Toxicology: 78 toxic compounds

  1. Nicotine: A parasympathomimetic alkaloid. Acts as a volume control in the CNS by binding to the nicotinic acetylcholine receptors in the CNS. It increases the release of neurotransmitters, providing a stimulant effect. More neurotransmitters gives the effect of the brain working faster and more efficiently. It also interacts with nicotinic receptors on the adrenal gland, stimulating the release of adrenaline giving a physiological stimulant effect. Nicotine poisoning results in excessive stimulation of the nicotinic acetylcholine receptors causing receptor depression. This causes nausea, vomiting, tachycardia and hypertension.
  1. Curare: Reversible competitive inhibitor of the nicotinic acetylcholine receptor. Turbocurarine is the most common curare toxin. Blocks neurotransmission via Ach, leading to paralysis. Onset is quick and has a long duration of action, therefore was used as a muscle relaxant.
  1. Muscarine: An alkaloid found in mushrooms. Binds to the muscarinic receptors and activates them. These receptors are located throughout the body; therefore effects of muscarine poisoning are widespread. Symptoms are caused by excessive activation of these receptors. Decreases HR via the M2 receptors. Can trigger convulsions and hypothermia via M1, M4 and M5 receptors in the brain. Can also trigger bronchoconstriction and severe gastrointestinal symptoms.

 

  1. Atropine: An alkaloid from deadly nightshade. Competitive antagonist of muscarinic receptors. Used to increase heart rate by blocking M2 receptors. Overdose of atropine will cause a set of symptoms known as anticholinergic toxidrome. Used to dilate pupils for ophthalmic examination. Also has a hallucinogenic effect.

 

  1. Scopolamine: Alkaloid found in the deadly nightshade family of plants. Competitive antagonist at the muscarinic receptors. Overdose results in tachycardia and arrhythmias. Also has a serious interaction with a range of medications.

 

  1. Strychnine: Prevent glycine from binding to Glycine receptors. These receptors allow movement of chlorine ions, preventing the nervous system from being too sensitive. Strychnine prevents this, causing the nervous system to become hypersensitive. Very low levels of neurotransmitter trigger action potentials. This causes constant muscle contractions. Death usually results from respiratory arrest and asphyxia.

 

  1. Brucine: Closely related to strychnine- has the same mechanism of action. Antagonism at glycine receptors causing the nervous system to become hypersensitive. Death also due to respiratory arrest.

 

  1. Amygdalin: a cyanogenic glycoside that breaks down to release HCN. In solution, HCN produces cyanide ions (CN-), which attach to the iron in cytochrome oxidase. This prevents the transfer of electrons from cyt c to oxygen. Leads to shut down of the electron transport chain, this means the cell is no longer capable of aerobic respiration. Poisoning occurs from hypoxia.

 

  1. Digoxin: Primary action is through increasing the heart contractility. Bind to the Na+/K+ pump and stabilize it in a transition state. This increases levels of Na+ in the cell. This inhibits the NCX pump which brings in Na+ and moves out Ca2+ – lead to an increase in Ca2+ levels in the cell which causes increases contractility.

 

  1. Digitoxin: glycoside from foxglove. Similar to digoxin, but longer lasting. Toxic effects are the same as for digoxin. Initial symptoms include nausea, vomiting, diarrhea, confusion and visual disturbances. High exposure will cause cardiac arrhythmias and arrest.

 

  1. Oubain: Used in the treatment of atrial fibrillation and congestive heart failure. Unlike digoxin, low levels of oubain can stimulate the Na/K pump.

 

  1. Solanine: A saponin glycoside found in potatoes and tomatoes. Have soap like properties, which make them detergent like. This causes haemolysis if injected. Toxic mechanism is likely due to disruption of mitochondrial membranes. Can also block acetylcholinesterase.

 

  1. Ricin: a lectin. Death usually results from circulatory shock due to a shutdown of metabolism. Ricin irreversibly hydrolyses a glycosidic bond in the rRNA of the 60S ribosomal subunit. This shuts down protein synthesis within cells.

 

  1. Abrin: a protein found in the seeds or the rosary pea. Symptoms are slow to present. Works by a similar mechanism to ricin, induces respiratory distress by inactivating ribosomes.

 

  1. Aresnic: Exists in 3 forms: Trivalent arsenicals, pentavalent arsenicals and organo-arsenicals. The trivalent forms are the principal toxic forms and inhibit succinic dehydrogenase activity, which uncouples ox phos. This leads to a decrease in intracellular ATP and increases H2O2 levels.

