Module 3 Flashcards
Drugs distribute into what where they may be stored, metabolized, excreted or exert their pharmacological effect?
compartments in the body
List the body compartments relevant to distribution in pharmacokinetics
- Interstitial Space
- Total body water
- Plasma
- Adipose Tissue
- Muscle – Some drugs bind tightly to muscle tissue.
- Bone – Some drugs adsorb onto the crystal surface of bone with eventual incorporation into the crystal lattice. Bone can be a reservoir for the slow release of some drugs.
- Other tissues
Define interstitial space
The extracellular fluid that surrounds cells.
Low molecular weight, water soluble drugs distribute in the interstitial space.
What is included in total body water?
Includes the fluid in the interstitial space, intracellular fluid and the plasma
Define plasma
The non-cell containing component of blood. Drugs strongly bound to plasma protein and high molecular weight drugs typically distribute in plasma.
Define adipose tissue
The body’s fat. Lipid soluble (lipophilic) drugs distribute into adipose tissue.
What is drug distribution determined by?
- Blood flow to tissues (a key determinant of drug distribution)
- Ability of drug to move out of capillaries.
- Ability of drug to move into cells.
True or False: The more drug that distributes out of the blood, the lower the concentration of drug in the blood.
True
Where is drug distribution rapid?
In well perfused tissues such as the liver, kidney, and brain
What is drug distribution in pharmacokinetics?
Distribution in pharmacology is a branch of pharmacokinetics which describes the reversible transfer of a drug from one location to another within the body. Once a drug enters into systemic circulation by absorption or direct administration, it must be distributed into interstitial and intracellular fluids. - Wikipedia
Where is drug distribution slow?
In tissues with lower blood flow such as skin, fat, and bone
Which population have limited blood flow and therefore may have limited drug distribution.
Neonates
True or false: Poor blood flow rarely limits drug distribution in adult patients (however some exceptions exist)
True
Solid tumours have what (in regards to blood flow)
low regional blood flow
The outer portion of tumours has a high blood flow but the blood flow progressively decreases towards the middle. Therefore it is difficult to attain high drug concentrations within solid tumours.
What have no blood supply and are therefore difficult to treat with antibiotics?
Abscesses (infection filled with pus). They are often drained prior to drug therapy.
What is P-glycoprotein?
P-glycoprotein is the most widely studied efflux transporter.
With the exception of the brain, drug movement out of the capillaries into the interstitial space occurs rapidly due to what?
the permeable nature of the capillary wall.
Drugs move out of the capillary through fenestrations, gaps in the endothelial cells.
Once drugs leave the vasculature they must do what to have an effect?
enter their target organ/cells
What is a significant barrier to drugs reaching their targets?
the cell membrane
In order for drugs to enter cells they must be what in order to cross the cell membrane?
sufficiently lipophilic
Some drugs are what from cells by efflux transporters?
extruded (removed)
What is the function of P-GP?
P-GP is protective because it facilitates drug efflux (removal) from cells, promotes drug excretion and protects the body from exposure to drugs and other toxins.
P-glycoprotein is an active transporter which means that it requires what in order to transport drugs against a concentration gradient?
energy (ATP)
P-GP in the liver pumps drugs into where?
the bile to facilitate excretion
P-GP in the intestine pumps drugs where?
into the lumen of the intestine preventing absorption into the blood
P-GP in the kidney pumps drugs where?
into the lumen facilitating excretion
P-GP in the brain pumps drugs where?
into the blood limiting exposure to the brain
In plasma, drugs can either be what or what?
Bound to plasma proteins or free (unbound).
Only free drug is available to elicit a pharmacological response.
Proteins are large and therefore drugs that are bound to plasma proteins are unable to do what?
pass through capillary fenestrations
What are the two major plasma proteins that bind drugs in plasma
- Albumin – Has a high affinity for lipophilic and anionic (i.e. weakly acidic) drugs. Albumin is responsible for the majority of protein binding.
- Alpha 1 acid glycoprotein – Binds primarily cationic (i.e. weakly basic) and very hydrophilic drugs.
In order for any drug to reside in the cell, it has to what?
Overcome P-GP
In the liver, P-GP is expressed in what?
Hepatocytes (cells of the liver)
In the intestine, P-GP is expressed in what?
Enterocytes (cells of the intestine)
Plasma protein binding is what?
Reversible
The binding of drugs to plasma proteins is reversible
There are a number of conditions that can affect the protein binding of drugs, which conditions decrease plasma albumin and in turn a decrease of plasma protein binding?
