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BIO367 - Forensic Toxicology > WEEK 1-7 OBJs > Flashcards

WEEK 1-7 OBJs Flashcards

1
Q

Necrosis

A

o Non-programmed cell death
o Caused by accidental damage of a cell – does not follow a specific cellular program
• Membrane integrity is lost - cell body swells
• Eventually, cell bursts open
• Cellular contents are released as the cell bursts
• This can cause an inflammatory response

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2
Q

Apoptosis

A

o Programmed cell death
o Enables individual cells to commit suicide when they are dysfunctional
o During apoptosis, the dying cells fragment into membrane-bound apoptotic bodies
o Cellular contents are not released so cannot affect neighbouring cells

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3
Q

What are the three primary causes of necrosis?

A
  • ATP depletion
  • Excitotoxicity
  • Oxidative stress
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4
Q
  1. What are the four key mechanisms by which ATP can be depleted?
A

1- Inhibition of electron transport
e.g. cyanide inhibits cytochrome oxidase phosphorylation
2- Inhibition of oxygen delivery
e.g. cocaine, carbon monoxide
3- Inhibition of ADP
e.g. DDT
4- Damage to mitochondria
e.g. chronic ethanol abuse

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5
Q

What is the role of ion gradients in necrosis?

A
  • A key consequence of ATP depletion is the loss of control of ion gradients
  • This is a positive feedback loop: as more Na+ and Ca2+ enter the cell, more voltage-gated channels open and more ions enter
  • This causes loss of volume control: water influx, cell swelling
  • Eventually, the cell lyses: necrosis
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6
Q

Why are the levels of calcium ions tightly regulated within a cell?

A
  • Calcium is toxic to the cell if present at high levels in the cytoplasm
  • Consequence of increased intracellular Ca2+ is excitotoxicity
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7
Q

What are four consequences of excitotoxicity? (Calcium)

A
  1. Depletion of ATP
    - Mitochondrial ATP production is decreased; activation of Ca2+ ATPase uses ATP
  2. Activation of Ca2+-dependent hydrolytic enzymes
    - Leads to disintegration of membranes, proteins etc.
  3. Production of reaction oxygen and nitrogen species
    - Leads to disintegration of membranes, proteins etc.
  4. Microfilament dysfunction
    - Disrupted morphology and function, impaired motility
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8
Q

Define the term ‘oxidative stress’. What causes oxidative stress? How can it be avoided within a cell?

A
  • Oxidative stress occurs when the balance between free radicals and antioxidants is disrupted, meaning that more oxidants are present
  • Oxidative stress is caused by reactive oxygen (ROS) and nitrogen (RNS) species
  • Having enough antioxidants in diet
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9
Q

What are the cellular consequences of ROS production? List at least six.

A
  • ROS directly oxidise proteins affecting their function
  • ROS can also mutate DNA causing cellular dysfunction
  • Lipid peroxidation
  • Cell swelling
  • Cell lysis
  • Inactivate Ca2+ ATPase, increasing intracellular Ca2+
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10
Q

Define the terms toxicodynamics and toxicokinetics.

A

Toxicodynamics refers to the signs and symptoms a toxic agent causes.

Toxicokinetics refers to how the body metabolizes and eliminates the agent.

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11
Q

Define the terms ED50 and LD50. How can these values be derived?

A
  • ED50 (median effective dose): The dose of a substance that produces the desired effect in 50% of the population that takes it
  • LD50 (median lethal dose): The dose of a substance that is required to kill 50% of the population that takes it
  • Dose-effect relationship
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12
Q

What is meant by the therapeutic index of a drug?

A
  • The therapeutic index of a drug is a quantitative measurement of the relative safety of a substance. Therapeutic index = LD50/ED50
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13
Q

What is first-pass metabolism and how can it be avoided?

A
  • The first-pass metabolism or the first-pass effect or presystemic metabolism is the phenomenon which occurs whenever the drug is administered orally, enters the liver, and suffers extensive biotransformation to such an extent that the bioavailability is drastically reduced, thus showing subtherapeutic action - determines the concentration of drug (active metabolite that will act on the target site and in systemic circulation)
  • One effect of this process is the liver can make drugs inactive (biotransform) before they arrive at their site of action.
  • First pass metabolism is why pain control is hard to achieve by oral means only
  • It is the fraction of lost drug during the process of absorption which is generally related to the liver and gut wall.
  • Notable drugs that experience a significant first-pass effect are imipramine, morphine, propranolol, buprenorphine, diazepam, midazolam, demerol, cimetidine, and lidocaine.
  • Avoided by subcutaneous administration/ injection
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14
Q

What is bioavailability when applied to a substance?

