Beruflich Dokumente
Kultur Dokumente
James W. Paxton
Dept of Pharmacology & Clin Pharmacology
Learning Objectives
To describe the various mechanisms of drug
passage through biological membranes
To understand the major factors involved in
passive drug diffusion
To apply the Henderson-Hasselbalch equation
to calculate % non-ionized, drug pKa, and pH of
a solution.
Lecture Outline
Mechanisms
Drugs
as weak electrolytes
(acid drug )
(basic drug )
Binding to
plasma proteins
(albumin)
Metabolites
Free drug concentration
in extracellular
water
Binding and
storage in tissues
inactive or active
Biliary excretion
enterohepatic recirculation
Renal excretion
(protein, fat)
glomerular filtration
tubular secretion
passive reabsorption
Receptor occupancy
Intensity of pharmacological effect
Drug
ADP
ATP
Lymph
Blood
Lymph
Transcellular diffusion
Drug
Active transport
Drug
Drug
Facilitated diffusion
Endocytosis
Passive diffusion :
Most
important mechanism
Applies to non-polar drugs
(ie, lipid/oil/fat soluble)
Conc
Concentration
Ionization and pH
Most
Weak
10
Cell
(A- or HB+)
11
HA D A- + H+
[ A- ] [ H + ]
[ HA]
= Ka
(Association
constant)
12
[ A- ] [ H + ]
[ HA]
= Ka
(acid drug )
(basic drug )
13
0 = Log [AH]
[ A -]
1 = [AH]/ [A-] = 1/1
14
So what ? Is it important ?
Biological
excreted in urine
The
15
Benzoic
acid
COOH
%
nonionized
99.9
Aniline
NH3+
%
nonionized
0.01
99
0.1
90
50
10
COO-
NH2
10
50
90
0.1
99
16
% absorbed at
pH 4 pH 5 pH 7 pH 8
2.3
3.0
3.5
4.2
40
64
41
62
27
35
27
36
Bases
aniline
aminopyrine
quinine
4.6
5.0
8.4
40
21
9
48
35
11
0
30
0
35
58
48
41
0
10
0
5
61
52
54
17
Breast milk
(pH 7.0)
Plasma
(pH 7.4)
ionised
ionised
nonionised
nonionised
nonionised
nonionised
ionised
ionised
18
[1]
BH+
Milk pH = 6.4
BH+ [ 10 ]
[1]
[1]
10 = [BH+]
[B]
19
breast milk
serum