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Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology. GENERAL PHARMACO- DYNAMICS. Assoc. Prof. I. Lambev E-mail: [email protected]. 1. PHARMACO- DYNAMICS OF DRUGS - DEFINITION. Pharmacodynamics: (1) How the drugs act on the body? - PowerPoint PPT Presentation
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Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology
GENERALPHARMACO-
DYNAMICSAssoc. Prof. I. LambevE-mail: [email protected]
1. PHARMACO-DYNAMICSOF 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 the interaction betweendrug molecules andbiological structuresof organism.
The effect representsthe final results fromthe drug action.•The effect can be observed and measured, but the action not.
50
100
150
1 min (Effect or action?) ...B
lood
pre
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re {
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ACh2 g i.v.
ACh50 g
Hypotensive effect of acetylcholine (ACh)
ACh
2. SITES OF DRUG ACTION
They can be divided into:•specific and•non-specific
•osmotic diuretics
Mannitol
•osmotic laxative drugs
DuphalacMgSO4
•antiacids (antacids) NaHCO3
Non-specific action have:
Specific actionIt is connected with interaction of the drugwith specific site(s) on the cell membrane or inside the cell.
3. MOLECUALARASPECTS OFSPECIFIC DRUG ACTION
How drugs act?
Main specific targetsfor drug actions are:
DNA microbial organelles target macroproteins
Alkylating agents bind covalently to siteswithin DNA such as N7 of guanine andblock DNA-replication.
DNA
Doxy-cyclin
Peni-cillins
Nystatin Rifampicin
Microbial organelles
• receptors (> 140 types with many subtypes)• ion channels• enzymes• carrier molecules
Target macroproteins
P. Ehrilch (18541915)
“Corpora nonagunt nisi fixata”(a drug will notwork unless it isbound).
are theregulatory macroproteins – sensitive elements in thesystem of chemical commu-nications that coordinatesthe function of the differentcells in the body.
A. Receptors
Receptors bind•endogenous ligands (such as the):
- neurotransmitters (mediators)- hormones- autacoids (tissue mediators)- growth factors etc.
•exogenous ligands:- many (but not all) drugs - some other xenobiotics
Partial Agonist (unfull antagonist)
Main receptor ligands are:• agonists activate the receptors• antagonists block the receptors
(Full)
(Full)
The interaction between the ligandand receptor does not involve cova-lent bonds but weaker, reversible forces, such as:
•Ionic bonding•Hydrogen bonding•Hydrophobic bonding•Van der Waals forces
The receptors have a three-dimensionalorganization in space and require thedifferent aspects of a ligand to be pre-sented in the correct 3-D configuration(like fitting a hand into the glove).
The numbers of receptors may bealtered during chronic drug treatment,with either an increase in receptornumbers (up-regulation) or a decrease(down-regulation).
The therapeutic effect of -blockersdevelops slowly. This is probablyrelated to adaptive regulationof receptor numbers.
There are pre- andpostsynaptic receptors.
Presynaptic receptorsmay inhibit or increasetransmitter release(feedback mechanism: +/-)
Presynaptic autoreceptors presynaptic regulation of transmitterrelease from noradrenergic terminals
There are 4 main types of recep-tors, according to their molecu-lar structure and the nature of receptor-effector linkage.
The location of type 1, 2 and 3receptors is on (into) the cellmembranes; type 4 into thecell 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-gatedion channel receptorsEffectorCouplingTime scaleExamples
ion channel (Ca2+, Na+, K+, Cl+)directmillisecondsnACh-receptorsGABAA-receptors5-HT3-receptors
N-receptor: 5 subunits
BDZ –benzo-diaze-pines
Ca2+
Valproates Succinimides
(–) (–)
Ca2+Ca2+
Ca2+
G-protein-coupled receptors
All comprise 7 membrane-spanningsegments. One of the intracellularloops is larger than the others andinteracts with G-protein.
•The G-protein is a membrane protein comprising 3 subunits (). The alpha-subunit possessing GTP-activity.
•When the agonists occupy receptor, the alpha-subunit dissociates and is than free to activate an 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 phos- phorylation of various enzymes, carriers and other proteins.