A
  • Bioavailability (F) refers to the fraction of a substance that reaches the systemic circulation
  • When given intravenously, the bioavailability is 100%
  • Administration by other routes is typically lower, and is compared to the intravenous bioavailability
  • Many substances have the lowest bioavailability after oral administration, due to first-pass metabolism
  • Bioavailability is determined by plotting the plasma concentrations of the substance administration, and calculating the area under the curve
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15
Q

Describe the four components of ADME.

A
  • Absorption: The process of the substance being taken up into the circulation
  • Distribution: The transfer of the substance from the bloodstream to the tissues
  • Metabolism: The conversion of the substance by enzymes into metabolites, which can either activate or deactivate the substance
  • Elimination: Removal of the substance from the body by the kidneys, gut, lungs or skin
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16
Q

What is the volume of distribution of a substance?

A
  • The volume of distribution (VD) is a theoretical volume that represents the degree to which the substance is taken up by the tissues rather than staying in the plasma
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17
Q

What is the function of phase I, II and III metabolism?

A

Phase I metabolism:
- The first stage of metabolism, whereby the substance is converted to a more polar metabolite by adding or changing a functional group
- This phase includes reactions such as oxidation, reduction and hydrolysis
o Often involves the cytochrome P450 enzyme system
- If sufficiently polar, the metabolite may be eliminated at this point without undergoing further metabolism
- This phase activates or deactivates the original substance
Phase II metabolism:
- In this phase, the metabolite is conjugated with a charged compound such as glutathione
- This increases the molecular weight and the hydrophilicity
o Deactivates the substance if Phase I did not
- Phase II reactions are catalysed by a family of nonspecific transferases
o These require endogenous co-factors in order for the reaction to proceed
Phase III metabolism:
- This phase further processes metabolites that could not be eliminated after Phase I and II
- Further modifications may be made to conjugates, such as acetylation
o Products of Phase II and III metabolism are removed from the cell by various transporter proteins, where they can be eliminated

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18
Q

What are the two components that make ICP-MS a hyphenated technique?

A
  1. An ionisation source: inductively-coupled plasma
  2. A detector: mass spectrometer
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19
Q
  1. Explain how the ICP ionization source allows elements to be analysed.
A
  • An ICP-MS instrument uses a plasma (ICP) to ionize the elements in a sample and then measures the ions using a mass spectrometer (MS)
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20
Q

How are samples typically prepared for ICP-MS analysis?

A
  • Due to the nature of the instrument, samples must be either liquids or solids that are fully dissolved
  • This is usually achieved using acid, most commonly nitric acid (HNO3) – to break it down an analyse its molecular or elemental composition
  • For complex solid samples, a period of digestion in acid (often at high temperature) may be required – often overnight
  • Other digestion methods are available, e.g. microwave
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21
Q

What are the two phases involved in any chromatographic technique? Explain how HPLC uses these two phases.

A
  • The mixture is dissolved in fluid, the ‘mobile phase’
  • It is passed through a solid material, ‘the stationary phase’
  • Different components of the mixture will separate based on partitioning between the stationary and mobile phases
  • Solid phase extraction most commonly used
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22
Q

For what types of sample is HPLC analysis most suited?

A
  • Liquid state
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23
Q

Explain the difference between reversed-phase and normal-phase chromatography.

A

Reversed-phase chromatography:

  • The most popular type of HPLC
  • Non-polar stationary phase and moderately-polar (aqueous) mobile phase
  • Hydrophobic (non polar) molecules will be retained by the stationary phase and eluted when the mobile phase gradient changes

Normal-phase chromatography:
- Polar stationary phase and non-polar mobile phase
- Hydrophilic molecules will be retained by the stationary phase and eluted when the mobile phase gradient changes
- Aqueous normal-phase (ANP) allows the use of the same solvents as for reversed-phase chromatography
o Hydrophilic interaction (HILIC) is another variant of NP that is widely used

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24
Q

What is solid phase extraction, and how is it related to HPLC?

A
  • SPE is essentially a form of chromatography that is used to purify or concentrate samples before we analyse them
  • The sample in fluid (mobile phase) is passed through a stationary phase to achieve separation – same as HPLC
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25
Q

What chromatographic parameter do we commonly use in analysis of HPLC data?

A
  • The column contains the stationary phase, of which many chemistries are available
  • Other important parameters:
    1. Internal diameter (ID): determines sensitivity and analyte loading
    o Most common: 2.1 mm, 4.6 mm
    2. Particle size: the size of the stationary phase beads
    o Smaller = more surface area but higher pressure
    3. Pore size: porosity increases surface area for separation
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26
Q

Explain how GC uses the two phases of chromatography.

A
  • The ‘mobile phase’ is a carrier gas such as helium or hydrogen
  • The ‘stationary phase’ is a layer of liquid or polymer contained within a column made of glass or metal
  • Separation occurs primarily on the basis of differences in boiling point
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27
Q

For what types of sample is GC analysis most suited?

