Intro-PK-PD made easy 2014aaa

Information about Intro-PK-PD made easy 2014aaa

Published on August 10, 2014

Author: drahmedabulhadia

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Introduction to pharmacology, simplified PK, PD: Introduction to pharmacology, simplified PK, PD Handout for Lecture 1, Updated 2014 بسم الله الرحمن الرحيم سؤال من يذكرنا دعاء الملائكه للتائبين وبشراهم لاهل الايمان والاستقامه لحظة وداع الدنيا وتهنئتهم للصابرين بعد دخولهم الجنه من سور غافر وفصلت والرعد دعاء التيسير تعاونو ليكون الكورس سهلا Topics: Topics What is pharmacology ? Why we study It ? What is a drug ? Rational use of drugs. Drug characteristics ? sources, classification, names ; SDL , group activity , Animation for receptors , pharmacokinetics You should be familiar with many Important terminology Factors leading to alteration of drug response . Read some drug inserts you have We appreciate creative work to make course simple and enjoyable PowerPoint Presentation: √√√ Drugs : Substances that interact with living system and alters biologic activity . ( in clinical practice ) a drug means chemical agents that can be used to diagnose, prevent and treat illness & other medical uses. √√√ Clinical Pharmacology : Study of drugs in humans (patients and volunteers) Drug profile Its History, chemical structure, source Its pharmacodynamics (PD ) Its pharmacokinetics (PK) Its clinical indications & contraindications Its adverse drug effects (ADE) & management of toxicity. Available preparations , dose , cost . * drugs may be also used To promote healing; To control or slow progress of disease; To decrease risk of complications;; As replacement therapy, or lifestyle change ( management of obesity ) Major Uses for Drugs: Major Uses for Drugs 1—Symptomatic: Relieve disease symptoms. E.g Aspirin, Tylenol . 2—Preventative: To avoid getting a disease. Hepatitis B vaccine, Flu vaccine . 3—Diagnostic: Help determine disease presence. Radioactive dyes. 4—Curative: Eliminate the cause of the disease. Antibiotics. 5—Health Maintenance: Drugs for weight control. 6—Contraceptive: Risk-benefit ratio: Risk-benefit ratio we usually consider the following Effectiveness Indications Action Safety Contraindications ADVERSE REACTIONS interactions with other drugs & food Route & Dosage Other Cost availability of the drug Patient compliance Rational use of drugs الاستخدام الرشيد للادويه All members of health care team must exercise care to promote therapeutic effects and minimize drug induced harm Concept no 1: Concept no 1 Almost ALL DRUGS ARE POISONS The only thing that determines if a drug provides a benefit or kills a patient is how we administer it ( dose, route, age ,etc ) Examples : sodium nitoprosside IV ( drug ) , orally very toxic 1 tablet of acetaminophen ( panadol ) treatment of headache , 10-12 tablets ( liver failure if not treated ) Concept II : Our Therapeutic Goal: Concept II : Our Therapeutic Goal Optimal pharmacotherapy : ie maximum efficacy & minimal toxicity ? i.e To achieve drug concentrations at the site of action (target tissue)…that are sufficiently high enough…to produce the intended effect without producing adverse drug reactions . PowerPoint Presentation: Therapeutic Classification حسب الاستخدام Is based on therapeutic use of certain group of drugs . For example: Anticoagulants. مضاد للتجلط Antidepressants. مضاد للاكتئاب Antineoplastics. مضاد للسرطان Pharmacologic Classification حسب الية العمل More specific than therapeutic classification Requires understanding of biochemistry and physiology Based on how the drug produces its effect at molecular, tissue, or body-system level Ex : Cholinergic agonists { act on the receptors that are activated by Aceylcholine (Ach ) direct acting indirect acting reversible irreversible Classification of Drugs Don’t wary they are just example , you are not requested to memorize Further Classification of drugs: Further Classification of drugs Therapeutic action e.g: Antibiotics sub class. in view of Mechanism Cell - wall inhibitors Chemistry B-lactam antibiotics Pencillins Cephalosporins spectrum Cephalosporin's are classified as 1 st , 2 nd , 3 rd generation Sources of Drugs: Sources of Drugs Plants Microorganisms Animals Chemical synthesis Biotechnology Some drug characteristics : Some drug characteristics Physicochemical charctestics Solid ; Liquid & Gaseous drugs Hydrophilic , lipophilic water solubility , Many drugs are weak acids or bases . Drug Size & Mol. Wt some are small simple molecules, others complex structures Most drugs have molecular weights