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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.

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Drug-receptor interactions

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  1. Drug-receptor interactions Vladimír Moravec, M.D.

  2. Farmakodynamics What is it ????????

  3. 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)

  4. 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

  5. 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.)

  6. 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.

  7. 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)

  8. 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.

  9. 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

  10. RECEPTORY NA IONTOVÝCH KANÁLECH („ionotropní receptory“) GABAA receptor - pentamerní struktura - receptor pro GABA, pro modulující látky (např. benzodiazepiny) Remedia 1998

  11. 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

  12. Dopaminergic receptor

  13. Dopaminergic receptor- aktivated.

  14. 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,...

  15. Types of Second mesengers: • Ca2+ ions • cyclic adenosine monophosphate (cAMP) • inositol-trisphosphate • diacylglycerol • fosforylation(tyrozinkinazy, proteinkinazy)

  16. 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)

  17. 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.

  18. Relation between drug concentration and response

  19. Verry important termins: • 1. Affinity. • 2. Intrinsic efficacy.

  20. 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.

  21. 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.

  22. Drugs termins for receptors: • 1. Agonists - (morfin) • 2. Antagonists– competitive - (buprenorfin) 3. Antagonists - irreversible (phenoxybenzamine) • 4. Parcial agonists (dualismus) – (naloxon)

  23. 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.

  24. 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)

  25. ANALGESIE % 100 1 F M účinnost - „E F F I C A C Y“ Vnitřní aktivita 0,5 50 B N 0 0 0.01 0.1 1 10 100 DÁVKA mg/kg Afinita „miligramová“ účinnost („P O T E N C Y“)

  26. Thank you. Webpage: www.lf3.cuni.cz/ustavy/farmakologie

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