 

  1. Cadmium: Acute toxicity occurs through ingestion of relatively high levels of cadmium and results in nausea, vomiting and abdominal pain. Chronic cadmium toxicity results from long term exposure. Cadmium displaces zinc in many metallo-enzymes and many of the symptoms of cadmium toxicity can be traced to cadmium-induced Zn deficiency.

 

  1. Lead: impairs the plasticity of cell-cell communications during development resulting in rearranged neuronal circuitry. Lead disrupts calcium metabolism and homeostasis in neuronal cells, impairing calcium homeostasis. Can cause lead induced anemia. Also competes for calcium uptake into the mitochondria and binds to calcium-binding proteins involved in signal transduction such as calmodulin.

 

  1. Mercury: exists in 3 forms- elemental mercury- which is 80% absorbed by lungs and has preferential uptake by the brain but has reversible effects. Inorganic salts- absorbed 7-20% by gut, effects can be reversible. Will ccause damage to the GI tract including ulceration and bloody darrhoea. Organic mercury can be methylmercury or ethylmercury which bioaccumulates. Targets the CNS

 

  1. Chromium: Chromium (II) is non-toxic and poses no health risk. Chromium (III) can be cytotoxic, however is not readily taken up into cells. Chromium (IV) poses the highest risk. Is a powerful oxidant at low or neutral PH. The acute effects are due to oxidation. With chronic exposure, hexavalent chromium is able to enter the cell where it is converted to chromium (III) and chromate which are able to interact with cellular DNA resulting in cancer or apoptosis.

 

  1. Nickel: often a skin allergen. Sensitized individuals may get dermatitis. Acute exposure can also produce toxic effects and lead to death by cardiac arrest.

 

  1. Succinylcholine: Attaches to the nicotinic receptor and depolarizes the junction as acetylcholine does. However it is not destroyed by the AchE and so its action persists. Exposure results in muscle fasciculation followed by exhaustion and flaccid paralysis within one minute.

 

  1. NSAIDs: act by blocking the COX enzymes. This lowers the levels of circulating prostaglandins and thromboxanes, which reduces prostanoid-mediated inflammation. An example of an NSAID is aspirin. Reduce inflammation and pain.

 

  1. Paracetamol: Low level cyclooxygenase inhibitor. A para-aminophenol derivative that exhibits analgesic and anti-pyretic activity. It does not possess anti-inflammatory activity. Given for mild to moderate pain and fever. Acute overdoses of paracetamol can cause potentially fatal liver damage, which may be heightened by chronic alcohol abuse. Damage to the liver results from NAPQI a metabolite of paracetamol, which depletes liver glutathione.

 

  1. Opiates: bind to GPCRs and inhibit adenylyl Cyclase. Causes hyperpolarization for nerve cells, which inhibits nerve firing and inhibits the release of neurotransmitters. Morphine causes analgesia, euphoria, respiratory depression and depression of cough reflex.

 

  1. Barbiturates: exert their effects via their interaction with GABA receptors where they potentiate the inhibitory effects of GABA, leading to decreased neuronal activity. GABA A receptors allow the passage on Cl- ions into the cell which causes hyperpolarization and decrease neuronal activity.

 

  1. Tricyclic antidepressants: block the re-uptake of serotonin and NA into the neuron. This blocks the major route of neurotransmitter removal and maintains elevated levels in the synaptic cleft. All members have the same therapeutic efficacy. Also block serotonergic, alpha-adrenergic, histaminic and muscarinic receptors.

 

  1. Insulin: classes as an oral hypoglycemic agent. Used in the treatment of diabetes mellitus. Binds to the insulin receptors and helps to regulate blood sugar levels. Mismanagement of insulin treatment, generally overdose will result in rapid lowering of blood sugar levels resulting in hypoglycaemic shock.

 

  1. Ethanol: Acts on the GABAA receptors that allow the passage of chloride ions through the ion gates channel and cause neuronal inhibition. Act on NDMA receptor by inhibiting glutamate-stimulated Ca2+ reflux and cGMP production Ethanol inhibits fast excitatory transmission. Prevents tonic inhibitory control of release of dopamine which leads to an increase in the release of dopamine. Also interacts with the d opiod receptors. Interacts with caecholamines to form condensation products, hydroisoquinolines, that possess opiod-like properties. Inhibits the relase of acetylcholine from the CNS neurons. Inhibits oxytocin, hydrocortisone metabolism and increase ACTH secretion.

