Unit 2 - Biological barriers & ADME 2 Flashcards
What is the approximate volume of total body fluid?
42 litres
What is the approximate volume of intracellular fluid?
28 litres
What is the approximate volume of extracellular fluid?
14 litres
What is the approximate volume of interstitial fluid?
10 litres
What is the approximate volume of plasma?
5 litres
what are the categories body fluids are distributed into ?
body is 60% fluid
intracellular fluid - 40% body weight
Extracellular fluid - 20% body weight
(Plasma & interstitial fluid)
How can drug sequestration take place?
Lipid sequestration - drug in plasm Binding to a host of tissue components - plasma proteins - tissue proteins
What percentage of the blood is plasma?
55%
What percentage of the blood is red blood cells?
45%
What percentage of the blood is white blood cells and platelets?
1%
What are the major drug-binding plasma proteins?
Plasma is protein rich
Albumin
Alpha1-acid glycoprotein
Lipoproteins
- variable
What is able to cross cellular barriers to access tissues, intracellular targets and bind to receptors?
Unbound drug
- free drug
What does drug binding have an effect on?
Distribution and Elimination of drug
Pharmacologic response
What is Fu?
Fraction of total mass of drug in plasma (blood) that is unbound
How can fraction unbound be calculated?
Fu = drug concentration [free] / drug concentration plasma [total]
[Total] = free + bound
Describe the concept of reversible equilibrium
Drug enters the plasma
Equilibrium between free drug in plasma and bound drug in plasma
Equilibrium between free drug in plasma and free drug in tissue compartment
Equilibrium between free drug in tissue and bound drug in tissue
How much albumin is produced a day by hepatocytes?
9 - 12g/day
What is the concentration of albumin in plasma?
40 g/L
How many binding sites does albumin have?
Two
Which type of molecules bind to albumin in plasma?
Hydrophobic
Negative charge or electronegative feature
How can the affinity for a drug to albumin be increased?
More acidic (pKa < 6) More hydrophobic
What is alpha1-acid glycoprotein?
Heavily glycosylated plasma protein synthesised in the liver
How many binding sites does alpha 1-acid glycoprotein have?
One
Which type of molecules bind to alpha 1-acid glycoprotein in plasma?
Hydrophobic
Positive charge or electropositive feature
Give examples of plasma lipoproteins
Triglycerides and cholesterol esters
Phospholipids
Cholesterol
Proteins
Give examples of plasma lipoprotein particles
High-density lipoprotein - HDL Low-density lipoprotein - LDL Intermediate density lipoprotein - IDL Very low density lipoprotein - VLDL Chylomicrons - CM
What is the function of plasma lipoproteins?
To transport various fat molecules around body to tissues
How do plasma lipoproteins sequest drugs?
Lipid solubilisation of drug into core Lipid interaction with surface phospholipids - non-restrictive - non-saturable Binding to surface apoproteins
What is the structure of a plasma lipoprotein?
Surface monolayer - phospholipids - free cholesterol - protein Hydrophobic core - triglyceride - cholesteryl esters
What might cause albumin levels to decrease?
Burns Liver damage - synthesises albumin Renal disease - eliminates albumin Malnutrition - can't synthesise albumin
What might cause alpha 1-acid glycoprotein levels to increase?
Inflammatory disease - rheumatic arthritis - Crohn's disease Cancer Trauma
What might cause alpha 1-acid glycoprotein levels to decrease?
Liver disease
- synthesises alpha1-acid glycoprotein