A
  • Liquid or gas state
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28
Q

What is the function of the inlet of the GC?

A
  • The inlet is used to introduce the sample into the gas flow
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29
Q

What factor is most important in selection of a column for GC analysis?

A
  • Polarity of the sample
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30
Q

What factor is most important in sample preparation for GC analysis? How does derivatisation allow this to be achieved?

A
  • Sample must be in liquid or gas state
  • Separation occurs on basis of different boiling points
  • Derivatisation is used to chemically transform a compound into a derivative with different physical properties
  • For GC, this is done to reduce the boiling point of the molecule
  • It is achieved by adding non-polar groups
  • Derivatisation allows us to use GC on molecules that would otherwise not be possible
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31
Q

Explain how the three basic components of a mass spectrometer allow this type of analysis to be achieved.

A
  • Components are ion source, mass analyser and detector
  • The sample (solid, liquid or gas) must first be ionised in an ion source
  • The ions are then separated in an electromagnetic field (deflection directly related to mass) - This is known as the mass analyser
  • The ions must then be detected (detector)
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32
Q

Explain the concept of the mass-to-charge ratio (m/z).

A
  • Mass spectro measure the mass-to-charge ratio or m/z
  • An ion of mass 100 with 1 charge will have a m/z of 100
  • An ion of mass 100 with 2 charges will have a m/z of 50
  • Particles with the same m/z will behave the same when subjected to electromagnetic fields
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33
Q

Explain the key differences between the electron and electrospray ionization sources.

A
  • Electron ionisation (EI) is where gas-phase molecules interact with electrons to produce ions
  • Electrospray ionisation (ESI) applies a high voltage to a liquid to create an aerosol containing ions
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34
Q

Explain the terms ‘resolution’ and ‘accuracy’ as related to mass analysers.

A
  • Resolution: the ability to distinguish two peaks of similar m/z - e.g. 50.1 and 50.2, or 50.005 and 50.006
  • Accuracy: the ratio of the measurement error to the true m/z • Usually measured in ppm
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35
Q

Briefly explain how quadrupole, triple quadrupole and time of flight mass analysers function.

A
  • Quadrupole systems consist of four rods that are electrically connected
  • Oscillating electric fields are applied to the rods, allowing specific masses to be transmitted
  • By varying the voltage applied to the quadrupole, the entire mass range can be scanned continuously
  • Triple quadrupole systems have three quadrupoles connected in series for tandem MS analysis
  • The first quadrupole is used to select the mass(es) of interest
  • The second quadrupole is a collision cell, where ions are fragmented by collision with a gas (e.g. argon)
  • The third quadrupole is used to scan for specific product masses of the mass of interest
  • QQQs are very fast instruments, so hundreds of pairs of ions can be scanned (multiple reaction monitoring, MRM)
  • Time-of-flight instruments accelerate ions in an electric field
  • Ions then move through the mass analyser at a velocity defined by the m/z (smaller = faster)
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36
Q

What are the two types of data generated by MS analysis? How does this differ between hard and soft ionization techniques?

A
  1. Mass chromatogram
    o x-axis is time, y-axis is signal intensity
    o Mass information is not visualised
  2. Mass spectrum
    o x-axis is m/z, y-axis is signal intensity/abundance
    o The most abundance m/z is the base peak
    - Hard ionisation techniques (e.g. EI) will fragment the molecule
    - Soft ionisation techniques (e.g. ESI) will not fragment the molecule to the same extent
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37
Q

Outline the advantages and disadvantages of analysis of urine for drugs.

A

Advantages:
- Most drugs or metabolites of drugs are excreted into the urine at high concentrations
o Detection is indicative of recent exposure (1-3 days)
- Collection of samples in non-invasive
- Urine is not a complex matrix, so sample preparation is minimal
- Analytical procedures are well-established for common drugs (amphetamines, cocaine, marijuana, opiates, PCP)
o Analysis can be automated
o Cheap

Disadvantages:
- Samples can be adulterated, substituted or diluted
o Collection requires strict supervision (privacy?)
- Surveillance window is short (1-3 days)
o Infrequent use is not detected by random testing
o Screening can be delayed to avoid detection
- Consumption of large volumes of water may dilute urine and avoid detection
- Drug concentrations in spot samples cannot be related to intensity of drug use
Cannot distinguish between light, moderate or heavy use

38
Q

What factors affect the incorporation of a drug molecule or metabolite into hair?

A
  1. Molecular size and structure of the drug
  2. Concentration gradient (blood:hair:root)
  3. Lipid solubility of the drug
  4. Ratio of ionised:unionised forms of the drug (pKa of the drug)
39
Q

What are the five basic steps involved in analysis of hair for drugs?