between 100 and 1,000 Some drugs are chairal ( optically active ) Nomenclature: Nomenclature Chemical name Acetylsalicylic acid √√√ Generic or nonproprietary name Aspirin Trade name (Name brand) many Specific Forms of Adverse Effects: Specific Forms of Adverse Effects Hypersensitivity Extension of pharmacological effect . Idiosyncratic reactions Iatrogenic reactions Teratogenic Interactions with other drugs Synergism ( 1+1 = 5 ) Antagonism ( 1+1 = zero ) Potentiation (1+1 = 1.5 ) Examples of ADE : Examples of ADE Classification with regard to prescription: Classification with regard to prescription I Drugs with high abuse potential and no accepted medical use II Drugs with high abuse potential and accepted medical use III Drugs with moderate abuse potential and accepted medical use IV Drugs with low abuse potential and accepted medical use V Drugs with limited abuse potential and accepted medical use 1-OTC ( out of the counter ,) بدون وصفه 2-Prescription drugs لا تصرف الا بوصفه 3-Controlled substances (1-V) ادويه مقيدة الصرف - جدول Pregnancy Classifications ( optional ): Pregnancy Classifications ( optional ) A—No risk demonstrated to the fetus in any trimester. B—No adverse effects in animals—no human studies C— animal studies show adverse reactions Only given after risks to the fetus is considered D—Definite fetal risks. Only given in life threatening situations X —Absolute fetal abnormalities PowerPoint Presentation: Factors that determine the intensity of drug response (optional for your carrier ) More definitions : More definitions Prototype” Drug—Serves as Model for a Drug Class Is well understood Has known action and adverse effects Is used to compare other drugs in same pharmacologic class …………………………………………………………………………………………………………………………………………………………………………………………………. Key Points: Key Points The objective of drug therapy is to provide maximum benefit within minimum harm. This requires knowledge the drug Pk & PD and variables affecting these properties. Patients are unique, drug therapy must be provided in individual basis. Rational use of drugs is responsibility of all staff involved in health care الاستخدام الرشيد للدواء مسؤولية جميع العاملين في المجال الطبى Pharmacokinetic (PK) (2013-2014): Pharmacokinetic (PK) (2013-2014) Objectives : To define the basic pharmacokinetic process To list the important variables affecting these process Topics ً What is pharmacokinetics? Variables affecting absorption & Bioavailability Drug distribution &Protein binding. Metabolism : Phase 1 & Phase II reactions ; enzyme induction & inhibition . Elimination SDL : ROUTES OF ADMINISTRATION *** = you must know **= it is important to know ADME = Pharmacokinetics Drug Absorption, Distribution, & Metabolism Excretion: ADME = Pharmacokinetics Drug Absorption, Distribution, & Metabolism Excretion Animation http://www.icp.org.nz/ ***What is pharmacokinetics ?: *** What is pharmacokinetics ? PK deals with the processes to which drug is subjected within the body i.e Absorption , Distribution, , Metabolism & Excretion ( ADME ). PK deals with variables affecting the above processes. It includes a mathematical description of these process PK concerned with optimization of pharmacotherapy: i.e optimal dose, dosing interval in individual basis , avoiding drug interaction . Summary of PK process (ADME) ***: Summary of PK process (ADME) *** A : Absorption , the movement of drug from the site of administration to the blood circulation. The term commonly used to describe the rate and extent of drug input is bioavailability . Drugs administered by intravenous routes exhibit essentially 100% bioavailability. D = Distribution , the process by which drug diffuses or is transferred from intravascular space to extra vascular space (body tissues). M = Metabolism , the chemical conversion or transformation of drugs into compounds which are easier to eliminate. E = Excretion , the elimination of unchanged drug or metabolite from the body via renal, biliary, or pulmonary processes. etc Routes of admin. ( practical ), very important : Routes of admin. ( practical ), very important Some Factors Affecting Drug Absorption (oral route ): Some Factors Affecting Drug A bsorption (oral route ) Mechanism of transport Most drugs absorbed by passive diffusion ) few drugs requires active transport Lipid soluble (unionized ) drugs , usually well absorbed Many Other factors ( see bioavailability ) ATP ADP + Pi A - BH + The diagram explains the active transport & effect of ionization Active transport **Ionized drug poorly absorbed HA