Pharmacology Course PDF

Pharmacology 1 9/30/2024 PHARMACOLOGY COURSE  2 General objectives  The student must know the main information regarding drugs necessary for general pr...

Pharmacology 1 9/30/2024 PHARMACOLOGY COURSE  2 General objectives  The student must know the main information regarding drugs necessary for general practice:  Pharmaco-kinetics  Pharmaco-dynamics  Adverse effects, toxicology, interactions  Treatment principles:  therapeutic bases  administration modes Pharmacology 9/30/2024  3 Topics 1. General Pharmacology. 1. Hormones  General Pharmacokinetics.  Steroid hormones.  General Pharmacodynamics.  Thyroid hormones.  Pharmacovigilance.  Diabetes treatment. Oral antidiabetics. Insulins. 2. Neurotransmitters and chemical modulators.  Sexual hormones  Cholinergic autonomic system.  Adrenergic autonomic system.  Serotonin. Serotonin antagonists.  Histamine. Histamine antagonists. 9/30/2024 Pharmacology  4 References 1. Karen Whalen PharmD – Lippincott Illustrated Reviews: Pharmacology- Seventh, North American Edition, 2018 2. Ritter J. Rang and Dale’s Pharmacology 10th ed., Elsevier Churchill Livingstone, 2023 3. Erickson A, Parker J (Editors-in-Chief). Essential MedNotes 2023. 39th Edition. Toronto Notes for Medical Students, Inc., Toronto, 2023. 4. Vanderah TW. Katzung’s Basic and Clinical Pharmacology (16th edition) - McGraw Hill, 2023 5. Bruton L and Knollmann B. Goodman and Gillman's. The Pharmacological Basis of Therapeutics (14th edition). McGraw Hill Publishing, 2022 Pharmacology 9/30/2024  5 Evaluation  Prerequisite conditions  Physiology - regarding endogenous signal pathways – 1st semester  Essential microbiology – 2nd semester  The exam  Theoretical part – 70%  Practical part – 30% Pharmacology 9/30/2024  6 9/30/2024 Pharmacology Introduction in pharmacology  7 Learning objectives Upon completion of this chapter, you will be able to  Define pharmacology and its domains, drug and dosage form  Classify drugs based on different criteria  Describe the relationship between generic versions of drugs and their branded product.  Describe the relationship between generic name and brand names of drugs  Outline the mechanisms by which drugs are absorbed in the body to reach their sites of action  List the chemical characteristics of drugs and other factors that influence drug absorption. Pharmacology 9/30/2024  8 What is Pharmacology ?  a science –  Pharmacon + logos  the study of substances that interact with living systems through chemical processes  binding to regulatory molecules  activating or inhibiting normal body processes Pharmacology 9/30/2024  9 What is Pharmacology ? All the aspects regarding the drugs Pharmacology Pharmacokinetics Pharmacodynamics What body does to drug What drug does to body Pharmacotherapy (clinical pharmacology) Toxicology Pharmacology Pharmacogenomics 9/30/2024  11 Pharmacology 9/30/2024  12 What is Pharmacology ?  Pharmacotherapy (clinical pharmacology) – the correct usage of the drugs  Toxicology – side effects  Pharmacogenomics (pharmacogenetics) -genetic variations that cause individual differences in drug response Pharmacology 9/30/2024  13 Pharmacology  All the aspects regarding the drugs:  Origin, composition  Physical and chemical properties  Interaction with the body  The effects of the drugs  Clinical aspects  Administration mode Pharmacology 9/30/2024  14 Definition of drug  Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis.  Directive 2004/27/EC of the European Parliament (March 2004) Pharmacology 9/30/2024  15 The origin of the drugs  Natural  Plants, animal, minerals  Synthesis  Bio-technology – DNA recombinant technique, transgenic mice, PCR Pharmacology 9/30/2024  16 Drug classification 1. Origin 2. Composition – simple/combined 3. Chemical composition – acids/bases/salts 4. Physical aspect – dosage forms 5. Type of drugs Pharmacology 9/30/2024  17 Composition  Simple drug – a single active substance  Complex drug – more than one active substance  Chemical composition  Acids  Bases  Salts Pharmacology 9/30/2024  18 Physical nature  Solid  Liquid  Gaseous  Determine the best route of administration Pharmacology 9/30/2024  19 Types of drugs  Prophylactic treatment  Substitution treatment  Etiologic treatment  Pathogenic