Pharmacodynamics What the drug does to the body? Tay Ju Lee MD INTI

Overview Drug(Ligand) + Receptor ⇋ Drug-receptor complex  Biologic effect “A drug doesn’t work unless it is bound” Drugs only modify underlying biochemical and physiological processes, they do not create effects de novo (anew) “A drug doesn’t work unless it is bound”

Topics of Discussion Drug receptor interaction Drug Dose-response relationship Therapeutic INdex

Chemistry of Receptors and Ligands Drugs typically exert their effects by interacting with a receptor Chemical bonds Electrostatic Hydrogen bond Van der Waals Binding Receptor selective Requires exact fit Usually reversible + Handful are covalent bonds VDW is the sum of the attractive or repulsive forces between molecules (or between parts of the same molecule) Synonym of totality of intermolecular forces. Van der Waals forces are relatively weak compared to normal chemical bonds,

Mnemonic KING Kinase-linked receptors ligand gated Ion channels Nuclear receptors G-protein-coupled receptors Types of receptor-effector linkage: E, enzyme; G, G-protein; R, receptor.

Major Receptor Families Ligand-Gated Ion Channels Regulation of flow of ions across cell membranes Depolarization/Hyperpolarization of membrane Associated with receptors for fast neurotransmitters Nicotic receptor - Na+

Major Receptor Families G-Protein coupled receptors – Largest family 3 components 7 membrane-spanning α helices G protein – α subunit - GTPase & βγ cAMP / IP3/ Phospholipase A2/ ion Ch Four Steps Ligand binding G protein activation (cytoplasmic side) Activity of effector (ion channel or enzyme) changed Intracellular second messenger concentration changes cAMP: effector enzyme -- adenylyl cyclase, converting ATP to cAMP – phosphorylates proteins Guanine - Go between These are sometimes called metabotropic receptors. Structures comprise seven membrane-spanning α-helices, often linked as dimeric structures. One of the intracellular loops is larger than the others and interacts with the G-protein. The G-protein is a membrane protein comprising three subunits (α, β, γ), the α subunit possessing GTPase activity. When the trimer binds to an agonist-occupied receptor, the α subunit dissociates and is then free to activate an effector (a membrane enzyme or ion channel). In some cases, the βγ subunit is the activator species. Activation of the effector is terminated when the bound GTP molecule is hydrolysed, which allows the α subunit to recombine with βγ. There are several types of G-protein, which interact with different receptors and control different effectors. Examples include muscarinic acetylcholine receptors, adrenoceptors, neuropeptide and chemokine receptors, and protease-activated receptors. receptor – Gets the job done once authorised by hormone

G-Protein Coupled Receptor The function of the G-protein. The G-protein consists of three subunits (α, β, γ), which are anchored to the membrane through attached lipid residues. Coupling of the α subunit to an agonist-occupied receptor causes the bound GDP to exchange with intracellular GTP; the α-GTP complex then dissociates from the receptor and from the βγ complex, and interacts with a target protein (target 1, which may be an enzyme, such as adenylate cyclase, or an ion channel). The βγ complex may also activate a target protein (target 2). The GTPase activity of the α subunit is increased when the target protein is bound, leading to hydrolysis of the bound GTP to GDP, whereupon the α subunit reunites with βγ. Zoya Maslak, Yuri Rashkin - The G Protein Story.flv http://www.youtube.com/watch?v=K7WSMybZeA8

Major Receptor Families Kinase-linked receptors Cytosolic enzyme activity as integral structure or function Most common tyrosine kinase activity (Kinase = Phosphate) Addition of phosphate changes 3D structure of protein Insulin

Insulin Tyrosine Kinase Animation TK Receptor Animation.flv http://www.youtube.com/watch?v=-iBb1sH-Eh4 Insulin Signaling (Signal Pathways).flv http://www.youtube.com/watch?v=FkkK5lTmBYQ