HA Amount of drug absorbed depends on:: Amount of drug absorbed depends on: PKa of the drug and pH of the environment. In general, acids are absorbed better than bases in the stomach; bases are absorbed better than acids in the small intestine. Lipid solubility of the unionized form. Food may slow transit through the gut, bind drug, and/or compete with the drug for absorption. Physical Factors 1- Blood flow to the absorption site 2- Total surface area available for absorption 3- Contact time at the absorption surface PowerPoint Presentation: *** Bioavailability : Fraction of a administrated drug that reaches systemic circulation ( in active form ) Amoxicillin shows very good bioavailability after oral administration First Pass Metabolism: First Pass Metabolism Drug biotransformation that occurs before the drug reaches its site of action . Occurs Primarily in the Liver and Gut wall "First pass metabolism: " First pass metabolism Refers to the elimination that occurs when the drug is first absorbed from the intestine and passes through the liver via the portal circulation before drug enters the systemic circulation so that a significant fraction of the drug is inactivated before it becomes available to the whole body. Clinical importance of first –pass clearance *: Clinical importance of first –pass clearance * May render a drug ineffective by mouth e.g.. lignocaine, insulin higher dose needed orally to produce the same effect e.g.. 5mg propranolol IV = 100mg propranolol PO We use alternative route of administration to avoid e.g sub-lingual PowerPoint Presentation: This is bypassed by rectal, buccal, sublingual, and parenteral administration.   First-pass metabolism occurs in the liver, in intestinal muosa, , in the bronchial mucosa. √Some factors affecting oral absorption or Bioavailability: √ Some factors affecting oral absorption or Bioavailability First-pass hepatic metabolism F actors related to the drug Physiochemical properties Stability Lipid solubility Mol wt Chemical instability (insulin, penicillin G). Factors related to the formulation Syrup ready for absorption > tablet Sustained release tab. slow absorption particle size, salt form, crystal polymorphism, and the presence of excipient Factors related to the patient Physiological : age related change in Gastric pH, motility , gastric emptying time Pathological : certain disease e.g. diarrhea , vomiting drug distribution: drug distribution Distribution allows the drug to reach the site of action e.g. cardiac muscles, CNS, lung and sites of biotransformation Drug Distribution: Drug Distribution ***Distribution is the process by which the drug reversibly leaves the blood stream and enters the extra cellular fluids. *Drugs may distribute into any or all of the following compartments: Plasma Interstitial Fluid Intracellular Fluid ; … Apparent volume of distribution: (Vd) : Apparent volume of distribution: (Vd) Vd is defined as the volume of plasma that would contain the total body content of the drug at a concentration equal to that in the plasma V d = amount of drug in the body /plasma concentration SDL : http://www.icp.org.nz/ ( half life ??, bioavailability ) , Importance of drug distribution:: Importance of drug distribution: 1- Distribution is the process by which the drug reversibly leaves the blood stream and enters the extra cellular fluids and or cells of tissues. 2- Distribution allows the drug to reach the site of action e.g. cardiac muscles, CNS Some Factors affecting drug distribution : Some Factors affecting drug distribution Drug Chemical structure Mol.wt , polarity, lipid solubility Binding to blood components (, RBC, plasma albumin) Age : body composition ( water, lean body & fat ) Physiological state : pregnancy.( reduced albumin , larger amount of body fluids Rate of blood flow Capillary permeability ( see next figure ) Diseases Liver disease ( low plasma protein levels ) Renal impairment ( uraemia, low albumin ) Diabetes ( increase free Fatty acid ) Cystic fibrosis ( increase blood volume ) Binding of drugs to proteins to plasma proteins: Binding of drugs to proteins to plasma proteins *** Only free drug molecules can penetrate biological membranes and act at receptor site Many drugs bound to circulating plasma proteins such as albumin albumin : binds many acidic drugs and a few basic drugs b -globulin and an a 1 acid glycoprotein have also been found to bind certain basic drugs Drug - METABOLISM: Drug - METABOLISM *** Possible consequences of biotransformation include: 1- the production of inactive