Drug-receptor interactions

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Drug-receptor interactions

• Vladimír Moravec, M.D.

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Farmakodynamics

• What is it ????????

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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)

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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

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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.)

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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.

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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)

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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.

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RECEPTORY NA IONTOVÝCH KANÁLECH (ionotropní
receptory)
Nikotinový receptor
Katzung 2-12 ale radeji GABAA
pentamerní struktura - pet jednotek obklopuje
kanálek, který je v klidu zavrený
Katzung BG, 2001
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RECEPTORY NA IONTOVÝCH KANÁLECH (ionotropní
receptory)
GABAA receptor
- pentamerní struktura - receptor pro GABA, pro
modulující látky (napr. benzodiazepiny)
Remedia 1998
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RECEPTORs COUPLET WITH G PROTEINS (serpentins
receptors)
Katzung Fig 2-14
Katzung BG, 2001
sedminásobný prunik membránou, extracelulární
cást (NH2 konec), intracelulární cást
(karboxylový konec), místa pro vazbu ligand, G
proteinu
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Dopaminergic receptor
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Dopaminergic receptor- aktivated.
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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,...

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Types of Second mesengers

• Ca2 ions
• cyclic adenosine monophosphate (cAMP)
• inositol-trisphosphate
• diacylglycerol
• fosforylation(tyrozinkinazy, proteinkinazy)

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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)

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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.

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Relation between drug concentration and response
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Verry important termins

• 1. Affinity.
• 2. Intrinsic efficacy.

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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.

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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.

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Drugs termins for receptors

• 1. Agonists - (morfin)
• 2. Antagonists competitive - (buprenorfin)
• 3. Antagonists - irreversible (phenoxybenzamine)
  
• 4. Parcial agonists (dualismus) (naloxon)

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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.
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AGONISTS - ANTAGONISTS

• full agonists intrinsic eficasy ? 1, affinity ?
  1
• napr. M (morfin) a F (fentanyl)
• parcial agonists 0 lt intrinsic eficasy lt 1 ,
  affinity ? 1
• napr. B(buprenorfin)
• antagonists intrinsic eficasy ? 0, affinity ? 0
• napr. N (naloxon)

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ANALGESIE

100
1
F
M
úcinnost - E F F I C A C Y
Vnitrní aktivita
0,5
50
B
N
0
0
0.01
0.1
1
10
100
DÁVKA mg/kg
Afinita
miligramová úcinnost (P O T E N C
Y)
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Thank you.

• Webpage
• www.lf3.cuni.cz/ustavy/farmakologie