Pharmacodynamics Lecture Notes 2024 PDF

Pharmacodynamics Dr.Leila Ablowi 2024 Lecture Objectives 01 02 03 Understand the mechanism of Explore receptor-mediated and Identify key types of drug-receptor drug actions and their targets in non-receptor-mediated drug...

Pharmacodynamics Dr.Leila Ablowi 2024 Lecture Objectives 01 02 03 Understand the mechanism of Explore receptor-mediated and Identify key types of drug-receptor drug actions and their targets in non-receptor-mediated drug interactions and signalling the body. mechanisms. pathways.  Pharmacodynamics Why is that one drug affects cardiac function? Why do antibiotics effectively kill bacteria but rarely harm patients?  Pharmacodynamics Is the study of actions of the drugs on the body and their mechanism of action It includes the study of biochemical and physiological effect of drugs It describe the relationship between drug conc. at the site of action and pharmacological response: ❖ Plasma drug level vs Pharmacological response ❖ Dose-effect relationship How drugs produce action? What are targets for drug binding ? Drugs Receptor-mediated Non-receptor-mediated mechanisms mechanisms Drug actions Drug mechanisms I. Receptor mechanisms​ ○ Most drugs exert their effects by binding to receptors​ ○ This has the effects of either mimicking the endogenous substances binding to receptors (simulation) or preventing their binding or action (inhibition) II. Non-receptor mechanisms​ ○ Changing cell membrane permeability (ion channels)​ ○ Enzyme inhibition​ ○ Carrier molecules (transporters)​ ○ Changing physical activity​ ○ Combining with other chemicals chemically​ ○ Anti-metabolite  Receptor–mediated mechanisms Drugs can produce actions by binding with biomolecules (Protein Targets) Protein targets for drug binding: 1. Physiological receptors 2. Enzymes 3. Ion channels 4. Transporters 5. Structural protein  What are targets for drug binding ? Receptors o Is a special target macromolecule (protein) that binds the drug and mediates its pharmacological actions. o Protein molecule which recognize and respond to endogenous ligands. Where are receptors located? Cell membrane. Cytoplasm. Nucleus. Ligands Ligand = a small molecule that bind to a site on receptor protein (drug and endogenous ligand). Types of endogenous ligands: ▪ Neurotransmitters >> released by neurons. ▪ Hormones >> released by endocrine glands. ▪ Mediators (e.g. inflammatory) >> mostly locally acting chemicals.  Receptor–mediated mechanisms Classified into six major groups: 4) Intracellular receptors, including: (1) Transmembrane ion channels Enzymes Signal transduction molecules (2) Transmembrane receptors coupled to Transcription factors intracellular G proteins Structural proteins (3) Transmembrane receptors with Nucleic acids linked enzymatic domains (5) Extracellular targets (6) Cell surface adhesion receptors Major types of interactions between drugs and receptor Heptahelical receptors spanning the plasma membrane are Drugs can bind to ion channels functionally coupled to intracellular G proteins. spanning the plasma membrane, causing Drugs can influence the actions of these receptors by an alteration in the channel’s conductance. binding to the receptor's extracellular surface or transmembrane region. Major types of interactions between drugs and receptor Drugs can bind to the extracellular domain of a Drugs can diffuse through the plasma membrane transmembrane receptor and cause a change in and bind to cytoplasmic or nuclear receptors. signalling within the cell by activating or inhibiting This is often the pathway used by lipophilic drugs an enzymatic intracellular domain (e.g., drugs that bind to steroid hormone (rectangular box) of the same receptor molecule. receptors).  Transmembrane Ion Channels Many cellular functions require the passage of ions and other hydrophilic molecules across the plasma membrane Specialized transmembrane channels regulate these processes. (Regulating the flow of ions across cell membrane.)​ Functions of ion channels: 1. Neurotransmission 2. Cardiac conduction 3. Muscle contraction 4. Secretion  Transmembrane Ion Channels Three major mechanisms of transmembrane ion channels: Cannel Typer MOA Function Ligand-gated channels Conductance controlled by ligand binding to the Altered ion e.g. cholinergic nicotinic channel. conductance receptor Voltage-gated channels changes in voltage across the plasma membrane. Altered ion e.g. voltage-gated calcium conductance channels Second messenger- Binding of ligand to transmembrane Second messenger regulated channels receptor with G protein-coupled regulates ion cytosolic domain, leading to second conductance of channel messenger generation Transmembrane Ion Channels Two important classes of drugs altering ion channel conductance: Local anaesthetics Benzodiazepines  Transmembrane Ion Channels Local anaesthetics Targeting Sodium Channels: Blocking voltage-gated sodium channels in the neuronal cell membrane. Inhibition of Action Potential: By inhibiting sodium channels, local anesthetics prevent the influx of sodium ions, which is essential for the initiation and propagation of action potentials along the nerve fiber Inhibit pain perception (nociception) by blocking pain signal transmission from the periphery to the central nervous system. Reversible Blockade: The blockade is reversible, meaning that once the anesthetic is removed or metabolized, normal nerve function can resume.  