Department of Pharmacology & Toxicology

Lecturers & Examiners:

Prof. MUDr. Radomr Hrdina, CSc.
Prof. PharmDr. Frantiek taud, Ph.D.
Doc. PharmDr. Frantiek Trejtnar, CSc.
Conditions for credits (both terms)
compulsory seminar attendance
credit test at the end of each term
In case you need to discuss any issue dealing with
pharmacology lessons/seminars make an appointment
through email first!!!
Literature
Rang & Dale's Pharmacology
Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th Edition
Study materials at: www.faf.cuni.cz
Pharmacology
- studies interactions of drugs with organism
General pharmacology
General relations between drug and body
(pharmacokinetic and pharmacodynamic)
Special pharmacology
Individual drugs/groups of drugs in therapy
Pharmacology
Pharmacokinetics
Fate of drugs in the organism(absorption, distribution,
metabolism, excretion)
Pharmacodynamics
Effect of a drug on organism interactions with target
molecules (receptor, enzyme, transporter) >
pharmacological/toxicological response
Pharmacology in drug development
Transport of drugs
across biological membranes
Prof. PharmDr. Frantiek taud, Ph.D.
Department of Pharmacology & Toxicology
Faculty of Pharmacy, Charles University
Literature: Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12th Edition
Ziegler, Mohr, Bieger, Lullmann Color Atlas of Pharmacology
Rang & Dale Pharmacology
Drug disposition
Interactions of drugs with organism
absorption
(first- pass)
Tissue
Extravascular
administration
i.v. administration
Plasma
bound fraction
free fraction
elimination
Pharmacokinetics Pharmacodynamics
Therapeutical effect
B
i
o
l
o
g
i
c
a
l

m
e
m
b
r
a
n
e
distribution
Pharmacological effect
Biological membrane
Examples of biological barriers in body
Physicochemical properties of drugs
Lipid-solubility partition coefficient
oil/water.
Degree of ionization ionized (charged)
molecules cannot cross biological
membranes.
Weak electrolytes and influence of pH
AH H
+
+ A
-
acid
B + H
+
BH
+
basis
In acidic pH: AH
BH
+
In basic pH: A
-
B
Henderson-Hasselbalch equation
AH H
+
+ A
-
acid
B + H
+
BH
+
base
pH pK
form ed unprotonat
form protonated
a

log
If pK
a
of the drug equals pH of the environment, then 50%
of the drug will be ionized.



Ka
H B
BH

AH
H A
Ka

Ionization of aspirin (pKa = 3)

pH
Protonated
(non-ionized) fraction
(%)
Unprotonated
(ionized) fraction (%)
1 99.9 0.10
2 90.0 10.0
3 50.0 50.0
4 9.09 91.9
5 1.00 99.0
6 0.10 99.9
pH within the body
Plasma 7.4
Stomach 1-3
Duodenum 5-6
Ileum, colon 8
Milk 7.0-7.3
Cerebrospinal fluid 7.3
Urine 4-8
Fetus 7.3
Effect of ionization on drug movement across biological
membranes
Ion trapping
Effect of ionization on drug movement across
biological membranes
Drug transport across biological membranes
A) Passive diffusion
B) Filtration and bulk flow
C) Active transport
Facilitated diffusion
D) Transport of ion-pairs
E) Endocytosis
F) Efflux transporters
A) Passive diffusion
The most common transport of drugs
across membranes.
Depends on lipid solubility and ionization.
(only non-ionized fraction can cross)
Governed by Ficks law:
h
C C A P
dt
dm ) ( * *
2 1

B) Filtration
Molecules do not penetrate across
membrane but through pores or paracellular
channels (different from diffusion).
Depends on gradient and size of the
molecule.
MW < 100 (urea, lithium, methanol).
B) Bulk flow
Fast movement through inter-cellular pores.
Transport across endothelia extravasation (except brain).
Driven by hydrostatic and oncotic pressure.
e.g. glomerular filtration through fenestrations in
capillaries of the glomerulus.
C) Facilitated transports
Mediated by a carrier.
These carriers are:
specific
saturable (T
max
)
inhibitable (competition)
Includes: active transport and facilitated
diffusion.
C) Active transport
Mediated by a carrier.
Energy-dependent (in the form of ATP).
Can run against the concentration gradient.
Is saturable (Tmax) and inhibitable (competition).
Runs in one direction only.
Substrates: mostly endogenous molecules or compounds
with structural similarity (levodopa, a-methyldopa).
Example: active tubular secretion and reabsorption
C) Facilitated diffusion
Mediated by a carrier.
Is not energy-dependent (in contrast to active transport).
Driven by concentration gradient.
Is saturable (Tmax) and inhibitable (competition).
D) Transport of ion pairs
E.g.: absorption of quarternary ammonium compounds
from GIT.
Formation of neutral complex (with endogenous mucin)
> passive diffusion > dissociation.
E) Endocytosis
Cellular uptake of
molecules.
Useful in controlled
delivery/gene therapy.
Physiologically:
transport of IgG from
mother to fetus.
E) Endocytosis
transport of IgG from
mother to fetus
F) Efflux ABC transporters
Efflux transporter
pumping lipophilic drugs
out of cell.
Important role in:
chemotherapy (resistance)
pharmacokinetics (affects
absorption, distribution,
elimination).
E.g. P-glycoprotein, BCRP, MRP
Extracellular space
Intracellular space