 

  1. Chloral hydrate: A sedative hypnotic that induces sleep in about 30 minutes and lasts for 6 hours. metabolized in vivo to trichloroethanol, which is responsible for enhancing the GABA-receptor complex. This decreases the activity of the nerve cells.

 

  1. Canthandrin: the main ingredient in Spanish fly. Absorbed by the lipid membrane of epidermal cells causing the activation of serine proteases. These enzymes cleave peptide binds, ultimately leading to the loss of cellular connections.

 

  1. Benzodiazepine: Has anxiolytic effects. Enhance the binding of GABA to their receptors. This causes more Cl- to enter the cell, which hyperpolarizes the cell. This reduces neural excitability.

 

  1. Midazolam: used as an anesthetic pre-medication and for long term sedation of patients in the ICU. Causes rapid sedation and has anxiolytic, anticonvulsant and muscle relaxing properties. Rapidly hydroxylated and excreted as glucuronide.

 

  1. Flunitazepam: An intermediate acting benzo that acts as a hypnotic, sedative and skeletal muscle relaxant. Enhances the GABA-receptor complex, causes an influx of Cl- ions, which hyperpolarizes the cells.

 

  1. Flumazenil: A GABA receptor antagonist. Reverses the CNS effects of benzodiazepines by competitive inhibition. Causes an influx and Cl- ions.

 

  1. GHB: weak agonist of the GABA B receptor. Found in the CNS and PANS. Stimulate the opening of K= channels, which bring the neuron closer to the equilibrium potential of K and hyperpolarizing the cell. This prevents sodium channels from opening and so stops action potentials from being generation Thus these are considered inhibitory.

 

  1. Ketamine: A dissociative agent that induces a trance-like state of cateptic sensory isolation. antagonist at the NMDA receptor. NMDA receptor antagonism is responsible for the anesthetic, amnesic and dissociative effects. Also a dopamine re-uptake inhibitor which causes euphoria.

 

  1. Z-drugs: selectively bind to the omega-1 receptor subtype. This is the alpha subunit of the GABA A receptor.

 

  1. Organophosphates: act by inhibiting acetylcholinesterase. This leads to an increase of Ach and overstimulation of the Ach receptors. Overstimulation of Ach receptors in the muscles can cause fatigue, weakness and paralysis. In the CNS leads to headache, convulsions and coma. Overstimulation of the muscarinic receptors can lead to salivation, sweating and difficulty breathing. Cause of death is usually respiratory paralysis. Malathion is an example.

 

  1. Organochlorines: Organic compounds containing at least one covalently bound chlorine. Endocrine disruption is the main toxic effect, can be agonists or antagonists of estrogen receptors, this changes the homeostatic mechanisms.

 

  1. DDT: primary action is to open sodium channels on neurons causing them to fire spontaneously, causing spasm. Linked with cancer, diabetes and Alzheimer’s. Metabolized to DDE and DDD, which are also toxic.

 

  1. Deildrin: antagonist at the GABA receptors, making the nervous system hypersensitive by blocking the action of GABA and making the neuron more responsive causing muscle twitches and convulsions.

 

  1. Pyrthroids: Prevent the closure of voltage gated sodium channels on neuronal cells. Have low toxicity in humans. Neurotoxic activity is negatively correlated with temp.

 

  1. Permethrin: at very high doses, permethrin will have neurotoxic effects on humans. Classified as a likely carcinogen.

 

  1. Neonicotinoids: Structurally similar to nicotine. Ach receptor agonists. Cause overstimulation of the nicotinic receptors. High levels will cause overstimulation, eventually reducing sensitivity; this leads to paralysis and death.

 

  1. DEET: blocks AchE activity. This causes Ach to build up at the neuromuscular junction. Toxicity is likely due to this action.

 

  1. Anticoagulants: prevent the formation of essential blood clothing factors. Also cause damage to capillaries, which causes hemorrhage. Block VKOR action, which decreases the amount of vitamin K available to the cell. This means that necessary Gla proteins, which are clotting proteins, cannot be made. Internal hemorrhages occur, typically leading to death from circulatory shock or anemia.

 

  1. Metal phosphides: phosphide is converted to phosphine, which is an acetylcholinesterase inhibitor. Can also interfere with the mitochondrial ETC. exposure can cause respiratory paralysis.

