Distribution Flashcards
What does the distribution of chemicals depend on (2)
- the properties of the chemicals (solubility; tendency to bind to proteins)
- physiological factors (blood flow; organ volumes; enzyme activity etc)
What is a compartment
A compartment is a collection of tissues into which a chemical distributes at approximately the same rate (NB blood is a considered a type of tissue)
What is the single-compartment model (2)
- Chemicals or drugs are distributed evenly and rapidly between blood and other tissues within the compartment
- Tissues outside of this single compartment are not considered
What is the two-compartment model (3)
- Chemicals or drugs are distributed rapidly between blood and other tissues within one compartment
- Chemicals or drugs are distributed more slowly to other tissues in a second compartment
- Models can be generated considering every tissue as a separate compartment
Here we will only consider a maximum of 2 compartments
What is the importance of blood flow in distribution (2)
- The rate of distribution to tissues is proportional to blood flow
- Two compartments may be derived by “lumping” highly perfused tissues together into compartment 1 and considering slowly perfused tissues together in compartment 2
What are the differences between single-compartment and two-compartment models? (5)
In the single-compartment model:
- The dose (D) rapidly equilibrates through Volume (V)
- Elimination from Compartment 1
- Compartment 1 contains highly-perfused organs (liver, kidney, lungs) where excretion/elimination predominantly occurs
In the two-compartment model:
- Dose (D) rapidly equilibrates through Volume (V) and slowly equilibrates through Volume (V2) back and forth
- Elimination from Compartment 1
What is the volume of distribution (V) (5)
- Vd is a theoretical (or apparent) volume into which a drug distributes given its concentration measured in blood
- It does not represent an actual physical volume.
- For a given dose of drug we can measure the concentration in blood.
- If the drug predominantly remains in the blood, blood concentration will be higher relative to a drug that is highly distributed into tissues.
- V = Dose / Conc in blood
What factors affect the volume of distribution (5)
- V is a measure of the tendency of a drug to move out of the blood and into the tissues.
- Drugs that are highly bound to tissue macromolecules or readily partition from water into phospholipid membranes can have very high V
- Drugs that readily cross membranes but have little affinity for binding to biomolecules have intermediate V
- Drugs that are highly bound to plasma proteins (albumin) or have difficulty passing through membranes tend to remain in blood and have low V
- high distribution to muscle – may be reduced in elderly
How does the binding of drugs affect distribution (5)
- Free (unbound) drug can cross membrane and concentrations equilibrate.
- Bound drug does not cross membrane.
- In blood may bind to protein (albumin; a1 acid glycoprotein)
- In tissue may bind to proteins, nucleic acids, lipids - more may be bound on one side or the other influencing V
- Similarly ion trapping causes acidic drugs to accumulate in (relatively) basic environments and basic drugs to accumulate in acidic environments
How is V normalised to body weight (3)
- V is often reported in L - there is an assumption that the average adult weighs approx 70 kg.
- Administering a fixed dose to individuals who are significantly smaller or larger can result in different blood concentrations. This may lead to an ineffective dose or a toxic dose being administered
- V may be converted to L/kg (i.e. litres per kilogram body weight). This enables dosage to be adjusted for patients of different weights
How can we achieve a blood concentration of 15 mg / L in a 50 kg patient. theophylline V = 35 L (assuming a 70kg average adult)
V theophylline = 35 L / 70 kg = 0.5 L/kg
(i) For 50 kg patient; V = 0.5 L/kg x 50 kg = 25 L
(Require conc of 15 mg/L)
V = dose / conc - rearrange to - V x conc = dose
25 L x 15 mg/L = 375mg
How can we achieve a blood concentration of 15 mg / L in a 90 kg patient. theophylline V = 35 L (assuming a 70kg average adult)
V = 35L/70kg → 0.5L in 1kg
For a 90 kg patient; V = 0.5 L/kg x 90 kg = 45 L
V x conc = dose
45 L x 15 mg/L = 675 mg
How do body types affect distribution (4)
- Dose adjustments based on weights are reasonably accurate for normal body types
- For obese patients a higher proportion of body weight is fat.
- A water-soluble drug (such as digoxin) will not distribute well into fat and calculating V using body weight may lead to too high a dose being administered
- Can use an “ideal weight” based on height to calculate dose rather than actual body weight
What are Physiologically-Based Pharmacokinetic Models PBPK used for
predicting the concentration of drugs or other chemicals in organs
What are the physiological and anatomical information used in physiologically-based Pharmacokinetic Models PBPK (3)
- size/volume of organ
- blood flow to the organ
- capacity for metabolism/excretion etc
What are Physiologically-Based Pharmacokinetic Models PBPK Adapted for (5)
- Different routes of administration
- Size (or age)
- paediatrics
- Disease states - polypharmacy
- liver/kidney disease geriatrics
What is the difference between a single-compartment and a two-compartment model? (simplified)
Drug is assumed not to equilibrate equally and rapidly through entire system – it distributes to one compartment more quickly than another
“Lumping” is a process used to group what?
Compartments with rapid equilibration are lumped separately to those with slow equilibration – which relates to perfusion by blood
Give an example of a highly perfused organ and a poorly perfused organ
High e.g. liver, kidney, brain
low = e.g. bone, adipose
A patient receives a 20 mg dose of Drug Z. The concentration of Drug Z measured in her blood is 25 ug/L. What is the volume of distribution of this drug and what does this tell you about its tendency to move out of blood into tissues?
V = dose / Conc
V = 20 mg / 0.025 mg/L → 25ug/L = 0.025 mg/L
V = 800L – the drug has a large volume of distribution, therefore tends to move out of the blood into tissues – may be bound within tissues
Drug M is available as its salt in 75% w/w preparation. The drug has a V recorded as 100 L (assuming a 70 kg average adult). If we wish to achieve a blood concentration of 20 mg/L in a 55 kg patient how much drug M should we administer?
V = 100L per 70 kg → 100/70 = 1.4 L/kg
For 55kg patient → V = 1.4 x 55 = 77 L
V = dose / conc
77 L = dose / 20 mg → Dose = 77 L x 20 mg/L = 1540mg = 1.54mg
Dose of salt = Dose of drug required/Salt factor
DoS = 1.54/0.75 = 2mg
Complete the following:
1000ng = ……..mg
10mg = ………..mg
0.001g/mL = …..mg/L
1mg/L = ………..mg/mL
1000 ng = 1mg
10 mg = 10,000 mg
0.001g/mL = 1000 mg/L
1mg/L = 1 mg/mL