A
  1. Sample collection
  2. Decontamination
    o Phosphate buffer
    o Detergent (including shampoo)
    o Surfactants
  3. Preparation
    o Pulverisation
    o Segmentation
  4. Extraction
    o Organic solvents
    o Acids or alkali
  5. Analysis
    o Immunoassay
    o. GC-MS
40
Q

Advantages of hair analysis for drugs

A
  1. Widest surveillance window of any biological matrix – because hair can be very long
  2. Growth rate allows timing of sampling
  3. Opportunity to collect a second sample
  4. Drugs highly stable when incorporated in hair
  5. Hair can be matched to individual using microscopy
  6. Not possible to adulterate or dilute the sample
  7. Sampling is non-invasive
  8. Higher capture than urine
41
Q

Disadvantages of hair analysis for drugs

A
  1. Variation in growth rate can be problematic
  2. Hair colour results in variation of the uptake of certain drugs
  3. Environmental contamination
  4. Washing to remove external contamination is highly variable in its effectiveness
  5. Cosmetic treatment of hair can influence drug entrapment
  6. Hair cannot identify alcohol abuse
  7. Hair cannot provide of drug use 6-7 days immediately after ingestion
  8. Hair analysis is more expensive than urine analysis
  9. No more effective than urine in terms of marijuana
  10. Lack of international standardisation
42
Q

Define the term ‘alkaloid’. What are the two main classes? How are alkaloids synthesized?

A
  • Organic compounds containing nitrogen
  • Two main classes are heterocyclic and non-heterocyclic
  • Synthesised from the amino acids phenylalanine, tryptophan and tyrosine
43
Q

Outline the mechanism of action of nicotine. How can this lead to a toxic effect? Be sure to describe the physiological consequences of nicotine toxicity.

A
  • Nicotinic acetylcholine receptors (CNS & PNS)
  • Release of dopamine, acetylcholine and norepinephrine (CNS) - multiple receptors though
  • Increased heart rate and blood pressure (PNS), epinepherine
  • Initial symptoms include nausea, vomiting, hypertension, tachycardia, dizziness and seizure
  • After excessive stimulation, receptor levels are depressed
  • Subsequent symptoms include hypotension, bradycardia, CNS depression, coma and paralysis
44
Q

Outline the mechanism of action of muscarine. How can this lead to a toxic effect? Be sure to describe the physiological consequences of muscarine toxicity. How is atropine used to treat muscarine toxicity?

A

o Muscarine acetylcholine receptors
o G protein-coupled receptors = slow response

o Binds to the muscarinic acetylcholine receptors and activates them (same as ACh)
o As muscarinic receptors are located throughout the body, effects of muscarine poisoning are widespread

o Symptoms are caused by excessive activation of the receptors, opposed to nicotine’s stimulant and then depression
o M2 receptors are responsible for decreasing heart rate to lower blood pressure
o Muscarine can trigger cardiac arrest via M2 receptors
o It can trigger convulsion and hypothermia via M1, M4 and M5 receptors in the brain
o It can also trigger bronchoconstriction and severe gastrointestinal symptoms
o Competitive antagonist at the muscarinic receptors (muscarine is the agonist)
o Used to increase heart rate by blocking M2 receptors
o Antidote to muscarine poisoning

45
Q

Outline the mechanism of action of strychnine. How can this lead to a toxic effect? Be sure to describe the physiological consequences of strychnine toxicity.

A

o Glycine receptors, an ionotropic receptor that regulates chloride movement – activation makes it less likely to generate an action potential

o Strychnine prevents glycine from binding to GlyR
o Without inhibition, the nervous system becomes hypersensitive
o Action potentials are triggered by very low levels of neurotransmitter
o This causes constant muscle contractions

o Initial symptoms include restlessness, muscle twitching and stiffness of the neck
o Later symptoms include convulsions and dilation of the pupils
o Death usually occurs as a result of respiratory arrest and asphyxia

46
Q

Outline the mechanism of action of ricin. How can this lead to a toxic effect?

A

o Ricin irreversibly hydrolyses a glycosidic bond in the rRNA of the 60s ribosomal subunit
o This rapidly and completely inactivates the ribosome

o This shuts down protein synthesis within the cells

o Main symptom is severe diarrhea
o Death usually results from circulatory shock, due to a shutdown of metabolism

47
Q

Outline the mechanism of action of cyanide. How can this lead to a toxic effect? Be sure to describe the physiological consequences of cyanide toxicity.

A

o Cyanogenic glycoside

o CN- attaches to the iron in cytochrome c oxidase (a + a3)
o This binding prevents the transfer of electrons from cytochrome c to oxygen
o Shuts down the mitochondrial electron transport chain

o Poisoning occurs as a form of hypoxia, as the cells are unable to use oxygen for metabolism
o Initial symptoms include weakness, confusion, dizziness and headache
o This is followed by loss of consciousness
o Final symptoms include seizures and cardiac arrest
o Skin may appear cherry read due to increased haemoglobin oxygen saturation (oxygen is not being used, so accumulates)

48
Q

Explain how the mechanism of action of cardiac glycosides allowed them to be developed into a therapeutic medication.

