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BIOP211 Session 4 Pharmacology Toxicology Department of Bioscience www.endeavour.edu.au BIOP211 Pharmacology Toxicology – broad areas of study Toxicodynamics o Overdose of pharmaceuticals, herbs and poisons. o Lifespan issues. o Adverse Drug Reactions (ADR) and Risk Management / Characterisation by the TGA. Toxicokinetics: Absorption, distribution and excretion of toxins, Biotransformation of xenobiotics. New drug investigations (or old drug, new developments). © Endeavour College of Natural Health www.endeavour.edu.au 2 Toxicology o Scope of Toxicology includes Pharmacology, Adverse Drug Reactions (ADR) and interactions explained by toxicokinetic and toxicodynamic studies. o Risk Assessment puts together all the available toxicity data on drugs, herbs. o Overdose of certain toxins including drugs, is treated with antidotes, if available. Lifespan issues (age, pregnancy, lactation, childhood, elderly) also affect the risk assessment picture in overdose situations. © Endeavour College of Natural Health www.endeavour.edu.au 3 Scope of Toxicology “A toxin is any agent capable of producing a deleterious response in a biological system” (Eaton & Gilbert in Klaasen & Watkins, 2010, p5) Toxic Agents: Social aspects e.g. Alcohol, tobacco, prohibited substances (Schedule 9) Environmental & Occupational poisons e.g. Pesticides, heavy metals, air pollutants, solvents, vapours. Schedule 5 (agricultural, industrial, domestic substances - caution). Schedule 6 (caution or poison if for internal or external use), Schedule 7 (dangerous poison) Ecological aspects & toxic plants, fungi, algae. Toxic terrestrial animals , envenomations. Medical aspects & other biological toxins (xenobiotics) Radiation Xenobiotics (foreign organic chemicals that enter a biological system) also include herbs, foods, Schedule S2, S3, S4, S8 drugs, OTC drugs, CAM, plant- animal- or microbial-origin toxins © Endeavour College of Natural Health www.endeavour.edu.au 4 Scope of Toxicology – Toxins (inorganic, organic including xenobiotics) Deleterious Agent Ethanol CH3CH2OH recreational drug not Schedule 9 Sodium chloride Na Cl Ferrous sulphate FeSO4 Morphine sulphate C17H19NO3)2 H2SO4.5H2O Schedule 8 LD50 (mg / kg body mass) 10 000 Dose in mg/kg 4 000 body mass causing death in 1 500 50% of exposed 900 animals = LD 50* Phenobarbital sodium C 11 H 17 N 2 O 3 Na Schedule 8 150 Strychnine sulfate (C21H22N2O2)2.H2SO4.5H2O Schedule 7 2 Nicotine C10-H14-N2 in recreational drug not Schedule 9 1 Tubocurarine C37H41N2O6 naturally occurring alkaloid 0.5 Tetrodotoxin C11H17N3O8 (puffer fish 2nd most toxic vertebrate) 0.10 Dioxin (carcinogenic, teratogenic DCDD C12H6Cl2O2) 0.001 Botulinum toxin (Clostridium botulinum bacteria most deadly neurotoxinC6760H10447N1743O2010S32 0.00001 ** acute toxicity does not give information about chronic toxicity e.g. oncogenic, carcinogenic or teratogenic effects © Endeavour College of Natural Health * Depends on animal system used – see Material Safety Data Sheets MSDS for acute toxicity data ** www.endeavour.edu.au 5 Principles of Toxicology Principles of Toxicology : based on exposure to toxin, but depends on dose; and this leads to a measureable response. Time is also a critical parameter Factors to consider: • Basic areas of Toxicokinetics are dose–response calculations e.g. TD 50 & other parameters, including vol. of distribution, which for toxins, often involves many tissues. • Routes & sites of exposure, timing of exposure: In studying Hazards and exposed populations, exposure assessment, Risk characterization, Risk management & legislation issues. • Consider idiosyncratic reactions in population data though • Acute lethality, LD50, studies for material safety data sheets (MSDS), and Sub-acute (repeated dose), Skin & eye irritation and Skin sensitization studies. • Subchronic studies or repeated dose studies require measurement of the LOAEL. • Chronic Toxicity, Oncogenicity studies are needed to find MTD, max tolerable dose. © Endeavour College of Natural Health www.endeavour.edu.au 