Pharmacokinetic and Pharmacodynamic Principles PDF

PHARMACOKINETIC PARAMETERS LEARNING OBJECTIVES Upon completion of this chapter, you will be able to  Describe the importance of steady state concentration and its role in obtaining therapeutic effects  Explain the concept of compartment model in pharmacokinetic evaluation  Analyze time-concen...

PHARMACOKINETIC PARAMETERS LEARNING OBJECTIVES Upon completion of this chapter, you will be able to  Describe the importance of steady state concentration and its role in obtaining therapeutic effects  Explain the concept of compartment model in pharmacokinetic evaluation  Analyze time-concentration relationship  List and describe the main targets for drugs  Explain the concept of drug interaction with its own target  List the characteristics of drug interaction with receptors  THERAPEUTIC CONCENTRATION  pharmacological effects of a drug - accessible concentration in target tissue  concentration of drug at its sites of action - related to the concentration of it in the systemic circulation  therapeutic effect - attain a sufficiently high concentration in the body  critical concentration - the amount of a drug needed to cause a therapeutic effect  THERAPEUTIC CONCENTRATION  Drug evaluation studies - determine the critical concentration required to cause a desired therapeutic effect  Recommended dose - based on the amount that must be given to eventually reach the critical concentration  too much - toxic (poisonous) effects  too little – no desired therapeutic effects  a drug concentration in the body - results from a dynamic equilibrium involving pharmacokinetic processes  COMPARTMENT MODEL  The analysis of the compartments – permits to establish a mathematic model starting from the concentration curve according to time unit  The models – can permit to obtain the final result using mathematic formula  Basic idea – the drug is uniform distributed in many compartments with the same speed  COMPARTMENT MODELS  Bi-compartment model K1 K2  Mono-compartment model Design and optimization of dosage regimens  THERAPEUTIC WINDOW  the therapeutic goal - maintain steady-state drug levels within the therapeutic window  limited number of drugs – effect easy to measure  used to optimize dosage using a trial-and- error approach  change dosage by no more than 50% and no more often than every 3-4 half-lives  many drugs - the effects are difficult to evaluate or the therapeutic index is narrow DOSE The amount of the drug administered to obtain a therapeutic effect Types of doses Therapeutic dose – assures the steady state concentration and the desired therapeutic outcome Toxic dose – average dose which may produce side effects Lethal dose – induces patient’s death In practice – dose/dose and dose/24 hours or dose/entire therapy MAINTENANCE DOSE  a series of repetitive doses or as a continuous infusion  to maintain a steady-state concentration of drug associated with the therapeutic window.  calculation of the appropriate maintenance dosage - a primary goal  chooses the desired concentration of drug in plasma  clearance and bioavailability for that drug in a particular patient,  the appropriate dose and dosing interval - can be calculated  THE EQUILIBRIUM STATE  Obtained after an interval of 4-5xT1/2  More easy to obtain it – loading dose  Dloading = Css ·Vd  Followed by maintenance dose Dloading = Css ∙ Vd D maintenance= Css ∙ Cl ∙ T  THERAPEUTIC WINDOW therapeutic window - a concentration range that provides efficacy without unacceptable toxicity lower limit – give half the greatest possible therapeutic effect, upper limit - no more than 5-10% of patients will experience a toxic effect THERAPEUTIC WINDOW  efficacy and toxicity - depend on concentration  small number of drugs - a small (2-3 fold) difference between concentrations resulting in different efficacy and toxicity  digoxin, theophylline, lidocaine, aminoglycosides, warfarin, cyclosporine, tacrolimus, sirolimus, anticonvulsants  plasma concentration range associated with effective therapy  drug concentrations – measured, dosage is adjusted  IV ADMINISTRATION  a single administration  a single compartment for distribution  first order pharmacokinetic  concentration in plasma = steady- state value  the infusion is discontinued - the concentration falls exponentially towards zero according to T1/2  REPEATED ADMINISTRATION  More frequent compared with single dose