Unit 2 - Pharmacokinetics - distribution Part 2

Question 1

The imaginary bodily parts model is used for what?

Answer 1

Study model to understand how drugs distribute, once the drugs have been absorbed. (i.e. in the bloodstream)

Question 2

What are the 4 patterns of drug distribution?

Answer 2

Pattern 1 - Stays in the blood
Pattern 2 - Total body water
Pattern 3 - Specific organ or tissues, including site of action, target and non-target tissues
Pattern 4 - Various organs, i.e. kidneys, muscle, liver

Question 3

What type of drugs fall under pattern 1?

Answer 3

Drugs with a high affinity to plasma proteins will remain in the plasma.
Large drugs
ex: heparin

Question 4

Heparin and warfarin both fall under pattern __ of drug distribution.
They are often administered by ___ and are too ____ and too ____ to move from the blood to other tissues.

Answer 4

1
IV
big
polar

Question 5

What are symptoms of FASD?

Answer 5

Growth retardation, CNS abnormalities, craniofacial abnormalities

Question 6

Describe drugs that fall under pattern 2 of distribution.

Answer 6

Tend to be small molecules that distribute uniformly throughout the body.

Question 7

Give some examples of pattern 2 drugs.

Answer 7

D2O, alcohol, sulfonilamide, antipyrine

Question 8

Why does it make sense for type two drugs to be small molecules?

Answer 8

Tend to be smaller than 500Da and able to pass through different pores more easily. (see Fenestrated)

Question 9

What are different ways in which pattern 2 drugs can be administered?

Answer 9

orally or through injection

Question 10

Describe pattern 3 drugs.

Answer 10

Concentration at a particular tissue or organ.

This occurs when the drug has a specific activity/affinity towards an organ or tissue-specific molecules

Question 11

Pattern four of drug distribution is a mixture of patterns __ and ___.

Answer 11

1 and 2

Question 12

What is the reasoning for the non-uniform distribution of the drug for pattern 4?

Answer 12

Due to body’s compartments (macromolecules binding) and drug properties

Question 13

The majority of drugs we use fall under what pattern?

Answer 13

Pattern 4

Question 14

What is chloroquine used for?

Answer 14

Malaria

Question 15

Where will chloroquine concentrate? Why?

Answer 15

Chloroquine is a pattern 3 drug.

It will concentration in the liver due to its high specificity for a liver-specific biomolecule

Question 16

Tetracycline (antibiotic) will accumulate where?

Answer 16

In bones

Question 17

Chloroquine can also be found in high concentrations where?

Answer 17

The eye due to its affinity for the retinal pigment melanin

Question 18

Tetracycline has high affinity for what?

Answer 18

Calcium

Question 19

Thiopental accumulates where?

Why?

Answer 19

adipose tissue

Highly lipophilic drug

Question 20

Accumulation is usually a _______ equilibrium process and as such, the accumulating organ can function as a drug ________.

Answer 20

reversible

reservoir

Question 21

What is accumulation?

Answer 21

Accumulation is usually an equilibrium process and as such, the accumulating organ can function as a drug reservoir

Question 22

Draw a graph of percent of initial dose over time of thiopental in a patient.
It has a pka of 7.4 and a logP value of 2.3.

Answer 22

Pka of the drug is near the pH of blood
the P value indicates it is very lipophilic and partitions well

Plasma concentration quickly drops and increases in drug content in non-perfusion limited organs is completed.
The drug then leaves these organs.
(brain first, then muscle)
The drug then enters the adipose tissue (perfusion limited) and functions as a reservoir for the drug

Question 23

Why does thiopental permeate out of the brain and muscle but stay in the adipose tissue?

Answer 23

The drug redistributed back to the blood since there is no biomolecule to capture it in the brain or muscle.
However, since the p-value is so high, this drug can permeate into any lipid like feature, and stay there.

Question 24

What is the method of administration for pattern 1 drugs?

Answer 24

Injection

Question 25

Pattern two drugs tend to have what feature?

Answer 25

Low MW

Question 26

Pattern 4 drugs are found where?

Answer 26

Blood and different tissues

Question 27

What is Vd?

Answer 27

Apparent volume of distribution volume of fluid into which the drug distributes

Question 28

Is Vd a real number?

Answer 28

No, hypothetical

Question 29

What is the equation for Vd?

Answer 29

vd = A/Cp A - total amount of drug in the body Cp - plasma concentration of drug

Question 30

If vd is low, the plasma concentration of the drug is ____. | If vd is high, the plasma concentration of the drug is ______.

Answer 30

high | low

Question 31

Describe the body fluid rule.

Answer 31

Rule of 60:40:20 Body water that is easily accesible - 60% Intracellular fluid - 40% Extracellular fluid - 20%

Question 32

Plasma constitutes what percent of body water?

Answer 32

4%

Question 33

What would be the vd for heparin for a 70 kg man?

Answer 33

70*4% --> 3L

Question 34

How do we know the pattern of drug distribution and Vd?

Answer 34

Experiments during a preclinical trial | Experiments during a clinical trial

Question 35

What are experiments during a preclinical trial?

Answer 35

Biochemical studies of the drug properties - ability to enter and be retained in a tissue and to bind (interaction) to protein in the compartment

Question 36

What is done during experiments during a clinical trial?

Answer 36

Blood and tissue sampling

Question 37

240 mg of a drug were given. Cp = 8 mg/L What is the apparent volume of distribution?

Answer 37

Vd = A/cp =240mg / 8mg/L = 30 L

Question 38

How can the loading dose be determined?

Answer 38

Loading dose = Vd * Cp | basically A

Question 39

What is the loading dose?

Answer 39

Initial dose required to reach a desired Cp.

Question 40

Calculate the loading dose of theophylline at the start of an IV infusion if Vd = 0.5L/kg and the desired Cp = 10 mg/L. The man weighs 70 kg.

Answer 40

``` Vd = A/Cp A = Vd * Cp A = 0.5L/kg / 10mg/L A = 5mg/kg ``` 5mg/kg * 70 kg = 350mg

Question 41

What are the two terms used in describing distribution limitation?

Answer 41

Perfusion-limited | Permeability-limited

Question 42

Describe perfusion-limitation.

Answer 42

Used in describing the lack or slowness of the drug action due to the target organs having low perfusion rates

Question 43

Describe permeability limitation.

Answer 43

Used in describing the lack or slowness of the drug action due to the drug's inability to move across biological membranes to target organs/sites

Question 44

What factors affect the rate of distribution?

Answer 44

Blood perfusion | Membrane permeability

Question 45

What factors affect the extent of distribution?

Answer 45

Lipid solubility pH-pKa Plasma protein binding Intracllular binding

Question 46

Penicillin has a pKa of 2.8. | It has limited action in brain tissue, why?

Answer 46

Its limited action is due to its permeability (more often charged) than perfusion (the brain gets lots of blood flow)

Question 47

Thiopental has a pKa of 7.5. Describe why it has a limited action in the muscle. Why does this not occur in the brain

Answer 47

Muscles have low perfusion rates and thus this drug is perfusion limited. Thiopental acts rapidly in the brain due to its high permeability and high perfusion rate.