14.9 Toxicology And Drugs Of Abuse

Question 1

Calssify:
Poison
Toxin
Venom

Answer 1

• Poison is a broad term for any chemical substance that has a detrimental effect on life. The term is used in a wide range of scientific fields and industries, where it is often specifically defined.
• A toxin is a naturally occurring organic poison produced by the metabolic activities of living cells or organisms. If you bite it, and you die – it is a toxin.
• Less strict understandings embrace naturally occurring non-organic toxins, such as arsenic.
• A venom is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. If it bites you, and you die – it is a venom.

Question 2

What affects the toxicity of a substance

Answer 2

• Dosage – LD 50 (if dose is given to 100 people, 50 will die; the lower the LD the more toxic it is)
  ➡️ The amount of a substance, that when given, kills 50% of test subjects at once.
  ➡️Determines acute lethality/ toxicity – does not say anything about the long-term
  effects.
  ➡️ANIMAL MODELS used (rats/ mice/ guinea pigs)- difficult to correlate to the human population.
  ➡️Low LD50= More toxic
  ➡️Does not compensate for different metabolic or physical variations in humans.
• Biological factors
  ➡️Absorption, Storage in the body, Distribution, Excretion, Tolerance
• Chemical factors
  ➡️Specific receptors (e.g. haemoglobin – CO, cholinesterase- organophosphates)
  ➡️Biotransformation to toxic metabolites (e.g. methanol)
• Route of administration
  ➡️ Skin (agrochemical), lungs (volatile substances), GIT (oral and rectal), parenteral
• Genetic factors (renders you unable to absorb or metabolise something)
  ➡️ Congenital enzyme deficiencies (aldehyde dehydrogenase)
  ➡️Slow metabolisers of INH and other drugs – show poisoning with small doses
  ➡️Abnormal reactions, e.g. Porphyria
• Diverse reactions
  ➡️Synergistic/antagonistic effects of drugs (alcohol and benzodiazepines or barbiturates)
  ➡️Anaphylactic reactions
  ➡️Concomitant effects, e.g. cancer treatment affects sick cells and normal cells in intended effect
  ➡️Suppression of normal cell function - Aplastic anaemia, e.g. Chloramphenicol

Question 3

Median effective dose

Answer 3

The MEDIAN EFFECTIVE DOSE (ED50) or median effective concentration (EC50) is a dose or concentration at which a drug produces a biological response in half of the population to whom it has been administered.

Question 4

Median toxic dose

Answer 4

The MEDIAN TOXIC DOSE (TD50) - is the dose at which toxicity occurs in 50% of cases.
• The type of toxicity should be specified for this value to have meaning for practical purposes. The median toxic dose encompasses the category of toxicity that is greater than half the maximum effective concentration (ED50) but less than the median lethal dose (LD50).

Question 5

Median lethal dose

Answer 5

The MEDIAN LETHAL DOSE (LD50) - is a toxic unit that measures the lethal dose of a toxin, radiation, or pathogen. The value of LD50 for a substance is the dose required to kill half the members of a tested population after a specified test duration.

Question 6

NB Major Toxidrome

Answer 6

• Toxidromes are combinations of specific signs and symptoms that reflect drug class effects on particular neuroreceptors.
• ANTICHOLINERGIC
• SYMPATHOMIMETIC
• CHOLINERGIC
• NARCOTIC
• HYPNOTIC
• YOU ABSOLUTELY HAVE TO KNOW THESE – YOU CANNOT WAIT FOR THE TOXICOLOGY RESULTS TO COME OUT – OTHERWISE, YOUR PATIENT BECOMES MY PATIENT!!!!!

Question 7

NB The major toxidromes – ANTICHOLIN- ERGIC

Answer 7

• The anticholinergic toxidrome is reflected by tachycardia, warm and dry skin, hypoactive bowel sounds, mydriasis, and urinary retention. A delirium occurs in more severe cases.
• This toxidrome is noted after overdosing on antihistamines, tricyclic antidepressants, and many antipsychotics.
• Blind as a bat, mad as a hatter, red as a beet, hot as hell, and dry as a bone.
• Physostigmine is the antidote!!!!

Question 8

NB The major toxidromes – SYMPATHOMEMETIC “MATHS”

Answer 8

• The sympathomimetic toxidrome involves:
  M - mydriasis
  A – arrhythmias cardiac, angina, agitation
  T–Tachycardia
  H-Hypertension,Hyperthermia
  S–Sweating(diaphoretic).

