of a drug in ionized and unionized forms while inside the body?

Answer 7

Always = 100%

Question 8

How does the ionization status of a drug affects its ability to be absorbed?

Answer 8

• Ionized compounds have lower lipid solubility, and do not easily diffuse across lipid bi-layer of membranes
• Unionized compounds have higher lipid solubility and easily diffuse across lipid bi-layer of membranes

Question 9

The ionization status of a drug in the body depends on what 2 factors?

Answer 9

1) pKa of the drug
2) pH of membrane-gradient/milieu

Question 10

Lower the pKa the _____the acid

Answer 10

Stronger

Question 11

Which 2 important areas of the body have a lot of pH variance, which commonly impacts ionization status?

Answer 11

1. GI tract
2. Kidneys

Question 12

When pKa=pH what is the ratio of ionized:unionized drug?

Answer 12

50%:50%

Question 13

In a basic enviornment weak acids will have what type of ionization status and how will this affect their absorption?

How about in an acidic enviornment?

Answer 13

• Will be mostly ionized and will not easily pass through membranes
• A weakly acidic drug in an acidic environment will pass through membranes more readily than if it is in an alkaline environment

Question 14

How does ionization status of a drug affects its reabsorption or elimination in the GI tract and renal tubules?

Answer 14

• Highly ionized drugs DO NOT readily get absorbed in GI tract or re-absorbed from renal tubules, therefore they are eliminated
• Highly unionized drugs DO readily get absorbed in GI tract or re-absorbed from renal tubules back into systemic circulation and are NOT eliminated

Question 15

What are 3 characteristics of active absorption/transport?

Answer 15

1) Energy-requiring**
2) Saturable: can experience competitive inhibition by other drugs
3) Movement against gradients

Question 16

What does the alpha of a drug represent?

Answer 16

• The unbound (free) fraction of a drug
• A small alpha = large % protein bound

*Codeine is only 7% bound so its alpha = 0.93

Question 17

Are drugs with high alphas more or less affected by drug-drug interaction?

Answer 17

• Less; not as much bound so don’t have to compete
• Low protein binding, so there will be low displacement by another drug competing for binding

Question 18

How do you calculate the net change of a drug-induced, bound-drug displacement?

Answer 18

(New % unbound - old % unbound) / (old % unbound x 100%) = absolute change

Question 19

What 5 drugs are inhibitors of CYP450?

Answer 19

• Fluoxetine
• Omeprazole
• Cimetidine
• Ketoconazole
• Isoniazid

FOCKI

Question 20

What 3 drugs are inducer’s of CYP450?

Answer 20

• Phenytoin
• Carbamazepine
• Phenobarbital

PCP

Question 21

What are the 3 main processes of renal elimination?

Each depends on what?

Answer 21

1) Passive glomerular filtration: blood flow dependent
2) Passive tubular diffusion: prox. or distal tubules
- Ionization and concentration status dependent
3) Active tubular secretion: weak acids/bases secreted into prox. tubule

Question 22

What is the rate of elimination of first-order drugs?

Which value remains constant?

Answer 22

• Proportional to plasma concentration (Cp)
• Amount of drug removed per unit time will vary proportionately with Cp
• The percentage (fraction) of the total amount change in Cp remains constant over time
• If you start with 100 and lose 50% every hour, the amount lost will change, but it will always be a 50% loss every hour

Question 23

What are the kinetic properties of zero order drugs?

What is the rate of elimination of these drugs like?

Answer 23

• Saturable (Vmax)
• Rate of elimination is NOT proportional to Cp; amount of drug removed per unit time stays the same over time
• The percentage (fraction) of the total amount of change in the Cp is not constant over time

*If you start with 100, and lose 10 every hour, the percent loss is changing every hour, but the amount lost will be fixed at 10

Question 24

Label A-E

Answer 24

A) Cmax

B) Tmax

C) Cmin

D) MEC

E) MTC

Question 25

The duration of a drugs actions lies between which 2 values graphically?

Answer 25

Onset of action and Minumum Effective Concentration (MEC)

Question 26

What is MTC?

Answer 26

Maximum therapeutic concentration

Question 27

What is Cmin?

Answer 27

Minimum drug concentration

Question 28

Between what 2 values does the therapeutic range reside?

Answer 28

Maximum therapeutic concentration (MTC) and Minimum Effective Concentration (MEC)

Question 29

What is the bioavailability (F) for a drug given IV?

Answer 29

• F=1
• Means it’s 100% absorbed

Question 30

Bioavailability (F) describes what about absorption?

Answer 30

Describes the extent of absorption, does NOT describe the rate

Question 31

How is bioavailability calculated?

Answer 31

(AUCoral / AUCiv) x 100

Question 32

What 3 factors determine the amount of drug absorbed?

Answer 32

1) Dose
2) Bioavailability (F)
3) Salt factor (S)

Question 33

What must be done with Vd before using in an equation?

Answer 33

Must multiply by REFERENCE Vd value by body weight (in kg) to get Vd value used in equation to proper units (L)

Question 34

What is the formula for IBW in both males and females?

Answer 34

Males: 50 kg + (2.3 kg x (height (in.) - 60 in.))

Females: 45 kg + (2.3 kg x (height (in.) - 60 in.))

Question 35

How to calculate Adjusted Body Weight for individuals with an ABW of >40% of their IBW?

Answer 35

AdjBW = (0.4 x (ABW - IBW)) + IBW

Question 36

What is clearance and the units?

Answer 36

Volume of blood per unit of time that is cleared of drug (L/hr)

Question 37

What is Tau and the units?

Answer 37

• Represents the dosing interval
• Hours

*q8h would have a Tau = 8*

Question 38

What is the Tau value for continous infusion administration?

Answer 38

Tau = 1 (q1h)

Question 39

What is K_el and its units?

Answer 39

• Elimination rate constant; percentage (fraction) of drug removed per unit of time
• Units = x^{<strong>hours</strong>}

Question 40

How many half-lives to reach steady state (Cp_ss)?

Answer 40

4-5 half-lives

Question 41

After reaching steady state (Cp_ss) how does changing the dose change the concentration of the drug?

Answer 41

• Proportionally
• Double the dose then double the level
• Cut the dose by 50% then drop the level by 50%

Question 42

How to calculate Creatinine Clearance (eGFR)?

Answer 42

[(140-age) x IBW (in kgs) / (72 x SCr)]

x0.85, if patient is female