General Principles of Pharmacology Lecture: Slide 7

Introduction: General Principles--Lecture II, slide 2

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Chemical Aspects of Drugs
Chirality
Anesthetic agents administered as racemic mixtures
Drug-Receptor Interactions: Binding Forces
Henderson-Hasselbalch Equation

Drug Transfer
- Aqueous diffusion
- Lipid diffusion
- Carrier-mediated Transfer
Endocytosis/Exocytosis

Henderson-Hasselbalch equation
log (protonated)/(unprotonated) = pK_a - pH The lower the pH relative to the pKa: greater fraction of protonated drug (protonated drug may be charged or uncharged) Weak acids at acid pH are more lipid-soluble, because they are uncharged and the uncharged form more readily passes through biological membranes. Note that a weak acid at acid pH will pick up a proton a become uncharged. RCOO^- + H⁺ ⇄ RCOOH Weak bases at alkaline pH are more lipid-soluble, because they are uncharged and the the uncharged form more readily passes through biological membranes. Note that a weak base at more alkaline pH will lose a proton, becoming uncharged. RNH₃⁺ ⇄ RNH₂ + H⁺ Lipid diffusion depends on adequate lipid solubility Drug ionization reduces a drug's ability to cross a lipid bilayer. Many drugs are weak acids or weak bases: A weak acid is a neutral molecule that dissociates into an anion (negatively charged) and a proton (a hydrogen ion) Example: C₈H₇O₂COOH ⇄ C₈H₇O₂COO^- + H⁺ Neutral aspirin (C₈H₇O₂COOH) in equilibrium with (in a balance with) aspirin anion, C₈H₇O₂COO^-,and a proton H⁺ Weak acid, if in the protonated form is electrically neutral and therefore more lipid-soluble A weak base is a neutral molecule that can form a cation (positively charged ion) by combining with a proton. Example: C₁₂H₁₁CIN₃NH₃⁺ ⇄ C₁₂H₁₁CIN₃NH₂ + H⁺ The pyrimethamine cation (C₁₂H₁₁CIN₃NH₃⁺) in equilibrium with neutral pyrimethamine, C₁₂H₁₁CIN₃NH₂ and a proton H⁺ The weak base in the protonated form is charged and therefore less lipid-soluble and less able to move through biological membranes.

Models of Drug Transfer

Above figure courtesy of Professor Steve Wright and the University of Arizona (©), used with permission

Aqueous diffusion

Occurs within large aqueous components (e.g.,interstitial space, cytosol)
Occurs across epithelial membrane tight junctions

"Structure of tight junctions. a | Freeze-fracture replica electron microscopic image of intestinal epithelial cells.
Tight junctions appear as a set of continuous, anastomosing intramembranous particle strands or fibrils (arrowheads) on the P face with complementary vacant grooves on the E face (arrows). (Mv, microvilli; Ap, apical membrane; Bl, basolateral membrane.)
- Scale bar, 200 nm.
b Ultrathin sectional view of tight junctions. At kissing points of tight junctions (arrowheads), the intercellular space is obliterated. Scale bar, 50 nm.
c Schematic of three-dimensional structure of tight junctions. Each tight-junction strand within a plasma membrane associates laterally with another tight-junction strand in the apposed membrane of an adjacent cell to form a paired tight-junction strand, obliterating the intercellular space (kissing point)."--from Nature Reviews Molecular Cell Biology 2; 285-293 (2001) MULTIFUNCTIONAL STRANDS IN TIGHT JUNCTIONS

Occurs across endothelial blood vessel lining
- through aqueous pores: allows diffusion of large molecules with molecular weights up to 20,000 -- 30,000.
Driving force: drug concentration gradient (described by Fick's Law )

Fick's Law

Definition: Fick's Law describes passive movement molecules down its concentration gradient.

Flux (molecules per unit time) = (C₁ - C₂) · (Area ·Permeability coefficient) / Thickness

where C₁ is the higher concentration and C₂is the lower concentration
area = area across which diffusion occurs
permeability coefficient: drug mobility in the diffusion path
- for lipid diffusion, lipid: aqueous partition coefficient -- major determinant of drug mobility
  - partition coefficient reflects how easily the drug enters the lipid phase from the aqueous medium.
thickness: length of the diffusion path

Katzung, B. G. Basic Principles-Introduction , in Basic and Clinical Pharmacology, (Katzung, B. G., ed) Appleton-Lange, 1998, p 5.

Plasma protein-bound drugs cannot permeate through aqueous pores
Charged drugs will be influenced by electric field potentials {membrane potentials, especially important in renal, trans-tubular drug transport}