1.4 Drug Distribution Flashcards
Drug binding to plasma proteins Passage across blood capillaries Passage across cell membranes Drug distribution to different compartments Factors effecting Distribution
What effects the rate at which drugs leave the blood?
Lipid solubility
Molecular weight
Degree of protein binding
What are the three types of capillaries?
Continuous
Fenestrated
Sinusoids
Describe Continuous capillaries
Only allow diffusion of water and small solutes through intercellular clefts.
Located in skeletal and smooth muscle, connective tissue and lungs
Describe Fenestrated capillaries
More permeable than continuous. Allow rapid exchange of fluid and solutes as well as small and large peptides. Located in kidney, small intestine.
Describe Sinusoidal capillaries
Wider and more winding than other capillaries. Incomplete basement membrane, larger fenestrations, very large clefts. Allow large proteins to pass through. Drug delivery to those tissues is greatest. Located in liver and spleen.
What are the 3 ties of passage across membranes?
Diffusion
Transport
Receptor mediated endocytosis
What is the rate of Diffusion effected by?
Molecular size
Oil/Water partition coefficient
Ionisation state
Describe receptor mediated endocytosis
Drug binds to receptor present on target cell type then subsequently endocytosed. Allows for selectivity of target tissues.
What factors will effect distribution of a drug?
Permeability across tissue barriers
Binding within the compartments
pH partitioning
Fat:water partitioning
What is order of drug distribution in the four compartment model?
Blood –> Vessel Rich –> Muscle –> Fat
What form of the drug (bound/unbound) drug is able to move between compartments
Unbound. Unbound is able to cross membranes, can have its cellular effect and can be eliminated.
What prevents drug distribution to the brain despite it’s high blood flow?
The Blood Brain Barrier
Describe the Blood Brain Barrier
Tight endothelial junctions in capillaries.
Absence of fenestrations
Diminished trans-endothelial vesicle movement (that could potentially take up drugs)
What criteria do drugs need in order to cross the BBB?
Lipid soluble
A molecular weight <400 daltons
Not a substrate for an active transport process.
What diseases can increase blood brain barrier permeability?
Meningitis and encephalic inflammation. This allows for IV administration of antibiotics for these conditions.