Major Receptor Families Nuclear receptors TWO main categories Those present in cytoplasm form complex with ligand – migrate to the nucleus eg. Steroid hormones Present in nucleus – ligands usually lipids Binds to specific DNA sequences resulting in regulating gene sequences – protein synthesis Longer time course of action Responsible for 10% of pharmacology and the pharmacokinetics of 60% of all prescription drugs A family of 48 soluble receptors that sense lipid and hormonal signals and modulate gene transcription. Two main categories: those that are present in the cytoplasm, form homodimers in the presence of their partner, and migrate to the nucleus. Their ligands are mainly endocrine in nature (e.g. steroid hormones). those that are generally constitutively present in the nucleus and form heterodimers with the retinoid X receptor. Their ligands are usually lipids (e.g. the fatty acids). A third subgroup transduce mainly endocrine signals but function as heterodimers with retinoid X receptor (e.g. the thyroid hormone). The liganded receptor complexes initiate changes in gene transcription by binding to hormone response elements in gene promoters and recruiting coactivator or corepressor factors. The receptor family is responsible for the pharmacology of approximately 10%, and the pharmacokinetics of some 60%, of all prescription drugs.

Topics of Discussion Drug receptor interaction Drug Dose-response relationship Therapeutic INdex

Drug Dose-Response Relationship Graded dose-response relations Drug-Receptor binding Relationship of binding to effect Potency Efficacy Nature of interactions Agonists Antagonists Functional antagonism Partial agonists

Drug-receptor Binding Effect of dose on the magnitude of drug binding Relationship of binding to effect assumes Magnitude proportional to receptors bound Maximum efficacy when all receptors bound Binding does not show cooperation Interactive Pharmacology

Potency Graded dose-response curve shows potency Determine Effective Concentration 50% EC50 50%

Efficacy Efficiency is dependent on number of drug-receptor complexes formed and corresponding cellular response A drug with more efficacy is better than drug with more potency http://www.icp.org.nz/icp_t7.html

Nature of Interactions Agonist If a drug binds to a receptor and produces a biologic response that mimics the response to the endogenous ligand Partial agonist Has intrinsic activity less than that of a full agonist

Theoretical occupancy and response curves for full vs partial agonists The occupancy curve is for both drugs, the response curves a and b are for full and partial agonist, respectively. The relationship between response and occupancy for full and partial agonist, corresponding to the response curves in A. Note that curve a produces maximal response at about 20% occupancy, while curve b produces only a submaximal response even at 100% occupancy.

Nature of Interactions Antagonist Drugs that decrease the actions of the endogenous ligand. Reversible vs Irreversible Functional antagonism (physiologic antagonism) Antagonist binds completely separate receptor initiating effects functionally opposite of the agonist Epinephine binding to (β2 adrenergic receptor ) reversing Histamine-induced bronchoconstriction (H1 receptor)

Reversible vs irreversible competitive antagonists Reversible competitive antagonism – log concentration-effect curve shifts to right without change in slope maximum Irreversible competitive antagonism – Covalent bond formed with receptor eg. Aspirin & Omeprazole 1 = 50% occupancy http://www.icp.org.nz/icp_t14.html

Body adapts to drugs Change in receptors Loss or addition of receptors Refractory period after effect of first dose - Desensitisation Loss or addition of receptors Internalization of receptors due to prolonged exposure to agonist – and converse. Exhaustion of mediators Amphetamine release cathecholamine – stores depleted Increased metabolic degradation of drug Tolerance Physiological adaptation

Topics of Discussion Drug receptor interaction Drug Dose-response relationship Therapeutic INdex

Therapeutic Index Therapeutic index is the ratio of the dose that produces toxicity : dose for clinically desired effective response (50% o f population) Therapeutic Index = TD50/ ED50 http://www.icp.org.nz/icp_t7.html?htmlCond=3

Summary Drugs only modify underlying biochemical and physiological processes, they do not create effects de novo (anew) 4 ways drugs and receptors interact - KING Dose-Response Curve Potency vs Efficacy 4 Nature of Interactions Body adapts to drug Therapeutic Index

References Howland et al (2006) Lippincott’s Pharmacology 3rd Ed. Rang et al (2007) Rang & Dale’s Pharmacology 6th Ed. Videos and websites in slides