VMB, Drug Distribution

Drug Distribution, Know determinants of drug distribution

Distribution is dependent on drug properties, concentration gradient, blood flow, plasma protein binding, and affinity for tissue constituents like fat, muscle, and bone.

Drug Distribution, Define distribution

The transfer of drug between the vascular space (blood) and the extravascular space (tissue).

Drug Distribution, How do drugs move from blood to tissues?

Drugs move from the blood to tissues by passive diffusion or active transport.

Drug Distribution, Understand implications of plasma protein binding

Albumin and alpha-1-acid glycoprotein are plasma proteins that bind drugs; large molecular weight binding precludes movement from circulation.

Drug Distribution, What is the relationship between free and bound drug?

Free and bound drug are always in equilibrium; free drug is available for distribution while protein-bound drug remains in plasma.

Drug Distribution, What does plasma protein binding depend on?

Binding depends on affinity, number of binding sites, and drug concentration.

Drug Distribution, Which plasma protein binds acidic/neutral drugs?

Albumin binds acidic and neutral drugs.

Drug Distribution, Which plasma protein binds basic drugs?

Alpha-1-acid glycoprotein binds basic drugs.

Drug Distribution, What happens to drug clearance as protein binding increases?

As protein binding increases, free drug available for distribution and elimination decreases, which decreases clearance and increases half-life.

Drug Distribution, Discuss physiochemical characteristics of drugs and how this affects storage in fat

Long-term exposure to lipophilic compounds can lead to accumulation in adipose tissue; decreased body weight can mobilize stored compounds, increasing circulating concentrations.

Drug Distribution, What happens to Vd and half-life when adipose tissue is lost?

When body weight decreases, Vd decreases and elimination half-life decreases as stored compounds are mobilized.

Drug Distribution, Discuss specialized sites of drug distribution (CNS)-importance of transporters

The blood-brain barrier is a specialized barrier with continuous capillaries, glial membrane, and efflux pumps that limits entry of many drugs into the CNS.

Drug Distribution, What determines CNS penetration of drugs?

Drugs that readily cross the BBB tend to be low molecular weight, lipophilic, unionized, and unbound (free).

Drug Distribution, How do transporters affect CNS penetration?

Transporters at the BBB (e.g., P-glycoprotein) can actively limit CNS penetration, even for lipophilic drugs.

Drug Distribution, Describe how drug distribution changes with changes in the volume of distribution of a drug

Vd is the proportionality factor relating amount of drug in the body to concentration in a biological fluid; Vd reflects balance between drug remaining in plasma and distributing into tissues.

Drug Distribution, What is the formula for volume of distribution?

Vd = Dose / Plasma concentration at time 0 (C0); Cp = Dose / Vd.

Drug Distribution, What factors keep drug in the plasma and lower Vd?

Plasma protein binding keeps drug in plasma; increased plasma protein binding leads to decreased Vd.

Drug Distribution, What factors promote tissue distribution and increase Vd?

Tissue binding, lipid solubility, membrane permeability and transporters, and physiologic factors/body composition promote tissue distribution and increase Vd.

Drug Distribution, What does a low Vd indicate?

A low Vd indicates drug largely remains in the vascular space, with high plasma concentration at time 0.

Drug Distribution, What does a high Vd indicate?

A high Vd indicates drug distributes extensively into tissues, with low plasma concentration at time 0.

Drug Distribution, Describe drug binding in tissue

Drugs can bind to tissue proteins and components, which can increase apparent Vd, some tissues act as drug reservoirs, and may prolong drug persistence.

Drug Distribution, Give examples of tissue binding

Lipophilic drugs bind to fat, tetracyclines and bisphosphonates bind to bone, aminoglycosides bind to kidney/ear, and digoxin binds to skeletal muscle.

Drug Distribution, Choose the correct statement about plasma protein binding

Plasma protein bound drug molecules are restricted to the systemic circulation.

Drug Distribution, A small volume of distribution is common for lipophilic substances easily penetrating barriers and widely distributing in plasma, interstitial and cell fluids

False.

Drug Distribution, Which statement is true regarding the blood-brain barrier?

Efflux pumps keep many drugs from entering the CNS