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GENERAL
PHARMACODYNAMICS
Assoc. Prof. I. Lambev
E-mail: [email protected]
1. PHARMACODYNAMICS
OF DRUGS
- DEFINITION
Pharmacodynamics:
(1) How the drugs act
on the body?
(2) The mechanism of action
of drug and its effects.
The mechanism
of action represents
the interaction between
drug molecules and
biological structures
of the organism.
The effect represents
the final results from
the drug action.
The effect can be
observed and measured,
but not the action.
Blood pressure {mm Hg}
Hypotensive effect of acetylcholine (ACh)
1 min
(Effect or action?) ...
150
100
50
ACh
2 mg i.v.
ACh
50 mg
ACh
2. SITES OF
DRUG ACTION
They can be divided into:
•specific and
•non-specific
Non-specific action have:
•osmotic
diuretics
•osmotic
laxative drugs
•antiacids (antacids)
Mannitol
Duphalac
MgSO4
NaHCO3
Specific action
It is connected with
interaction of the drug
with specific site(s) on the
cell membrane or
inside the cell.
3. MOLECULAR
ASPECTS OF
SPECIFIC
DRUG ACTION
How drugs act?
Main specific targets
for drug actions are:
 DNA
 microbial organelles
 target macroproteins
 DNA
Alkylating agents bind covalently to sites
within the DNA such as N7 of guanine
and block DNA-replication.
 Microbial organelles
Doxycyclin
Penicillins
Nystatin
Rifampicin
 Target macroproteins
• receptors (> 150 types
with many subtypes)
• ion channels
• enzymes
• carrier molecules
P. Ehrilch
(1854-1915)
“Corpora non
agunt nisi fixata”
(a drug will not
work unless it is
bound).
A. Receptors are the
regulatory macroproteins
which mediate the action of
endogenous and exogenous
ligands (chemicals).
Receptors bind to
•Endogenous ligands:
- neurotransmitters (mediators)
- hormones
- autacoids (tissue mediators)
- grouth factors
- inhibitory factors, etc.
•Exogenous ligands:
- many (but not all) drugs
- some other xenobiotics
The main receptor ligands are
• agonists - activate the receptors
• antagonists - block the receptors
(Full)
(Full)
Partial Agonist
(unfull antagonist)
The interaction between ligand
and receptor involve weaker,
reversible forces, such as:
•Ionic bonding
•Hydrogen bonding
•Hydrophobic bonding
•Van der Waals forces.
The numbers of receptors may be
altered during chronic drug treatment,
with either an increase in receptor
numbers (up-regulation – e.g.
beta-antagonists) or a decrease
(down-regulation – desensitization:
e.g. beta-2 agonists).
The numbers of receptors may be
altered during chronic drug treatment,
with either an increase in receptor
numbers (up-regulation) or a decrease
(down-regulation).
The therapeutic effect of b-blockers
develops slowly. This is probably
related to adaptive regulation
of receptor numbers.
There are pre- and
postsynaptic receptors.
Presynaptic receptors
may inhibit or increase
transmitter release
(feedback mechanism: +/-)
Presynaptic receptors in adrenergic synapse
and their role in the regulatory negative and
positive feedback
There are 4 main types of receptors, according to their molecular structure and the nature of
receptor-effector linkage.
The location of type 1, 2 and 3
receptors is on (into) the cell
membranes; type 4 - into the
cell nucleus.
 Ionotropic receptors
(ligand-gated ion channel receptors)
•These receptors are involved
mainly in fast synaptic transmission.
•They are proteins containing several
transmembrane segments arranged
around a central channel.
•Ligand binding and channel opening
occur on a millisecond time-scale.
Ligand-gated
ion channel receptors
Effector
Coupling
Time scale
Examples
ion channel (Ca2+, Na+, K+, C–)
direct
milliseconds
nACh-receptors
GABAA-receptors
5-HT3-receptors
N-receptor: 5 subunits
GABAAreceptors
(-)
(-)
Antiseizure drugs, induced reduction of
current through T-type Ca2+ channels.
