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Transcript
VM 8314 Drug Distribution Dr. Wilcke VM 8314 Physical and Physiologic “spaces” Vascular space = Plasma/plasma water + (extracellular space) Many RBC’s (intracellular space) + A few WBC’s (intracellular space) Tissue space Interstitial fluid (extracellular space) + Cells of the body (intracellular space) Dr. Wilcke VM 8314 Physical and Physiologic “spaces” Tissue Vascular ICF ECF ECF ICF Dr. Wilcke VM 8314 Physical and Physiologic “spaces” Point to: Tissue ECF Tissue ICF Vascular ECF & ICF Dr. Wilcke VM 8314 Vascular space ~ 7% of body weight (mammals) Equilibria Water ↔ plasma and serum proteins Ioniozed drug ↔ unionized drug Plasma water ↔ inside of WBCs and RBCs Uniform mixing and distribution in 10 to 30 minutes. Dr. Wilcke VM 8314 Tissue space the rest of the volume (water) neither structural proteins nor bone matrix (no water) Equillibria Water ↔ tissue proteins (e.g. albumin) Ionized drug ↔ unionized drug Extracellular fluid ↔ intracellular fluid Reaches equillibrium in minutes to hours (even days and weeks is possible) Dr. Wilcke VM 8314 Extracellular space Present in both vascular and tissue spaces ~15 – 20% of body (by weight) Larger in neonates Equillibria Ionized and unionized (Protein) bound and unbound Dr. Wilcke VM 8314 Intracellular space Present in both vascular and tissue spaces ~35 – 45% of body (by weight) Equilibria Ionized and unionized drug Distribution in 30 minutes to +12 hours Dr. Wilcke VM 8314 Reserved spaces “Protected tissues” CSF Aqueous humor Prostatic fluid Distribution in minutes to never Most dosing situations not relevant Important if the disease is in the reserved space. Dr. Wilcke VM 8314 Movement between spaces Vascular (ECF) ↔ Tissue (ECF) Transcytotic http://www.bio.davidson.edu/people/kabernd/BerndCV/Lab/EpithelialInfoWeb/Transcytosis.html Endothelial junctions Especially with inflammation Diffusion Carried in WBCs (rare) Dr. Wilcke VM 8314 Movement between spaces ECF to ICF Diffusion Active uptake WBCs seem to be particularly able… Dr. Wilcke VM 8314 “Diffusion limited” distribution In general, diffusion is the rate-limiting step drug distribution TO the tissues ECF ↔ ICF Dr. Wilcke VM 8314 “Blood flow limited” distribution IF diffusion is rapid Tissue saturation by the drug (reaching equilibrium) is controlled by drug delivery to tissue Drug delivery to tissues is controlled by blood flow Tissue blood flow is not uniform Brain and kidneys - high portion of flow Muscles intermediate Skin and fat - small portion Dr. Wilcke VM 8314 “Blood flow limited” distribution Ultra-short acting barbiturates Brain is saturated FIRST Muscle is saturated LATER Animals wake up because the muscle keeps soaking up drug (not because drug is metabolized) Not all barbiturates Does not apply to gas anesthetics Dr. Wilcke VM 8314 Enterohepatic circulation = drug molecule paths Dr. Wilcke VM 8314 Enterohepatic circulation How does it work Drug taken up by liver cells Drug or phase II conjugate excreted in bile Drug reabsorbed from intestine (Phase II conjugate cleaved to liberate drug if necessary) Dr. Wilcke VM 8314 Enterohepatic circulation What does it mean Volume of distribution is increased The cycle itself is a space where drug “remains” It takes longer to eliminate the drug than you might expect (for drugs excreted by the liver) Dr. Wilcke VM 8314 Enterohepatic circulation Why do you care? Interrupt to improve drug elimination Poisonings, barbiturate overdoses, etc. Dr. Wilcke VM 8314 Mammary excretion Distribution from one perspective Simple diffusion of unionized drug Ion trapping (normal milk is slightly acidic v blood) Inflammation reduces barrier Elimination from another Drug actually does leave the body if it’s in milk Just not much of it (Absorption from a third ;-) If you’re the baby… Dr. Wilcke VM 8314 Salivary excretion Distribution from one perspective Drug in saliva is likely to be absorbed from GI tract Acts very much like enterohepatic circulation Actually important in ruminants Elimination from another Drug is probably not 100% absorbed from GI tract Dr. Wilcke