A

o Glycosides that can affect the contractile force of cardiac muscle
o Most are extremely toxic as they can disrupt the normal functioning of the heart
o Have been traditionally used as poisons and medicines
o Have provided lead compounds for the development of a number of important drugs for the treatment of arrhythmias and congestive heart failure
o Target sodium-potassium (Na+/K+) pumps in cell membranes
o These pumps bring K+ into the cell and move Na+ out

49
Q
  1. Describe the absorption, distribution and metabolism of ethanol in the human body.
A

Absorption
- Begins in stomach 5-10min
- Primarily duodenum
- Delayed when taken with fatty food
Distribution
- Uniformly on water content of organs
- Males higher
- Also distributed to alveolar air
Metabolism
- Primarily metabolised in liver – alcohol dehydrogenase and cytochrome P450
- Oxidised to acetate – metabolised to CO2 and H2O

50
Q

Describe the mechanisms by which ethanol affects the central nervous system.

A
  • Activates GABA receptors (inhibitory)
    o Inhibits CNS and has a sedative effect
    o Effects on GABA are linked to development of tolerance
  • Inhibits NMDA receptors (excitatory)
    o Secondary effect is to increase dopamine release
    o Reduces behavioural inhibition
    o Effects on NMDA linked to dependence
  • Also has opioid-like effects (sedative, analgesic)
    o Ethanol interacts with catecholamines to form hydroisoquinolines
    o These have opioid-like properties
    o Also inhibits release of acetylcholine (sedative)
51
Q

Describe the non-CNS effects of ethanol.

A
  • Blocks action of vasopressin (ADH)
    o Prevents reabsorption of water in kidney
    o Increased urine output
  • Interferes with temperature regulation causing vasodilation
    o Causes you to feel warm
  • EtOH is an irritant so causes increased gastric and salivary secretions
  • Also interferes with normal function of the endocrine system
    o Primarily affects steroid hormones
52
Q

Describe the mechanism of action of benzodiazepines. List other potential drink-spiking agents that have the same mechanism.

A
  • CNS depressants
  • Agonists at GABA receptors
  • Benzodiazepines interact with the GABAA receptors, which are ligand-gated ion channels
    o When activated, GABAA allows chloride ions into the neuron
    o This hyperpolarises the cell, making it more difficult to generate an action potential
  • Overall effect is to make the CNS less sensitive
  • Common examples:
    o Diazepam (Valium)
    o Flunitrazepam (Rohypnol)
    o Temazepam
  • Chloral hydrate
  • Methaqualone
  • Propofol
  • Zolpidem
53
Q

Describe the mechanism of action of ketamine.

A
  • NMDA receptors
  • N-methyl-D-aspartate receptor
  • Ionotropic glutamate receptor
  • When activated, channel opens
    o Na+ and Ca2+ enter cell
    o K+ leaves cell
54
Q

List six ways that prescription drugs can be toxic.

A
  1. Overdose
  2. Hypersensitivity
  3. Lack of selectivity
  4. Allergy
  5. Cutaneous reactions
  6. Pregnancy and lactation
55
Q

Describe the mechanism of action of the following prescription drug: Succinylcholine

A

– Binds to NAChR and depolarizes

56
Q

Describe the mechanism of action of the following prescription drug: Non-steroidal anti-inflammatory drugs

A

– NSAIDs block cyclooxygenase-2 enzymes that produce inflammatory mediators, also COX-1 which regulates gastrointestinal secretions

57
Q

Describe the mechanism of action of the following prescription drug: Barbiturates

A

– Interact with GABA receptors to reduce sensitivity of nervous system, ligand-gated ion channels, activation allows chloride to flood into neuron

58
Q

Describe the mechanism of action of the following prescription drug: Opiates

A

Opioid receptors

59
Q

Describe the mechanism by which paracetamol can be toxic.

A
  • Normal metabolism produces non-toxic metabolites
  • If GSH is depleted, NAPQI builds up
  • NAPQI is toxic
  • Reacts with proteins to cause cell death

GSH or glutathione is an antioxidant, paracetamol can deplete this

NAPQI is a toxic metabolite from paracetamol breakdown

60
Q

Describe the mechanism of action of the following illicit drug: Heroin

A

Bind to opioid receptors and provide euphoria, analgesia and anxiolytic effects

61
Q

Describe the mechanism of action of the following illicit drug: Cocaine

A

Blocks sodium channels, inhibits reuptake of neurotransmitter, inhibition of dopamine transporter