metabolites (most common), 2- metabolites with increased or decreased potencies, 3- metabolites with qualitatively different pharmacologic actions, 4- toxic metabolites, or 5-active metabolites from inactive prodrugs. … Aim of metabolism: Aim of metabolism Covert the drug to a more polar metabolite than the parent compounds. This increased polarity may lead to a more rapid rate of clearance Many Factors affecting drug metabolism: Many Factors affecting drug metabolism Genetic factors e.g. acetylation status Liver disease Other drugs hepatic enzyme inducers hepatic enzyme inhibitors Age ( extremes ) Impaired hepatic enzyme activity Elderly Children < 6 months (especially premature babies) This may lead to reduced clearance and longer half life Drug Metabolism (cont’d) ***: Drug Metabolism (cont’d) *** Two Phases: I and II Phase I: conversion to lipophilic cpds Phase II: conjugation Phase I involves the cytochrome P-450 system Ultimate effect is to facilitate elimination Drug Phase I Phase II Oxidation Reduction Hydrolysis Activation/Inactivation Conjugation Products Glucuronidation EXCRETION: EXCRETION The removal of intact drug molecule or its metabolites from the body Generally urine is the main route, Occasionally in bile , Little amount may be excreted. in milk, saliva volatile agents (general anesthetics) via lungs It is important for drugs that mainly eliminated by renal route Renal elimination is greatly affected by age & gender. Some drugs are nephrotoxic and reduce elimination of other drugs 1- Renal: most important route of elimination. : 1- Renal: most important route of elimination. Glomerular filtration: drugs are filtered into the urine depending on their molecular weight. Small molecules are completely filtered.   Active transport in the proximal tubule: drugs that are acids or bases in the plasma can be actively secreted into the tubular lumen by anionic and cationic transport systems.   Reabsorption in the distal tubule: nonionic diffusion back into the plasma, especially of lipid-soluble compounds.   Resources SDL, library &valuable web: Resources SDL, library &valuable web Introduction to pharmacology ( handout ) valuable web www.icp.org.nz (pK animation) www.rxkinetics.com/pktutorial SDL : visit the library , see Lippincott's What are the routes of administration , advantages and disadvantages ENTERAL: Oral – Sublingual- Rectal Parenteral : IV – IM- SC Others : Inhalation intranasal intrathecal ( into CSF ) S hare / Save E -mail A dd to Favorites        Fa cebook        De licious        Ya hoo Buzz        My Space        Wi ndows Live Favorites        Ya hoo Bookmarks        Tw itter        Di gg        Go ogle Bookmarks        Re ddit        St umbleUpon        Be bo Section 1 - Pharmacokinetic Concepts                                                                                                                                           www.rxkinetics.com ©Copyright 1984 - 2009, All rights reserved. RxKinetics, Plattsburg, MO 64477 This is a Norton safe site                                                                                                                                                                                                                           Pharmacodynamics: 10/08/2014 47 Pharmacodynamics What is Pharmacodynamic (PD)? What are receptors ?? Ligands- receptors interaction ? Major receptor families ? Dose response curve Agonist & Antagonist (types) Partial agonist Potency & Efficacy Therapeutic index &Therapeutic range Desensitization and Tachyphylaxis Optional further reading ( during summer vacation slides 20 -28 SDL ) Spare Receptors Details of about types of receptors What is Pharmacodynamic (PD): 10/08/2014 48 What is Pharmacodynamic (PD) PD deals with interaction of drugs with receptors. ( mechanism of drug action ) PD deals with relationship between the drug concentration at the site (s) of action and the magnitude of the pharmacological response What are receptors ?? : 10/08/2014 49 What are receptors ?? Receptors are cellular macromolecules to which a drug can bind to initiate a pharmacological response. Many Receptors are protein molecules , some are enzymes or nucleic acid. NB : Drugs only modify an already existing biochemical processes The term ligand may be used to describe any chemical substance that attach selectively to a particular receptor Explain Ligands- receptors binding ?: 10/08/2014 50 Explain Ligands- receptors binding ? The binding of drugs to receptors involve all types of chemical interaction