Basics II

Página 1

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 molecule

Inhibition 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 agonist

Agonist - Molecule that binds to and activates receptor If agonist is stabilized = partial agonist

Inverse agonist - affinity for Ri

Antagonist - 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 response

Regulatory 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 dimers

STAT (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 binding

K3 - reflects intrinsic activity of bound receptor K3 = 1 Agonist K3 = 0 Antagonist 0

Potency - concentration requited to achieve a certain effect Ec50 = produce 50% of max. effect. usually = Kd

Efficacy - magnitude of drug action at limit of concentration Emax

Threshold 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 activation

Sub-types - single agonist recognized by group of GPCR's

Bronchial smooth muscle

Antigenic Challenge ----> Activation Mast Cell ------> Histamine ---------> H1 ---> Ca2+ -----> Contract

Antihistamine / beta2 \ epinephrine

(too long)

Desensitization - Phosphorlylation of the receptor

Down 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 approach

Phases of Clinical Drug Development

Safety and Tolerability

Dose finding

Therapeutic ratio

Submission to NDA or FDA

Post-Marketing surveillance

New Page

New Page

New Page