Medical University of Sofia, Faculty of Medicine Department of Pharmacology and Toxicology

Medical University of Sofia, Faculty of MedicineDepartment of Pharmacology and Toxicology

GENERALPHARMACO-

DYNAMICSAssoc. Prof. I. LambevE-mail: itlambev@mail.bg

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.

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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