Hydrogen bonding other weak electrostatic interaction Usually interaction is reversible Few cases , strong covalent bonds are formed ( long duration of action ) What are the major receptor families ?: 10/08/2014 51 What are the major receptor families ? Ligand – gated ion channels G-Protein coupled receptors* Enzyme – linked receptors** Cytokine receptors Intracellular receptors Animation : http://bcs.whfreeman.com/thelifewire/content/chp44/4403s.swf guanine nucleotide binding protein ** Also named Tyrosine – kinase linked receptors * PowerPoint Presentation: 10/08/2014 52 Ligand – gated ion channels: 10/08/2014 53 Ligand – gated ion channels Confined to excitable tissues and involved mainly in fast synaptic transmission Responsible for the flow of ions across cell membrane. Peak of Response is very rapid & Duration is very short ( both takes few milliseconds ) Ex Cholinergic Nicotinic _R ( acetylcholine,.. Na+ influx,.. contraction of Skeletal muscle ) -amino butyric acid (GABA A ) R (benzodiazepine, … Cl influx, … hyper polarization ) Ligand gated ion channel: 10/08/2014 54 Ligand gated ion channel Enzyme –linked receptors: 10/08/2014 55 Enzyme – linked receptors Binding of a Ligand to two of such receptors activates the kinaze , resulting in the phosphorylation of tyrosine residue of specific protein. (modification of the three dimensional structure of protein , molecular switch ) Ex. Insulin receptors. Duration of response is on order of min to hours. Intracellular receptors: 10/08/2014 56 Intracellular receptors The receptors are entirely intracellular. Ex Steroid hormones, thyroid hormones , Vit D The hormone which is lipid soluble diffuse through the cell membrane and binds to an intracellular receptor. This triggers dissociation of a small peptide. Ligand- receptor complex migrate to the nucleus In the nucleus it form homodiamer which binds to specific DNA SEQUENCE This alter gene transcription which lead to a change in specific cellular proteins expression. *some receptors are located in the nucleus Dose response relationship: 10/08/2014 57 Dose response relationship The intensity and duration of a drug ’ s effects are a function of drug concentration at the effect site Two types of Dose-response relationship Graded : Relates dose to intensity of effect e.g ……………………………………………… . Quantal : Relates dose to frequency of effect (All-or-none pharmacologic effect ) e.g ……………………………………………… .. Agonist & partial agonist : 10/08/2014 58 Agonist & partial agonist Agonist : A drug which binds to a receptor and activates it, producing a pharmacological response (contraction, relaxation, secretion, enzyme activation, etc.). Partial agonist : A drug A drug which binds to a receptor and activates it, producing a pharmacological response but less than full agonist Antagonist: 10/08/2014 59 Antagonist competitive bind reversibly to the receptors Their effect Can be overcome by increasing the concentration of agonist Example ……… A drug which binds to the receptors in common with an agonist, without causing their activating non competitive bind irreversibly to the receptors. Their effect Can’t be overcome by increasing the concentration of agonist Example……………. Partial agonist & Competitive antagonists: : 10/08/2014 60 Partial agonist & Competitive antagonists : Irreversible antagonist: 10/08/2014 61 Irreversible antagonist Their effect can’t be overcome by adding more agonist They causes downward shift of the Emax. Potency & Efficacy ***: 10/08/2014 62 Potency & Efficacy *** Potency is related to the amount of drug needed to produce a given effect. In graded dose-response potency of drugs are compared using EC50 (The dose producing 50 % of the maximum effect ) Efficacy Is the maximum effect an agonist can produce (Emax) Its More clinically important than potency . Potency & efficacy ***: 10/08/2014 63 Potency & efficacy *** drug A or B are more potent than drug C. Drug A has higher efficacy than drug B Quiz : Compare A & C ? Therapeutic Index: 10/08/2014 64 Therapeutic Index Is the ratio of the TD 50 to the ED 50 It represents an estimate of relative safety of the drug. For eample penicillin has a high therapeutic index as compared to digoxin which have a low therapeutic index Therapeutic range is clinically more important examples …………………………………………………………………………………………………………………………………………………………………………………………………………… .. Quantal dose response curve (A); Therapeutic index (B): 10/08/2014 65 Quantal dose response curve (A); Therapeutic index (B)

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