Download Toxic Doses

BIOP211
Session 4
Pharmacology
Toxicology
Department of Bioscience
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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).
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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.
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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
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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
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* Depends on
animal system
used – see
Material Safety
Data Sheets
MSDS for acute
toxicity data **
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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.
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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.
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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.
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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.
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LD50 as a Dose Estimate
Courtesy of: A. Nair
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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.
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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)
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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.
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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)
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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.
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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)
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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.
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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
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U-shaped Dose-Response Curve –
Essential Nutrient
Response
Death
Deficiency – vitamin
or trace element
homeostasis
toxicity
Eaton & Gilbert in Klaasen et al
2010)
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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).
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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)
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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).
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Toxicology & Toxicokinetics
Toxicology
• Absorption, distribution and excretion of toxins.
• Biotransformation of xenobiotics.
• Toxicokinetics.
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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
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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).
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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.
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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).
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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.
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Biotransformation &
elimination cont’d
o Toxin excreted in bile, first-pass effect, some
enters systemic circulation
o Urinary excretion of toxins, active at
transporters
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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
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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.)
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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)
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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)
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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.
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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.
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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.
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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.
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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.
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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).
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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).
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Summary, Toxicology - Toxicokinetics
Toxicology - exposuredose 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.
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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.
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Stages of Drug Development
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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.
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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
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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)
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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
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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
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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
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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
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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).
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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).
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52
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o
o
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o
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Brunton, L. Chabner, B. and Knollmann, B.2011. Goodman and Gilman‘s The pharmacological. basis of therapeutics, 12th edn, McGraw-Hill Publishing, NY
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Ambili Nair acknowledged for computer-generated graphs
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• 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
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• Wiley, JL, 1999, Cannabis: discrimination of "internal bliss"? Pharmacol Biochem Behav. Vol 64 (2), pp 257-60
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