administration  Giving several doses – to obtain the steady state concentration  Oscillation between Cmax and Cmin  Minimize the amplitude of this oscillation – dose adjustment according to dosage forms  STEADY STATE CONCENTRATION. CSS  Equilibrium between administered doses and drugs elimination  Into the therapeutic window  Depends on  Administered dose  Frequency of administration  The oscillation between Cmax and Cmin – in the therapeutic window  ORAL ADMINISTRATION  cmax Complex process Dissolution of dosage forms Dissolution of active substance into the intestinal fluids Absorption through intestinal mucosa +/-First pass metabolism Tmax ORAL ADMINISTRATION  presence of drug into the blood – depends on 2 parameters  Cmax - peak of concentration – the maximal concentration  T max - the time to obtain Cmax  IV ADMINISTRATION Continuous pefusion  Q =Css · Cl  Q (or Kin) – perfusion debit  = the rate of perfusion (infusion) - the quantity to maintain the steady state concentration (= Css),  Cl=total clearance IV ADMINISTRATION IV ADMINISTRATION ORAL REPEATED ADMINISTRATION KEY MESSAGES  Critical concentration represents the amount of a drug needed to cause a therapeutic effect  Steady state concentration represents the equilibrium between administered doses and drugs elimination  Steady state concentration is obtained after an interval of 4-5xT1/2  Steady state concentration depends on administered dose and frequency of administration  Pharmacologic PHARMACODYNAMIC targets INTRODUCTION  Describe the effect of the drug  Drug’s effect – the results of its interaction with a final target  The interaction – a mutual recognition between the drug and the final target  Drugs – different affinity for the target  Intensity and duration – depend direct to drug concentration  1st concept Drugs influence quantitatively the physiologic functions of the target cell, but they do not initiate new functions  2ND CONCEPT. DRUG-TARGET INTERACTION “Corpora non agunt nisi fixata ”  The substances don’t act if they are not fixed on other structure. Paul Ehrlich (1854-1915, Nobel Prize 1908) 3RD CONCEPT. PHARMACOLOGIC EFFECT The intensity and duration of pharmacological effects are directly proportional to the concentration of the drug at its site of action The criteria used to evaluate a response to a specific drug is different according to the evaluation level IUPHAR – CELLULAR CONSTITUENTS THAT BIND DRUGS= TARGETS https://www.guidetopharmacology.org/targets.jsp MOLECULAR MECHANISMS - TARGETS  TARGETS  Interaction of the drugs with: 1. Receptors – antihistamines H 2. Enzymes – ACE inhibitors 3. Channels – calcium channel blockers 4. Transporters - diuretics  Physical interaction - lactulose  Chemical interaction – antacids  Pathogenic agents – bacteria, viruses  new drugs approved - therapeutic biologics (genetically engineered enzymes and monoclonal antibodies)  RECEPTORS AND CELLULAR RESPONSE  Receptors - proteins or glicoproteins which selectively recognize specific molecules  Ligands  Binding site - a specific part of the receptor with a high affinity for the ligand 37  RECEPTORS AND CELLULAR RESPONSE  Ligand-receptor interaction activates the receptor  A cascade of reactions follows (mediated by transductors)  Modifies one or more cellular functions  RECEPTOR – THE MAIN TARGET  Ligand - could be  hormone, neurotransmitter - endogenous ligand  drug – exogenous ligand  Agonist  Antagonist physiological receptors - 2 major functions ligand binding - LBD message propagation - transmembrane and intracellular signaling- effector domain 39 1. RECEPTOR  regulatory actions - exerted  directly on its cellular target(s),  effector protein(s),  conveyed by intermediary cellular signaling molecules - transducers  proximal cellular effector protein - not the ultimate physiological target  creates, moves, or degrades a small molecule or ion -second messenger system Drugs influence quantitatively the physiologic functions of the target cell, but they do not initiate new functions  ACTIVE BINDING SITES ON RECEPTORS  Orthosteric binding site – response (effect)  Allosteric binding site – regulation (intensity, velocity, parameters of the orthosteric activity) PHARMACOLOGIC RECEPTORS 44 19.10.2024 PHARMACOLOGIC RECEPTORS I. Transmembrane A. Ionotropic B. Receptors linked to G proteins C. Receptors linked to enzimes or with enzyme activity II. Intracellular – nuclear receptor 