Drug Absorption Lecture 4

Absorption n Movement from administration site into circulatory system n Complete when... l concentration at target equals l site of administration n Controlled by membranes l cell l capillary walls l blood-brain barrier l placental barrier ~

Cell Membranes n Lipid bilayer l semipermeable n Fluid Mosaic Model l Phospholipids l Proteins ~

Membrane Proteins OUTSID E INSIDE

Movement Across Membrane n Passive diffusion n Carrier assisted transport l diffuse through gated channels n Active transport l requires energy ~

Capillaries n Exchange of materials l b/n blood and cells n Capillary walls one cell thick l Pores l materials can move in/out ~

n Barrier b/n circulatory system & brain l peripheral vs. CNS blood supply n Capillaries l cells in wall tightly packed n astrocytes l glia l wrap around capillaries l tight seal ~ Blood-Brain Barrier (BBB)

T Blood Brain Blood-Brain Barrier

Typical Capillary Blood-Brain Barrier Fenestra Intercellular cleft Brain Capillary tight junction No fenestra astrocytes

BBB: Function n Maintains stable brain environment l large fluctuations in periphery n Barrier l to poisons l Retains NTs & other chemicals n Regulates nutrient supplies l glucose levels l active transport ~

BBB: Development n Incomplete at birth l up to 2 yrs old l vulnerable during pregnancy n Weakening of BBB l trauma l infection l aging ~

Chemical Trigger Zone (CTZ) n Area Postrema in brainstem l BBB weaker n Substances can enter brain l safety mechanism l neurons monitor blood rapid  in blood concentration triggers vomiting l dopaminergic neurons ~

T Blood Brain CTZCTZ Chemical Trigger Zone

Placental Membrane n Exchange nutrients & wastes w/ mother n Less selective than BBB l all lipid soluble substances n Fetus is vulnerable l incomplete BBB l lack enzymes for metabolism ~

Placental Membrane n Teratogens l chemicals that cause birth defects l alcohol, nicotine, cocaine, etc. n Smoking  CO l reduced O 2 levels  brain damage ~

Lipid Solubility n Ability to dissolve in a medium n water-soluble n lipid-soluble l easily crosses membranes l also BBB n Molecular size l small absorbed easily ~

Solubility: Ionization n Ionization decreases solubility l ion = charged particle n Lipid-soluble  little ionization n Water-soluble  ionizes easily l requires carrier assisted or active transport ~

n Polarity l positive & negative poles lH2OlH2O n Polar  hydrophilic l tend to ionize l will not cross membrane n Nonpolar  hydrophobic l crosses membrane easily ~ Solubility: Polarization

O H H Water + - Polar Ethanol C H H H C H H OH Nonpolar

Solubility: pH n pH scale: 0-14 n Drugs in solution can ionize l H 2 O  H+ and OH- n # of H+ in solution relative to OH- l High % H+ = acidic l Low % H+ = basic (alkaline) ~

pH Scale acidic alkaline Water = neutral GI = 1.2Blood = 7.4

Ion Trapping n Drug & pH important n Ionization decreases solubility l acidic drug in alkaline ---> ionize l alkaline drug in acidic ---> ionize n Per Os ? l acidic drug best ~

Redistibution n Dynamic equilibrium maintained n Example: acidic drug in blood l 40% ionized to 60% un-ionized n As drug is metabolized l some ionized  un-ionized l ratio ionized to un-ionized retained u 4:6 ~

Best Absorption n Lipid soluble n Small n Nonpolar n Un-ionized l pH matches environment ~