Week 1: Pharmacodynamics Flashcards
Pharmacodynamics vs. Pharmacokinetics
Dynamics - what the Drug Does to the body Kinetics - what the body does to the drug
Working Definition of a Receptor (2 parts)
Working Definition: 1. BINDING site for drugs/endogenous substances 2. TRANSDUCES binding into BIOLOGICAL RESPONSE
Four Types of Drug Specificity
- Biological - types of tissue have different effects 2. Chemical - changing drug potency changes effects & stereospecificity changes effects 3. Selective Antagonism - specific antagonists may inhibit one agonist over another even if both activate identical pathways 4. Molecular Biology - cloning/sequencing/expression of receptors can be modified - leading to receptor subtype specificity
Enzyme Kinematics Changes for Competitive, Uncompetitive, Noncompetitive Inhibitors
Competitive - Increase Km, No change Vmax Noncompetitive - No change Km, Decrease Vmax Uncompetitive - Decrease Km, Decrease Vmax
Definition of EC50, Kd, Efficacy, Potency
EC50 - concentration of agonist that produces half-maximal biological response Kd - concentration of agonist that binds to half of all receptors - represents thermodynamic driving force (low Kd, easier to bind, low deltaG, more favorable rxn) Efficacy: ability of a drug to produce maximal biological response (~Vmax) Potency = 1/EC50 (highly potent drug has low effective concentration) FOR DRUG BINDING: Kd = EC50 FOR BIOLOGICAL REPONSE: Kd ~= EC50
Competitive Antagonist
- binds to orthosteric site (agonist binding site) 2. Complementary shape to receptor agonist for tighter fit 3. Overcome by increasing [agonist] 4. Decreases potency (Increases EC50) 5. No change to efficacy (max response) dose-response curve parallel shift to the right
Noncompetitive Antagonist
- binds irreversibly to orthosteric site, or binds to allosteric site and prevents activation 2. Reduces the number of available receptors without affecting agonist binding at others 3. Decreases efficacy (lower max response) 4. No Change to potency (EC50 constant)
Uncompetitive Antagonist
- allosteric binding to only activated receptors 2. low effect at low [agonist] due to small amount of activated channels 3. Decreases efficacy (lower max response) 4. Increases potency (lower EC50)
Full Agonist
produces maximal biological response in both quiescent and constitutively active systems
Partial Agonist
- Binds to same site as full agonist but gives partial response in both quiescent and constitutively active systems 2. Acts as competitive antagonist for the full agonist
Inverse Agonist
- produces no effect on quiescent systems; acts as a competitive antagonist on quiescent systems 2. reduces activity of constitutively active receptors (turns them off - useful in cancers and viral infections)
Spare Receptors
Why EC50 ~= Kd for biological response, because there are more receptors than necessary to achieve maximal response 1. at low doses of antagonist, noncompetitive behaves identical to competitive because reducing the number of receptors does not reduce max response (no change in efficacy) 2. Delineate between noncompetitive and competitive by increasing [antagonists], eventually noncompetitive will have an effect
4 types of cooperativity and 2 models of cooperativity
- Cooperative binding - binding of 1 mLc increases binding of another (Hb O2) 2. Independent binding, but requires >1 mLc to activate (MOST CHANNEL RECEPTORS) 3. Cooperative relationship between binding and response - multiple active states possible depending on what is bound 4. Receptors exist as subunits A. constrained model - all subunits are inactivated or activated together - 2 states exist in equilibrium, and agonist binding LeChatlier shifts equilibrium toward active state B. Sequentially Activated model - different ligands induce specific conformational shapes - full agonists open the channel widest, partial agonists open channel less widely
Quantal-Dose Response Curve
quantifies all-or-none responses (pregnancies, deaths, seizures, etc.), typically a cumulative curve, used to identify therapeutic index
ED50, LD50, TI
ED50 - median effective dose - 50% of population gets desired effect at dosage LD50 - median lethal dose - 50% of population dies at dosage TI - Toxic ED50 / Beneficial ED50: measure of drug safety Wide TI - safer drug