1.1. LIGAND ACTIVATED CHANNELS Nicotinic Receptor   1. IONOTROPIC RECEPTORS  Na+ K+  Ca 2+  Ligands – rapid mediators  Cl -  The action – milliseconds  The ion channel – inside the membrane (proteins)  Voltage gated channel and ligand gated channel  Drug coupled direct with the channel – permits to enter a selective ion, according to a chemical gradient  Receptor activation – membrane depolarization or hyperpolarization  The effect – a action potential, contraction, secretion, etc.  1. IONOTROPIC RECEPTORS Ligand Extracellular - Ach, GABA Intracellular - K dependent ATP-ase, G protein, cGMP Ions current – passive according to concentration gradient 1.2. G-PROTEIN LINKED RECEPTORS (GPCR) 1.2. G-PROTEIN LINKED RECEPTORS (GPCR) Large family of transmembrane receptors - 825 human GPCRs Ligands neurotransmitters -ACh, NE all eicosanoids and other lipid-signaling molecules peptide hormones opioids amino acids –GABA peptide and protein ligands the targets for many drugs - 30% of marketed drugs Orphan and other 7TM receptors Metabotropic glutamate receptors 5-Hydroxytryptamine receptors Motilin receptor Acetylcholine receptors (muscarinic) Neuromedin U receptors Adenosine receptors Neuropeptide FF/neuropeptide AF Adhesion Class GPCRs receptors Adrenoceptors Neuropeptide S receptor Angiotensin receptors Neuropeptide W/neuropeptide B Apelin receptor receptors Bile acid receptor Neuropeptide Y receptors Bombesin receptors Neurotensin receptors Bradykinin receptors Opioid receptors Calcitonin receptors Orexin receptors Calcium-sensing receptors Oxoglutarate receptor Cannabinoid receptors P2Y receptors Chemerin receptor Parathyroid hormone receptors Chemokine receptors Peptide P518 receptor Cholecystokinin receptors Platelet-activating factor receptor Complement peptide receptors Prokineticin receptors Corticotropin-releasing factor receptors Prolactin-releasing peptide receptor Dopamine receptors Prostanoid receptors Endothelin receptors Proteinase-activated receptors Estrogen (G protein-coupled) receptor Relaxin family peptide receptors Formylpeptide receptors Somatostatin receptors Free fatty acid receptors Succinate receptor Frizzled Class GPCRs Tachykinin receptors GABAB receptors Thyrotropin-releasing hormone Galanin receptors receptors Ghrelin receptor Trace amine receptor Glucagon receptor family Urotensin receptor Glycoprotein hormone receptors Vasopressin and oxytocin receptors Gonadotrophin-releasing hormone VIP and PACAP receptors receptors GPR18, GPR55 and GPR119 Histamine receptors Hydroxycarboxylic acid receptors Kisspeptin receptor Leukotriene receptors Lysophospholipid (LPA) receptors Lysophospholipid (S1P) receptors Melanin-concentrating hormone receptors Melanocortin receptors Melatonin receptors G-PROTEIN LINKED RECEPTORS (GPCR) G-PROTEIN LINKED RECEPTORS  receptor activation – interaction with a protein G  7 trans-membrane domains  multiple receptor subtypes within families of receptors  differ from each other in  ligand selectivity  coupling to G proteins (Gq, Gi, and Gs),  tissue distribution  exploited therapeutically through the development and use of receptor-selective drugs G-PROTEIN LINKED RECEPTORS G Proteins influences the activity of other enzymes  Adenylate cyclase  Phospholipase C Activating a second  Phospholipase A2 messenger system G PROTEINS  GPCRs couple to a family of heterotrimeric GTP-binding regulatory proteins - G proteins  signal transducers - convey the information from the receptor to one or more effector proteins  G–protein-regulated effectors  enzymes - adenylyl cyclase, phospholipase C, cyclic GMP phosphodiesterase (PDE6)  membrane ion channels selective for Ca2+ and K heterotrimer - composed from a guanine nucleotide-binding α subunit - specific recognition to both receptors and effectors, associated dimer of β and γ subunits - confer membrane localization of the G protein 23 α subunits - products of 17 genes 7 β subunits 12 γ subunits  DIMERIZATION regulate affinity and specificity of the complex for G proteins sensitivity of the receptor to phosphorylation by receptor kinases permit binding of receptors to other regulatory proteins - transcription factors G PROTEIN  G PROTEIN  four families - Gs, Gi, Gq, and G12/13  coupling GPCRs to relatively distinct effectors  Gs subunit - activates adenylyl cyclase  Gi subunit - inhibit certain isoforms of adenylyl cyclase  Gq subunit - activates all forms of phospholipase