Drug Distribution

Question 1

What is drug distribution?

Answer 1

after the drug reaches systemic circulation following any route of administration, it must be distributed from the central compartment (blood) to peripheral tissues

Question 2

How are drugs typically distributed?

Answer 2

• numerous tissues at once
• stored in tissues and slowly released back into systemic circulation (low blood flow/mass ratio)

Question 3

Why must there be special consideration to drug distribution in food-producing species?

Answer 3

tissue storage of drugs at the time of collection could result in residues in the edible meat products

Question 4

What are the 5 major factors that determine drug distribution to and from tissues?

Answer 4

1. drug lipid solubility and its ability to penetrate cell membranes
2. regional blood flow (flow/mass ratio)
3. concentration gradient established between blood and tissue
4. degree to which the drug is bound to plasma or tissue proteins
5. presence of transport proteins

Question 5

What tissues typically have high blood flow/mass ratio? Intermediate? Low?

Answer 5

HIGH: brain, heart, liver, kidney, endocrine glands
INTERMEDIATE: muscle, skin
LOW: adipose tissue, bone

Question 6

How is blood distributed in the kidneys?

Answer 6

renal cortex receives about 25% of cardiac output
- renal medulla receives a small fraction of this blood flow

Question 7

What are 3 possible transporters of drugs once they enter the circulatory system?

Answer 7

1. plasma proteins**
2. red blood cells
3. lymph

Question 8

How does the pH of drugs affect their binding to plasma proteins?

Answer 8

weakly acidic drugs tend to bind to albumin

weakly basic drugs tend to bind to α1-glycoprotein

Question 9

Why are the bonds formed between therapeutic drugs and plasma proteins considered covalent?

Answer 9

the binding is reversible and the drug will likely be released once it gets to the desired location

Question 10

What is dissociation?

Answer 10

the affinity for another tissue component for the drug is greater than that for the plasma protein

(drugs bound to plasma proteins will move throughout circulation until it dissociates)

Question 11

How does plasma protein binding affect drug distribution? Ability of drug to reach site of action? Glomerular filtration? Metabolism/secretion?

Answer 11

only free drugs can cross membranes, so when drugs are still bound, they cannot cross into their site of action

doesn’t prevent it from reaching the site of action, but it does slow it down

limits glomerular filtration because the protein makes it too large to be filterable

slows down the rate of metabolism and/or secretion

Question 12

How is protein binding expressed? When does protein binding tend to fall?

Answer 12

in terms of a percentage of the drug bound

when the drug concentration exceeds the value that saturates the binding site - more drug than available protein leaves some drugs unbound and free, leaving it unable to move to its target and vulnerable

Question 13

What is displacement?

Answer 13

competition for the same site on plasma proteins between different drugs, especially important when one of the potential ligands has a very high affinity

Question 14

If drug A were bound 98% and 10% of it is displaced by drug B, how much does the amount of free drug increase?

Answer 14

2% free
10% of 98 = 9.8
2 + 9.8 = 11.8

goes from 2% to 12%

Question 15

Drug A with 30% binding and 10% displaced by drug B results in an increase of how much of free drug?

Answer 15

70% free
10% of 30 = 3
70 + 3 = 73

goes from 70% to 73%

Question 16

What is distribution equilibrium (DE)? Pseudoequilibrium?

Answer 16

AKA steady-state
the amount of drug leaving plasma for tissues is equivalent to the amount of drug leaving tissues for plasma

DE is never truly reached because a drug is continually being eliminated

Question 17

What drugs are less likely to reach distribution equilibrium? More likely?

Answer 17

drugs with short half-lives, particularly when administered at a long dosing interval

drugs that accumulate (given at a dosing interval shorter than half-life)

Question 18

What type of barrier does the blood-brain barrier use to only allow certain molecules into the brain? What does it use to send things out?

Answer 18

selective transport mechanisms that accumulate specific chemicals against their concentration gradients, like glucose, L-amino acid, and transferring transporters

drug efflux transport mechanisms that remove a drug from the protected sites, like MDR1 (P-glycoprotein)

Question 19

What are ivermectin-sensitive Collies? What are the common symptoms?

Answer 19

Collies with a mutation that causes the formation of non-functional MDR1 proteins at the BBB, which allows for the passage of neurotoxic drugs into the CNS

depression, ataxia, somnolence (drowsiness), salivation, tremor, coma, death

Question 20

Why are the MDR1 proteins in Ivermectin-sensitive Collies nonfunctional?

Answer 20

a 4 bp deletion causes the immature formation of a stop codon, making the protein much smaller than usual (1281 AS to 91 AS)

Question 21

What MDR1 drug substrates used in veterinary medicine show increased toxicity in Ivermectin-sensitive Collies? Have no clinical studies? Safe at therapeutic doses?

Answer 21

TOXIC: Ivermectin, Doramectin (antiparasitics); Vincristine, vinblastine, doxorubin (antineoplastic); Ondansetron (antiemetics); Digoxin (cardiovascular therapeutic)

NO STUDIES: Famotidine, Cimetidine (gastric secretory inhibitors); Metoclopramide (antiemetic); Doxycyclin, Levofloxacin (antibiotics); Ketoconazole, Itraconazole (antifungals); Dexamethasone, Prednisolone (glucocorticoids); Phenobarbital, Levitiracetam (anticonvulsants)

SAFE: Moxidectin, Selamectin (antiparasitics)

Question 22

What is volume of distribution?

Answer 22

the amount of tissue to which a drug is distributed - the volume to which a drug would have to be distributed if it were throughout the body in the same concentration as that measured in the plasma after IV administration of a known dose

Question 23

5 g (5000 mg) of dextrose is added to each of two beakers containing a different unknown volume of water. The dextrose is allowed to distribute equally throughout the beakers. If the concentration of beaker A is 5% (50mg/ml), what is the volume of beaker A? If the concentration of beaker B is 2.5% (25mg/ml), what is the volume of beaker B?

Answer 23

A: VD = (5000/50) = 100 mL

B: VD = (5000/25) = 200 mL

Question 24

What kinds of diseases tend to increase the volume of distribution? Decrease?

Answer 24

diseases associated with fluid retention or obesity increase volume of distribution and decrease plasma drug concentration

dehydration and weight loss decrease volume of distribution and increase plasma drug concentration

(PCD and response to a drug at a known dose vary inversely with VD)

Question 25

Any factor that increases the volume of distribution tends to _____ plasma drug concentration, but prolongs the ______ ______, and thus the presence of drug in the body.

Answer 25

decrease; elimination half-life

Question 26

What is drug redistribution? In which drugs are they relevant in?

Answer 26

a phenomenon involving the rapid distribution of drugs to a high-blood flow organ (brain) followed by rapid redistribution to lean tissues and then to fatty tissue

drugs for which an immediate effect can be realized (general anesthetics) and are highly lipid soluble

Question 27

Why do Greyhounds (and other sight-hounds) take so long during recovery for surgery?

Answer 27

propofol and thiobarbiturates undergo redistribution
- after administration, they distribute first into a central drug pool, and high blood flow organs
- what typically causes drug effect to terminate is its redistribution from these organs to muscle, and then into fat
- since sighthounds are such lean dogs, there is not much fat for it to be moved into

Question 28

Which one of the following factors negatively affects the distribution of a drug?
a. concentration gradient
b. lipid solubility
c. binding capacity
d. nonionized status of a drug

Answer 28

C