Pharmacokinetics- Drug Distribution

Question 1

1. Explain the influence of pH on the ionization of weak acid/weak base drugs.

Answer 1

-Rate of distribution is generally not of clinical consequence (most drugs display single compartment kinetics).
Drug distribution affected by:
-Anatomic considerations (sites where drugs must pass through cells and not between).
-Tight junctions limit movement of large, protein-bound, ionized, water-soluble drugs.
-There is negligible absorption in the GI mucosa, and limited distribution in the BBB and placenta. More excretion at the renal tubules.

• pH of fluids –> determines % of non-ionized/lipid-soluble form of drug (can use HH to determine percent)
• Lipid solubility of non-ionized form (this is a property of the drug itself that determines its ability to cross membranes via passive diffusion)
• Drug binding to plasma proteins (only free drug is active and diffusible; bound drug can’t leave it’s compartment)

-Drugs are weak acids (lose proton, -COOH) or weak bases (gain proton, -NH3+). Non ionized forms are more easily absorbed (HA or B); ionized forms get trapped and don’t cross membrane. HH tells you what percent of drug is ionized.
HH  pH – pKa = log (non-protonated/protonated) (i.e. base over acid).

Question 2

2. Use the Henderson-Hasselbach equation to qualitatively predict the ratio of ionized to unionized species of a weak acid or weak base drug in various body compartments.

Answer 2

If pH > pKa, protonated form dominates = HA and BH+.
If pH < pKa, deprotonated form dominates = A- and B.
If pH = pKa, acid = base.
Weak acids are non-ionized/lipid soluble in acid solutions (pH pKa).

In ion trapping, a lipid barrier separates 2 different pH’s, and only the non-ionized form of drug can cross. At equilibrium, concentration of non-ionized form is same on both sides. However, there’s a separate equilibrium on each side between ionized and unionized form. The TOTAL [drug] is greater on side where ionized drug is greater = ion trapping. Acidic drugs trapped in basic solutions; basic drugs trapped in acidic solutions. Ionized forms can’t cross tight junctions; can cross capillary walls.

- altering urine pH to trap drugs to hasten excretion
- basic drugs concentrate in acidic breast milk
- weak base toxins concentrate in acidic stomach contents.

Question 3

3. Explain the therapeutic consequences of anatomic “barriers” (GI mucosa - blood-brain barrier - renal tubule cells) to distribution and selective accumulation of drugs.

Answer 3

• GI, BBB, placenta, and renal tubules have tight junctions that drugs have to pass through –> small, unbound, unionized, and lipid soluble.
• If drug administered orally, negligible absorption in GI.
• BBB and placenta have limited distribution because of tight junctions in capillaries (versus large gaps between cells in peripheral system that drug can move between into different tissues).
• Pregnant women get heparin, not warfarin.
• Renal tubules have reduced reabsorption back into blood, which enhances excretion.
• Drugs can be selectively accumulated in kidney, eye, lung, bone, ear (why?).

Question 4

4. Describe how drug binding to plasma proteins can effect drug distribution and elimination as well as being a potential source of drug-drug interactions.

Answer 4

• Only free drug is diffusible; if bound to plasma proteins, it is stuck in its compartment.
• Acidic drugs bind albumin;
• basic drugs bind alpha-1 acid glycoprotein.
• Protein binding decreases concentration of active, free drug (limits fetal exposure), hinders metabolic degradation/reduces excretion (decreases elimination rate, increases half-life and creates a drug reservoir that prolongs action), decreases Vd (by increasing apparent solubility), and decreases ability to cross BBB into CNS. -Unbound drug can go to site of action or be more easily eliminated.
• You can administer a second drug to displace the 1st drug from binding to proteins to increase its free levels (small transient effect).
• This only matters if drug has narrow therapeutic index, the displaced drug is started in high doses, the Vd is small, or the response to drug happens quicker than redistribution of drug.
• Can’t be absorbed, can be excreted, can’t do it’s job if bound.
• When bound, more likely to have DDI’s if another drug upsets how it’s bound. (Can make it toxic)

Question 5

5. Explain the derivation and clinical relevance of the pharmacokinetic parameter volume of distribution (Vd). Describe its use in designing dosage regiments -> converting drug dose to Cp, selecting loading dose (LD), implications of high or low values.

Answer 5

Bioavailability (F): Adjustment of dose for oral vs. parenteral administration.
-Bioavailability is the % of the initial dose reaching systemic circulation.

• Can use to adjust dose when the route is changed (ex: IV dose [or other parenteral] will be WAY lower than an oral dose since it’s bypassing the 1st pass metabolism).
• Oral bioavailability varies for many factors.

-Volume of distribution (Vd): Converting drug dose to plasma concentration, selecting loading dose, implications of high or low values.
Vd = kg/L = volume of body fluids into which the drug distributes; indicates the extent to which drug passes from plasma to tissue.
Vd = Ab/C0.
Vd is an apparent value and it can give an indication as to where the drug is (plasma, interstitial fluid, intracellular fluid).
Can use Vd to determine LD or effect of a dose on Cp.
High Vd = drugs located outside plasma (more lipid solubility);
low Vd value = drugs inside plasma (low lipid solubility or bound to proteins or large).
Cp and Vd are inverse values.
If Vd > 40L, it’s getting into subcellular compartments and peripheral tissues. (3L = plasma, 15 L = in extracellular fluids, 40L = it’s in all extra- and intra-cellular fluids).
Can vary between people; depends on body weight, body composition, and the degree of protein binding.