C  G12/13 subunits - couple to guanine nucleotide exchange factors (GEFs)  the signaling specificity of the large number of possible combinations is not yet clear  SECOND MESSENGER SYSTEM Cyclic AMP synthesized by the enzyme AC stimulation - mediated by the Gsα subunit inhibition – mediated by the Giα subunit 9 membrane-bound isoforms of AC and one soluble isoform three major targets in most cells: cAMP-dependent PKA cAMP-regulated GEFs termed EPACs via PKA phosphorylation, a transcription factor termed CREB In cells with specialized functions - additional targets 61  SECOND MESSENGER SYSTEM Gq-PLC-DAG/IP3-Ca2+ Pathway Ca2+ - is an important messenger in all cells regulate diverse responses gene expression, contraction, secretion, metabolism electrical activity 1.3. ENZYME-LINKED RECEPTORS 1.3. ENZYME-LINKED RECEPTORS 1. Guanylyl-cyclase receptors 2. Tyrosine-kinase type receptors 3. Serine/Threonine kinase type receptors 4. Tyrosine-phosphatase type receptors TYROSINE-KINASE TYPE RECEPTORS  Insulin receptor 67 Enzyme-linked receptors ENZYME-LINKED RECEPTORS  extracellular ligand-binding domains  an intrinsic enzymatic activity - on the cytoplasmic surface of the cell  tyrosine kinases (RTKs)- epidermal growth factor (EGF) and insulin receptors - intrinsic tyrosine kinases in the cytoplasmic domain of the receptor;  tyrosine kinase-associated receptors without enzymatic activity - receptors for interferon and cytokines, which recruit the cytoplasmic Janus tyrosine kinases (JAKs) ENZYME-LINKED RECEPTORS 1. receptor serine-threonine kinases -TGF- receptor 2. linked to other enzyme activities - receptors for natriuretic pepides 3. linked to cytoplasmic guanylate cyclase activity - NO receptors 4. receptors responsible for innate immunity, the Toll-like receptors 5. receptor for tumor necrosis factors (TNF-α)  1.4. INTRACELLULAR RECEPTORS  nuclear receptors - a superfamily of 48 receptors  respond to a diverse set of ligands.  receptor proteins - transcription factors able to regulate the expression of genes  controlling numerous physiological processes - reproduction, development, and metabolism  Intracellular receptors  receptors for steroid hormones, thyroid hormone, and vitamin D  receptors for a diverse group of fatty acids, bile acids, lipids, lipid metabolites  retinoic acid receptor (RXR)  liver X receptor (LXR)  farnesoid X receptor (FXR)  peroxisome proliferator-activated receptors (PPARs γ)  Steroid receptors  LXR and FXR receptors  in the inactive state - reside in the  reside in the nucleus cytoplasm  activated by changes in the  translocate to the nucleus upon concentration of hydrophobic binding ligand lipid molecules 72 73  INTRACELLULAR RECEPTORS  four major domains in a single polypeptide chain.  N-terminal domain - an activation region (AF-1) essential for transcriptional regulation  the DNA-binding domain - a very conserved region with two zinc fingers that bind to DNA  ligand-binding domain or LBD - responsible for binding the hormone or ligand  second activation region - specific sets of amino acid residues - binding co-activators and co-repressors 2. ION CHANNELS  gateways in cell membranes - selectively allow the passage of particular ions  open or close - variety of mechanisms  2 types - ligand-gated channels and voltage-gated channels  Ligand gated channels  open only when one or more agonist molecules are bound  properly classified as receptors  Voltage-gated channels - gated by changes in the transmembrane potential 2. ION CHANNELS ION CHANNELS  drugs - affect ion channel function  binding to the channel protein – extracellular ligand  affect channel function by an indirect interaction (G-protein) – intracellular ligand  plugs the channel physically blocking ion permeation – local anaesthetics (mechanically gated)  vasodilator drugs of the dihydropyridine - L-type calcium channels  benzodiazepine tranquillizers - GABAA receptor-chloride channel complex  sulfonylureas - ATP-gated potassium channels  3. ENZYMES  many drugs - target enzymes  drug molecule - substrate  a substrate analogue -competitive inhibitor of the enzyme - ACE inhibitors  irreversible and non-competitive inhibitors – aspirin  false substrates - drug molecule undergoes chemical transformation to form an abnormal product that subverts the normal metabolic pathway (fluorouracil, molnupiravir)  4. MEMBRANE TRANSPORTERS  movement of ions and small