Module 3 Flashcards
Drugs _________ into compartments in the body where they may be _______, _________, ________ or exert their ___________ effect.
distribute stored metabolized excreted pharmacological
The extracellular fluid that surrounds cells. Low molecular weight, water soluble drugs distribute here.
Interstitial space
Includes the fluid in the interstitial space, intracellular fluid and the plasma
Total body water
The acellular component of blood.
plasma
Lipid soluble drugs tend to distribute here. The body’s fat stores.
Adipose tissue
Drug distribution is determined by three factors, what are they?
Blood flow to tissues
Ability of drug to move out of capillaries
Ability of drug to move into cells
The more drug that distributes out of the blood, the ______ the concentration of drug in the blood.
lower
What are well perfused organs/tissues (i.e. name them)?
Liver, kidney, brain
What are poorly perfused tissues/organs?
Fat, (muscle), bone, skin
Describe blood flow in newborns
Neonates have limited blood flow
Describe how heart failure or shock affects blood flow.
Decreased CO or BP reduces blood flow and can limit distribution
Describe blood flow in solid tumours.
The outer portion of solid tumours are well perfused; the innner region is not - hard to attain high drug concentrations within the tumour
Describe blood flow in abscesses.
They have no blood supply and are thus hard to treat with antibiotics. Often drained before drug therapy.
Drugs move out of capillaries through ________ except in the _______.
fenestrations
brain
What are the different ways in which drugs can pass the cell membrane?
Lipophilic - pass membrane
Transporter - hydrophilc drug
- efflux - pumps out
- uptake - pumps in
Most widely studied efflux transporter.
P-glycoprotein
P-glycoprotein is an _______ transporter, meaning it requires ______ in order to transport drugs _________ a concentration gradient.
active
ATP
against
How does P-gp function in the liver?
Pumps drugs into the bile to facilitate excretion
How does P-gp function in the SI?
Pumps drugs into the lumen, preventing drug absorption into the blood
How does P-gp function in the kidney?
Pumps drugs into the lumen to facilitate excretion.
How does P-gp function in the brain?
Pumps drugs into the blood, limiting exposure to the brain
For each of the following organs, describe which side (lumenal or towards the blood) that p-gp is located. Liver SI Kidney Brain
Liver - transcellular (bile canalicular membrane) - pumps into bile duct
SI - lumenal (apical membrane)
Kidney - lumenal (apical side)
Brain - blood
Where is P-gp expressed in the liver?
Intestine?
hepatocytes
enterocytes
Where is P-gp found in the kidney?
PCT
What are the two major plasma proteins that bind drugs in the plasma?
Albumin
Alpha 1 acid glycoprotein
Albumin has high affinity for what types of drugs?
lipophilic and anionic (weakly acidic)
Alpha 1 acidic glycoprotein has high affinity for what types of drugs?
cationic (weakly basic) and very hydrophilic drugs
Plasma protein binding is ________.
reversible
What are pathologies that decrease plasma albumin concentration
Malnutrition, trauma, aging, liver and kidney disease
How does decreased plasma albumin concentration affect drug concentration?
Will increase free drug concentration, which may lead to toxicity
What factors/pathologies affect alpha 1 acidic glycoprotein levels?
Hepatic inflammation, aging, trauma cause increased alpha 1 acidic glycoprotein
How does increased alpha 1 acidic glycoprotein affect drug concentration?
causes decreased free drug concentration
apparent volume into which a drug distributes
Volume of distribution
What is the equation for Vd?
Vd = D/C
D - dose
C - concentration in the blood
What are the characteristics of drugs with a small Vd?
Where do they distribute into?
What volume per kg, and what percentage of body weight is their Vd?
High affinity for plasma proteins
Large MW
Distribute into the plasma
0.0057L/kg or 5.7% of body weight
What are the characteristics of drugs with an intermediate Vd?
Where do they distribute?
What volume per kg, and what percentage of body weight is their Vd?
Low MW
Very hydrophilic
Intermediate affinity for plasma proteins
Distribute into the ECF
0.2L/kg
20% of body weight
What are the characteristics of drugs with a large Vd?
Where do they distribute?
What volume per kg, and what percentage of body weight is their Vd?
Low MW
Lipophilic
Minimal protein binding
Distribute into the body compartments
> 0.2L/kg
When the Vd of a displaced drug is small, where does it distribute?
Stays in the plasma - so free drug concentration increases
When the Vd of a displaced drug is large, where does it distribute?
Distributes into the tissues.
This decreases plasma drug concentration, but increases the apparent Vd.
Describe how age affects distribution (Vd) of certain drugs (do not describe the effects on plasma proteins).
There is typically more fat as part of body mass as we age - thus drugs distributing into fat will have a larger Vd.
There is typically less muscle mass as we age and thus drugs distributing into muscle will have a lower Vd.
Describe how total body water changes with age? Consider obese individuals as well.
Decreases from infancy to elderly. (obese people are lower than healthy adults)
Describe how muscle mass changes with age, include obese people in your answer.
Highest in healthy adults, decreases to obese individuals, elderly than infants.