treatment  Symptomatic treatment Pharmacology 9/30/2024  20 Classification  Molecular mechanisms – pharmacological classification (agonist, antagonist, ie)  Therapeutic actions – clinical classification (analgesics, anti-inflammatory, anti- hypertensive, ie) Pharmacology 9/30/2024  21 Drug denomination 1. Chemical name : N-(4-hydroxyphenyl)acetamide 2. Official=international=approved =generic name paracetamol 3. Brand=commercial=proprietary name (trade mark) Panadol Pharmacology 9/30/2024  22 Drug denomination Pharmacology 9/30/2024  23 Pharmacology 9/30/2024  24 1. Original drug – the first one approved on the market 2. Generic drug Pharmacology 9/30/2024  25 Types of drugs 1. Original drug – the first one approved on the market 2. Generic drug  a drug product that is comparable to a brand/reference listed drug product in dosage form, strength, quality and performance characteristics, and intended use  the same active ingredients as the original formulation  identical or within an acceptable bioequivalent range to the brand-name counterpart with respect to pharmacokinetic and pharmacodynamic properties  lower prices  biopharmaceuticals (monoclonal antibodies) = biosimilars Pharmacology 9/30/2024  26 Bioequivalence Two drugs, containing the same active substance, in the same amount have the same bioavailability OR NOT depends on the excipients used the pharmaceutical formulation and preparation It is not depending on the synthesis of the active principle, which is always equivalent by definition! Pharmacology 9/30/2024  27 Key messages  Pharmacology – a complex science with different branches  A drug - substance or combination of substances used for preventing or treating disease in humans  Classification of drugs – different criteria: origin, composition, physical nature, intervention in pathological process  Drug’s names – generic name and brand names  Drugs’ type – original vs generic Pharmacology 9/30/2024 28 Pharmacology 9/30/2024 Pharmacokinetic Information which allow to choose the optimal route of administration and to adjust the dose for a correct use of drug information that makes it possible to know the therapeutic indications and the effects of the drug  30 Introduction  The study of drug transformation into the body  Provides a scientific basis for dose selection  4 stages  absorption from the site of administration  distribution within the body  metabolism  excretion Pharmacology 9/30/2024  31 Drugs effect 1. General action – the drug acts at long distance from the site of administration 2. Local action – topical administration (skin, aerosols)  absorption - not required for the drug to act  the drug - enter plasma Pharmacology 9/30/2024  What happens after drug administration on a certain route?  Drug at site of administration Absorption Passage across different body membranes  33 Absorption  the passage of a drug from its site of administration into the plasma  important for all routes of administration (except iv and topical route)  Local (topical administration) - systemic absorption is not required for the drug to act Pharmacology 9/30/2024  34 Absorption  2 phases 1. Pharmaceutical phase  Release of the active substance from the dosage forms  Different duration – type of the dosage form 2. Absorption – passage across different membranes to systemic circulation  Route of administration Pharmacology 9/30/2024 Absorption Disintegration and dissolution ABSORPTION Absorption Drug passage across the membranes  For a drug to permeate a cell, it must obviously cross its cellular membrane. Barriers to drug movement may be  a single layer of cells (intestinal epithelium)  several layers of cells (skin).  38 Cell Membranes  a bilayer of amphipathic lipids,  hydrocarbon chains oriented inward to form a continuous hydrophobic phase  hydrophilic heads oriented outward.  membrane proteins embedded in the bi-layer - as receptors  elicit electrical or chemical signaling pathways and provide selective targets for drug actions. Pharmacology 9/30/2024  39 Pharmacology 9/30/2024  40 Membranes. Types of Membranes 1. Cell Membranes  permeable to many drug molecules but not to others,  depending on their lipid solubility.  