 

  1. Hypercalcemic agents: poisons that affect calcium and phosphate metabolism. In trace quantities, vit D is essential for normal body functioning. Too much vit D causes hypervitaminosis, which can be fatal. Allows too much ca2+ to circulate in the blood, eventually the blood vessels and key organs calcify.

 

  1. Fluoroacetate: combines with coenzyme A and reacts with citrate synthase to form fluorocitrate. This binds to aconitase but does not react. This shuts down the TCA cycle, depriving the cell of energy. It also inhibits 2 enzymes in the mitochondrial membrane that are required to transport citrate into the mitochondrion. This prevents movement.

 

  1. 2,4-D: a synthetic plant hormone that stimulates uncontrolled growth. Growth cannot be sustained and leads to the death of the plant. Major concerns for humans is the presence of dioxin impurities in the formulation.

 

  1. Agent orange: A mixture of 2,4-d and 2,4,5-T. The 2,4,5-T was contaminated with TCDD a toxic dioxin.

 

  1. Paraquat: an electron acceptor in redox reactions. Accepts electrons in plants from photosystem I. Paraquat is chemically similar to the polyamines putrescence and spermine. in the lungs. It can therefore bind to the same active transport mechanisms and become concentrated in the lungs. Once in the lung it generates ROS and causes oxidative damage. Can also cause neurodegeneration.

 

  1. Glyphosate: Inhibits the enzyme EPSP synthase which catalyses an essential step in the synthesis of aromatic amino acids (Phe, Trp and Tyr). It is a competitive inhibitor, binding in the place of PEP. Humans do not have this enzyme however it can bind to other enzymes.

 

  1. Caffeine: A central nervous system stimulant. Lipid soluble so it can readily cross the blood-brain barrier and bind to the adenosine receptors. Antagonist at the A1 and A2A receptors. Leads to an increase in heart rate and increased levels of dopamine in the brain due to decreasing inhibition of the CNS. Also a phosphodiesterase inhibitor, prolonging the activity of cAMP in cells.

 

  1. Sulfur dioxide: Widely used as an antibiotic and antioxidant. Block nerve signals from pulmonary stretch receptors meaning that the lungs do not fully inflate.

 

  1. Melamine: organic base used in foods to increase apparent protein content. Metabolism of melamine produces metabolites, which crystallize in the kidney and bladder. Causes obstructive urolithiasis, which can lead to renal failure.

 

  1. Methanol: Like ethanol is a CNS depressant of the nervous system. This is by stimulation of some inhibitory neurotransmitters and inhibition of stimulatory neurotransmitters. Toxicity is due to a toxification reaction in metabolism.

 

  1. Formic acid: Inhibits cytochrome C oxidase causing cellular hypoxia and causes metabolic acidosis by decreasing the blood pH.

 

  1. Thujone: interacts with GABAA receptors allowed chloride ions into the neuron which hyperpolarizes the cell. Can also lead to porphyria by increasing the production of 5ALA, which is the first compound in the synthesis of porphyrins.

 

  1. Ethylene glycol: Toxicity is due to its metabolites oxalic acid and NADH. Oxalic acid is structurally similar to succinic acid. It binds and inhibits the action of succinate dehydrogenase, shutting down the TCA cycle. It also associates with Ca2+ to form calcium oxalate, which precipitates in the brain and renal tubules. Excess NADH produces drives pruvate to be converted to lactic acid, this causes blood pH to drop.

 

  1. Diethylene glycol: through that DEG is metabolized to 2-hydroxy-ethxy-acetaldehyde by alcohol dehydrogenase. This is then converted to HEAA, which causes metabolic acidosis. Also causes damage to the kidneys and liver.

 

  1. Heroin: once in the brain it is deacylated into 6-MAM and morphine. Both are mu opioid receptor agonists, which bind to receptors present throughout the brain, spinal cord and cut. Morphine also binds to the O and k opioid receptors. Binding strongly to the mew receptors results in the drugs euphoric, analgesic and anxiolytic effects. Repeated use of heroin results in decrease of the mew opioid receptors. When heroin binds to the mu opioid receptors it causes the release of GABA from that neuron. GABA binds to the adjacent cell and triggers the release of dopamine from that cell.

 

  1. Methadone: binds to the mu opioid receptors it causes the release of GABA from that neuron. GABA binds to the adjacent cell and triggers the release of dopamine from that cell. This decreases the need to heroin.