6 Toxicokinetic parameters Dose range and safety margin, pharmacokinetic and toxicokinetic parameters are CL, Vd, t1/2 • therapeutic range (minimal toxicity). Range predicted EC50 individual dose. Margin of safety e.g. TI=TD50/ED50, population dose-response curves • clearance (CL) - drugs (maintenance dose), xenobiotic (non-drug) clear from all compartments. • volume of distribution (Vd) – drugs(loading dose), xenobiotic (non-drug), often ≥2 compartments. • half life elimination (t½) - drugs ( dosing interval), xenobiotics (non-drug) sufficient t1/2 to clear toxin. © Endeavour College of Natural Health www.endeavour.edu.au 7 Dose-response Curves • The dose-response relationship is a fundamental and essential concept in toxicology. • On exposure, generally, the higher the dose, the more severe the response. • Dose-response curve should also correlate to the effects induced. • The dose-response relationship is based on observed data from experimental animal, human clinical, or cell studies. © Endeavour College of Natural Health www.endeavour.edu.au 8 Principles – Dose estimates for drugs/other xenobiotics o Dose-response curves are used to measure dose estimates of chemical substances (dose estimates are used to predict the risk / effects induced). o Dose Estimates of Toxic Effects are the LD, ED or TD (lethal dose, effective dose or toxic dose). o For acute toxicity the dose estimate used is the LD50 (Lethal Dose 50%). o LD50 is a statistically derived dose at which 50% of the individuals will be expected to die. © Endeavour College of Natural Health www.endeavour.edu.au 9 LD50 as a Dose Estimate Courtesy of: A. Nair © Endeavour College of Natural Health www.endeavour.edu.au 10 Other Dose estimates for xenobiotics o Other dose estimates also may be used. LD0 represents the dose at which no individuals are expected to die. This is just below the threshold for lethality. o LD10 refers to the dose at which 10% of the individuals will die. o For inhalation toxicity, air concentrations are used for exposure values. Thus, the LC50 is utilized which stands for Lethal Concentration 50%, the calculated concentration of a gas lethal to 50% of a group Occasionally LC0 and LC10 are also used. © Endeavour College of Natural Health www.endeavour.edu.au 11 Effective Doses (EDs) o Effective Doses (EDs) are used to indicate the effectiveness of a substance o Normally, effective dose refers to a beneficial effect (relief of pain). o ED might also stand for a harmful effect (paralysis). Thus the specific endpoint must be indicated. o The usual terms are: Term Meaning ED10 Effective dose for 10% of the population compared to a control population ED50 Effective dose for 50% of the population (compared to control) ED90 Effective dose for 90% of the population (compared to control) © Endeavour College of Natural Health www.endeavour.edu.au 12 Toxic Doses (TDs) o Toxic Doses (TDs) are used to indicate doses that cause adverse toxic effects. o The usual dose estimates, calculated from dose response curves, are: Dose Estimate Meaning TD0 Dose that is toxic to 0% of the population TD10 Dose that is toxic to 10% of the population TD50 Dose that is toxic to 50% of the population TD90 Dose that is toxic to 90% of the population o In vitro tests can predict toxic doses in populations of animals or humans. o E.g. epidermal keratinocytes & corneal epithelial cell models in vitro used to predict cutaneous & ocular toxicity in vivo. © Endeavour College of Natural Health www.endeavour.edu.au 13 o Toxicology - Comparison of ED & TD Knowledge of the effective dose and toxic dose levels helps the toxicologist and clinician in determining the relative safety of therapeutic goods (pharmaceuticals, herbs etc) o A drug has been tested at increasing doses in a population of individuals. Note on the doseresponse curve that the dose that is 50-75% effective does not cause toxicity. o However, note on the doseresponse curve that a dose that is 90% effective, overlaps the doseresponse curve for the specified toxic response o Thus at the ED90 there may be a small amount