PK2 - Distribution

Question 1

What is distribution and when does it occur?

Answer 1

It is the movement of drug from SYSTEMIC CIRCULATION –> OTHER TISSUES

It begins shortly after the first drug molecules enter the bloodstream

Question 2

What are the three parts of the distribution pathway?

Answer 2

Blood plasma –> extracellular tissue fluids –> cells

Question 3

Does a majority of each dose reach target receptor sites?

Answer 3

No, only a small fraction does

Most of each drug dose goes where it ISNT needed. Like a lipid soluble drup accumulating in fat

Question 4

What 4 factors affect drug distribution (just name them)

Answer 4

1. Physicochemical properties of the drug
2. Anatomy and physiology of the animal
3. Plasma protein binding
4. Tissue drug binding

Question 5

What are the three physicochemical properties of the drug

Answer 5

-solubility
-degree of ionization
-size, molecular weight (if too large it will stay in bloodstream and only pass through glomeruli)

Question 6

What happens with drugs and tissue perfusion? Short and long term

Answer 6

-In short term; organs with higher blood flow receive more drug (brain, kidney, heart, liver)

-Longer term, the majority of the dose redistributes to larger but less well perfused tissues (muscle, fat, viscera) as equilibration between tissues occur

Question 7

What can change clinical results relating to tissue perfusion? Example

Answer 7

Disease/trauma can reduce flow to an organ which changes them

Ex avascular fragments of bone w compound fracture

Question 8

How long does it take for drug to distribute to entire blood volume once it enters?

Answer 8

1-2 minutes

Question 9

What type of substances enter CNS very slowly due to BBB?

Answer 9

Water soluble substances will enter CNS very slowly.

Systemic administration of these are useless if intended site is CNS

Question 10

What type of drugs cross the BBB well?

Answer 10

Drugs with high lipid solubility and low protein binding

Question 11

What molecules cannot cross BBB at all

Answer 11

BBB is totally impermeable to plasma proteins

Question 12

What do glial cells do for the BBB?

Answer 12

They make the capillaries much less permeable to water soluble substances

Question 13

What drugs are highly bound to plasma proteins?

Answer 13

-NSAIDs ; aspirin
-Anticoagulants; warfarin

Question 14

What are the features of plasma protein binding?

Answer 14

-Binding is reversible, a molecule can bind and unbind repeatedly
-Bound and unbound drugs are in equilibriud

Question 15

What is the main plasma protein binder that affects drug distribution?

Answer 15

Mainly albulin, its a major carrier of weak acids

Question 16

What is the effect of a protein bound drug on half life and ability to enter tissues?

Answer 16

Protein bound fractin of drug cant enter tissues to produce desired effect and cant be excreted. So they circulate through the blood until they dissociate from the carrier protein, which INCREASES THE HALF LIFE of the drug but DECREASES INTENSITY of effect

Question 17

What happens when certain drugs distribute preferentially to tissues other than blood?

Answer 17

-They can bind to tissue proteins, nucleic acids, phospolipids

-Fat soluble drugs can accumulate in adipose and other fatty tissues (more easily cross BBB)

-Some drugs can bind to bone (and irreversibly become part of the growing bone/teeth)

Question 18

When giving lidocaine (weak base) that needs to be ABSORBED into neurons to reach target receptors. Will the lidocaine be more or less effective in the infected tissue if its more acidic than normal tissue?

Answer 18

Less effective…. since more of the ionized form of the drug, so you would need a higher dose

Question 19

What are the two major compartments from a pharmacokinetic POV?

Answer 19

-Vascular compartment
-Everything else

Question 20

What does Vd tell you?

Answer 20

Volume into which a dose of drug appears to have been diluted in the body

Question 21

What does a high Vd tell you?

Answer 21

-increased amt of drug in tissues
-decreased rate of excretion

Question 22

What does a Vd equal to blood volume mean?

Answer 22

It means none of the drug has diffused out of the blood compartment

Question 23

What will the Vd be if half the drug given diffuses out of the bloodstream?

Answer 23

Only half of the dose will be left in the blood so the Vd = it will be double the blood volume

Question 24

What will the Vd be if 2/3 the drug given diffuses out of the bloodstream?

Answer 24

Only 1/3 of the dose left in the blood so the Vd would be triple the blood volume

Question 25

What does a Vd of 10x the normal blood volume tell us?

Answer 25

That only 1/10 of the dose still remains in the patients blood

Question 26

What are the acceptable units for Vd?

Answer 26

L/kg of BW
mL/kg BW

Question 27

What dosing adjustments do you have to make when a drug has a small Vd?

Answer 27

It may require larger doses to be effective since only a small proportion of molecules leave the bloodstream to reach the target tissue

Question 28

What changes to exretion can you expect when a drug has a large Vd?

Answer 28

Drugs with large Vd take longer to excrete since they must be in the vasculature to be delivered to an organ of elimination

Question 29

What is the Vd of water soluble drugs?

Answer 29

-These drugs tend to stay in the ECF (plasma space and interstitial fluid)
-Usually IONIZED
-They have small-intermediate Vd values
-DOES NOT include intracellular fluids

Question 30

What is the Vd of lipid soluble drugs?

Answer 30

-They have high Vd values
-Drugs bind extensively to tissue sites outside of the plasma space
-Usuall UNIONIZED

Question 31

What is Vd useful for calculating?

Answer 31

A loading dose of a drug needed to achieve a specific plasma drug concentration

Question 32

If a patient is overdosing on a weak acid, what form is excreted more?

Answer 32

Favours A- form so more can be excreted

Question 33

If a patient is overdosing on a weak base, what form is excreted more?

Answer 33

Favours BH+ form so more can be excreted