Drug-receptor interactions

Vladimír Moravec, M.D.

Farmakodynamics

What is it ????????

Medical pharmacology

• Science of chemicals that interact with the human body.

• Two classes:• 1. Pharmacodynamics – the effects of the

drug on the body.• 2. Pharmacokinetics – the way the body

affects the drug with time (absorption, distribution¨, metabolism, excretion)

Drug action

• 1. Non specific drug action – act by virtue of their physicochemical properties (f.ex: general anestetics, osmotic diuretics,…)

• 2. Specific drug action - receptors

Receptors

• These are protein molecules with are normally activated by transmiters or hormones. (Many receptors hawe now been cloned and their amino acids sequences determined.)

Intramolecular forces• 1. Drug molecules in the environment of

receptors are attracted initially by relatively long-range electrostatic forces.

• 2. Then, if the molecule is suitably shaped to fit closely to the binding site of the receptor, hydrogen bonds and Wan der Waals forces briefly bind the drug receptor.

• Irreversible antagonists bind to receptors with strong covalent bonds.

Receptors - types 1:

• 1. Ions chanel. Agonist gated channels made up of protein subunits which form a central pore.(Nicotinic r., GABA)

• 2.G-protein coupled receptors form a family of receptors with sewen membrane helices. (Dopaminergic r., Opioids r.)

(next)

Receptors - types 2:

• 3. Receptors for steroid hormones and thyroid hormones are present

on the cell nucleus and regulate transcription and thus protein synthesis.

• 4. Insulin receptors are directly linked to tyrosine kinase.

RECEPTORY NA IONTOVÝCH KANÁLECH(„ionotropní receptory“)

Katzung 2-12 ale raději GABAA

Katzung BG, 2001

Nikotinový receptor

pentamerní struktura - pět jednotek obklopuje kanálek, který je v klidu zavřený

Remedia 1998

RECEPTORY NA IONTOVÝCH KANÁLECH(„ionotropní receptory“)

GABAA receptor

- pentamerní struktura

- receptor pro GABA, pro modulující látky (např. benzodiazepiny)

RECEPTORs COUPLET WITH G PROTEINS („serpentins receptors“)

Katzung Fig 2-14

Katzung BG, 2001sedminásobný průnik membránou, extracelulární část (NH2 konec), intracelulární část (karboxylový konec), místa pro vazbu ligand, G proteinu

Dopaminergic receptor

Dopaminergic receptor- aktivated.

Mechanism of transmission signal inside to the cell.

1.ligand disolute in the fat

2.transmembran receptor protein

3.transmembran ionic chanel

4.coupled receptors with G-proteins.

5.Unknown: growth factors, interferon, lymfokins,...

Types of Second mesengers:

• Ca2+ ions

• cyclic adenosine monophosphate (cAMP)

• inositol-trisphosphate

• diacylglycerol

• fosforylation(tyrozinkinazy, proteinkinazy)

Macromolecular nature of drug receptors

• Regulatory proteins – (neurotransmitters, hormones)

• Enzymes- (dihydrofolate reductase-antineoplastic drug-metotrexate)

• Transport proteins- (Na/K ATPase – cardioactive digitalis glycosides)

• Structural proteins- (tubulin-the receptor for colchicine)

Receptor and drug:

• 1. Receptor largely determine the quantitative relations between

dose or concentration of drug and pharmacologic

effects.• 2. Receptors are responsible for

selectivity of drug action.• 3. Receptors mediate the actions of

pharmacologic antagonists.

Relation between drug concentration and response

Verry important termins:

• 1. Affinity.• 2. Intrinsic efficacy.

1. Affinity:

• This is measure of how avidly a drug binds to its receptor.

• It is characterized by the equilibrium dissociation constant Kd.The reciprocal of Kd is called the affinity constant Ka and is the concentration of drug that produces 50% of the maximum response.

2. Intrinsic efficacy:

• This is the ability of an agonisst to alter the conformation of receptor in such a way that it elicits a response in the system.

• It is defined as the affinity of the agonist-receptor complex for a transducer.

Drugs termins for receptors:

• 1. Agonists - (morfin)• 2. Antagonists – competitive - (buprenorfin)

3. Antagonists - irreversible (phenoxybenzamine)

• 4. Parcial agonists (dualismus) – (naloxon)

1.Curve A shows agonist response in the absence of antagonist.

2.Curve B after treatment with low concentration of antagonist.Cuve is shifted to the right.

3.Curve C, D, E after higely concentration of antagonist.

AGONISTS - ANTAGONISTS:

full agonists: intrinsic eficasy 1, affinity 1

např. M (morfin) a F (fentanyl)

parcial agonists: 0 < intrinsic eficasy < 1 , affinity 1

např. B(buprenorfin)

antagonists: intrinsic eficasy 0, affinity 0

např. N (naloxon)

0

50

100%

ANALGESIE

0.01 0.1 1 10 100 DÁVKA mg/kg

F

B

M

„miligramová“ účinnost („P O T E N C Y“)

účin

n ost

- „

E F

F I

C A

C Y

“

Afinita

Vn

itřn

í akt

ivit

a1

0,5

0N

Thank you.

Webpage:

www.lf3.cuni.cz/ustavy/farmakologie