of toxicity (TD1 or TD2) Courtesy of: A. Nair) © Endeavour College of Natural Health www.endeavour.edu.au 14 NOAEL and LOAEL o Margins of safety are estimated using threshold measures. o Threshold is a dose where a response is just seen (LOAEL) or it just disappears from the population. Margin Meaning of Safety NOAEL Highest data point on the dose-response curve where no significant toxic or adverse effect was observed (no observed adverse effect level). LOAEL Lowest data point on the dose-response curve where there was an observed toxic or adverse effect (lowest observed adverse effect level) that was significant. © Endeavour College of Natural Health www.endeavour.edu.au 15 Toxicology – NOAEL & LOAEL from dose – response curve, population data Threshold measures from the dose response curve: • No Observed Adverse Effect Level (NOAEL) • Lowest Observed Adverse Effect Level (LOAEL) © Endeavour College of Natural Health www.endeavour.edu.au 16 Therapeutic Index, TI, and Margin of Safety (MofS) o The Therapeutic Index (TI) is used to compare the therapeutically effective dose to the toxic dose. o To find the relative safety of a drug, TI is calculated as follows: TI = the ratio of the dose producing toxicity to the dose needed to produce the desired therapeutic response, TD/ED or LD/ED. o TI calculation commonly uses the 50% dose-response points, TD50 and ED50. o For example, if the TD50 is 200 mg and the ED50 is 20 mg, the TI would be 200/20 = 10. o A drug is considered safer if TI = 10 than if the drug had a TI of 3. o The lower the therapeutic index the more dangerous the drug. o Low therapeutic index e.g. digoxin, lithium. o Margin of safety = NOAEL – estimated “exposed dose” human population. E.g. A clinician must use caution in prescribing a drug with a Margin of Safety less than 1. © Endeavour College of Natural Health www.endeavour.edu.au 17 Comparison of TD & LD LD50 = Median measure of dose of a xenobiotic or other toxin producing death in 50% of lab animals tested. Limited to animal testing. Lethal dose for 50% of a population does not usually get ethical approval (Aldred, 2009). • Uses of LD50, material safety data sheets (MSDS). • Flaws with LD50 as a measure of toxicity: o Toxicity that is non-lethal is not measured. o No substitute in vitro or in silico test unlike TD50 © Endeavour College of Natural Health www.endeavour.edu.au 18 U-shaped Dose-Response Curve – Essential Nutrient Response Death Deficiency – vitamin or trace element homeostasis toxicity Eaton & Gilbert in Klaasen et al 2010) © Endeavour College of Natural Health www.endeavour.edu.au 19 Hormesis o Hormesis: A U-shaped dose-response curve with some xenobiotics, nutrients and other toxins. o Clinical and epidemiological evidence that low to moderate dose is protective. o No dose could theoretically increase incidence of a toxic effect in a population. o High dose is adverse e.g. long-term, chronic effects in population studies. o Classic example of a non-nutritional xenobiotic is alcohol for which there may be a U-shaped dose response curve. (Note that through alcohol dehydrogenase, ethanol in high doses can provide an ATP source in some cells (calorie value)). o micronutrients, zero dose is toxic, homeostatic range beyond which high doses are toxic to a population e.g. vitamins C (diarrhoea), A (neurotoxicity). © Endeavour College of Natural Health www.endeavour.edu.au 20 Theoretical J-shaped dose-response curve – hormesis, e.g. alcohol Doses where a deficiency may theoretically low doses lead to adverse effects e.g. coronary disease, stroke (CVA) Homeostasis (doses at which a beneficial effects may be seen in populations, but no toxic dose is seen Toxic doses – for alcohol the specified toxic effect could be fatty liver, cirrhosis, oesophageal cancer (Eaton & Gilbert, in Klaasen et al 2010; Roerecke & Rehm, 2012) © Endeavour College of Natural Health www.endeavour.edu.au 21 Summary – Dose-Response Curves Toxicology Uses and shapes – Population data o Measure theoretical therapeutic index by using median measures, TD50/ED50. o Measure margin