Pharmacokinetics I - Lecture 3 Flashcards
Factors that Determine Rate and Extent of Drug Distribution
Blood flow and tissue mass/volume Capillary permeability Lipid solubility of the drug Extent of drug ionization and tissue pH Transport mechanisms available Extent of drug binding to plasma and tissue proteins
Significance of Blood Flow and Tissue Mass/Volume
Larger mass of muscle —> accumulates more drug, but lower CO/mass slows time to reach pharmaceutical effect
What is necessary to produce a pharmacological effect?
Critical drug concentration
Capillary permeability
Peripheral capillaries are porous - liver and kidney extremely porous
Capillaries in brain are non-porous - tight junctions and astrocyte foot form BBB to preclude bulk flow, so drugs MUST enter via passive diffusion or transporters
Lipid solubility of drug vs lipid content of tissue
Highly lipophilic drugs tend to accumulate in fatty tissues, therefore slower to leave fat and body
Extent of ionization of drug in the different body fluids
pH in cell is usually lower (more acidic) than plasma (basic media)
For drugs transported by passive diffusion…
WA: [drug] higher in plasma (higher pH, basic)
WB: [drug] higher inside the cell (lower pH, acidic)
Weak Acid Drugs
Higher concentration in plasma
Weak Basic Drugs
Higher concentration inside the cell
Ion Trapping
Concentration of charged species is higher in tissue than in plasma and the drug accumulates in tissue
Acidic drugs trapped in basic environments and vise Versa
Compounds charged at all physiological pHs…
Diffuse poorly across lipid membrane and rely on carrier-mediated transport to cross the membrane
Nicotinic cholinergic receptor antagonist
Blocks ACh binding
Skeletal muscle relaxant targets…
Diaphragm
Apparent Volume Distribution (Vd)
Relationship between the amount of drug in the body via IV (X0) and the concentration of drug in the plasma (Cp) immediately after admin
How is the immediate concentration determined?
Non-linear regression and extrapolate regression back to T=0
Inverse Relationship of Cp and Vd
For a constant drug (X0):
Decreased Cp = increased Vd
Increased Cp = decreased Vd
What does Vd represent?
When a drug is injected into the bloodstream and allowed to distribute to the different tissues of the body, a certain plasma concentration (Cp) is obtained
Vd equals the volume that X0 occupiers in body to yield a Cp
Volume of Fluid for a 70kg Male
Plasma - 7L
Extracellular fluid outside the blood - 12L
Total body water - 42L
What does it mean if the volume of distribution is 13L?
3L < Vd < 15L
Drug is bound to plasma proteins and increases the Cp
Decreased Vd, increased Cp
If the drug gets into total body fluid (42L) and is bound to albumin, what would be the Vd?
15L < Vd < 42L
Drugs that enter the total body water but bind plasma proteins
Decreased Vd, increased Cp
What does it mean if the Vd is 100L? Is the pt 100L in volume?
Drug occupies total body water and bonds to tissue proteins and/or stored in fat. More drug is in the tissues than expected.
Vd > 42L
Increased Vd, decreased Cp
What would the volume of distribution be if the drug entered the total body water and was stored in fat tissue?
Vd > 100c considered stored in fat
Drastic increase in Vd, drastic decreased in Cp
Clinical relevance of volume of distribution
Estimation of the amount of drug in the body tissues or blood
Proportion available for therapeutic effect or excretion
Utilized in the calculation of doses and dose rates
Where the drug goes within the body
Drugs with larger Vd
More lipophilic Easier to cross BBB Accumulate in tissues or fat Maintained longer in body Requires hepatic metabolism for elimination
Drugs with smaller Vd
More hydrophobic
Remains in blood with little accumulation in fat, tissue, or brain
Large MW or bind to plasma proteins
Eliminated primarily by kidney
Distribution Within Blood Plasma Protein Binding
Drug in blood can be free and bound to plasma proteins
Free/bound equilibrium based on affinity for proteins
Free and bound percentages are characteristic for each drug at therapeutic levels (% bound remains relatively constant, binding is saturable, drugs/xenobiotics with similar affinities can displace drug)
Albumin binds mainly acidic drugs
Alpha-1 acidic glycoprotein bonds mainly basic drugs
Only free drug can…
Be transported
Enter tissues
Bind receptors
Deliver a pharmacological effect or be eliminated via kidney
Distribution Within Tissues - Tissue Binding
Some drugs bind tissue/cellular constituents (proteins - bind to receptors (functional) or non specific (non-functional), (lipids - highly lipophilic drugs prone to accumulation in adipose tissue)
Liver - drugs with “high extraction ratios” can be taken up by liver rapidly with the flow of blood
Lung - basic with large lipophilic groups and pKa > 8
Bone - complexes calcium and incorporated into bone lattice
