Topic 7 - Drug Absorption and Distribution Flashcards
ADME
Absorption
Distribution
Metabolism
Excretion
Absorption
Movement of drug from where it was administered into the bloodstream
Enteral
Administration that passes through the intestines
Passes through liver
What routes are Enteral
Oral (PO), Rectal (PR)
Parenteral
Route that bypasses the intestine
Avoids the liver
Parenteral Routes
Intravenous (IV)
Intramuscular (IM) Subcutaneous (SC)
Topical
Sublingual (SL)
What routes bypass the liver
Parenteral
Rectal Route (Overdose)
If drug is not pushed in deep enough then drug is absorbed by rectal walls –> Drug goes directly into blood vessels while avoiding the liver
How does polar impact lipid solubility
The more polar a drug is the less likely it can cross the lipid bilayer
The more N and O molecules in a drug the more?
The more polar it is meaning the less lipid soluble it is
Higher logP means?
The drug is very hydrophobic
Low Polar Surface Area means?
The drug is more lipid soluble
Fick’s Law of Diffusion
Drugs flow from high concentration to low concentration
The larger the gradient the higher the rate of flow
Why is Lipid Solubility important in crossing the membrane?
A very lipid soluble drug will partition into the bilayer quite easily
Forms a larger gradient within the bilayer which drives the rate of flow
There is way more drugs to move within the bilayer
Ionization effects on Absorption
Charged drugs do not diffuse across membranes as they are water soluble
Ionization effects on Absorption (pH and pKa)
An acid in an acidic environment will be less ionized and will favour more of the lipid soluble form
Route that a drug takes when taken orally
Stomach –> Intestine –> Portal Vein –> Liver –> Systemic Circulation
First Pass Metabolism
Drugs taken orally have to pass through the Liver before they enter the systemic circulation
On average how many times will a drug past the liver
About once every four circuits will the drug pass through the portal vein and the liver again
What is oral bioavailability
The intact drug, a fraction of an oral dose that reaches the systemic circulation
Fraction Escaping Gut (Fg)
Amount of drug that enters the portal vein and leaves the intestines
drug in portal vein / drug dose
Fraction Escaping Liver (fH)
Amount of drug that is left over after being metabolized by liver
drug in systemic circulation / drug in portal vein
Hepatic Extraction Ratio (EH)
1-fH
1 - drug in systemic circulation
Amount of drug that is removed by liver
Oral Bioavailability (F)
fg x fh
Fraction of drug that escaped the intestines x Fraction of drug that escaped the liver
or
Amount of drug escaping liver / dose of drug taken
Thoracic Duct
Chylomicron carries lipophilic drugs through the thoracic duct to enter the systemic circulation
Apparent Volume of Distribution
AVd
A theoretical volume of plasma that contains all of the drug in the plasma
Creates a concentration equal to the plasmas
Calculating AVd
1) Check concentration of drug in plasma (10mg/L)
2) Check original dose given (100mg)
3) Determine volume of distribution
100mg/X = 10mg/L
X = 10L
Why do we use AVd instead of concentration of drug in systemic circulation
Amount of dose impacts the systemic circulation concentration, meaning it is not consistent
A change in dose will change concentration and thus, changes AVd, makes it a better value for comparison
Systemic Circulation and Distribution Relationship
High distribution means there is less concentration of drug in systemic circulation
What determines AVd (Tissue Factors)
Lipophilic unbound drugs will be partitioned in fat and will not be free for binding
What determines AVd (Blood Factors)
Plasma Protein Binding, Drugs bound to plasma proteins are unavailable for binding
AVd Formula
Plasma Volume + Volume of Tissue x (fu/fuT)
fu = fraction of unbound drug in blood
fuT = fraction of unbound drug in tissue
What happens where their is less plasma proteins
More unbound drug
fu/fuT ratio greater than 1 means that?
Low Tissue Unbound, lots of drugs bound and partitioned in fat
Very Lipophilic
Fraction of unbound drugs in blood is greater than the fraction of unbound drugs in tissue
fu/fuT ratio less than 1 means that?
Low plasma drug unbound –> Lots of drug is bound to plasma –> Drug is hydrophilic
Lipophilicity and Drugs Bound
Low amount of unbound drugs in plasma = Hydrophilic drug (Drugs are all bound to plasma proteins)
Low amount of unbound drugs in tissue = Lipophilic drug (Drugs are all bound to fat)
Competition for Plasma Binding Proteins
A competing drug can bind to plasma proteins and displace the initial drug
Leads to an increase in drugs in plasma = increase of drug in tissue = Larger response
Distribution Compartments
A model that helps us to understand drug behaviour and distribution
Not physically real
Central Compartment
Blood and other highly vascularized tissues (Brain) that distribute any incoming drug instantly
Drugs leave via Liver etc.
Is in equilibrium with tissue compartmentes
Shallow Tissue Compartment
Tissues and organs that rapidly distribute a given drug
Deep Tissue Compartment
Tissue and Organs that slowly distribute a given drug (Fat)