Agents:
• Cocaine
• Amphetamines
• Methamphetamines
• Ephedrine-containing drugs
• Noantidoteexists

Question 9

NB The major toxidromes – CHOLINERGIC “DUMBELLS”

Answer 9

Any fluid that wants to come out of you, will

The cholinergic toxidrome involves:
• Diarrhoea
• Urination
• Miosis
• Bradycardia
• Emesis
• Lacrimation
• Lethargy
• Salivation
• Severe exposure is lethal by bronchospasm and bronchorrhea.

• Agents include:
• Nerve agents – sarin, VX
• ORGANOPHOSPHATES – Atropine is the antidote!!!!!
• Nicotine poisoning

Question 10

NB The major toxidromes – OPIOID “CPR HHH”

Answer 10

• The opioid toxidrome consists of pinpoint pupils, respiratory depression, and unresponsiveness.
• The opioid includes Morphine, Fentanyl, codeine, hydrocodone.
• Naloxone is the antidote!

Question 11

NB The major toxidromes – HYPNOTIC

Answer 11

• Sedative-hypnotics are similar to opioids but without the pupillary changes and less respiratory depression.
• Barbiturates - Phenobarbital, Pentobarbital
• Benzodiazepines – the antidote is Flumazenil!!!!!
• Antiepileptics
• Antihistamines
• Chloral Hydrate

Question 12

Paracetamol

Answer 12

• Acetaminophen (US).
• Analgesic medication used to treat mild to moderate
  pain and fever.
• COX pathway, mechanism of action poorly understood.
• Overdoses of paracetamol, taking more than the recommended maximum daily dose of paracetamol for healthy adults of three or four grams, can cause potentially fatal liver damage
• Liver metabolism saturated – glutathione levels are depleted – liver necrosis = acute liver failure = DEATH.
• Can occur within a few hours.
• ANTIDOTE = N-ACETYL CYSTEINE.

Question 13

Aspirin

Answer 13

• Acetylsalicylic acid a type of NSAID - COX inhibitor.
• Used to reduce pain, fever, or inflammation, and as an
  antithrombotic.
• Uncoupling of oxidative phosphorylation - respiratory alkalosis and metabolic acidosis.
• Haemorrhages in GIT, Skin, and other organs.
• No antidote.
• ASPIRIN SHOULD NOT BE GIVEN TO CHILDREN OR ADOLESCENTS UNDER THE AGE OF 6 TO CONTROL COLD OR INFLUENZA SYMPTOMS, AS THIS HAS BEEN LINKED WITH REYE’S SYNDROME!!!!!

Question 14

Benzodiazephines
Diazepam
Lorazepam
Alprazolam

Answer 14

• These are antianxiety, and hypnotic agents.
• They have replaced barbiturates as hypnotics.
• Benzodiazepines work by increasing the effectiveness of the endogenous chemical, GABA, to decrease the excitability of neurons.
• They are prescribed to treat conditions such as anxiety disorders, insomnia, and seizures.
• Most oral forms are extremely safe if used alone.
• Deaths from overdoses are uncommon and are associated with the presence of another central nervous system depressant — often alcohol.
• The symptoms of a benzodiazepine overdose may include drowsiness, slurred speech, nystagmus, hypotension, ataxia, coma, respiratory depression, and cardiorespiratory arrest.
• FLUMAZENIL IS THE ANTIDOTE.

Question 15

Barbiturates
Phenobarbital

Answer 15

• Hypnotic and sedative agents.
• Before BZNs were available – wide spread abuse.
• Used as anantiepileptic drug, anxiolytic, sleeping tablet, and drug withdrawal. Veterinary use.
• Benzodiazepines work by increasing the effectiveness of the endogenous chemical, GABA, to decrease the excitability of neurons.
• Side effects include a decreased level of consciousness along with a decreased effort to breathe and non-cardiogenic pulmonary oedema.
• Barbiturate overdose may occur by accident or purposefully in an attempt to cause death. The toxic effects are additive to those of alcohol and benzodiazepines.
• At autopsy, the signs are of general cardiorespiratory failure, with often a cyanotic, congestive appearance.
• Though non-specific, probably the congested lungs in acute barbiturate poisoning are more intense than in any other condition.
• Noantidote.

Question 16

Opioids and Opiates

Answer 16

• Opiates refer to natural opioids such as heroin, morphine, and codeine.
• Opioids refer to all natural-, semisynthetic- , and synthetic opioids.

