Transcript Drug-receptor interactions

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“)
Nikotinový receptor
Katzung 2-12 ale
raději GABAA
pentamerní struktura - pět jednotek obklopuje
kanálek, který je v klidu zavřený
Katzung BG, 2001
RECEPTORY NA IONTOVÝCH KANÁLECH
(„ionotropní receptory“)
GABAA receptor
- pentamerní struktura
- receptor pro GABA, pro
modulující látky (např.
benzodiazepiny)
Remedia 1998
RECEPTORs COUPLET WITH G PROTEINS
(„serpentins receptors“)
Katzung Fig 2-14
sedminásobný průnik membránou,
extracelulární část (NH2 konec), intracelulární
část (karboxylový konec), místa pro vazbu
ligand, G proteinu
Katzung BG, 2001
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 reductaseantineoplastic 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 agonistreceptor 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)
ANALGESIE
Vnitřní aktivita
1
%
100
F
0,5
0
50
M
B
N
0
0.01
0.1
1
10
100
DÁVKA mg/kg
Afinita
„miligramová“ účinnost
(„P O T E N C Y“)
Thank you.
Webpage:
www.lf3.cuni.cz/ustavy/farmakologie