Transmembrane Ion Channels Benzodiazepines Benzodiazepines bind to the GABA receptor complex in the brain. GABA is the primary inhibitory neurotransmitter in the CNS. They enhance GABA’s ability to open chloride channels, increasing the flow of chloride ions into neurons The influx of chloride ions hyperpolarizes the neuron, making it more negatively charged and less likely to fire an action potential. Resulting in CNS Depression: sedation, anxiolysis, muscle relaxation, and anticonvulsant actions.  Transmembrane G Protein-Coupled Receptors G protein-coupled receptors (GPCRs): Most abundant class of receptors in the human body. Located at the extracellular surface of the plasma membrane Structure: GPCRs have seven transmembrane helices within a single polypeptide chain. Known as 7-transmembrane (metabotropicor - heptahelical) receptors. The extracellular domain usually contains the ligand-binding region. Intracellular G-protein (e.g. Gs, Gq, and Gi) >> 3 subunits (α, 𝛽, and 𝛄).  Transmembrane G Protein-Coupled Receptors Mechanism of Action (MOA) of G Protein-Coupled Receptors (GPCRs)  Mechanism of Action (MOA) of G Protein-Coupled Receptors (GPCRs) 1. Ligand Binding: An endogenous ligand (e.g., hormone, neurotransmitter) or exogenous drug binds to the extracellular domain of the GPCR. 2. Receptor Activation: The binding induces a conformational change in the GPCR. 3. G Protein Activation: The conformational change in the GPCR activates the associated G protein by promoting the exchange of GDP for GTP on the α subunit.  Mechanism of Action (MOA) of G Protein-Coupled Receptors (GPCRs) 4. G Protein Subunit Dissociation: The GTP-bound α subunit dissociates from the βγ subunits.* 5. Effector Interaction: The dissociated α subunit and βγ subunits interact with various effector proteins (e.g., adenylyl cyclase, phospholipase C, ion channels). 6. Second Messenger Production: Effector proteins generate second messengers: ((One major role of the G proteins is to activate the production of second messengers.)): ✓ Adenylyl Cyclase: Converts ATP to cyclic AMP (cAMP) (second messenger) ✓ Guanylyl Cyclase: Converts GTP to cyclic GMP (cGMP). (second messenger) ✓ Phospholipase C: Cleaves PIP2 into IP3 and DAG. (second messenger) Mechanism of Action (MOA) of G Protein-Coupled Receptors (GPCRs) 7. Intracellular Signalling:Second messengers activate downstream signalling pathways: Second Results Activation Results messenger cAMP Activates protein kinase A (PKA). ▪ Phosphorylates target proteins, altering their activity. ▪ Regulates metabolic pathways like glycogen breakdown. ▪ Promotes smooth muscle relaxation. cGMP Activates protein kinase G (PKG). ▪ Promotes smooth muscle relaxation. ▪ Inhibits platelet aggregation. ▪ Facilitates vasodilation in blood vessels IP3 Releases Ca2+ from intracellular stores. increasing cytosolic Ca2+ concentration and triggering downstream events. DAG Activates protein kinase C (PKC).. Regulates cell growth and differentiation. Smooth muscle contraction  The Major G Protein Families G Protein Isoforms: Numerous G protein isoforms exist, each with unique effects on targets. Isoforms are grouped into five major families: Gs, Gi, Go, Gq, and G12/13. Differential functioning of these G proteins is important for drug selectivity. Important class in the G protein-coupled receptor family Beta-Adrenergic Receptors: Stimulated by catecholamines A significant class within the G protein- (epinephrine and norepinephrine) binding coupled receptor family. to the receptor's extracellular domain. Includes β1, β2, and β3 receptors. Epinephrine binding induces a ✓ β1 receptors control heart rate. conformational change, activating G ✓ β2 receptors relax smooth muscle. proteins and increasing intracellular cAMP ✓ β3 receptors mobilize energy from levels, leading to downstream cellular fat cells. effects.  Transmembrane Receptors with Linked Enzymatic Domains Function: These receptors convert extracellular ligand-binding interactions into intracellular actions by activating a linked enzymatic domain. The enzymatic domain can be part of:1. the receptor itself or a 2. cytosolic protein recruited upon receptor activation.  Transmembrane Receptors with Linked Enzymatic Domains Structure: These receptors are single-membrane- spanning proteins, unlike the seven- membrane-spanning structure of GPCR They often form dimers or multi subunit complexes to transduce signals. Play roles in a diverse set of physiologic processes, including: 1. Cell metabolism 2. Growth 3. Differentiation Transmembrane Receptors with Linked Enzymatic Domains Mechanism: Receptors with linked enzymatic domains often modify proteins by adding or removing phosphate groups from specific amino acid residues. Classification: Five major classes based on their cytoplasmic mechanisms of action: 1. Receptor Tyrosine Kinases 2. Receptor Tyrosine Phosphatases 3. Tyrosine Kinase-Associated Receptors 4. Receptor Serine/Threonine Kinases 5. Receptor Guanylyl Cyclases  Receptor Tyrosine Kinases (RTKs) The largest group of transmembrane receptors with enzymatic cytosolic domains. Transduce signals from many hormones and growth factors by phosphorylating tyrosine residues on the cytoplasmic tail of the receptor.  