Question 17

Opioids

Answer 17

• Natural and synthetic substances derived from opium, from the poppy plant Papaver somniferum.
• Morphine Codeine Tramadol Heroine Hydrocodone Oxycodone Fentanyl Methadone
• Analgesia and anesthesia. Sedative. Narcotic.
• Also used as antidiarrhoea medication and cough
  suppressant.
• Opioids act by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract.
• These receptors mediate both the psychoactive and the somatic effects of opioids.
• The euphoria attracts recreational use, and frequent, escalating recreational use of opioids typically results in addiction.
• Are addictive and may result in fatal overdose.
• In the elderly – may predispose to falls and other injuries.
• An overdose or concurrent use with other depressant drugs like benzodiazepines commonly results in death from respiratory depression a lethal condition that can cause hypoxia from slow and shallow breathing.
• Opioids do not cause any specific organ toxicity, unlike many other drugs, such as aspirin and paracetamol. They are not associated with upper gastrointestinal bleeding and kidney toxicity.
• THE ANTIDOTE IS NALOXONE.

Question 18

Heroin (“Dope”, “Smack”, “China white”, “Nyaope”.

Answer 18

• Diacetyl morphine – therefor an OPIOID
• Recreation drug and – euphoric effects.
• No medical use.
• IV injected, skin popping, snorted, smoked, inhaled.
• May die very quickly – needles may still be in the arm!
• Use by injection can also result in abscesses, infected endocarditis, blood- borne infections, and pneumonia.
• Constricted pupils.
• 2-3 times more analgesic than morphine. •Crosses BBB easily.
• t1⁄2 is very short – rarely found in blood! •Metabolites measured in blood (if someone takes too much they can die with the needle still inside them)
• Inactive 3-monoacetylmorphine
• Active 6-monoacetylmorphine
• Morphine

Question 19

Downer drugs / Depressants

Answer 19

• Alcohol
• Benzodiazepines
• Barbiturates

Question 20

Stimulants / uppers

Answer 20

• Amphetamine and derivative
• MDMA
• Cocaine

Question 21

Amphetamine and Methamphetamine = Crystal Meth, Crystal, “Tik”, Ice, Speed

Answer 21

• Potent CNS stimulants.
• White-to-clear, odorless, bitter-tasting crystals.
• Mainly used recreational drugs.
• Meth = Equal amounts of levo- and dextro- free base enantiomers of N-methylamphetamine.
• Second-line treatment for – ADHD, Appetite suppressant, and narcolepsy (US – Adderall/ RSA – Vyvanse). Dextromethylamphetamine and Amphetamine – no levomethylamphetamine.
• Sympathomimetic.
• Increases noradrenaline, dopamine and serotonin release.
• In low to moderate doses, methamphetamine can elevate mood, increase alertness, concentration, and energy in fatigued individuals, reduce appetite, and promote weight loss. Aphrodisiac. Euphoriant.
• At very high doses, it can induce psychosis, rhabdomyolysis, seizures, and intracranial hemorrhages.
• Methamphetamine is neurotoxic to human midbrain dopaminergic neurons at high doses.
• Methamphetamine has been shown to have a higher affinity and, as a result, higher toxicity toward serotonergic neurons than amphetamine.
• Chronic high-dose use can precipitate unpredictable and rapid mood swings, stimulant psychosis (e.g., paranoia, hallucinations, delirium, and delusions), and violent behavior = “tik monsters”.
• Methamphetamine is known to possess a high addiction liability (i.e., a high likelihood that long-term or high-dose use will lead to compulsive drug use)
• Methamphetamine is known to possess a high dependence liability (i.e. a high likelihood that withdrawal symptoms will occur when methamphetamine use ceases).
• Psychologically more than physically addictive.
• Smoked, snorted, injected, swallowed, inhaled.
• Readily crosses the BBB. (Blood brain barrier)
• The primary metabolites are amphetamine and 4-hydroxy methamphetamine. Both are active metabolites.
• The elimination half-life of methamphetamine does not vary by route of administration.
• Doses of 200 mg or more of methamphetamine are considered fatal.
• The physical effects of methamphetamine can include:
  • Loss of appetite
  • Hyperactivity
  • Dilated pupils – mydriasis
  • Flushed skin
  • Diaphoresis
  • Ataxic
  • Dry mouth and teeth grinding (leading to “meth mouth”)
  • Headache
  • Dysrhythmias/ Tachycardia/ Tachypnoea/ Hypertension/ Hyperthermia