of safety by using threshold measures LD1/ED99. o On exposure to toxins, estimate margins of safety from reported threshold data NOAEL & LOAEL (LowestAdverse-Effect-Level), to estimate risk. o Hormesis - U-shaped dose-response curve. o LOAEL & TD50 are measured from population studies (compared to a control group, not exposed to the toxin). © Endeavour College of Natural Health www.endeavour.edu.au 22 Toxicology & Toxicokinetics Toxicology • Absorption, distribution and excretion of toxins. • Biotransformation of xenobiotics. • Toxicokinetics. © Endeavour College of Natural Health www.endeavour.edu.au 23 Toxicokinetics & Detoxification o Compartments where toxin is absorbed and distributed Two compartment model needed in toxicokinetics as toxins often inhaled, sequestered (bone, fat) One compartment simplification and use of Vd (theoretical) for measuring drug pharmocokinetics • Elimination includes biotransformation, exhalation, excretion = processes that will detoxify • t½ = time taken for the blood/plasma concentration of toxin to decrease by one half . Many half lives to eliminate toxin and detoxify body © Endeavour College of Natural Health www.endeavour.edu.au 24 Toxicology (absorption, distribution excretion effects) • Absorption = transfer of toxin from site of exposure to systemic circulation. • Gut absorption (xenobiotics in food, water). • Lung absorption (vapours, solvents, heavy metals occupational / industrial poisoning. • Skin absorption (e.g. Industrial poisoning) but mostly a good barrier (stratum corneum too dry, keratinocytes have no nucleus – biologically inactive). • dose Toxicity (but toxins redistribute to tissue with more target molecules, more toxic here). © Endeavour College of Natural Health www.endeavour.edu.au 25 Distribution of Toxins • Well perfused tissues first. • Then toxins redistribute to tissues, high affinity, many binding sites/more target molecules. • Blood brain barrier(BBB) is not fully developed at birth so toxins risk for newborns. © Endeavour College of Natural Health www.endeavour.edu.au 26 Distribution of Toxins - continued • Biological t ½ stored toxins, very long. • Albumin, transferrin, globulins, lipoproteins (blood). • but liver and kidneys contain protein ligands (bind organic toxins) and metallothionein (bind metals). • Fat stores organochlorine pesticides. • Bone stores fluoride (F) and radioactive strontium (Sr) and not lead (Pb). © Endeavour College of Natural Health www.endeavour.edu.au 27 Biotransformation of Xenobiotics – aim to increase elimination • Faecal normal flora bacteria biotransform xenobiotics into toxins. • Liver (same enzymes that metabolize drugs) detoxifies or activates xenobiotics. • Mixed function oxidases (cytochrome P450 in ER= microsomal & mitochondrial) hepatocytes. • Cytochrome P450 membrane bound. Isoforms classified based on amino acid sequences in common. © Endeavour College of Natural Health www.endeavour.edu.au 28 Biotransformation & elimination cont’d o Toxin excreted in bile, first-pass effect, some enters systemic circulation o Urinary excretion of toxins, active at transporters © Endeavour College of Natural Health www.endeavour.edu.au 29 Antidotes to Poisoning Antidote To treat Adverse effects or other considerations Penicillamine Potent chelator for a broad range of heavy metal poisoning. Eliminated by renal clearance. Cease therapy if hypersensitivity WCC. Physostigmine Reversible Ach I for agitated delerium (non-responsive to benzodiazapines), atropine poisoning. Not in pregnancy, cholinergic effects, prolongs succinylcholine & nondepolarizing Neuromuscular blockers. IV heavy metal chelator. Pain, phlebitis, nephrotoxicity. Vitamin K Over-warfarinization, rodenticide. Rare anaphylaxis. N-acetylcysteine Paracetamol poisoning (sulfhydryl donor to reduce drain on glutathione in liver). Mild anaphylactoid (angiooedema, flushed skin, rash). Naloxone Opioid antagonist to treat narcotic overdose and in paediatrics (neonate born to an addict). Can be used in paediatrics. ADR opioid dependency on the antidote and withdrawal symptoms. Sodium (EDTA) calcium edetate © Endeavour College of Natural Health www.endeavour.edu.au 30 Paracetamol overdose – liver toxicity – an adverse drug event ADE Fig. 53.1 Potential mechanisms of liver cell death resulting from the metabolism of paracetamol to N-acetyl-pbenzoquinone imine (NAPBQI). GSH, glutathione. (Based on data from Boobis A R et al. 1989 Trends Pharmacol Sci vl 10 pp 275–280 and Nelson S D, Pearson P G 1990 Annu Rev Pharmacol Toxicol vol 30 p.169.) © Endeavour College of Natural Health www.endeavour.edu.au 31 Toxicodynamics: Mechanisms of Toxicity (Drug Xenobiotics & Non-Drug Xenobiotics) • Drug delivery & then biotransformation may lead to a toxic metabolite. Exposure to toxin, utilizes the same pathways for detoxification. • Toxin or metabolite reacts with target, Effect is:o Dysfunction of target molecule o Destruction of target molecule – e.g. radiation & DNA o New antigen formation allergic response • Necrosis if role of target molecule is cell maintenance; • Apoptosis if role of target molecule is cell signalling and regulation o Cell repair (not toxic); dysrepair (then xenobiotic is toxic) o Efficiency of repair affects dose-response curve (e.g. TD50) © Endeavour College of Natural Health www.endeavour.edu.au 32 Mechanisms of Toxicity, Pain, inflammation & immune response, peripheral tissues Review • Bradykinin, no new drugs in clinical trials targeting this bioactive peptide in pain mediation, • Histamine, antihistamines old drugs with less ADR (less sedation) in drug development • Prostaglandins & COX; cyclo-oxygenase inhibitors COX-1 and COX-2 inhibitors – e.g. Drugs like celexocib (Celebrex™) – TGA “black box” in post-marketing surveillance Review • Tumour necrosis factor-alpha TNF-α (effect on PMNs & macrophages) IL-1 & CSF • Interleukin-1 (proliferation of T cells)and interleukin-2 (costimulator) cytokines • Interferons & colony stimulating factors (CSF) © Endeavour College of Natural Health www.endeavour.edu.au 33 Toxicology Principles e.g. alcohol • Xenobiotic, ingested toxin; source of kilojoules. • normal flora bacteria (endotoxin release, inflammatory mediators). • Absorbed stomach and small & large intestine. • Distributed in body water ( adipose tissue, BBB). • Elimination by excretion and metabolism. • Alcohol dehydrogenase (kidney, liver) metabolism. • Acetaldehyde (weak mutagen), acetic acid, excreted. • Theoretical hormetic dose-response curve and saturable metabolism. © Endeavour College of Natural Health www.endeavour.edu.au 34 Example – Alcohol Cont’d o Alcohol excreted directly exhaled & in urine. o Induces an isoform of P450 in liver. o Acute toxicity (mostly indirect morbidity & mortality). o Chronic toxicity (thiamine deficiency, induced reactive oxygen intermediates lipid peroxidation). o Epidemiology, Cirrhosis, liver becomes fatty, hard = fibrotic, leads to cancer. © Endeavour College of Natural Health www.endeavour.edu.au 35 Poisoning in Children: o Minimize exposure (prevention measures). o Risk assessment and picture of exposure often difficult in children. o GIT decontamination reserved for severe cases (risk assessment – risks outweigh benefits e.g. inhalation of vomitus in young children). o Enhanced elimination & antidotes – as for adults on mg/kg body mass except antivenoms (absolute dose used). o >6 yrs self-induced poisoning, treated as for adult (Murray et al, 2011). o Foetal alcohol syndrome. © Endeavour College of Natural Health www.endeavour.edu.au 36 Poisoning in Pregnancy / Lactation Pharmacokinetic changes in pregnancy due to • Absorption effects. • Distribution effects. • Elimination. • Overdose near term – risk-benefit of inducing labour. • Most drugs cross placental barrier. • Most drugs cross into breast milk. • Overdose or poisoning, greater risk for foetus: CO, Methaemoglobin inducing agents (drugs), lead, salicylates. • Serious risks to neonate with breastfeeding mothers consuming alcohol. © Endeavour College of Natural Health www.endeavour.edu.au 37 Poisoning in the Elderly o Risk assessment & management is challenging. o Higher complication rate in