-ad-reno-ceptor•7 sub- units
Adrenaline (1&2)
Gs AC
ATPcAMP
PKA Effects
Ex
In
(+)
• PLC (phospholipase C) catalyses the formation of two intracellular messen- gers InsP3 and DAG, from memb- rane phospholipids.• InsP3 (inositol-triphosphate) increases free cytosolic calcium by releasing Ca2+ from endoplasmic reticulum.• Free calcium initiates contractions, se- cretion, membrane hyperpolarization• DAG activates protein kinase C (PKC).
Noradrenaline (1)
PLC
PIP2
IP3
Ca2+
DAG
PKC
ADP
ATP
Ex
In
(+)
Gs
Regulation of intracelullular calcium
Effector Secondmessenger
Protein-kinase
AC cAMP PKA
PLC IP3
DAGPKC
GC cGMP PKG
Effector
CouplingTime scaleExamples
Enzyme (AC, GC, PLC);Ca2+ channelsG-proteinsecondsAT1-receptorsmACh-receptorAdrenoceptors ()H1H5-receptorsOpioid receptors ()
G-protein-coupled receptors
•Incorporate thyrosine kinase in their intracellular domain.
•These receptors are involved mainly in events controlling phosphorilation, cell growth and differentiation.
Tyrosine-kinase receptors
Kinase-linked receptors
EffectorCouplingTime scaleExamples
thyrosine kinase etc directminutes (to hours)Insulin receptorANP receptorgrowth factors rec.
• 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 receptors
Nuclear(steroid/thyroid) receptors
EffectorCouplingTime scaleExamples
gene transcriptionvia DNAhourssteroid receptorsthyroid receptorsvitamin D receptors
a) Cytoplasmic receptors: Steroid hormones, Calcitriol
Steroide hormone diffuse into the cell. When activated, the receptors translocate to the nucleus where they can upregulate gene transcription by action on specific DNA response elementsand recruiting co-activator proteins.
b) Directly at nuclear receptors: Thyroid hormones (T3, T4)
T3 or T4 penetrate the nucleus
Combine with their receptors
Alters DNA-RNA mediatedprotein synthesis
Types of receptor-effector linkage (R = receptor; G = G-protein; E = enzyme)
B. Ionchannels
ExInLAH+ (localanaesthetics)blockNa+
channels.
C. Enzymes
Drug Action on enzyme
Galantamine () ACh-esteraseDigoxin () Na+/K+-ATP-aseAspirin () COX-1/COX-2Obidoxim (+) ACh-esterase
Na+/K+
АТФ-аза
Na+/Ca2+
обмен
Ca2+
3Na+
3Na+
2K+
DIGOXIN
Ex In
(–)
D. Carriermolecules
4. DOSE-RESPONSERELATIONSHIPS
(introduction)
•Most drugs produced graded dose-related effects, which can be plotted as a dose-response curve.
•Such curves are often hyperbolic. They can be conveniently plotted on semi-logarithmic paper to give the sigmoidal shape.
Plotteddose-responsecurves:a) arith-meticallyb) semi-logarith-mically
Sigmoidalshape
Hyperbolicshape
The method of plotting dose-responsecurves facilitates quantitative analysisof: full agonists, which producegraded responses up to maximumvalue; antagonists, which produce noresponse on their own but antagonizethe response to an agonist; partialagonists, which produce some responsebut 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 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.
Affinity Intrinsic Efficacy Selec- activity tivity
Agonists + + ++ + + (Morphine)Antagonists + + (Naloxon)
Partialagonists(Pentazocine) + + +
Drugs
Bisoprolol
Metoprolol
Nebivolol
Propranol
1/2-blockingactivity
-blockers
50
25
293
1,9
S e l e c t i v i t y
Dose-response curve of two fullagonists (A, B) of different po-tency, and a partial agonist (C).
In the clinical situationdose-response curves are
influenced by many factorsincluding genetic, as well as
age, weight, nutrition; psychological and social
factors (that strongly influencecompliance and placebo effect).
5. FACTORS, AFFECTING DRUG CONCENTRATIONAT THE SITEOF ITS ACTION