small pores (8A) - small molecules such as alcohol and water to pass through. Pharmacology 9/30/2024  42 Membranes 2. Walls of Capillaries  pores between the cells  larger than most drug molecules - allowing them to pass freely  liposolubility - not a factor. Pharmacology 9/30/2024  43 Membranes 3. Blood/Brain Barrier  a protective environment for the brain.  speed of transport across this barrier - limited by the lipid solubility of the psychoactive molecule  inflammatory conditions - usually alter permeability Pharmacology 9/30/2024  45 4. Placental Barrier  separates two distinct human beings  very permeable to lipid soluble drugs Pharmacology 9/30/2024  46 The passage through membranes 1. Passive transport 2. Specialized transport – facilitated diffusion and active transport 3. Endocytosis  In several pharmacokinetic processes:  absorption  distribution  elimination Pharmacology 9/30/2024  47 The passage through membranes 1. Passive transport  For liposoluble, non - ionized molecule  Without energy consumption  According to a gradient concentration  Not saturable  There is no competition between drugs Pharmacology 9/30/2024 Passive transport  49 1. Passive transport  Non ionized, liposoluble molecule  Majority of the drug – ionized in solution (weak electrolytes)  pH partition theory – the amount of the transfer is depending on non ionized fraction  The ratio between ionized and non – ionized fraction – defined by Henderson- Hasselbach equation  Depending on pH and pKa  Weak base - pH = pKa + log [B]/[BH+]  Weak acid - pH = pKa + log [A-]/[AH] Pharmacology 9/30/2024  50 Pharmacology 9/30/2024  51 Pharmacology 9/30/2024  52 - 50% 50% a pH= 4.4 99% 1% a pH= 3.4 1% 99% a pH= 5.4 0,1% 99,9% a pH= 6.4 Pharmacology 9/30/2024  53 Pharmacology 9/30/2024  54 Ketoconazole Cp (mcg/ml) 8 Plasma concentration of 7 6 Keto 5 4 K + Sucral Ketoconazole 3 K + Ranit 2 1 0 0 0.5 1.5 2.5 4 6 12 Hours Pharmacology 9/30/2024  55 2. Specialised transport 2.1. Facilitated diffusion  According to a gradient – concentration, electrical  Higher speed  Using a transporter, ion channel  Saturable process  Competition between drugs  Different types – uniport, simport, antiport  Ex: the absorption of steroids and amino acids from the gut lumen, the absorption of glucose Pharmacology 9/30/2024  Facilitated diffusion 56 extracellular intracellular Pharmacology 9/30/2024  Facilitated diffusion 57 Pharmacology 9/30/2024  58 Facilitated diffusion Pharmacology 9/30/2024  Facilitated diffusion 59 Pharmacology 9/30/2024  60 Facilitated diffusion Pharmacology 9/30/2024  61 Facilitated diffusion Pharmacology 9/30/2024  62 Facilitated diffusion Pharmacology 9/30/2024  Facilitated diffusion 63 Pharmacology 9/30/2024  Facilitated diffusion 64 Pharmacology 9/30/2024  65 Facilitated diffusion Pharmacology 9/30/2024  66 2. Specialised transport 2.2. Active transport  Against to a gradient  With energy consumption – ATP  Low speed  Specificity for one substance, or group  Saturable process  Entrance and elimination of the drugs from the cells  Competition between drugs or substances  Drugs similar to physiological molecules Pharmacology 9/30/2024 Image source: Kaplan, Physiology  Active transport 68 Extracellular Intacellular Pharmacology 9/30/2024  Active transport 69 Pharmacology 9/30/2024  Active transport 70 ATP Pharmacology 9/30/2024  Active transport 71 ADP +P Pharmacology 9/30/2024  Active transport 72 Pharmacology 9/30/2024  Active transport 73 Pharmacology 9/30/2024  Active transport 74 Pharmacology 9/30/2024  75 Pharmacology Image source: Kaplan, Physiology 9/30/2024  76 2. Specialised transport  2 major family – SLC and ABC transporters  Coded by 300 genes  Polymorphic variation in the genes coding SLCs and P-gp - individual genetic variation in responsiveness to different drugs  Act mainly on endogenous substrates, important for drugs  Main sites of SLCs  the blood-brain barrier  the gastrointestinal tract  the renal tubule  the biliary tract  the placenta Pharmacology 9/30/2024  77 2. Specialised transport  SLC – 2 transporters – OCTs and OATs  facilitate the process of transmembrane equilibration of a single transported species – uniport  OCT – dopamine, choline, quinine, procainamide  OCT2 – in the nephron (proximal tubular cells) – concentrate cisplatin  Other SLC - coupled to the electrochemical gradient of Na+ or other ions across the membrane  OATs – responsible for renal secretion of urate, PG, vitamins, antibiotics, antiviral, NSAIDs Pharmacology 9/30/2024  78 2. Specialised transport  P-glycoproteins (P-gp) - belong to the ABC transporter superfamily,  second important class of transporters,  responsible for multidrug resistance in cancer cells  in renal tubular brush border membranes,  in bile canaliculi,  in astrocyte foot processes in brain microvessels,  in the gastrointestinal tract.  