Pharmacodynamics (2) PDF

Pharmacodynamics (2) By Harshika Patel KeMU 3rd year Medicine Course : Basics of Pharmacology and Toxicology Date : 26/09/2018  Structure Activity Relationship SAR is the r...

Pharmacodynamics (2) By Harshika Patel KeMU 3rd year Medicine Course : Basics of Pharmacology and Toxicology Date : 26/09/2018  Structure Activity Relationship SAR is the relationship between the chemical or 3D structure of a molecule and its biological activity. Determination of the chemical groups responsible for evoking a target biological effect in the organism. Quantitative SARs (QSAR)as a special case of SARs (when relationships become quantified)  Both agonists and antagonists share common structural features. Composition and arrangement of chemical functional groups, determines the type of pharmacologic effect ,it possesses. Example, many compounds containing tertiary amine groups became muscle relaxants when converted to quaternary ammonium compounds. Pancuronium, vecuronium, rocuronium, rapacu ronium, dacuronium (as in anaesthesia)  STEREOCHEMISTRY AND DRUG ACTION Stereo isomers are compounds containing the same number and kinds of atoms, the same arrangement of bonds, but different three- dimensional structures. 2 types: enantiomers and diastereoisomers If functional groups are in the proper 3D orientation, the drug can produce a very strong interaction with its receptor.  The physiochemical properties of a drug molecule dependent on (a) functional groups in the molecule (b) spatial arrangement of these groups. Enantiomers when introduced into an Asymmetric environment(human body) ,it will display different physiochemical properties, producing significant differences in their pharmacokinetic and pharmacodynamics behavior.  Easson and Stedman Hypothesis Reasoned that differences in biological activity between enantiomers resulted from selective reactivity of one enantiomer with its receptor. They postulated that such interactions require a minimum of a three-point fit to the receptor. (increase potency of enantiomers). Example : sedative thalidomide, antidepressant drugs escitalopram and citalopram* Determination of the Pharmacophore : The pharmacophore of a drug molecule is that portion of the molecule containing the essential organic functional groups that directly interact with the receptor active site Pharmacophore may constitute a small portion of the molecule.(very specific) Example: narcotic analgesic morphine. Alterations in Alkyl Chains: Chain Length, Branching, and Rings: Simply changing the length of an alkyl chain by one CH2 unit or branching the chain may alter its lipophilic character properties of absorption, distribution, and excretion alter. Alkyl chain is directly involved in the receptor interaction alter the binding characteristics. Conformational become less flexible  affect spatial relationship of functional groups  influence receptor binding. FUNCTIONAL GROUP MODIFICATION. ISOSTERISM AND BIOISOSTERISM Modify the compound to reduce or eliminate undesirable features without losing the desired biological activity. Done by Replacement or modification of functional groups with other groups having similar properties is known as "isosteric replacement" or "bioisosteric replacement“.  Technologies used Structural information obtained from- 1) X-ray crystallography 2) nuclear magnetic resonance spectroscopy  Regulatory Issues Drug development Drug scheduling  Drug development The Pharmaceutical Value Chain Understanding the full set of activities that occur prior to a patient receiving a medicine provides useful perspective on the pharmaceutical value chain. The Pharma Value Chain  Introduction What is the need or demand of drugs? According to the requirements drug discovery is taking place. Concepts and ideas second object of the drug discovery People who work in laboratories and physicians are giving the ideas of drug discovery  Research and study: on pathophysiology of drug and on drug physicochemical study Gene / genome sequencing: – Building a library of gene/protein (genome/proteome) sequences for information. Target discovery: Identifying the biological origin of a disease, and the potential targets for intervention, is the first step in the discovery of a medicine. – Look for proteins or mRNA expressed (or not expressed) in a disease. – Comparative gene expression assays, Comparative proteomic profiles. – Look for genes/proteins essential for infectious agent and distinct from host genes/proteins. – Look for genes and gene modifications associated with a disease. – Look for proteins or protein modifications associated with a disease. – Find regulatory pathways required for disease process. Target validation: https://www.nature.com/subjects/target- validation Molecular level Screen enzyme inhibitors or activators the structure-activity-relationship of analogs of the small molecule Cellular Level Verify the involvement of the protein in the disease state (often use knockdown or overexpression of the presumed target). Understand the protein pathways and interactions. Organismal level Verify critical nature of target and uniqueness.  