Lecture 3 Flashcards
Pharmacokinetics: Distribution (33 cards)
1
Q
Why are drugs distributed throughout the body?
A
- to be stored, metabolized, excreted, or exert their pharmacological effect
2
Q
What bodily compartments to drugs distribute to?
A
- interstitial space
- total body water
- plasma
- adipose tissue
- muscle
- bone
- other tissues
3
Q
Interstitial space
A
- extracellular fluid that surrounds cells
- low molecular weight, water soluble drugs distribute here
4
Q
Total body water
A
- includes fluid in IS, intracellular fluid, and the plasma
5
Q
plasma
A
- non-cell containing component of blood
- drugs strongly bound to plasma protein and high molecular weight drugs distribute here
6
Q
adipose tissue
A
- the body’s fat
- lipophilic drugs go here
7
Q
muscle
A
- some drugs bind tightly to muscle tissue
8
Q
bone
A
- adsorb onto crystal surface of bone with eventual incorporation into the crystal lattice
- can be reservoir for the slow release of some drugs
9
Q
What are the 3 things that drug distribution is determined by?
A
- blood flow to tissue
- ability of drug to move out of capillaries
- ability of drug to move into cells
10
Q
blood flow to tissues and distribution
A
- key determinant of distribution
- well perfused tissues (liver, kidney, brain) have rapid distribution
- lower blood flow tissues (fat, skin, bone) have much slower distribution
11
Q
Neonates and drug distribution
A
- have limited blood flow so have limited or unpredictable distribution of drugs
12
Q
Poor blood flow in adults and distribution
A
- rarely limits distribution in adult patients but some exceptions exist:
- heart failure or shock = lower blood flow and altered distribution
- solid tumours have low regional blood flow (high on outside, decreases toward middle)
- abscesses have no blood supply and therefore difficult to treat with antibiotics
13
Q
Ability of drugs to move out of capillaries and distribution
A
- (with exception of the brain) drug movement out of capillaries through fenestrations into the interstitial space occurs rapidly due to the permeable nature of the capillary wall
14
Q
Ability of drugs to move into cells and distribution
A
- once drugs have left the vasculature they must enter their target organ/cells to have an effect
- cell mem is sign. barrier
- drugs must be sufficiently lipophilic or carried by uptake transporter
- some drugs removed by efflux transports (another barrier)
15
Q
what is P-Glycoprotein (P-GP)?
A
- efflux transporter that plays an important role in drug distribution
- P stands for permeability but can be thought of as protective
- facilitates drug efflux from cells, promotes drug excretion, and protects the body from exposure to drugs and other toxins
- is an active transporter (aka requires ATP to transport drugs against concentration gradient)
16
Q
P-GP in the Liver
A
- pumps drugs from hepatocytes into bile to facilitate excretion
17
Q
P-GP in the Intestine
A
- pumps drugs out of enterocytes into the lumen preventing absorption into the blood
18
Q
P-GP in the Kidney
A
- pumps drugs out of promimat tubule cells and into lumen to facilitate excretion via urine
19
Q
P-GP in the brain
A
- pumps drugs out of capillary endothelial cells into the blood to limit exposure
20
Q
Plasma Protein Binding and Distribution
A
- drugs can be bound to plasma or free
- only free drug can elicit a pharm effect
- proteins are large so bound drugs + protein cannot pass through capillary fenestrations
21
Q
What are the two major proteins that bind drugs in the plasma?
A
- Albumin
- Alpha 1 acid glycoprotein
22
Q
Albumin
A
- has a high affinity for lipophilic and anionic (i.e weakly acidic) drugs
- responsible for the majority of protein binding
23
Q
Alpha 1 acid glycoprotein
A
- binds primarily cationic (i.e weakly basic) and very hydrophilic drugs
24
Q
Is plasma protein binding reversible?
A
- yes
- when free drug is in equilibrium with plasma protein and some free drug is removed, some of the protein bound drug will dissociate from the protein and become free to maintain equilibrium
25
Conditions affecting Albumin protein binding
- likes weakly acidic drugs
- malnutrition, trauma, aging, liver and kidney disease decreases plasma albumin concentration which = increase in free drug concentration which = toxicity
26
Conditions affecting alpha 1 acidic glycoprotein binding
- likes weakly basic drugs
- aging, trauma, and hepatic inflammation causes increased alpha 1 protein concentration which = decreased free drug concentration = ineffective therapy
27
What is the Volume of Distribution (Vd)?
- represents the APPARENT volume that a drug distributes into
- is the ratio of the total amount of drug in the body (D) to the plasma concentration of the drug (C)
Vd = D/C
- NOT PHYSICAL, just a calculated volume that determines the relative distribution of a drug within the body
28
Amount of fluid in compartments of the body for 70kg person
- total body water = 42L
- intracellular fluid = 28L
- extracellular fluid (interstitial fluid + Plasma) = 14 L
- Interstitial fluid = 10 L
- Plasma = 4 L
29
Characteristics of drugs with a small Vd
- highly protein bound (retained in plasma)
- large molecular weight (unable to pas through capillary fenestrations so unable to leave the plasma)
- tend to distribute into the plasma volume ( ~0.057 L/kg of a 70kg person/ ~4 L/ 5.7% of total body weight)
30
Characteristics of drugs with an intermediate Vd
- low molecular weight (can pass through fenestrations)
- very hydrophilic (cant cross cell membrane)
- intermediate protein binding
- can enter interstitial space but cant enter cells
- tend to distribute to extracellular fluid
- ~ 0.2 (20%) L/kg (~14L)
31
Characteristics of drugs with a large Vd
- low molecular weight (able to pass through fenestrations)
- lipophilic (able to cross cell membrane)
- minimal protein binding
- can distribute into fat, bone, muscle, and other tissue
- typically distribute into greater than 0.2L/kg
32
Drug displacement from proteins
- if two drugs present in the blood, one can displace the other from plasma protein
- fate of displaced drug depends on its volume of distribution
- small Vd: free drug concentration increases
- large Vd: total plasma drug concentration decreases, and apparent Vd increases
33
How does body composition affect drug distribution?
- elderly and obese people = increase body fat
- drugs that distribute in fat will have a larger Vd in obese or elderly people
- as you age muscle mass decreases, so drugs that distribute into muscle will have a lower Vd
