Lecture 7 Flashcards
Drug Distribution and Bioavailability
Distribution depends on… (4)
- Blood flow to and through tissue
- Drug solubility
- Drug ionization
- Binding to plasma proteins of tissues
Distribution is required for drug to reach its target, must get to target and USUALLY into cells
Where can drugs distribute? (6)
- Total water - small water-soluble molecules ex: ethanol
- Extracellular water - larger water-soluble molecules ex: gentamycin
- Plasma restricted - strongly plasma protein-bound molecules and very large molecules ex: heparin
- Fat - highly lipid soluble molecules ex: DDT
- Bone - certain ions ex: lead, fluoride, tetracycline
- Muscle, etc.
Distribution in Pharmacology
Vd = Volume of Distribution
Vd = Amount of drug in body / C
C = concentration of drug in blood, plasma, or water
Vd can be greater than actual volume in body
Tissue can be storage depot for drugs
Protein Binding + Distribution
- Plasma protein binding is related to metabolism, excretion, and drug effect
- Drug deposits in tissue “free up” plasma protein binding sites
- Binding is in equilibrium based on relative binding constants (affinities)
Capillary Permeability
- One cell thick
- Absorption properties apply (diffusion, etc.)
- Gaps between endothelial cells differ in specialized tissue (large in excretory tissue, small/tight in barriers)
Specialized Barriers
- Blood-Brain Barrier
- Placenta
Exclude certain drugs
Blood-Brain Barrier
AKA BBB
- Tight junctions of endothelium
- Astrocytes form additional barrier around capillaries
- Decrease in permeability to water-soluble or ionized molecules
- Lipid-soluble substances diffuse easily
- More permeable when disrupted by infection or injury
- Also has drug efflux transporters
- Not fully formed until about 6 months of age
Placenta
- Connects fetus with maternal uterine wall and has sinuses to take maternal blood to baby
- Lipid-soluble materials move easily
- Water-soluble materials move more slowly
- Large molecules are less likely to pass barrier
- Fastest equilibrium possible between mother and fetus is 40 minutes
Limited entry to body compartments can occur by…
- Physical barriers (tight junctions)
2. Transporter barriers - high concentrations of efflux transporters or low concentrations of influx transporters
Half-life
- Denoted by t1/2
- Time it takes for half a drug concentrations to be eliminated
- Simplest case is a single compartment
- Drug residence depends on Vd and CL (CL = clearance)
Delayed Effections
- Drug effect doesn’t usually parallel drug concentrations
- Can occur due to distribution to site of action
- Drug action can be indirect or require a cellular response for an affect to manifest
Therapeutic Window Definition
The range of dosage of a drug or of its concentration that provides safe effective therapy.
Distribution Definition
The dispersion or dissemination of substances throughout the fluids and tissues of the body.
Volume of Distribution Definition
The apparent volume in which a drug is
distributed (Vd).
Pregnancy Class A
Adequate, well-controlled studies in pregnant women have not shown an increased risk of fetal abnormalities.