Pharmacokinetics: Drug Distribution

• The lecture covers pharmacokinetics, specifically drug distribution.
• It aims to enable students to summarize the importance of calculating Vd (Volume of Distribution), list properties of drugs that highly bind to plasma, predict displacement interaction risks at the plasma protein level, and recall factors affecting drug distribution.

Body Water Compartments

• In a 70 kg person, plasma volume is 6% of total body weight, equating to 4.2L
• The total of plasma and insterstitial fluid (ECF) accounts to 14L or 20% of body weight
• Total body water i.e. plasma + interstitial + intracellular equates to 60% of total body weight or 42L

Volume of Distribution

• Volume of distribution is the volume that would accommodate body drug amount to plasma concentration
• Vd = Amount of drug in the body / Plasma concentration
• Vd = Dose/Conc.

Factors affecting Drug Distribution

• There are multiple factors, including perfusion (blood flow to the organs), diffusion across cell membranes, capillary permeability, binding of drugs to plasma protein, and binding to cell and tissue components

Perfusion

• Increased blood flow increases drug distribution in the particular organ
• Order rate of blood flow in organs: brain, liver, and kidney > skeletal muscles > adipose tissue
• Propofol, an anesthetic, has rapid distribution into the CNS due to high blood flow and lipophilicity

Diffusion

• The ability of a drug to cross cell membranes depends on its lipophilicity i.e. increased lipophilicity means increased distribution
• Diffusion depends on pH and the drug's pKa.

Capillary Permeability

• Capillary permeability affect drug distribution

Clinical Significance

• Lipid-soluble drugs cross the CNS
• Ionized polar drugs do not enter the CNS due to the blood-brain barrier.

Other Factors

• Binding of drugs to plasma proteins decreases diffusion to tissues, thus decreasing Vd.
• Binding to cell and tissue constituents increases Vd due to high affinity.
• Tetracyclines deposit in bones and teeth because they bind to Calcium (Ca2+).
• Iodides are located in thyroid and salivary glands.

Binding to Plasma Proteins

• Drug bound to plasma protein is inactive, unable to pass through blood vessels, is not highly distributed, and is not metabolized or excreted, resulting in a long duration
• Albumin binds acidic drugs
• Lipoprotein and alpha-1 acid glycoprotein bind basic drugs
• Free/unbound drug form is diffusible, active, and able to be eliminated

Plasma Protein Levels

• Increased plasma protein caused by infection lowers the amount of active antibiotic and may require a higher dose
• For serious drug interactions, the displaced drug needs to be highly bound (>95%) and have a low therapeutic index e.g. Warfarin

Volume of Distribution Calculation

• Estimates the extent of tissue drug uptake small Vd indicates limited tissue uptake large Vd indicates extensive tissue uptake

Drug Characteristics and Volume of Distribution

• Drug with high molecular weight e.g. Heparin: Vd ~ 4.2 L
• Drug with small molecular weight e.g. Insulin (0.2 L/Kg): Vd ~ 14 L
• Less lipid soluble drugs is Insulin (0.2 L/Kg) with an exrtacellular fluid
• Drugs with low molecular weight but lipid soluble e.g. alcohol (0.6 L/Kg): Vd ~ 42 L which encompasses total body water

Volume of Distribution Importance

• Small Vd of frusemide means limited tissue uptake
• Large Vd of digoxin indicates extensive tissue distribution
• Dialysis is not effective for drugs with high Vd because most of the drug is in tissues Dialysis is effective for drugs with low Vd because most of the drug is in blood and ECF
• Vd can calculate the loading dose
• LD = Vd x Steady state plasma concentration (Css)