Lesson 3 Pharmacodynamics PDF 2024/25

Lesson 3 Pharmacodynamics 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. Pharmacodynamics. 2. Mechanisms of drug action. Molecular pharmacology. 3. Receptors concepts. Agonists. Antagonists 4. Pharmacogenetics/Pharmacogenomics. 5. Recombinant...

Lesson 3 Pharmacodynamics 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1. Pharmacodynamics. 2. Mechanisms of drug action. Molecular pharmacology. 3. Receptors concepts. Agonists. Antagonists 4. Pharmacogenetics/Pharmacogenomics. 5. Recombinant drugs. 2 1. Farmacodynamics PHARMACOKINETICS Biological system Drug PHARMACODYNAMICS Pharmacodynamics: Is a branch of pharmacology that studies the mechanism of action of a drug and the drug-receptor interaction to give a pharmacological effect in organism. *what the drug does to the body and how it interacts with it 1. Farmacodynamics Pharmacodynamics studies – mechanisms of drug action and – the relationship between drug concentration and effect. – example is drug-receptor interactions as modelled by L R L R – where L=ligand (drug), R=receptor (binding site) UNIT 3: Pharmacodynamics 6 2. Mechanisms of drug action. Molecular pharmacology. Drug actions: Modification that a substance produces on the body's functions, increasing or depressing them. Principles of drug action Drugs produce an action that modifies normal functioning of the biological system. There are 5 main drug actions: » stimulation » depression » irritation » replacement » cells destruction (cytotoxicity)  2. Mechanisms of drug action. Molecular pharmacology. Drug actions: § Stimulation: : increased activity of specialised cells by improving their function. Repeated stimulation leads to exhaustion and depression. Example: Caffeine CNS § Depression: decreased functional activity of specialized cells. Example: Hypnotics CNS § Irritation: intense stimulation followed by anatomical injury and is exerted on non-specialized structures and functions. Drugs that cause inflammation, necrosis, corrosion. Example: vesicants, caustics § Replacement: treatment of deficiency diseases or diseases caused by insufficiency. hypothyroidism treatment Example: Thyroxine androgens and estrogens gonadal insufficiencies vit. B12 Pernicious anemia § Anti-Infectious Action. Example: antibiotics 2. Mechanisms of drug action. Molecular pharmacology. Targets of pharmacological action Most of drugs exert its effect by means of a selective interaction with a determinate biomolecule, usually a protein. Target proteins that drugs bind to in order to carry out their therapeutic action: § Ion channels § Carrier proteins § Enzymes § Receptors Receptor: protein that a ligand can selectively bind to, resulting in a constant and specific change in cellular function. Ligand: A molecule (drug) that binds to the receptor giving a pharmacological effect. 2. Mechanisms of drug action. Molecular pharmacology. Ion channels Ion channels are pore-forming proteins – allowing the selective flow of ions down their electrochemical gradient Proteins of the pore undergo a conformational change upon opening/closing The opening/closing of the channel (gating function) is regulated by transmitting substances or membrane potentials Ion channels help establish and control the small voltage gradient across the plasma membrane. 2. Mechanisms of drug action. Molecular pharmacology. Ion channels Some drugs modulate channel function directly by binding to a portion of the channel protein.. How DRUGS act on ION CHANNELS? » Drugs can bind on specific receptor in their structure (ligand-gate channel). » Drugs can block ion channels by binding on the pore (electric-gate channel/other types of gates). 2. Mechanisms of drug action. Molecular pharmacology. Carrier Proteins Proteins that transport a specific substance or group of substances through biological membranes (normallly molecules or ions against their concentration gradient) Passive transport (not energy dependent): Ø SINGLE: 1 ion/molecule 1 direction Ø UNDIRECTIONAL COTRASPORTERS: 2 o more ions/molecules 1 direction Ø BIDIRECTIONAL COTRANSPORTERS: Ion/Molecule exchange Active transport (needs energy): Pumps (Na+/K+ ATPase pump) 2. Mechanisms of drug action. Molecular pharmacology. Enzymes Protein catalysts that increase the rate of specific chemical reactions. Molecules at the beginning of the process are called substrates, and they are converted into products. All enzymes are potential drug targets What DRUGS can do over ENZYMES? – induce/reduce enzyme synthesis – Inhibit/activate the enzyme activity: Unspecific inhibition. Specific inhibition. » Competitive » Non-competitive 2. Mechanisms of drug action. Molecular pharmacology. Enzymes Specific inhibition. COMPETITIVE:The drug has a similar structure than the substrate Competitive (balance/equilibrium type): – compete for the binding on the active site of the enzyme – drug can be removed from the active site if the concentration of the substrate increases significantly. Competitive (non-equilibrium type): – reactions with the active site of the enzyme. – it cannot be removed by the substrate (irreversible bond) 2. Mechanisms of drug action. Molecular pharmacology. Enzymes Specific inhibition. NON-COMPETITIVE:The drug binds an allosteric site on the enzyme (a different site than substrate bond site) the enzyme looses its activity or increases its activity ALLOSTERIC SITE 2. Mechanisms of drug action. Molecular pharmacology. Enzymes 3. Receptors concepts. What is a receptor? Receptor literally means something that receives= a receptor is a region of tissue, or a molecule in a cell membrane, which responds specifically to a particular neurotransmitter, hormone, antigen, or other substance (Drug) called LIGAND 3. Receptors concepts. What is a Ligand? Ligand literally means something that binds= a ligand is the molecule that binds the receptor. Type of ligands: endogenous ligand/endogenous mediator (neurotransmitters, hormones…) pharmaceutical drugs toxins – Each kind of receptor can bind only certain ligand types. 