 

  1. Cannabinoids: activate Gi linked GPCR’s found in the brain. CB1 receptors are found on the plasma membrane of nerve endings and inhibit transmitter release by inhibiting calcium entry and hyperpolarization due to activation of potassium channels. They can increase the activity of some neuronal pathways by inhibition of connections (ie. GABA-ergic interneurons in the amygdala and hippocampus). Within the CNS, CB1 receptors have been found in the hippocampus, basal ganglia, cerebellum and brainstem. CB2 receptors are found on many immune cells and account for the inhibitory effects of cannabis on immune function.

 

  1. Cocaine: blocks sodium channels acting as a local anesthetic. Also inhibits the re-uptake of serotonin, norepinephrine and dopamine. Physically blocks sodium channels and interferes with the propagation of action potentials, this makes it act as a local anesthetic. Inhibitor of the dopamine transporter protein (DAT), this prevents recycling of dopamine, prolonging the post-synaptic effect of dopamine. Also inhibits the noradrenaline transporters in the nucleus accumbens increasing sympathetic NS activity. Inhibits the serotonin re-uptake transporter increasing the amount of serotonin in the synaptic cleft.

 

  1. LSD: causes dilated pupils, higher or lower body temp, sweating or chills, loss of appetite, sleeplessness, dry mouth and tremors. Causes delusions, visual hallucinations, artificial sense of euphoria etc.

 

  1. MDMA: causes re-uptake of serotonin in the brain to be inhibited. This results in an increase in 5-HT in brain regions followed by depletion. Similar but small changes also occur in relation to noradrenaline and dopamine. These cause euphoria and later rebound dysphoria.

 

  1. Crystal meth: increases the release of very high levels of dopamine in the brain. This is involved in motivation of the experience of pleasure and motor function.

 

  1. Chlorine gas: reacts with the water in the lungs to form hydrochloric acid. This destroys lung tissue and causes death by asphyxiation.

 

  1. Phosgene: Symptoms manifest over a period of 24 hours. Reacts with the amine groups of alveoli proteins and creates urea-like cross-linkages. This disrupts the blood-air interface reducing the ability of the lungs to exchange oxygen and carbon dioxide. Death is by asphyxiation. Also produces HCl, which damages lung tissue.

 

  1. Mustard gas: rarely fatal, but highly incapacitating. Forms a cyclic sulfonium ion that alkylates guanine in DNA, preventing cell division. This triggers apoptosis or tumorigenesis. It also causes oxidative damage to the cell.

 

  1. Lewisite: Arsenite bids to pyruvate dehydrogenase and inhibits the TCA cycle and aerobic respiration. This causes a lack of ATP, which primarily affects the nervous system, resulting in weakness and restlessness. Inhalation causes lung damage and coughing.

 

  1. Sarin: A G-series nerve gas. Inhibits acetylcholinesterase by binding to the active site. Without AchE, Ach builds up in the synapse and prevents the muscle from relaxing. Initial symptoms include difficulty breathing followed by loss of control of bodily functions, muscle jerks, spams and death is due to respiratory paralysis.

 

  1. VX: AchE inhibitor, results in muscle spasm followed by neuromuscular blockade. This causes paralysis, leading to asphyxiation.

 

  1. Dioxins: Highly lipophilic molecules that all contain 1,4-dioxin. Interact with the aryl hydrocarbon receptor. This is a transcription factor that regulates gene expression. Binding of dioxins to AHR induces expression of a group of cytochrome P450 enzymes that break down foreign compounds. These enzymes can also break down important endogenous compounds. Key effects include immunotoxicity, endocrine disruption and tumor promotion.

 

  1. Methyl isocyanate: Colorless, flammable liquid that is made in the production of carbamate pesticides. Most susceptible to those with respiratory or eye disease however mechanism is unknown.

 

  1. Acrylamide: Forms adducts with proteins including hemoglobin. Does have some neurotoxic effects with prolonged exposure, these include loss of sensation and weakness. Also known to be a carcinogen, can transform cells from normal to cancer.

 

  1. Formaldehyde: Used as a disinfectant and to preserve biological specimens. Also causes oxidative stress and inflammation. In addition to its corrosive and irritant properties, it will alter the basic functioning of a cell. It forms irreversible cross-linkages between amine groups of proteins and other molecules. These properties are due to the mannich reaction.
Advertisements

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s