Principles of Pharmacology: Pharmacodynamics Dennis Paul, Ph.D. dpaul@lsuhsc.edu

Learning Objectives: Understand the theoretical basis of drug-receptor interactions. Understand the determinants and types of responses to drug-receptor interactions. Know the four major families of receptors. Define potency and efficacy. Understand how to compare drug potency and efficacy. Understand the consequences of receptor regulation Understand measures of drug safety.

Biochemistry: L+S LS

Biochemistry: L+S LS (Langmuir equation) Pharmacology: L+R LR

Biochemistry: L+S LS Pharmacology: L+R LR Response

Pharmacodynamics

Drugs: Chemical agents that interact with components of a biological system to alter the organism’s function. Examples of such components, sites of drug action, are enzymes, ion channels, neurotransmitter transport systems, nucleic acids and receptors. Many drugs act by mimicking or inhibiting the interactions of endogenous mediators with their receptors

Receptors: Regulatory proteins that interact with drugs or hormones and initiate a cellular response Ion channels G-protein coupled receptors Receptor-enzymes Cytosolic-nuclear receptors Act as transducer proteins Receptor-effector signal transduction Post-receptor signal transduction provides for amplification of the signal

Ligand-gated Ion Channels Ca++ Mg++ Ca++ Ca++ K+ Mg++ Na+ Na+

Ligand-gated Ion Channels Mg++ Ca++ Ca++ Na+ Na+ Na+ Ca++ K+ Na+ Na+ Na+ Mg++ Na+

G-protein coupled receptors NH3+ COOH- g a b GTP

G-protein coupled receptors NH3+ COOH- g a b GDP

Receptor-enzyme Catalytic site

Receptor-enzyme Catalytic site

Cytosolic-Nuclear receptors

Cytosolic-Nuclear receptors

Classical Receptor Occupancy Theory Ka L+R LR Stimulus Response Kd L: Ligand (Drug) R: Receptor LR: Ligand-Receptor Complex Ka: Association rate constant Stimulus: initial effect of drug on receptor

Properties of drugs Affinity: The chemical forces that cause the drug to associate with the receptor. Efficacy: The extent of functional change imparted to a receptor upon binding of a drug.

Properties of a biological system Potency: Dose of drug necessary to produce a specified effect. Dependent upon receptor density, efficiency of the stimulus-response mechanism, affinity and efficacy. Magnitude of effect: Asymptotic maximal response Solely dependent upon intrinsic efficacy. Also called efficacy.

Determinants of Response Intrinsic Efficacy (ε): Power of a drug to induce a response. Number of receptors in the target tissue.

Spare receptors Some tissues have more receptors than are necessary to produce a maximal response. Dependent on tissue, measure of response and intrinsic efficacy of the drug.

Active vs Inactive states Receptors in an active state initiate cell signaling. For any cell, there is an equilibrium between receptors in active and inactive states. The inactive state usually predominates. Each state has its own affinity.

Classification of a drug based on drug-receptor interactions: Agonist: Drug that binds to receptors and initiates a cellular response; has affinity and efficacy. Agonists promote the active state. Antagonist: drug that binds to receptors but cannot initiate a cellular response, but prevent agonists from producing a response; affinity, but no efficacy. Antagonists maintain the active-inactive equilibrium.

cont. Partial agonists: Drug that, no matter how high the dose, cannot produce a full response. Inverse agonist: Drug that binds to a receptor to produce an effect opposite that of an agonist. Stabilizes receptors in the inactive state.

Graded dose-response curves Individual responses to varying doses Concepts to remember: Threshold: Dose that produces a just-noticeable effect. ED50: Dose that produces a 50% of maximum response. (EC50: blood concentration that produces a 50% of max response) Ceiling: Lowest dose that produces a maximal effect.

Dose-response curve Response Dose

Dose-response curve Response Dose

= Agonist

= Agonist

= Agonist

= Agonist

= Agonist

= Agonist

= Agonist

Dose-response curve Response Dose

Full vs Partial agonists % Effect Dose

Full vs Partial agonists These terms are tissue dependent on Receptor density Cell signaling apparatus Other receptors that are present Drug history Partial agonists have both agonist and antagonist properties.

Inverse Agonist % Effect Dose

Relative Potency Effect Dose

Relative Potency Effect Dose

Relative Potency =ED50B/ED50A 320/3.2=100

Relative Efficacy

Antagonists Competitive: Antagonist binds to same site as agonist in a reversible manner. Noncompetitive: Antagonist binds to the same site as agonist irreversibly. Allosteric: Antagonist and agonist bind to different site on same receptor Physiologic: Two drugs have opposite effects through differing mechanisms

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

Competition Effect ID50 or IC50 log [antagonist]

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

= Agonist = Antagonist

Competitive antagonists Response Dose

Noncompetitive antagonists Response Dose

Allosteric and Physiologic antagonists Response can be irregular

Allosteric Antagonism

Allosteric Antagonism

Allosteric Antagonism

Allosteric Antagonism

Allosteric antagonists 1 Response Dose

Allosteric antagonists 2 Response Dose

Quantal Dose-Response Curves Also known as concentration-percent or dose-percent curves Used when the dose of a drug to produce a specified effect in a single patient is measured (individual effective dose or concentration.) The percent of subjects responding at a dose is plotted.

Quantal Dose-Response Curves Percent Responders Dose

Cumulative Quantal Dose-Response Curves Percent Responders Dose

Cumulative Quantal Dose-Response Curves Percent Responders Dose

Receptor regulation Reduced responsivity: Chronic use of an agonist can result in the receptor-effector system becoming less responsive eg. alpha-adrenoceptor agents used as nasal decongestants Myasthenia gravis: decrease in number of functional acetylcholine nicotinic receptors at the neuromuscular junction.

Receptor regulation Increased responsivity: Chronic disuse of a receptor-effector system can result in an increased responsiveness upon re-exposure to an agonist. Denervation supersensitivity at skeletal muscle acetylcholine nicotinic receptors Thyroid induced upregulation of cardiac beta-adrenoceptors Prolonged use of many antagonists (pharmacological as well as functional) can result in receptor upregulation

Receptor Upregulation Most receptors are internalized and degraded or recycled with age and use. Antagonists slow use-dependent internalization Inverse agonists stabilize the receptor in the inactive state to prevent internalization. The cell continues to produce receptors.

Desired vs undesired effects: Indices of drug safety. Safety Index Therapeutic Index “Potency means nothing. I can always give a bigger pill.” J. Hunter

Safety index: LD1/ED99 ED99 Sleep Death LD1

Therapeutic index: LD50/ED50 Sleep Death

Safety Index vs. Therapeutic Index