Introduction: General Principles--Lecture II, slide
2
press above to
begin
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) = pKa
- pH
the lower the pH relative to the
pKa:
greater fraction of protonated drug (protonated
drug may be charged or uncharged)
weak acid at acid pH: more
lipid-soluble, becauses it is uncharged--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 base at alkaline pH: more
lipid-soluble, because it is uncharged--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:
Weak
acid: 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 aspirin anion (C8H7O2COO-
) and a proton (H+ )
weak
acid: protonated form -- neutral, more lipid-soluble
weak base: a
neutral molecule that can form a cation
(positively charged) by combining with a
proton. Example:
C12H11CIN3NH3+
<> C12H11CIN3NH2
+ H+
pyrimethamine cation (C12H11CIN3NH3+)
in equilibrium with
neutral pyrimethamine (C12H11CIN3NH2)
and a proton
(H+
)
weak base: protonated
form -- charged, less
lipid-soluble
Models of Drug Transfer
Above figure courtesy of Professor Steve Wright and the
University of Arizona (c), 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 C2
is 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}
above to
begin
Many
drugs are weak acids or weak bases:
