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Responding to ill Health Life Science Pharmacology Abinoam Jr. (2007) https://commons.wikimedia.org/wiki/File:Comprimidos.jpg 1 Learning Outcomes 1. Define the terms- pharmacodynamics, pharmacokinetics. Outline the different stages in pharmacokinetics, including first-pass metabolism. 2. Outline the concepts of drug half-life, steady state and therapeutic range. 3. Define and give an example of analgesics & antibiotics. Briefly explain their physiological effects and summarise common side effects of these drugs. 2 Pharmacology (revision) What is pharmacology? The study of how chemical agents affect the tissues or cells of the body What is a drug? Any chemical agent that affects the tissues or cells of the body 3 Pharmacokinetics and Pharmacodynamics (revision) 2 branches of pharmacology • Absorption Pharmacokinetics • what the body does to drugs • Distribution • Metabolism • Excretion Pharmacodynamics • what drugs do to the body (their mechanism or mode of action) Insulin • binds to specific receptors on target (liver, muscle, fat) cells • increases glycogen storage - lowers blood glucose 4 First-pass effect (revision) • Oral drugs absorbed from GI tract sent to liver through hepatic portal vein • Drugs partially metabolised by the liver enzymes before entering general circulation • If “first-pass” metabolism is extensive, very little drug survives to reach the systemic circulation – need other route of administration UWS Staff (2015) Drug plasma levels Concentration of drug in plasma over time depends on: – Route of administration – Rate of metabolism – Rate of excretion 6 Drug plasma levels - administration 140 Intravenous 120 Plasma Drug Concentration 100 80 Intramuscular 60 Oral 40 20 0 0 20 40 60 80 100 120 140 160 Time UWS Staff (2015) Drug plasma levels • speed of drug metabolism & excretion is important clinically • a rapidly metabolised/ excreted drug needs – higher dose – possibly more frequent administration • measure of speed of removal of drug from plasma = HALF LIFE 8 Elimination Half-life 140 Plasma Drug Concentration 120 100 80 60 40 Half-life 20 0 0 20 40 60 80 Time • Time taken for plasma drug concentration to fall to half the starting value • Half-life is characteristic of a particular drug • Drug half-lives vary from minutes → days. UWS Staff (2015) Drug elimination half-life Plasma drug concentration 100 Plasma Drug Concentration v Time (showing half-life determination) Can you determine the plasma drug concentrations after 40 minutes and 60 minutes? 50 ? ?? 0 0 Half-life 20 40 60 80 Time (minutes) UWS Staff (2015) Different drugs have different elimination half-lives 100 Plasma drug concentration Three drugs with different half-lives 50 ? 0 0 Half-life 20 40 60 80 Time (minutes) • slow metabolism/excretion – long half-life • rapid metabolism/excretion – short half-life • important in determining frequency of administration UWS Staff (2015) Dosing regimes Drugs only effective if: • present at target site at high enough concentration • maintained at target site for sufficient time • actual concentration and time needed depend on: – drug – clinical situation • adrenaline (cardiac rhythm) – seconds/minutes • antibiotics - days • dose must be correct to maintain blood levels within specific limits – Therapeutic range Dosing regimes & therapeutic range UWS Staff (2015) Repeated drug doses Dosing intervals for a particular drug depend on both: • Half –life – Short half-life - frequent administration – Long half-life - less frequent • Therapeutic range 14 Dosing intervals • Which dosing frequency is best? • Which dosing frequency is too low? UWS Staff (2015) Steady state • Eventually (if dosing frequency great enough) plateau reached - steady state • Drug input & excretion/metabolism roughly equal • Large initial dose (loading dose) followed by smaller repeated (maintenance) doses steady state more quickly • Age, genetic factors & health affect pharmacokinetics, also drug interactions Loading dose administered to achieve therapeutic range, prior to maintenance doses UWS Staff (2015) Variability in patient response Patient response is influenced by: – Body weight / Surface Area Different volume of body fluids different concentration of drug in the body different response – Age • Very young / elderly may show different response to norm: – Liver & renal function – Interactions (e.g. with alcohol) • 2 different drugs: each can influence handling of / response to the other – Pregnancy • Changes in blood volume, plasma protein levels, cardiac output – Illness • Liver & renal function 17 Pharmacodynamics How do drugs work (mechanism of action)? • usually by binding to a specific protein in or on cells • binding results in a biological response Biological Effect + Drug Protein • Drug target • Drug receptor UWS Staff (2015) Pharmacodynamics Drug Targets e.g. Receptor proteins on the surface of cells • Proteins