62
Q

Describe the mechanism of action of the following illicit drug: Cannabis

A

Mainly activate CB1 (inhibitory GPCR) – decrease cAMP in cells expressed in CNS and PNS. Or CB2 receptor (inhibitory GPCR) – decreased cAMP levels in cells expressed in immune cells

63
Q

Describe the mechanism of action of the following illicit drug: LSD

A

Act on serotonin receptors to produce vivid hallucinations

64
Q

Describe the mechanism of action of the following illicit drug: MDMA

A

MDMA inhibits both vesicular monoamine transporters (VMAT1 and VMAT2). MDMA also activates trace amine-associated receptor 1 (TAAR1)

65
Q

Describe the mechanism of action of the following illicit drug: Methamphetamine

A

Same as MDMA

66
Q

Explain the four main safety issues associated with herbal medicines.

A
  1. Standardisation
    - Uniformity between batches: based on ‘marker’ compounds
    - Plant secondary compound production is dependent on environment during growth, postharvest conditions, extraction conditions – may be a wide degree of variation of plants
  2. Contaminants
    - Accidental: pesticides, microorganisms, other plants
    - Intentional (adulteration): other plants, steroids, hormones, NSAIDs
  3. Interactions
    - Just because they can be obtained without prescription, does not mean that there is no need to consider drug interactions
    • Digoxin and warfarin have many interactions with herbs (some serious)
  4. Safety testing
    - Most complementary medicines have not been tested on pregnant women, breastfeeding mothers or children – lack of evidence does not mean that they are safe!
67
Q

What are the main safety concerns associated with nutritional supplements?

A
  • Some randomised clinical trials have demonstrated increased mortality from supplements such as vitamin A, E and betacarotene
    o A key concern are body-building supplements
    o Many others contain undisclosed steroids
  • Green tea pills are another concern as they contain very high levels of catechins, which can cause liver damage
  • Contaminants
68
Q

Outline the three main safety concerns associated with traditional Chinese medicines.

A
  • Toxicity
    o Many substances used routinely in TCM are now known to be toxic
    o Include extracts from fungi, beetles, centipedes and toads
    o Some plants are only safe if processed in specific ways
    o Herbal medicine is the leading cause of liver failure in China
  • Efficacy
    o Very few appropriately designed trials have been conducted
    o Effectiveness is therefore very poorly documented
  • Endangered species
    o Some species used in TCM are endangered, including tiger, rhinoceros, turtle and seahorse
    o The use of bear bile is also highly controversial
69
Q

Explain why traditional Japanese medicine (Kampo) does not share the same safety concerns as TCM.

A
  • Regulation is much stronger for kampo medicines
  • Kampo medicines must be composed of the same ingredients dictated by the standardised methodology
  • Medicines are prepared using strict manufacturing protocols akin to those used in the pharmaceutical industry
  • There is routine testing for heavy metals, purity and bacterial contamination
  • There is also quality control testing based on chemical composition (efficacy)
70
Q

What is the main safety concern associated with traditional Indian medicine (Ayurveda)?

A
  • Use of herbs containing pharmacologically-active metabolites
71
Q

Explain why homeopathic preparations are unlikely to be effective.

A
  • A key concept to homeopathy was that all diseases started as localised disorders (e.g. skin), but if these were treated with medicine, the cause would go ‘deeper’ into the body
  • Therefore, treating diseases by directly opposing symptoms is ineffective
72
Q

Outline the mechanism of action of organophosphate pesticides. How can this lead to a toxic effect? Be sure to describe the physiological consequences of OP toxicity.

A
  • Organophosphates act by inhibiting acetylcholinesterase (AChE)
  • This leads to accumulation of ACh and overstimulation of the ACh receptors
  • Symptoms:
    o Overstimulation of nicotinic ACh receptors in the muscles can cause fatigue, weakness and paralysis
    o Overstimulation of nicotinic ACh receptors in the CNS can lead to headache, convulsions and coma
    o Overstimulation of muscarinic ACh receptors can lead to salivation, sweating and difficulty breathing
    o Can cause personality changes and psychoses
  • Cause of death is usually respiratory paralysis
73
Q

Outline the primary mechanism of action of organochlorine pesticides. How can this lead to a toxic effect? Be sure to describe the physiological consequences of OC toxicity.

A
  • Endocrine disruption by binding at estrogen receptor
  • May trigger precocious puberty (secondary sexual development at 8-9 years of age)
  • May increase incidence of endometriosis (growth of uterine cells outside the uterus) and adenomyosis (growth of gland cells in muscles)
  • May reduce sperm count and motility
  • May affect progression of hormone-sensitive cancers, specifically breast cancer
  • May affect fetal development, although links have not been established
  • May affect neurodegenerative disorders, such as Alzheimer’s disease, as these are linked to steroid hormone activity
74
Q

Outline the mechanism of action of pyrethroid pesticides. Could this lead to a toxic effect in humans?

