Unit 2 - Pharmacokinetics - distribution Part 2 Flashcards
The imaginary bodily parts model is used for what?
Study model to understand how drugs distribute, once the drugs have been absorbed. (i.e. in the bloodstream)
What are the 4 patterns of drug distribution?
Pattern 1 - Stays in the blood
Pattern 2 - Total body water
Pattern 3 - Specific organ or tissues, including site of action, target and non-target tissues
Pattern 4 - Various organs, i.e. kidneys, muscle, liver
What type of drugs fall under pattern 1?
Drugs with a high affinity to plasma proteins will remain in the plasma.
Large drugs
ex: heparin
Heparin and warfarin both fall under pattern __ of drug distribution.
They are often administered by ___ and are too ____ and too ____ to move from the blood to other tissues.
1
IV
big
polar
What are symptoms of FASD?
Growth retardation, CNS abnormalities, craniofacial abnormalities
Describe drugs that fall under pattern 2 of distribution.
Tend to be small molecules that distribute uniformly throughout the body.
Give some examples of pattern 2 drugs.
D2O, alcohol, sulfonilamide, antipyrine
Why does it make sense for type two drugs to be small molecules?
Tend to be smaller than 500Da and able to pass through different pores more easily. (see Fenestrated)
What are different ways in which pattern 2 drugs can be administered?
orally or through injection
Describe pattern 3 drugs.
Concentration at a particular tissue or organ.
This occurs when the drug has a specific activity/affinity towards an organ or tissue-specific molecules
Pattern four of drug distribution is a mixture of patterns __ and ___.
1 and 2
What is the reasoning for the non-uniform distribution of the drug for pattern 4?
Due to body’s compartments (macromolecules binding) and drug properties
The majority of drugs we use fall under what pattern?
Pattern 4
What is chloroquine used for?
Malaria
Where will chloroquine concentrate? Why?
Chloroquine is a pattern 3 drug.
It will concentration in the liver due to its high specificity for a liver-specific biomolecule
Tetracycline (antibiotic) will accumulate where?
In bones
Chloroquine can also be found in high concentrations where?
The eye due to its affinity for the retinal pigment melanin
Tetracycline has high affinity for what?
Calcium
Thiopental accumulates where?
Why?
adipose tissue
Highly lipophilic drug
Accumulation is usually a _______ equilibrium process and as such, the accumulating organ can function as a drug ________.
reversible
reservoir
What is accumulation?
Accumulation is usually an equilibrium process and as such, the accumulating organ can function as a drug reservoir
Draw a graph of percent of initial dose over time of thiopental in a patient.
It has a pka of 7.4 and a logP value of 2.3.
Pka of the drug is near the pH of blood
the P value indicates it is very lipophilic and partitions well
Plasma concentration quickly drops and increases in drug content in non-perfusion limited organs is completed.
The drug then leaves these organs.
(brain first, then muscle)
The drug then enters the adipose tissue (perfusion limited) and functions as a reservoir for the drug
Why does thiopental permeate out of the brain and muscle but stay in the adipose tissue?
The drug redistributed back to the blood since there is no biomolecule to capture it in the brain or muscle.
However, since the p-value is so high, this drug can permeate into any lipid like feature, and stay there.
What is the method of administration for pattern 1 drugs?
Injection
Pattern two drugs tend to have what feature?
Low MW
Pattern 4 drugs are found where?
Blood and different tissues
What is Vd?
Apparent volume of distribution
volume of fluid into which the drug distributes
Is Vd a real number?
No, hypothetical
What is the equation for Vd?
vd = A/Cp
A - total amount of drug in the body
Cp - plasma concentration of drug
If vd is low, the plasma concentration of the drug is ____.
If vd is high, the plasma concentration of the drug is ______.
high
low
Describe the body fluid rule.
Rule of 60:40:20
Body water that is easily accesible - 60%
Intracellular fluid - 40%
Extracellular fluid - 20%
Plasma constitutes what percent of body water?
4%
What would be the vd for heparin for a 70 kg man?
70*4% –> 3L
How do we know the pattern of drug distribution and Vd?
Experiments during a preclinical trial
Experiments during a clinical trial
What are experiments during a preclinical trial?
Biochemical studies of the drug properties - ability to enter and be retained in a tissue and to bind (interaction) to protein in the compartment
What is done during experiments during a clinical trial?
Blood and tissue sampling
240 mg of a drug were given.
Cp = 8 mg/L
What is the apparent volume of distribution?
Vd = A/cp
=240mg / 8mg/L
= 30 L
How can the loading dose be determined?
Loading dose = Vd * Cp
basically A
What is the loading dose?
Initial dose required to reach a desired Cp.
Calculate the loading dose of theophylline at the start of an IV infusion if Vd = 0.5L/kg and the desired Cp = 10 mg/L.
The man weighs 70 kg.
Vd = A/Cp A = Vd * Cp A = 0.5L/kg / 10mg/L A = 5mg/kg
5mg/kg * 70 kg = 350mg
What are the two terms used in describing distribution limitation?
Perfusion-limited
Permeability-limited
Describe perfusion-limitation.
Used in describing the lack or slowness of the drug action due to the target organs having low perfusion rates
Describe permeability limitation.
Used in describing the lack or slowness of the drug action due to the drug’s inability to move across biological membranes to target organs/sites
What factors affect the rate of distribution?
Blood perfusion
Membrane permeability
What factors affect the extent of distribution?
Lipid solubility
pH-pKa
Plasma protein binding
Intracllular binding
Penicillin has a pKa of 2.8.
It has limited action in brain tissue, why?
Its limited action is due to its permeability (more often charged) than perfusion (the brain gets lots of blood flow)
Thiopental has a pKa of 7.5. Describe why it has a limited action in the muscle.
Why does this not occur in the brain
Muscles have low perfusion rates and thus this drug is perfusion limited.
Thiopental acts rapidly in the brain due to its high permeability and high perfusion rate.
