Basics II

Pharmacological effect (how it works) vs. Clinical response (what it does)Receptor activation.   Most drugs bind to a receptor to bring about an effect.D-R complex -> effector moleculeInhibition of metabolism of activator -> increased action (coupling molecule)(most) receptor ->protein  binds signaling molecule which generates signal of its own.Ri -> inactive  Ra -> active    Constitutive activity -> binds to Ra even without agonistAgonist - Molecule that binds to and activates receptor                     If agonist is stabilized = partial agonistInverse agonist - affinity for RiAntagonist - Molecule that prevents activation of receptor by agonist.                  Allostevic activators inhibitors

Cells have large arrays of receptors for hormones, etc.dose response relationship.    Without knowing what receptor to which drug binds (for most) cannot mech. of action; selectivity, dose responseRegulatory proteins - regulate (mediate) activity

5 Transmembrane signaling mechanisms Lipid soluble chemical signal crosses membrane.  Acts on intracellular receptor Signal binds to the EC domain activating enzyme activity of cytoplasm domain Signal binds to EC bound to tyrosine kinase which it activates Signal binds and directly regulates opening of ion channel Signal binds to cell surface receptor linked to effector enzyme by G protein.

Lipid soluble - Steroids     Onset 30 minutes to several hours.  Duration up to several days.JAK - Tyrosine Kinase.    Cytokine receptors  EC and IC domains and form dimersSTAT (Transcription)Ligand and voltage-gated ion channel        Ligand binds to EC site on subunit.  Receptor opens a central transmembrane aqueous ion channel and allows ion to pass into cytoplasm.  (common neurotransmitters)

Dose response (  Efficacy and Toxicity)Drug + Receptor- -> K1            Drug-receptor complex    ----> Effect                  Kd = K2/K1                         Kd (equilibrium dissociation constant) = [Drug] producing 1/2 max bindingK3 - reflects intrinsic activity of bound receptor    K3 = 1 Agonist   K3 = 0  Antagonist    0Potency - concentration requited to achieve a certain effect              Ec50 = produce 50% of max. effect.  usually = KdEfficacy - magnitude of drug action at limit of concentration EmaxThreshold dose;  Ceiling dose                  Graded dose response = dose increases; response increases   Quantal dose response = all or nothing

Antagonism Competitive - reversible with enough agonist Non-competitive - not reversible Chemical - binds to drug and blocks absorption (inactivates) Physiologic - exact opposite.  Works on different receptor.

G-coupled protein receptors - work by increasing concentration of IC 2nd messengers  (CAMP, calcium, or phosphoinositides)G-protein  Heterotrimeric configuration

Disassociates during activationSub-types - single agonist recognized by group of GPCR's

                                                                                                       Bronchial smooth muscleAntigenic Challenge  ----> Activation Mast Cell   ------>  Histamine --------->  H1  --->  Ca2+  ----->   Contract                                                                                Antihistamine    /        beta2        \  epinephrine                                                                                (too long)Desensitization - Phosphorlylation of the receptorDown regulation - receptor heterodimerization - endocytosis of the receptor

Drug Discovery       Broad search and screen       Clinical Serendipity       Design based on structure of natural substance       Molecular knowledge of receptor or enzyme       Endogenous proteins       Me-too approachPhases of Clinical Drug Development Safety and Tolerability Dose finding Therapeutic ratio Submission to NDA or FDA Post-Marketing surveillance

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