A
  • They prevent closure of voltage-gated sodium channels on neuronal cells
  • Humans have sufficient capacity in the liver to quickly metabolise pyrethroids and render them safe
    o Long-term effects are much less clear
    o Allergic reactions have been reported
75
Q

Outline the mechanism of action of neonicotinoid pesticides. How could this lead to a toxic effect in humans? What is the major concern with these pesticides?

A
  • Like nicotine, neonicotinoids are ACh receptor agonists
    o Do not inhibit AChE, unlike OPs and carbamates
  • Higher affinity for insect than mammalian ACh receptors (unlike nicotine)
  • Environmental impacts of greater concern than toxicity
  • Low level exposure will cause receptor stimulation
    o High levels will cause overstimulation, eventually reducing sensitivity
    o This leads to paralysis and death
76
Q

Outline the mechanism of action of anticoagulant rodenticides. How can this lead to a toxic effect? Be sure to describe the physiological consequences of such toxicity.

A
  • Anticoagulant drugs block the action of VKOR, decreasing the amount of vitamin K available to the cell
  • The Gla residue is no longer produced
  • Gla proteins include several clotting factors: II (prothrombin), VII, IX and X
    o Also includes clotting regulators: proteins C, S and Z
  • Without vitamin K, the body cannot activate these clotting factors and regulators
    o The blood can no longer be clotted
    o Internal haemorrhages occur, typically leading to death from circulatory shock or anaemia
77
Q

Outline the mechanism of action of metal phosphide rodenticides. How can this lead to a toxic effect? Be sure to describe the physiological consequences of such toxicity.

A
  • Metal phosphide toxicity
  • Once ingested, metal phosphides are transformed by the acid in the digestive system
    o The phosphide is converted into phosphine (PH3)
  • Phosphine is an acetylcholinesterase inhibitor
    o Can also interfere with the mitochondrial ETC
  • Exposure to phosphine above 50 ppm can be fatal
    o Initial symptoms include nausea, chest pain, thirst and difficulty breathing
    o Could result in respiratory paralysis
78
Q

Outline the mechanism of action of hypercalcemic rodenticides. How can this lead to a toxic effect? Be sure to describe the physiological consequences of such toxicity.

A
  • Vitamin D promotes calcium absorption from the gut, and mobilising from bone
  • Excess Ca2+ circulates in the blood
  • It eventually starts to calcify the blood vessels and key organs (kidney, stomach, lungs)
    o It also affects the heart, altering contraction frequency and force
  • This combination of effects is eventually fatal, usually within one week
79
Q

Outline the mechanism of action of fluoroacetate. How can this lead to a toxic effect? Be sure to describe the physiological consequences of such toxicity.

A
  • Fluoroacetate is chemically very similar to acetate
  • In cells, it combines with coenzyme A to form fluoroacetyl CoA
    o This reacts with citrate synthase to form fluorocitrate
  • Fluorocitrate binds to aconitase and will not react
    o This shuts down the TCA cycle, gradually depriving the cell of energy
  • It also inhibits two enzymes in the mitochondrial membrane that are required to transport citrate into the mitochondrion
    o Prevents movement of citrate in or out
  • Symptoms appear within 3 hours
    o Initial symptoms include nausea, confusion and agitation
    o Lack of ATP leads to cardiac effects and neurological problems (muscle twitching, seizure)
    o Eventually, arrhythmia and hypotension develop and can be fatal
80
Q

Why are the ‘rainbow’ herbicides so notorious?

A

Rainbow herbicides
- A group of chemicals, mostly containing 2,4-D or a derivative
- Used by the US military as a defoliant during the Vietnam War
- The aim of this program was to destroy foliage which provides enemy cover, and to limit food production in enemy territory
The most notorious of these was Agent Orange
Agent Orange
- Mixture of 2,4-D and 2,4,5-T, named for the orange stripe on the barrels in which it was shipped
- The 2,4,5-T was contaminated with TCDD, a toxic dioxin
o TCDD is considered ‘perhaps the most toxic molecule ever synthesised’
o Persists in soil for up to 10 years
- Use of defoliants has been almost entirely banned by the Environmental Modification Convention
- During the Vietnam War, almost 3 million people were exposed to Agent Orange
o 150000 children born with birth defects
- Soil contamination is 350 times greater than the recommended maximum
- Genetic diseases are prevalent, including mental and physical disabilities
- TCDD is a potent carcinogen, so rates of cancer are substantially higher in affected regions

81
Q

Outline the mechanism of action of paraquat. How can this lead to a toxic effect? Be sure to describe the physiological consequences of paraquat toxicity.

A
  • Functions as an electron acceptor and generates ROS
  • Selectively transported to the lungs, death by respiratory distress
82
Q

Outline the mechanism of action of glyphosate. Could this lead to a toxic effect in humans?