cases of poisoning. o Pharmacokinetic changes in elderly, delayed gastrointestinal tract (GIT) absorption, decreased protein binding, reduced hepatic metabolism, reduced Glomerular filtration rate (GFR). o Acute renal failure (secondary) leads to poisoning syndromes (e.g. chronic lithium toxicity, chronic digoxin toxicity). o Delayed recovery from acute toxicity. o Hospitalization leads to complications of immobility. o Concerns regarding alcohol consumption, depression, isolation in elderly. © Endeavour College of Natural Health www.endeavour.edu.au 38 Symptoms of Poisoning (classic syndromes) In self-poisoning, environmental/occupational toxicology & ADR o Anticholinergic syndrome (antimuscarinic syndrome). o Cholinergic syndrome, acetylcholinesterase inhibitors e.g. pesticides, SARAN. o Cholinergic syndrome, acetylcholine agonists (potentially lethal e.g. nicotine, mushrooms). o Serotonin syndrome occurs with psychoactive drugs, hallucinogens, anti-depressants including St John’s Wort – See Appendix 3 of Bryant and Knights(2007; 2011; 2015). © Endeavour College of Natural Health www.endeavour.edu.au 39 Serotonin Syndrome – Toxicology Serotonin syndrome – tremor, hyper-reflexia, clonus, muscle rigidity, (triad of CNS, autonomic & neuromuscular. dysfunction) >38°C, ocular clonus, agitation, diaphoresis – seen in overdoses of the following: o drugs of abuse LSD, ecstasy, amphetamines) Schedule 9 o other toxic overdoses e.g. selective serotonin reuptake inhibitors (antidepressants): SSRI, SNRI, MAOI. o Dietary supplements & herbal preparations e.g. Ginseng, St John’s Wort (Hypericum perforatum), produce same triad of symptoms in overdose (similar pharmacodynamic actions to non-selective SRI, MAO I i.e. blocks reuptake of 5-HT, NA, DA; inhibits enzymes e.g. monoamine oxidase) ↑↑ 5-HT levels in CNS in overdose). © Endeavour College of Natural Health www.endeavour.edu.au 40 Summary, Toxicology - Toxicokinetics Toxicology - exposuredose response) o Absorption, distribution and excretion of toxins, ≥ 2 compartments, many t ½ to clear toxin not only from systemic circulation but by reversible equilibrium, compartment 1 compartment 2 etc, to eventually detoxify the body. o Enhanced gut elimination in overdose aims to prevent distribution & compartmentalization of toxin. o Biotransformation of xenobiotics, cytochrome P450 major pathway, but other tissues and pathways also very important to explain toxicity and elimination. o Toxicokinetics, Clearance, Vd, T ½. o Alcohol – exposure principles, dose-response principles critical to its abstinence effects, binge and chronic dose effects. o Lifespan issues with toxins. Alcohol and Paracetamol as examples o Poisons and antidotes. Paracetamol as an example. © Endeavour College of Natural Health www.endeavour.edu.au 41 Toxicokinetics and New Drug Investigations • Therapeutic Goods Administration (TGA) uses international standards for Clinical Safety Data Management and reporting. Sponsor must register the trial with TGA, Clinical trial exemption or notification scheme. • Ethics committee approval of Randomized controlled clinical trials (RCCT) & other clinical trials. • animal studies or high throughput screening tests, knowledge applied to risk assessment. • Pharmacokinetics and pharmacodynamics applied to risk assessment. • Randomized controlled clinical trials (RCCT)to test efficacy and investigate likely hazards. • Then post-marketing surveillance once medicine/ device www.microsoft.com approved for registration with TGA. © Endeavour College of Natural Health www.endeavour.edu.au 42 Stages of Drug Development © Endeavour College of Natural Health www.endeavour.edu.au 43 New Drugs & New leads/old remedies o Alzheimer's disease – many new drug developments including 5-HT agonists, acetylcholinesterase inhibitors, tumour necrosis factor –alpha inhibitors. o 5-HT antagonists in migraine prophylaxis act by preventing the vasoconstriction (Mechanisms of Action, M of A) e.g. methysergide (derivative of ergot alkaloid, from a fungus of rye); feverfew (Tanacetum parthenium). o Thalidomide (immunomodulatory and used in rare cancer treatments). Still category X in pregnancy. o Cannabinoids (anandamide endogenous cannabinoid) agonists or antagonists, appetite control or enhancement, synergism with opiates. © Endeavour College of Natural Health www.endeavour.edu.au 44 Vasoconstriction then vasodilation migraine Fig. 12.2 Cerebral blood flow changes during migraine. (After Olesen et al. 1990 Ann Neurol. Vol 28, pp 791–798.) o Migraine pathogenesis - early 5-HT release ( by platelets, (?) proposed pathophysiology); then undersupply in CNS early vasoconstriction then vasodilation © Endeavour College of Natural Health www.endeavour.edu.au 45 Purines and Biologically-active peptides as Mediators Purinergic Agents (ADP, ATP, adenosine) as drugs in thrombotic and respiratory disorders (receptors still being studied pharmacodynamically) New drug developments: o Enkephalins & endorphins (endogenous opioids) o Bradykinin (endogenous pain mediator) o Cholecystokinin (CCK) & Neuropeptide Y (endogenous regulation of food intake & appetite) o Endothelin & nitrogen monoxide synthase (NO synthase) © Endeavour College of Natural Health www.endeavour.edu.au 46 Chemical Mediators – Regulating Pain in the CNS, Bliss in your Brain New drugs being developed: • Neuroactive peptides such as the enkephalins and endorphins which are endogenous analgesics at opioid receptors. • Endogenous bliss or cannabinoid receptors bind a neuroactive fatty acyl amide (anandamide). • Synergism between THC and opioid narcotics, means that lower concentrations of the narcotic e.g. morphine can be used with Cannabinoids as drugs (tetrahydrocannabinol = THC). Bliss receptors for arachindonyl-ethanolamide, anandamide, the endogenous cannabinoid (Badgaiyan, 2010, p. 1174; Shou, Y et al, 2013; Wiley, 2010) CB1 Distribution Human Brain, 2009, http://yourbrainonbliss.com/Blog/wpcontent/uploads/2009/02/cb1distributioninhumanbrain.jpg © Endeavour College of Natural Health www.endeavour.edu.au 47 Cell mediated immunity & cytokine production (Ag plus costimulator) • Interleukin 2, IL-2 has become a new drug target. • IL-2 is the target of thalidomide (old drug, new indication, approved with caution in TB treatment). • These indications bear no relation to original use as a sedative but caution Category X in pregnancy still applies © Endeavour College of Natural Health www.endeavour.edu.au 48 Chemical Mediators & New Drug Development • New disease modifying antirheumatic drugs that are antibodies or synthetic antibodies. These DMARDs affect Tumour Necrosis Factor (TNF) mediator; monoclonal antibodies (mab) as drugs e.g. infliximab - contraindicated in Multiple Sclerosis (MS). • Interleukin-1 cytokine (anakinra mode of action as antagonist of this proinflammatory cytokine); anakrina is therefore a DMARD as it blocks the mediator IL-1 in rheumatoid arthritis. Singh, H, 2010, Monoclonal antibodies and their role in pharmacology. Slideshare, http://www.slideshare.net/HarmanAman/monoclon al-antibodies-and-their-role-in-pharmacology © Endeavour College of Natural Health www.endeavour.edu.au 49 Immunostimulants - Targets for New Drug Development • Aldesleukin (still an orphan drug on TGA register), interleukin-2 made by recombinant DNA production; IL-2 (aldesleukin) enhances T cell function at destroying renal cell carcinoma. • Also made by recombinant DNA technology: Interferon alpha IFα, IF-α2a and IF-α2b, interferon beta (IF-β), for multiple sclerosis, MS • New unusual drug, glatiramer (synthetic tetra-peptide), used in MS © Endeavour College of Natural Health www.endeavour.edu.au 50 Pharmacokinetic and Pharmacodynamics basis of ADR and ADE: Adverse drug reactions and events are classified as: Type A - Augmented or predictable. Type B - Bizarre or Unpredictable/idiosyncratic [drug allergy or hypersensitivity]. Type C - Chronic; reactions that develop with long-term therapy. [development of drug tolerance and physical dependence]. Type D - Delayed effects such as carcinogenicity or teratogenicity [delayed fertility]. Type E - End of use; reactions after stopping (withdrawal). Type F - Failure of therapy (e.g. St John’s Wort and oral contraceptive pill). © Endeavour College of Natural Health www.endeavour.edu.au 51 Summary – Mediators & modulators: (New Drug Therapies ?) o Mediators, modulators – organic endogenous compounds and free radical NO, future drug developments: • 5-hydroxytryptamine (5-HT or serotonin) (LSD/amphetamine derivatives, hallucinations), migraine, platelet effects, appetite control. • Purines and prostaglandins (neuromodulators). • Peptides as mediators e.g. endothelin antagonists (affect NO levels) and some that may be investigated for appetite control. • Nitric oxide and the peptide endothelin e.g. treating cardiovascular disease e.g. 1° pulmonary hypertension, pre-eclampsia. • IL1 antagonists, IL-2 and interferons as drugs in MS and rheumatoid arthritis. • Thalidomide, immunomodulatory and used to treat rare cancers (Category X in pregnant women from previous epidemiology Phase IV post-marketing surveillance data). © Endeavour College of Natural Health www.endeavour.edu.au 52 Bibliography o o o o o o o o Alred, E.M. 2009, Pharmacology: A handbook for complementary health care professionals, Elsevier, Edinburgh Bryant, B & Knights, K 2007, Pharmacology for health professionals, 2nd ed, Mosby, Sydney Bullock, S, Manias, E & Galbraith, A 2006, Fundamentals of pharmacology, 5th ed, Pearson Education. Brunton, L. Chabner, B. and Knollmann, B.2011. Goodman and Gilman‘s The pharmacological. basis of therapeutics, 12th edn, McGraw-Hill Publishing, NY Klaasen CD 2007, Casarett and Doull’s Toxicology- the basic science of poisons, 7th ed. McGraw Hill, NY. Klaasen, CD & Watkins JB (III), 2010, Casarett and Doull’s Essentials of toxicology, 2 ed McGraw Hill, NY Kumar, P. and Clark, M. 2013, Clinical medicine, 8th ed, W.B. Saunders, Edinburgh. Weber, M., Black, H., Bakris, G., Krum, H., Linas, S., Weiss, R., Linseman, J., Wiens, B, Warrne, M. and Lindholm, L., 2009, A selective endothelin-receptor antagonist to reduce blood pressure in patients with treatment resistant hypertension: a randomised, double blind, placebo-controlled trial. The Lancet, Vol 374(969) pp 1423 - 1431, doi:10.1016/S0140-6736(09)61500-2 o Huether, K. and McCance, K., 2006, Understanding pathophysiology, 4th edition, Elsevier o Klaasen CD 2007, Casarett and Doull’s Toxicology- the basic science of poisons, 7th edition. McGraw Hill, NY. o Klaasen, CD and Watkins, JB(III) Casarett and Doull’s Essentials of toxicology 2nd edition McGraw, Hill, NY. o Murray, L., Daly, F., Little, M. and Cadogan, M., 2011, Toxicology handbook, 2nd edition, Elsevier, Sydney o Timberlake, K.C., 2013, General, organic and biological chemistry: Structures of life, 4th ed., Pearson, San Francisco. o Tortora, G. & Derrickson, B. 2014. Principles of anatomy and physiology, 14th ed, John Wiley and Sons, Hoboken, NJ. o Walker, B.R., Colledge, N.R., Ralston, S.H. & Penman I. 2014 Davidson’s principles and practice of medicine, 22nd, Elsevier, Edinburgh o World Health Organization. 1969. ‘WHO Expert Committee on Drug Dependence. Sixteenth report. (Technical report series. No. 407)’. World Health Organization, Geneva Ambili Nair acknowledged for computer-generated graphs References • Badgaiyan, R, 2010, Dopamine is released in the striatum during human emotional processing. Neuroreport, Vol 21(18) pp1172–1176. DOI: 10.1097/WNR.0b013e3283410955 • CB1 Distribution Human Brain, 2009, http://yourbrainonbliss.com/Blog/wp-content/uploads/2009/02/cb1distributioninhumanbrain.jpg • Roerecke, M and Rehm, J, 2012, Alcohol intake revisited: risks and benefits, Curr Atherosclero Rep vol 14, pp 556-562 DOI 10.1007/s11883-0120277-5 • Shou, Y et al, 2013, Electroacupuncture inhibition of hyperalgesia in rats with adjuvant arthritis: Involvement of Cannabinoid Receptor 1 and Dopamine Receptor Subtypes in striatum. Evidence-Based Complementary and Alternative Medicine, vol 2013 http://dx.doi.org/10.1155/2013/393460 • Wiley, JL, 1999, Cannabis: discrimination of "internal bliss"? Pharmacol Biochem Behav. 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