VMB, Physiochemical Properties

Physiochemical Properties, Discuss mechanisms of drug movement

Mechanisms of movement include passive diffusion, carrier-mediated transport, and endo/exocytosis.

Physiochemical Properties, What does drug movement depend on?

Concentration gradient, blood flow, molecular size, solubility, degree of ionization, and protein binding.

Physiochemical Properties, Describe passive diffusion

Includes transcellular and paracellular passive diffusion; determinants include size, degree of ionization, solubility (lipophilicity), membrane characteristics, and surface area.

Physiochemical Properties, Describe carrier-mediated transport

Includes passive facilitated diffusion (no energy, with concentration gradient, uniporters) and active transport (energy-dependent, against gradient, uniporters, antiporters, symporters).

Physiochemical Properties, Describe ABC transporters

Primarily efflux, protective mechanism, active transport; P-glycoprotein (MDR1) in GIT, liver, kidney, and brain with wide substrate specificity.

Physiochemical Properties, Describe solute carrier (SLC) transporters

Uptake and efflux via facilitative/active transport and ion channels; selectivity can be narrow (glucose, neurotransmitters, peptides) or broad (OAT, OCT).

Physiochemical Properties, Discuss physiochemical properties of drugs and how this affects movement across cellular membranes

Biological membranes are a lipid bilayer, so drugs need to be somewhat lipophilic to travel across membranes.

Physiochemical Properties, What is the octanol/water partition coefficient?

P = Co/Cw for the unionized drug; log P indicates lipid solubility.

Physiochemical Properties, Why does molecular weight matter for drug movement?

Small molecules like lithium (MW 7) and morphine (MW 285) are easily absorbed, while large molecules like erythromycin (MW 734) have difficult absorption.

Physiochemical Properties, Describe weak acid ionization

Conjugate acid is unionized (protonated) and lipid soluble; conjugate base is ionized (unprotonated) and water soluble.

Physiochemical Properties, Describe weak base ionization

Conjugate base is unionized (unprotonated) and lipid soluble; conjugate acid is ionized (protonated) and water soluble.

Physiochemical Properties, Which form do drugs preferentially diffuse in?

Drugs preferentially diffuse across cellular membranes in their unionized (non-charged) form.

Physiochemical Properties, State the Henderson-Hasselbalch equation for weak acids

pH = pKa + log([A-]/[HA]), where A- is ionized and HA is unionized.

Physiochemical Properties, State the Henderson-Hasselbalch equation for weak bases

pH = pKa + log([B]/[BH+]), where B is unionized and BH+ is ionized.

Physiochemical Properties, What does pKa tell us about a drug?

pKa does NOT tell us whether a drug is a weak acid or base.

Physiochemical Properties, Given pH and pKa, how do you determine ionization for a weak acid?

If pH > pKa, ionized form predominates; if pH < pKa, unionized form predominates.

Physiochemical Properties, Given pH and pKa, how do you determine ionization for a weak base?

If pH > pKa, unionized form predominates; if pH < pKa, ionized form predominates.

Physiochemical Properties, Example: weak acid pKa 3.5 in stomach pH 1.5

pH − pKa = −2, so [A-]/[HA] = 0.01; 1% is not absorbed and 99% is absorbed.

Physiochemical Properties, Example: weak base pKa 4.4 in blood pH 7.4

pH − pKa = 3.0, so [B]/[BH+] = 1000; 99.9% is absorbed and 0.1% is not absorbed.

Physiochemical Properties, What kind of substance can cross membranes by transcellular passive diffusion?

Lipid-soluble.

Physiochemical Properties, At physiologic pH (approximately 7.4), a drug that is a weak acid (pKa 3.4) would be predominately

Ionized.

Physiochemical Properties, The main mechanism by which most drugs are absorbed and distributed is

Passive diffusion (lipid diffusion).

Physiochemical Properties, Practical application: Tums prior to aspirin

pH 4 with aspirin pKa 3.5 gives 76% ionized and 24% unionized, so only 24% is in absorbable form.

Physiochemical Properties, Practical application: aspirin prior to Tums

pH 2 with aspirin pKa 3.5 gives 3% ionized and 97% unionized, so 97% is in absorbable form.

Physiochemical Properties, What is the practical conclusion for aspirin and Tums?

Taking aspirin first increases the absorbable form 4-fold compared to taking Tums first