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
 G-protein-coupled receptors
All comprise 7 membrane-spanning
segments. One of the intracellular
loops is larger than the others and
interacts with G-protein.
•The G-protein is a membrane protein
comprising 3 subunits (, b, ). The
alpha-subunit possesses GTP-activity.
•When the agonists occupy a receptor,
the alpha-subunit dissociates and
then activates a target (effector):
- enzyme (AC, GC, PLC)
- Ca2+ ion channels
• AC (adenylate cyclase) catalyses
formation on the intracellular
messenger (cAMP).
• cAMP activates various protein
kinases (PKA and others) which
control cell function in many
different ways by causing phosphorylation of various enzymes,
carriers and other proteins.
b-adrenoceptor
•7 subunits
Adrenaline (b1&b2)
Ex
(+)
Gs
AC
In
cAMP
PKA
ATP
Effects
• PLC (phospholipase C) catalyses the
formation of two intracellular messengers - InsP3 and DAG, from membrane phospholipids.
• InsP3 (inositol-triphosphate) increases
free cytosolic calcium by releasing
Ca2+ from the endoplasmic reticulum.
• Free calcium initiates contractions, secretion, membrane hyperpolarization
• DAG activates protein kinase C (PKC).
Noradrenaline (1)
(+)
Gs
Ex
PLC
In
PIP2
IP3
DAG
ADP
Ca2+
ATP
PKC
The regulation
of
intracelullular
calcium is
connected
with ryonidine
receptors.
Ryanodine receptors (RyRs) form a
class of intracellular calcium channels
in muscles and neurons. They regulate
+
the releasing of Ca in animal cells.
There are multiple isoforms of RyRs:
RyR1 is expressed in skeletal muscle
RyR2: in myocardium (heart muscle)
RyR3: in the brain.
Ryanodine
RyRs are named after the plant alkaloid
ryanodine, to which they show high affinity.
Ryanodine is a poisonous alkaloid found in
the South American plant Ryania speciosa.
Effector
Second
messenger
Proteinkinase
AC
cAMP
PKA
PLC
IP3
DAG
PKC
GC
cGMP
PKG
G-protein-coupled receptors
Effector
Enzyme (AC, GC, PLC);
Ca2+ channels
Coupling G-protein
Time scale seconds
Examples AT1-receptors
mACh-receptor
Adrenoceptors (, b)
H1 – H5-receptors
Opioid receptors (m, k, d)
 Tyrosine-kinase receptors
•Incorporate thyrosine kinase
in their intracellular domain.
•These receptors are involved
in events controlling
phosphorilation, cell growth
and differentiation.
Kinase-linked receptors
Effector
Coupling
Time scale
Examples
thyrosine kinase
direct
minutes (to hours)
Insulin receptor
ANP receptor
growth factors rec.
 Nuclear receptors
• They are nuclear proteins, so
ligands must first enter cells.
• Receptors have DNA-binding
domain.
• Stimulation of these receptors
increase protein synthesis by
the activation of DNA transcription.
Nuclear
(steroid/thyroid) receptors
Effector
Coupling
Time scale
Examples
gene transcription
via DNA
hours
steroid receptors
thyroid receptors
vitamin D receptors
a) Indirect nuclear receptors:
Steroid hormones and Calcitriol
b) Direct nuclear receptors:
Thyroid hormones (T3, T4)
T3 or T4 penetrate the nucleus
Combine with their receptors
Alters DNA-RNA mediated
protein synthesis
Types of receptor-effector linkage (R = receptor; G = G-protein; E = enzyme)
In
LAH+ (local
anaesthetics)
block
Na+
channels.