A
  • Inhibits aromatic amino acid synthesis, but can also interact with other enzymes
  • Glyphosate targets an enzyme not found in humans, so generally has very low toxicity
  • However, it can bind to some other enzymes, so at very high doses, it can have toxic effects
83
Q

Outline the mechanism of action of caffeine. How can this lead to the ‘desired’ effect?

A

Adenosine receptors

  • G protein-coupled receptors with adenosine as endogenous ligand
  • Four types:
    • A1 is involved in regulating heart rate; activation leads to decreased heart rate
    • A2A inhibits the central nervous system by decreasing levels of dopamine and glutamate
  • Caffeine is an antagonist at the A1 and A2A receptors
    • It is lipid soluble, so can readily cross the blood-brain barrier and affect these receptors
  • This will lead to increased heart rate and decreased inhibition of the central nervous system
    • Decreasing inhibition of the CNS will increase levels of neurotransmitters such as dopamine
    • Hence caffeine is a stimulant
  • Adenosine receptors are also involved in regulating the sleep-wake cycle (desired effect to stay awake)
  • Caffeine is also a phosphodiesterase inhibitor, prolonging the activity of cAMP in cells
84
Q

Explain the difference between caffeine dependency and overdose.

A

Caffeine dependency

  • Generally defined as consumption of over 1000 mg of caffeine every day
  • Symptoms include irritability, restlessness, insomnia, headache and heart palpitations
  • Gives a lower overall risk of cancer, but may increase the risk of some specific cancers
    • May also protect against cardiovascular disease, type 2 diabetes and liver disease
  • Diuretic effect is generally diminished in people who consume caffeine every day

Caffeine overdose

  • Ingestion of over 500 mg caffeine at one time can lead to toxicity
    • Initial symptoms include anxiety, insomnia, muscle twitching, heart palpitations
    • Extreme doses can result in mania, depression, hallucination and breakdown of muscle tissues
  • Death is by cardiac arrhythmia and arrest
  • Estimated LD50 is 200 mg/kg, which is approximately 100 cups of coffee
  • This is possible using caffeine tablets
85
Q

Briefly outline the potential risks linked to sugar substitutes. What is the molecular mechanism of ‘sweetness’?

A
  • Two proteins, T1R2 and T1R3 complex to form a G protein-coupled receptor that binds ‘sweet’ molecules
  • These molecules bind to the receptor and activate the G protein, gustducin
  • This activates adenylate cyclase, which produces cAMP
  • cAMP activates a protein kinase that phosphorylates and closes a potassium ion channel
  • Leads to build-up of potassium, which causes opening of a voltagegated calcium channel
    • Increase in calcium causes release of neurotransmitters, transmitting the response to the ‘sweet’ molecule
86
Q

Briefly outline the major toxicity concerns with parabens.

A

Preservatives added to many products • Contain parahydroxybenzoates • Bactericidal and fungicidal • Thought to act by disrupting membrane transport processes or by inhibiting synthesis of DNA and RNA or key enzymes • In the environment, parabens may have toxic effects on plankton and algae

• Cancer • Traces of parabens were found in breast tumours • No definitive link has been determined • Endocrine disruption • Can function as a xenoestrogen • May have developmental and reproductive effects • Sun damage • Can react with UV radiation to increase damage from sun

87
Q

Briefly outline the major toxicity concerns with surfactants used in shampoo.

A

SLS AND SLES

• No known cancer risk has been determined • No known interaction with DNA • Irritant • Like most detergents, irritate the skin and eyes • Contamination • Some formulations have been contaminated with dioxane

Cocamidopropyl derivatives - carcinogenic

88
Q

What is volatile substance use?

A

deliberate inhalation of substances, which produce a vapour or gas at room temperature, for their intoxicating effects

89
Q

How do antiperspirant deodorants exert their antiperspirant effect? Are these ingredients toxic?

A
  • Generally contain aluminium compounds • Aluminium chlorohydrate and aluminium-zirconium tetrachlorohydrate gly • React with electrolytes in sweat to form a gel plug in the duct of the sweat gland • Prevent the gland from excreting liquid • Removed by the natural sloughing of the skin • Also interact with the keratin fibrils in the sweat ducts and form a physical plug • Also cause pores to contract, preventing sweat from reaching the surface of the skin
  • Are they toxic? • Aluminium chlorohydrate has been investigated for links to Alzheimer’s disease and breast cancer • No definitive evidence has been found for either condition • Small amounts can be absorbed, which can be problematic for individuals with kidney dysfunction • Zirconium can cause allergic response in some individuals
90
Q

What are the three main types of ingredient in makeup that may be of concern in terms of toxicity? Give an example of each.

A

• Preservatives • Emulsifiers • Colours

91
Q
A

BIO367 - Forensic Toxicology (3 decks)

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