often co-located with SLC drug carriers Pharmacology 9/30/2024  79 P-glycoproteins (P-gp) Pharmacology 9/30/2024  81 3. Endocytosis and exocytosis  few substances - so large or impermeant  carried into the cell - newly formed vesicle inside the membrane  released inside the cytosol - breakdown of the vesicle membrane  vitamin B12, iron  the reverse process – exocytosis  secretion of many substances from cells  neurotransmitter – stored in membrane-bound vesicles Pharmacology 9/30/2024  82 3. Endocytosis and exocytosis Endocytosis Exocytosis Pharmacology 9/30/2024 83 Pharmacology 9/30/2024 1. Absorption  84 Absorption  The factors that influence the absorption  Depending on drug  Depending on patients Pharmacology 9/30/2024  85 Absorption  Depending on drug  Physical and chemical characteristics - pKa, concentration  Solubility - lipo or hydro solubility  Size  Dosage form – normal tablets, capsules, sustained release tablets  Quantity and concentration at the site of administration Pharmacology 9/30/2024  86 Pharmacology 9/30/2024  87 Size  Most of the drugs – 100-1000 MW  Lower limit - set by the requirements for specificity of action  Upper limit - determined primarily by the requirement that drugs be able to move within the body  Large drugs - administered directly into the compartment where they have their effect Pharmacology 9/30/2024  88 Absorption  Depending on patient  pH of the environment – gastric and intestinal pH  surface – larger surface – greater absorption Pharmacology 9/30/2024  89 Absorption  Time exposure – intestinal transit changes  Circulation – muscles vs fat tissue, vasodilators and vasoconstrictors  Age  Foods Pharmacology 9/30/2024  90 PK interactions influencing absorption 1. Chelation and binding of the drug 2. Alteration of gastric pH (with different ionized state of the drug) 3. Adsorbtion on non-absorbable compounds 4. Alteration of gastro-intestinal movements and transit 5. Alteration of physiological bacterial flora 6. Alteration of intestinal mucosa Pharmacology 9/30/2024 Chelation 91 Tetracycline + Al3+, Ca2+ o Mg2+ Chelation of tetracycline or iron salts resulting a (ex. Antiacids) non-absorbable complex Tetracycline absorbtion Pharmacology 9/30/2024 Gastrointestinal transit alterations 92 Anticholinergic (atropine) Antihistaminics Antidepressants Opioids (morphine, codeine) Delaying stomach evacuation + Reduced macrolide absorption Macrolides Pharmacology 9/30/2024  Gastrointestinal transit alterations 93 Prokinetics (domperidone, metoclopramide) Augmented gastric evacuation + Augmented macrolide absorption Macrolides Pharmacology 9/30/2024 Increase of gastric pH 94 Antiacids Gastric secretion inhibitors (Anti-H2, omeprazole) Increase of gastric pH, with disturbing ionization state and liposolubilty of several drugs + Reduced absorption Antibiotics and/or antimycotic Tetracycline Fluorochinolones Lincomicine Ketoconazole Itraconazole Pharmacology 9/30/2024  95 Key messages  Pharmacokinetic - the study of drug transformation into the body  4 stages – absorption, distribution, biotransformation (metabolism and excretion)  Absorption – passage across different membranes to systemic circulation  Absorption – depends to route of administration  Factors that influence drugs’ absorption are related to drug’s properties or patients’ characteristics Pharmacology 9/30/2024  96 Key messages  The cell membrane functions as a fluid barrier made of lipids and proteins. The arrangement of the lipoprotein membrane controls what enters and leaves the cell.  Passage through cell membranes – passive and specialised transport (facilitated diffusion and active transport), endocytosis.  Specialized transporter - 2 major family – SLC and ABC transporters Pharmacology 9/30/2024