organic molecules across cell membranes - transporters  sodium pump (Na+-K+-ATPase)  MDR transporters  transport of organic molecules coupled to the transport of ions (Na+)  same direction - symport  opposite direction -antiport  the recognition sites - targets for drugs whose effect is to block the transport system 4. MEMBRANE TRANSPORTERS KEY MESSAGES  Pharmacodynamic describes the effect of the drug  Pharmacologic effect of a drug includes therapeutic and adverse effects  Drugs’ effects can be evaluated at different levels – molecule, cells, tissue, organs and body  To produce the pharmacologic effect a drug has to interact with a target  Drugs modulate the physiologic functions of the target cell, but they do not initiate new functions  KEY MESSAGES  The main targets are – receptors, enzymes, channels and transporters  There are 4 types of receptors: ionotropic, protein G coupled receptors, enzyme-linked and intracellular receptors  A drug is a ligand which recognize a specific binding site on receptor surface  There are 2 types of ion channels – voltage gated and ligand gated channel  A drug that interacts with an enzyme is named substrate DRUG RECEPTOR INTERACTIONS  DRUG RECEPTOR INTERACTION “Corpora non agunt nisi fixata ”  The substances don’t act if they are not fixed on other structure. DRUG RECEPTOR INTERACTION reversible – ligand dissociates after existing for a short time irreversible– ligand does not dissociate, is an inhibitory process Drug receptor interaction 86  DRUG RECEPTOR INTERACTION  Agonists - bind to physiologic receptors and mimic the regulatory effects of the endogenous signaling compounds  primary agonist - binds to the same recognition site as the endogenous agonist (the primary or orthosteric site on the receptor)  allosteric (allotopic) agonists - bind to a different region on the receptor (allosteric or allotopic site)  Partial agonists - only partly as effective as agonists regardless of the concentration employed  Antagonists - block or reduce the action of an agonist  Inverse agonists - drugs that stabilize receptors in an inactive conformation  some substances exhibit affinity without efficacy 88 19.10.2024  CHARACTERISTICS OF RECEPTOR BINDING 19.10.2024 89  CHARACTERISTICS OF RECEPTORS BINDING Affinity – a measure of how easily a drug will bind to a target protein  Concept of key and lock  Saturable and reversible (irreversible) process  The receptors -distributed differently between different organs Specificity = capacity of a drug to interact with a specific type of receptors Selectivity = capacity of a drug to interact with one specific receptor sub – type AFFINITY AND SPECIFICITY  Determined by the chemical structure of both the drug and the receptor  Chemical structure of the drug – specificity  interacts with a single type of receptor that is expressed on only a limited number of differentiated cells - high specificity (H2 receptor antagonist)  a receptor is expressed ubiquitously on a variety of cells throughout the body, drugs acting on such a widely expressed receptor - widespread effects (lidocaine, digoxin)  AFFINITY AND SPECIFICITY  Drugs - administered as racemic mixtures of stereoisomers  Enantiomers  Can exhibit different pharmacodynamic and pharmacokinetic properties  Sotalol, labetalol  The enantiomers have different therapeutic effects  One of the enantiomers has significant side effects  93 19.10.2024 AFFINITY AND SPECIFICITY  minor changes on drug molecule - major changes in its pharmacological properties  altered affinity for one or more receptors  exploit of structure-activity relationships - synthesis of valuable therapeutic agents  not alter all actions and effects of a drug equally  to develop a congener with  more favorable ratio of therapeutic to adverse effects  enhanced selectivity among different cells or tissues  more acceptable secondary characteristics  given drug - multiple mechanisms of action - depend  receptor specificity  the tissue-specific expression of the receptors  drug access to target tissues  drug concentration in different tissues  pharmacogenetics  interactions with other drugs KEY MESSAGE  The substances act as long as they stay fixed on target structure  The interaction could be reversible or irreversible  The interaction depends on drugs affinity, selectivity and specificity to their targets  Drugs can interact with their own targets as agonist of antagonist