Lead Discovery A leading compound in drug discovery is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, but may nevertheless have suboptimal structure that requires modification to fit better to the target. Discover leads that affect the target gene, protein or pathway  Inhibit defective protein  Activate a defective protein  Inhibit expression of a protein/pathway  Activate expression of required protein/pathway  Stimulate protein modifications or cellular location  Contd’.. Lead Discovery – Screening natural compound collections – Screening corporate compound collections – In silico screening (Autodock) – Rational drug design – Combinatorial chemistry Lead validation Lead optimization  Pre-Clinical Study To evaluate its actual therapeutic and undesirable effects Done by choosing small animals also on big animals Animal tests of toxicity and efficacy of therapy Rodents (mice and rats) Mammals (pigs) Primates (monkeys and chimpanzees) Mouse Lemurs (Microcebus)  Clinical study When a compound deserving trial in man ‘investigational new drug’ (IND) licence Required ‘Good Clinical Practice’ (GCP)*  guided by ICH = International Conference on Harmonization, or National agencies in most countries Also need ethical clearance by local institutional committee / review board Because of these processes clinical trial will take longer time to discover the drugs (almost 15 years) Informed consent  includes all detail information should be mentioned regards to the clinical trials.  Different phases of clinical trials 1. Phase 0: aka micro dosing phase – Applied to minimized cost reduction – Subjects: 10-15 – Days: 07 days – Evaluate the p’kinetics and p’dynamic effcets 2. Phase I (to evaluate Human pharmacology and safety): Small group of healthy volunteers (20-80) to determine safety, tolerability and toxicity. – Maybe some members of target group. – No blinding is done: the study is open label 3. Phase II(Therapeutic exploration and dose ranging): – Subjects:100-500 (disease specific subject, like anticancer drugs for camcer pt only) – patient population to determine efficacy, dosage, safety and conducted by a trained physicians 4. Phase III(Therapeutic confirmation/ comparison): – Subjects: 500 to 3000 of patients controls (normal) – to determine efficacy, dosage, safety, side effects, and interactions. The aim is to establish the value of the drug in relation to existing therapy Each prospective patient group (men, women, children, elderly and ethnic groups). 5. Phase IV(Post-marketing surveillance/ studies): – Subjects: 10,000’s of patients/, measure (observed) toxicity – Uncommon/idiosyncratic adverse effects, or those that occur only after long-term use and unsuspected drug interactions are detected at this stage – Off label used also evaluate in this phase Drug scheduling  Pharmacogenetics  “Is the study of inherited genetic differences in drug metabolic pathways (and other pharmacological principles, like enzymes, messengers and receptors) which can affect individual responses to drugs, both in terms of therapeutic effect as well as adverse effects.” Most powerful of the new genetic techniques is the ability to breed animals  the gene for the receptor or its endogenous ligand has been "knocked out," i.e., mutated so that the gene product is absent or nonfunctional. (suppression of that functions).  Behavior, biochemistry, and physiology of the knockout mice  describe the role of the missing gene product clearly. Knockdown model : with only limited suppression of function. Knockin model: mice have been bred that overexpress certain receptors of interest.  Toxicology Toxicology is the study of potential adverse effects of foreign chemicals and their dose-response relationships to protect public health. Inherent capacity of a chemical to cause injury. All chemicals have toxicity at some extent, including drug. first documented by the physician Paracelsus. He stated, “All substances are poisons: Common antidotes  References Books : Katzung, chapter 1 Lippincott. Internet : https://www.nature.com/subjects/ target-validation Thank You ?