Malnutrition, trauma, aging, liver and kidney disease
Decreased albumin results in an increase in free drug concentration which may result in what?
toxicity
Which conditions cause increased alpha 1 acidic glycoprotein concentration?
Aging, trauma, and hepatic inflammation (hepatitis)
Increased alpha 1 acidic glycoprotein concentration results in decreased free drug concentration which may lead to what?
ineffective therapy
What does the volume of distribution (Vd) represent?
the APPARENT volume that a drug distributes into
What is volume of distribution (Vd)?
Vd is the ratio of the total amount of drug in the body (D) to the plasma concentration of the drug (C), therefore:
Vd = D/C
Volume of distribution is the amount of drug in the body divided by the plasma concentration
True or False: Vd is a physical, anatomical space
False
It is important to note that Vd is NOT a physical, anatomical space, rather it is a calculated volume that helps determine the relative distribution of a drug within the body.
What are the fluid compartments in the body?
Plasma, Interstitial fluid, Intracellular fluid
Define plasma
the liquid (non-cell) portion of blood
Define interstitial fluid
the fluid that surrounds the cells of the body
Define intracellular fluid
the fluid found inside cells
What are the characteristics of drugs with a small Vd?
o Highly protein bound (retained in plasma).
o Large molecular weight (unable to pass through capillary fenestrations).
Drugs with a small Vd are unable to leave where?
the vascular space (plasma).
Therefore these drugs tend to distribute into the plasma volume which is approximately 0.057 L/kg (or ~ 4 L in a 70 kg person).
What are the characteristics of drugs with an intermediate Vd?
o Low molecular weight (able to pass through capillary fenestrations).
o Very hydrophilic (can’t cross cell membranes).
o Intermediate protein binding.
Drugs with which Vd are able to leave the vascular space and enter the interstitial space however they are unable to enter cells?
Drugs with an intermediate Vd.
Drugs with an intermediate Vd tend to distribute in which space?
These drugs tend to distribute into the extracellular fluid (plasma + interstitial space).
What are the characteristics of drugs with a large Vd?
o Low molecular weight (able to pass through capillary fenestrations).
o Lipophilic (able to cross cell membranes).
o Minimal protein binding.
Drugs with which Vd are able to leave the vascular space and the interstitial space?
Large Vd
Drugs with which Vd tend to distribute into body compartments such as fat, bone, muscle, and other tissues
Large Vd
True or False: drugs may have a Vd larger than total body water
True
How is this possible? Remember that Vd is mathematically derived and is NOT an actual physical volume.
In regards to plasma protein binding, if two drugs are present in the blood, what may happen?
One drug may displace the other drug from plasma protein.
The fate of the displaced drug depends on its volume distribution.
If a small Vd:
* When the Vd of the displaced drug is small, displaced drug does NOT distribute into tissues, it stays in the plasma. This means the free drug concentration increases.
If a large Vd:
* When the Vd of the displaced drug is large, displaced drug leaves the plasma and distributes into the tissues. This causes the total plasma drug concentration to decrease, and the apparent Vd to increase even further.
What happens as we age?
Our body composition changes
Elderly persons have an increased proportion of what?
body mass as fat
Drugs that distribute in fat will have a larger Vd in which people?
Obese and elderly persons (compared to young healthy adults)
What are the three instances in which low blood flow in adults likely will impact drug distribution?
- heart failure or shock - may have reduced blood flow
- solid tumours - low regional blood flow
- Abscesses - no blood supply
In order for any drug to reside within a cell, it has to overcome what?
Efflux drug transporter called P-GP (P-Glycoprotein)
What happens when a drug with a small Vd is displaced from plasma protein?
Drugs with a small Vd tend to stay in the plasma. Therefore if a drug with small Vd is displaced from protein it will stay in the plasma. This will result in an increase in the free drug concentration but no change in the total plasma drug concentration.
Drugs with a small Vd typically distribute in only plasma volume which is typically what?
approximately 0.057 L/kg
(ex. in 70 kg person - 0.057*70=4L)
Drugs with an intermediate Vd typically distribute into the extracellular space (plasma and interstitial space) which is typically what volume?
approx. 0.2 L/kg
(approx. 14 L in a 70 kg person)
Drugs with a large Vd typically distribute into extracellular and intracellular spaces which is typically what volume?
greater than 0.2 L/kg
Calculation can equal more than total body water.
Remember that Vd is mathematically derived and not a what?
an actual physical space/volume