designed to respond to natural molecules (hormones, neurotransmitters) • Activation changes the activity of the cell Drugs may be designed to bind to these receptors • Shape of drug molecules “fits” into receptor Endogenous hormones or neurotransmitter Drugs can mimic the effect (agonist) Binds to then activates a receptor Change in cell activity Or drugs can fit into the receptor but not activate it (but block endogenous agents) Hottuna080 (2013) https://commons.wikimedia.org/wiki/File:Lock_and_key.png 20 adapted by UWS Staff (2105) Drug Classes Agonists Hormone • Drugs that activate the receptor, bringing about the “natural” change in the cell Drug • Mimic natural ligand e.g. hormone • Adrenaline (hormone) • β-adrenoreceptor agonists (drug) UWS Staff (2015) Drug Classes Antagonists – Do not activate the receptor – Block binding by “natural” activators – Prevent activation of the receptor – e.g. beta-blockers antagonist UWS Staff (2015) Specificity of drug binding Drug X Drug Y Drug Z binds B binds A SIDE EFFECTS! SPECIFIC Receptor A Cell A Receptor B Cell B UWS Staff (2015) Analgesics Analgesia (an- “without”; algesia – “the sensation of pain”) • Tissue damage pain receptors stimulated • “message” cortex of brain interpreted as pain 2 major pharmacological groups of analgesics: • Opioids act on CNS • Non-opioids: e.g. NSAIDS & paracetamol act on site of tissue damage NSAID – Non-Steroidal Anti-Inflammatory Drug) 24 NSAIDS & paracetamol • Tissue damage inflammatory response • Brought about by e.g. prostaglandins, make pain receptors more sensitive to pain • Cyclooxygenase (COX) enzymes needed to make prostaglandins • NSAIDS inhibit COX enzymes (NB mechanism of paracetamol not entirely clear) • Therefore reducing sensitivity of pain receptors & reducing pain 25 Perception of pain • After tissue injury, “pain message” peripheral nerves spinal cord brain • Can this message pathway can be blocked ??? • Endorphins (and others) - body’s “natural” painkillers • Gentle rubbing eases pain by stimulating touch receptors → blocks passage of pain signals at synapses • Drugs? • Opioid analgesics mimic action of endorphins 26 Opioid action UWS Staff (2015) Opioid side effects • Euphoria (high) • Sedation (Morpheus) • Respiratory depression • Chronic use – dependence • Cross placenta – respiratory depression in newborn. 28 Other mechanisms • Local anaesthetics (e.g. for use in dental surgery or epidural administration during childbirth) • Other classes of analgesics do not act through previously mechanisms (e.g. flupirtine, amitriptyline and gabapentin) and are not discussed here. 29 WHO analgesic ladder Discussed further by HNM staff STEP 3 strong-moderate pain strong opioid (e.g. morphone) ±nonopioid ±adjuvant adjuvant STEP 2 Mild-moderate pain Weak opioid (e.g. codeine) ±nonopioid ±adjuvant adjuvant STEP 1 Mild pain Non-opioid (e.g. paracetamol, aspirin or other NSAIDs) ±adjuvant Modified from WHO, UWS Staff (2015) Antibiotics • Antibacterials (drugs used to treat bacterial infection) • Bacteriocidal • Bacteriostatic Problems • Selective toxicity (should be toxic to bacteria but not to patient) • Resistance (many bacteria now able to survive drug treatment) 31 Mechanisms of action 1. Inhibition of cell wall synthesis •Penicillins, cephalosporins •Prevent cell wall formation as cells divide •Drug activity relies on a β-lactam ring •Some bacteria produce an enzyme β-lactamase antibiotic resistant •Side effect - allergy! Vaccinationist (2013) https://commons.wikimedia.org/wiki/File:Hetacillin_structure.svg 32 Mechanisms of action 2. Inhibition of DNA or protein synthesis • Prevent bacteria dividing • Cells cannot synthesise essential components transcription DNA translation mRNA protein UWS Staff (2015) Author: Kendrick Johnson https://commons.wikimedia.org/wiki/File:Antibiotics_Mechanisms_of_action.png Wiki commons Antibiotic mechanisms 34 Other drug mechanisms Where else do drugs act? • Ion channels • local anaesthetics (block sodium channels) • Transport molecules • antidepressants (block neurotransmitter transport) • Enzymes – ACE (protease) inhibitor - hypertension • Nucleic acid interference e.g. DNA replication blocked • anti-cancer (chemotherapy) drugs, as well as antibiotics Drug Interactions • People often take more than one drug • Different drugs may interact causing changes in their activity – Interactions may affect pharmacokinetics (absorption, distribution, metabolism, excretion) – Interactions may affect pharmacodynamics - drugs effects on the body • Beneficial interactions – e.g. cytotoxic ‘cocktail’ for cancer chemotherapy • Adverse interactions 36 Adverse drug interaction e.g. sulphonamides and warfarin • Interactions in plasma changing protein (albumin) binding • Albumin binding creates drug ‘reservoir’ • Interaction ↑ free warfarin to dangerous levels UWS Staff (2015) Sources of Information • Pharmacology textbooks • British National Formulary www.bnf.org 38