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Mechanisms of Toxicity, Screenshot 2023-08-31 at 9.35.43 pm - Coggle…

- - - - Depersonalised
      - Invisible
      - Silent
      - Easy to overcome a stronger victim
      - Can poison essential aspects: food, drink, air
      - Uses victim's physiology to kill them
      - 6% of homicides are result of poisoning
    - - Colourless
      - Odourless
      - Tasteless
      - Cheap
      - Easily obtained
      - Soluble
      - Undetectable
      - Delayed action
      - Lethal at low dose
      - Mimics a natural disease
  - - - Reports magnitude of the effect of a substance on the biological target or organism
      - Can be used to determine the ED50, LD50 & therapeutic index of the substance
      - ED50 (median effective dose) - Dose of a substance that produces the desired effect in 50% of the population that takes it
      - LD50 (median lethal dose) - Dose of a substance that is required to kill 50% of the population that takes it
      - Therapeutic index (therapeutic window) - quantitative measurement of relative safety of a substance
        
        Therapeutic index = LD50/ED50
        
        The narrow the therapeutic window, the less safe a substance is
    - - First pass metabolism
        
        Substance is metabolised in gut or liver before reaching the general circulation (usually hepatic enzymes)
        
        Sometimes increase potency if substance is converted into an active metabolite e.g. codeine into morphine
        
        Substances with a high first-pass effect typically need a much higher oral dose to achieve the same effect as another route would achieve
        
        Combining different substances may increase or decrease first-pass metabolism
      - Bioavailability (F)
        
        Fraction of a substances that reaches the systemic circulation
        
        When given intravenously, bioavailability is 100%
        
        Administration by other routes is typically lower, & is compared to the intravenous bioavailability
  - - - Process differs between routes, with oral administration usually taking the longest
      - Inhalation - fastest route
      - Substance can't take effect in body until it's absorbed
    - - Affected by blood flow, vascular permeability, perfusion rate of the tissue, lipid solubility of the substance, ability of the substance to bind to plasma proteins
      - Highly perfused organs (liver, kidney, heart) easily take up the substance
      - Harder for muscle & fat to take up the drug
      - Unbound substance is moved from plasma into tissue until equilibrium is reached
      - Physical volume of the organism, removal rate of the substance & propensity of the substance to bind to tissues have biggest impact on distribution
      - Volume of distribution (VD) - theoretical volume that represents degree to which substance is taken up by the tissues rather tahn staying in the plasma
      - Non-polar substances & those with low plasma protein binding activity have the highest VD
      - Liver or kidney failure can increase VD
    - - If deactivated, action of the substance is terminated
      - If activated by metabolism, the substance has a greater effect or potency after conversion into active metabolites
      - Some substances are eliminated unchanged & don' undergo metabolism
      - Converts substance into a more hydrophilic compound, which speeds up the rate of excretion of the kidneys
      - Reduces the reabsorption of the metabolite back into the renal tubules, as it is less lipid soluble
    - - Substance & its metabolites removed from body through several mechanisms
        
        Exit body in urine, faeces, sweat or exhaled breath
        
        Rarely, a substance may accumulate in the body
      - Models of elimination
        
        First order elimination
        
        Elimination rate of the substance is directly proportional to its concentration
        
        Plasma concentration of the substance decreases exponentially over time
        
        Zero order elimination
        
        Elimination rate is independent of the concentration
        
        Plasma concentration of the substance decreases in a linear fashion over time
- - - - Programmed cell death
      - Enables indiv cells to commit suicide when they are dysfunctional
      - Dying cells fragment into membrane-bound apoptotic bodies
      - Cellular contents not released so can't affect neighbouring cells
  - - - Inhibition of ETC - e.g. cyanide inhibits cytochrome oxidase
      - Inhibition of O2 delivery - cocaine, carbon monoxide
      - Inhibition of ADP phosphorylation - e.g. DDT
      - Damage to mitochondria - e.g. chronic ethanol abuse
      - Loss of control of ion gradients
        
        As more Na+ & Ca2+ enter cell, more voltage-gated channels open & more ions enter
        
        Causes loss of volume control: water influx, cell swelling
        
        Cell lyses: necrosis
    - - Consequence of increased intracellular Ca2+ is excitotoxicity
        
        Depletion of ATP
        
        Mitochondrial ATP production decreased; activation of Ca2+ ATPase uses ATP
        
        Activation of Ca2+ dependent hydrolytic enzymes
        
        Leads to disintegration of membranes, proteins
        
        Production of reaction oxygen & nitrogen species
        
        Leads to disintegration of membranes, proteins
        
        Microfilament dysfunction
        
        Disrupted morphology & function, impaired motility
        
        Ca2+ - toxic to cell if present at high levels in cytoplasm
    - - Increased intracellular Ca2+ generates ROS/RNS
        
        Activation of dehydrogenases in TCA cycle - increases electron output via the ETC, causing increased production of superoxide
        
        Activation of Ca2+ dependent proteases - convert xanthine dehydrogenase to xanthine oxidase, which also produces superoxide & hydrogen peroxide
        
        Activation of constitutively expressed nitric oxide synthases in neuronal & endothelial cells - increased NO production, which reacts with superoxide to form highly reactive peroxynitrite
        
        Oxidants
        
        Molecules that can accept an electron - they are very reactive molecules
        
        Oxidative stress occurs when the balance is disrupted, more oxidants present
        
        ROS & RNS
        
        Generated directly by
        
        Transition metals
        
        Activation of foreign compounds (e.g. benzene)
        
        Redox cycling (e.g. paraquat)
        
        Inhibition of mitochondrial electron transport
        
        Generated indirectly by
        
        Activation of cytochrome P450
        
        Increased intracellular Ca2+
        
        Drain ATP reserves
        
        Nitric oxide is a reversible inhibitor of cytochrome oxidase
        
        Peroxynitrite - irreversible inhibitor of several ETC complexes & aconitase (TCA cycle)
        
        ROS can also damage mitochondrial membranes, which disrupts the electrochemical gradient needed for ATP synthase to function
        
        Inactivate Ca2+ ATPase, increasing intracellular Ca2+
        
        ROS can mutate DNA causing cellular dysfunction
        
        Peroxynitrite causes single strand breaks in DNA
        
        Activates a polymerase that consumes NAD+
        
        Reduces ATP synthesis
        
        ROS & RNS also cause - lipid peroxidation, cell swelling, cell lysis
        
        Lipid peroxidation: Peroxidative degradation of lipids by removal of hydrogen from fatty acids - produces a lipid radical
- - - - Ca2+ stored in ER or mitochondria
  - - - First stage of metabolism ,whereby the substance is converted to a more polar metabolite by adding or charging a functional group
      - Phase includes reactions such as oxidation, reduction & hydrolysis
      - If sufficiently polar, metabolite may be eliminated at this point without undergoing further metabolism
      - Phase activates or deactivates the original substance
    - - Metabolite is conjugated with a charged compound such as glutathione
      - Increases the molecular weight & hydrophilicity
      - Deactivates the substance if Phase I did not
      - Catalysed by a family of non-specific transferases
      - Requires endogenous co-factors in order for the reaction to proceed
    - - Phase further processes metabolites that could not be eliminated after Phase I & II
      - Further modifications can be made to conjugates, such as acetylation
      - Products of Phase II & III metabolism are removed from the cell by various transporter proteins, where they can be eliminated