3. Receptors concepts. TYPES OF RECEPTORS 1 2 3 4 § § § § § § 3. Receptors concepts. RECEPTORS 1) Ligand-gated ion channels Also called ionotropic receptors. Mainly involved in rapid synaptic transmission. Several structural families. Ligand binding and channel opening takes place within milliseconds. Examples: nicotinic Ach receptors, (GABA A)…  3. Receptors concepts. RECEPTORS 2) G-proteins-Coupled receptors (GPCRs) Metabotropic receptors. The structures include 7 α-transmembrane helices. They consist of a polypeptide chain (500 aa). The extracellular portion is composed of an N-terminal domain to which the ligand binds, and the intracellular domain is carboxy-terminal and interacts with the G-protein. G-proteins are membrane proteins with 3 subunits (α,β,γ) and the α subunit has GTPase activity. There are several types of G-proteins, which interact with different receptors and control different effectors that triggers signal transmission. Examples of G-protein-coupled receptors : Ach muscarinic receptor, adrenergic receptor a.... 3. Receptors concepts. RECEPTORS Receptores ligados a cinasas y relacionados 3) Kinase-linked receptors Catalytic activity When they are activated, they dimerize and the receptor undergoes a change in conformation Slow signal transduction rate. Involved in growth regulation events, cell differentiation and act indirectly in the regulation of gene transcription. Examples: Hormone receptors (insulin), growth factors, interferons. Enzyme-associated receptor (tyrosine kinase) 3. Receptors concepts. RECEPTORS 4) Nuclear Receptors Receptors that regulate DNA transcription. Two types of nuclears receptors: Ø Present in the cytoplasm that form homodimers and migrate to the nucleus in the presence of the ligand (steroid hormones). Ø Present in the nuclei. Lipophilic ligands (e.g. fatty acids) Ligand-receptor complexes trigger the modification of gene transcription. Examples: steroid hormone receptors, thyroid hormones, glucocorticoids, mineralcorticoids, retinoic acid and vitamin D. 3. Receptors concepts. DRUG-RECEPTOR INTERACTION How do ligands (DRUGS) act on the receptor? AGONIST: activates receptors producing a similar effect than the biological ligand 1) The AR binding depends on the AFFINITY: the ability of the drug to bind the receptor 2) The AR* depends on the EFFICACY: drug ability to produce a pharmacological effect Full agonist: high efficacy and maximum EFFICACY response occupying little % of available R Partial agonist: low efficacy and unable to give the maximum response even using all the availables R * prevents the binding of the complete/full agonist. 3. Receptors concepts. DRUG-RECEPTOR INTERACTION POTENCY : is a measure of a drug's biological activity expressed in terms of the dose required to produce a pharmacological effect 3. Receptors concepts. DRUG-RECEPTOR INTERACTION How do ligands (DRUGS) act on the receptor? INVERSE AGONISTS: binds to the same receptor as an agonist but induces a pharmacological response opposite to that of the ligand. 3. Receptors concepts. DRUG-RECEPTOR INTERACTION How do ligands (DRUGS) act on the receptor? ANTAGONIST: binds to the receptor, without activating it, preventing the binding of the endogenous ligand or an agonist. There are 2 types of antagonists: Ø Competitive Antagonist: reversibly binds to the R decreasing binding sites for agonists Ø Non-competitive antagonists: They bind irreversibly to the R, reducing availables R (the body has to synthesise new R = longer half- life of the drug) or bind to a different receptor site, inhibiting the activity of the agonist. 3. Receptors concepts. DOSE-RESPONSE RELATIONSHIP The dose-response relationship: The dose is the appropriate amount of drug to produce a determinate response in a patient. The dose must be selected as a function of the desired response. Dose-response curve 3. Receptors concepts. DOSE-RESPONSE RELATIONSHIP Exercise: How potent and efficacious are the ligands A,B,C,D? Reminder 3. Receptors concepts. MECHANISMS OF REGULATION OF RECEPTORS Receptors become: 1. Hyper-sensitized: with a long lasting lack of the agonist 2. Under-sensitized :High stimulation 4. Pharmacogenetics/Pharmacogenomics Pharmacogenetics is the study of inherited genetic differences in drug metabolic pathways which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects. The term pharmacogenetics is often used interchangeably with the term pharmacogenomics  5. RECOMBINANT DRUGS Recombinant DNA (rDNA) molecules are DNA molecules formed by laboratory methods of genetic recombination (such as molecular cloning ) to bring together genetic material from multiple sources, creating sequences that would not otherwise be found in biological organisms. – Recombinant DNA :DNA molecules from all organisms share the same chemical structure. – differ only in the nucleotide sequence within that identical overall structure. Recombinant DNA is widely used in biotechnology, medicine and research. Questions?????