B. Ion
channels
Ex
C. Enzymes
Drug
Action on enzyme
Galantamine (-) ACh-esterase
Digoxin
(-) Na+/K+-ATP-ase
Aspirin
(-) COX-1/COX-2
(+) ACh-esterase
Obidoxim
Ex
3Na+
Na+/K+
АТФ-аза
(–)
2K+
3Na+
Na+/Ca2+
обмен
Ca2+
In
DIGOXIN
D. Carrier molecules (are transport proteins)
Amitriptyline
NA (noradrenaline) = NE (norepinephrine)
4. DOSE-RESPONSE
RELATIONSHIPS
(introduction)
Most drugs produce graded
dose-related effects, which can be
plotted as a dose response curve.
Such curves are often hyperbolic (a),
but they can be conveniently
plotted on semi-logarithmic paper
to give sigmoidal shape (b).
Plotted
doseresponse
curves:
(a) arithmetically
(b) semilogarithmically
Hyperbolic
shape (a)
Sigmoidal
shape (b)
The method of plotting dose-response
curves facilitates quantitative analysis
of: full agonists, which produce
graded responses up to maximum
value; antagonists, which produce no
response on their own but antagonize
the response to an agonist; partial
agonists, which produce some response
but to a lower maximum than that of
a full agonist and antagonize its effect.
•The affinity of a drug is its ability
to bind to the receptor.
•The intrinsic activity of a drug is
its ability after binding to the receptor
to produce effect.
•The efficacy of a drug is its ability
to produce maximal response.
•The selectivity of a drug is the extent
to which it acts preferentially on
particular receptor types.
Drugs
Agonists
(Morphine)
Antagonists
(Naloxon)
Partial
agonists
(Pentazocine)
Affinity Intrinsic Efficacy Selecactivity
tivity
+
+ ++
+
+
+
-
-
+
+
+
-
+
Selectivity
b-blockers
b1/b2-blocking
activity
Bisoprolol
50
Metoprolol
25
Nebivolol
293
Propranol
1,9
Dose-response curve of two full
agonists (A, B) of different
potency, and a partial agonist (C).
In the clinical situation
dose-response curves are
influenced by many factors
including genetic, as well as
age, weight, nutrition;
psychological and social
factors (that strongly influence
compliance and placebo effect).
5. FACTORS,
AFFECTING
DRUG
CONCENTRATION
AT THE SITE
OF ITS ACTION.
STRUCTURE
ACTIVITY
RELATIONSHIP
Phenothiazines:
Neuroleptic action in humans
Sedative action in animals
Benzodiazepines:
Anxiolytic action
in humans and animals
Penicillins:
Antibacterial action
in humans and animals
6. Factors, influencing
the drug kinetics and actions
•Drugs
•Age of patient
•Sex of patient
•Compliance of patient
•Environment
•Doctors
8. DIFFERENT TYPE OF DOSES
The dose is the amount of drug administered to a patient.
According to their size there are:
• dosis minima – the lowest dose,
• dosis optima (therapeutica) – best or therapeutic dose,
• dosis maxima – maximum tolerated dose,
• dosis toxica – poisonous dose,
• dosis letalis – lethal dose (LD). The latter can be:
LD05 – minimum lethal dose that causes death
in 5% of the animals,
LD50 – lethal dose causing death in 50% of test animals,
LD100 – absolutely lethal (deadly) dose.
According duration and schedule
of treatment there are:
• dosis pro dosi – single dose,
• dosis pro die – daily dose (DD),
• dosis pro cura (cursu) – course dose,
• loading dose (representing a large initial dose),
• maintenance dose.
Median effective dose (ED50) is the dose at which
a therapeutic effect is observed in 50% of cases.
It is calculated graphically by using
the dose-response curves.
The Therapeutic Index (TI) is the ratio between
the LD50 and the ED50: TI = LD50/ED50
It is calculated on the experimental animals and
gives an idea of the therapeutic width. Drugs with
low TI (e.g., Digitoxin) have a narrow therapeutic
window and can easily be overdosed while drugs
with a high TI (e.g., penicillins with TI > 100) have
a large therapeutic window and very low toxicity.
Index of Sure Safety is determined in humans.
Is the ratio between TD1 (dose causing toxic effects
in 1% of treated patients) and ED99 (dose causing
a curative effect in 99% of cases): ISS = TD1/ED99