Receptor Tyrosine Kinases (RTKs) MOA: 1. Binding of a specific ligand (such as a growth factor) to the extracellular domain of RTKs induces receptor dimerization (pairing of two receptor molecules). 2. Autophosphorylation: The dimerized receptors undergo autophosphorylation on specific tyrosine residues in their intracellular domains. 3. Activation of Signaling Pathways: The phosphorylated tyrosines serve as docking sites for various intracellular signaling proteins, leading to the activation of downstream signaling pathways like the MAPK, PI3K/Akt, and PLCγ pathways. 4. Regulation of Cellular Processes: including cell growth, differentiation, survival, and metabolism. 5. Role in Cancer: Dysregulation or mutation of RTKs is often associated with cancer and other diseases, making them important targets for therapeutic intervention.  Receptor Tyrosine Kinases (RTKs) Insulin Receptor Structure: This receptor consists of: Two extracellular α subunits covalently linked to Two membrane-spanning β subunits  Receptor Tyrosine Kinases (RTKs) Insulin Receptor Mechanism: 1. Insulin binds to the extracellular alpha subunits of the insulin receptor. 2. Upon insulin binding, the receptor undergoes dimerization and Type 2 diabetes autophosphorylation on specific tyrosine residues located on the mellitus may, in some cases, be associated intracellular beta subunits. with defects in 3. The phosphorylated tyrosine residues then act to recruit other post-insulin receptor cytosolic proteins, known as insulin receptor substrate (IRS) proteins. signaling 4. These pathways result in cellular responses such as increased glucose uptake ,glycogen synthesis, and overall regulation of glucose metabolism.  Intracellular Receptors and Drug Targets The plasma membrane acts as a barrier for drugs targeting intracellular receptors. Many such drugs are: ✓ Small or lipophilic drugs can cross the membrane by diffusion. ✓ Other drugs require specialized protein transporters, facilitated diffusion, or active transport.  Intracellular Receptors and Drug Targets Intracellular Enzymes Enzymes: are common intracellular drug targets Many drugs that target intracellular enzymes exert their effect by altering the enzyme’s production of critical signalling or metabolic molecules Key Examples: 1. Vitamin K Epoxide Reductase: an enzyme involved in certain coagulation factors, is the target of the anticoagulant drug warfarin 2. HMG-CoA reductase: the rate limiting enzyme in cholesterol synthesis, is the target of atorvastatin and the other lipid lowering statins Intracellular Receptors and Drug Targets Transcription Factors Definition: Transcription factors are important intracellular receptors targeted by lipophilic drugs. Role: Control the transcription of DNA into RNA and the subsequent translation of RNA into protein. Transcription of many genes is regulated by the interaction between: lipid-soluble signalling molecules and transcription regulatory factors. Steroid hormones are a class of lipophilic drugs that diffuse through the plasma membrane and bind to transcription factors in the cytoplasm or nucleus. Intracellular Receptors and Drug Targets Nucleic Acids RNA and Ribosome Binding: Some small-molecule drugs bind directly to RNA or ribosomes. Examples: Antibiotics: Doxycycline and azithromycin block translation in target microorganisms. DNA- and RNA-binding chemotherapeutic agents (such as doxorubicin) are mainstays of treatment for many cancers.  Extracellular Targets Many important drug receptors are enzymes with active sites located outside the plasma membrane. Can influence physiologic processes such as: ✓ Vasoconstriction ✓ Neurotransmission  Extracellular Targets Enzymatic Targets Angiotensin-Converting Enzyme (ACE): Function: Converts angiotensin I to angiotensin II, a potent vasoconstrictor. Drugs: ACE inhibitors lower blood pressure by inhibiting this conversion. Some extracellular targets are not enzymes Soluble Cytokines: Function: Several drugs, including monoclonal antibodies, target soluble cytokines to prevent them from interacting with their endogenous receptors. Examples: Anti-TNF Agents: Etanercept, infliximab, and others are used to treat autoimmune diseases such as rheumatoid arthritis  Cell Surface Adhesion Receptors Function: Facilitate direct cell-cell interactions for communication and specific functions. Examples: Formation of tissues, migration of immune cells to inflammation sites. Therapeutic Applications ✓ Thrombosis ✓ Inflammatory Bowel Disease ✓ Multiple Sclerosis Thank you…. Any Q???