Question 22

MDMA = “Ecstasy”, “Molly”, “Mandy”, “Adam”, “Eve”

Answer 22

• 3,4-Methyl​enedioxy​methamphetamine
• Tablets or crystal forms.
• Sympathomimetic: MDMA acts primarily by increasing the activity of the neurotransmitters serotonin, dopamine, and noradrenaline in parts of the brain.
• Empathogens. “Profound self-insight and empathy with others”.
• Recreational drugs. MDMA is commonly associated with dance parties, raves, and electronic dance music.
• Limited medical indications.
• The desired effects include altered sensations, increased energy, empathy, and pleasure.
• Short-term adverse effects include bruxism, blurred vision, diaphoresis, tachycardia, hypertension, insomnia, loss of appetite, and erectile dysfunction.
• Prolonged hyperactivity of dancing and “raving”):
  • Dehydration;
  • Hyperthermia;
  • Rhabdomyolysis;
  • Acutekidneyinjury;
  • Intracranial haemorrhages, Cerebral oedema, Convulsions;
  • ARDS.
  • Toxichepatitis.
• MDMA overdose symptoms vary widely due to the involvement of multiple organ systems
• Extended use can also lead to addiction, memory problems, paranoia, and difficulty sleeping.

Question 23

Cocaine = “Coke”, “Snow”, “Blow”, “Crack”

Answer 23

• Derived from coca plant Erythroxylum coca and E. novogranatense (originally from Peru).
• CNS stimulant sympathetic rush (therefore subsequent crash).
• Crosses the BBB-via a proton coupled organic cation antiporter.
• Cocaine stimulates the reward pathway in the brain:
• At lower levels cocaine inhibits the reuptake of Dopamine, and at higher levels increases dopamine receptor activation. Also inhibits the reuptake of Serotonin and Noradrenaline.
• Mainly used recreationally. Euphoric effect.
• Local anaesthetic in ENT and ophthalmological procedures.
• Snorted, topically applied to the gingivae, dissolved, and injected.
• Crack cocaine is the free base form – heated and smoked.
• Mental effects may include an intense feeling of happiness, sexual arousal, loss of contact with reality, or agitation.
• Addicts who abstain from cocaine experience cocaine craving and drug withdrawal, with depression, decreased libido, decreased ability to feel pleasure, and fatigue.
• Physical effects may include tachycardia, diaphoresis, and mydriasis.
• High doses can result in hypertension or hyperthermia.
• Excited delirium (can also happen with other stimulants)
• Aggression, delirium, hyperpyrexia, rhabdomyolysis.
• Causes of death:
  • Myocardial infarction.
  • Cerebral haemorrhage.
  • Cardiac arrhythmias.
  • Acute lung injury.
  • Status epilepticus (those not known with epilepsy that take large quantities).

Question 24

Lysergic acid diethylamide = LSD / “Acid”

Answer 24

• Potent psychedelic drug – recreational use.
• No medical indications.
• Effects typically include intensified thoughts, emotions, and sensory perception.
• Oral administration.
• At sufficiently high dosages LSD manifests primarily mental, visual, as well as auditory, hallucinations.
• Physical effects: Dilated pupils, increased blood pressure, increased body temperature and diaphoresis.
• LSD is considered to be non-addictive with low potential for abuse.
• Adverse psychological reactions are possible, such as anxiety, paranoia, and delusions = bad trips.
• NO direct causes of death – rather doing stupid things while hallucinating:
• “no documented human deaths from an LSD overdose“.

Question 25

Psilocybin = “shrooms”, “Magic mushrooms”

Answer 25

- A naturally occurring psychedelic compound produced by more than 200 species of fungi. - Psilocybin is itself biologically inactive but is quickly converted by the body to psilocin, which has mind-altering effects similar to those of LSD. - Oral administration - The effects include euphoria, visual and mental hallucinations, changes in perception, a distorted sense of time, and perceived spiritual experiences. - It can also cause adverse reactions such as nausea, confusion, agitation, disoriented, and panic attacks. - Self injury. - Mydriasis, tachy-or bradycardia,hypo or hypertension, tremors, dysmetria.

Question 26

Cannabis “Marijuna”, “MJ”, “Mary Jane”, “dagga”, “boom”, “zol”

Answer 26

- Cannabis is a psychoactive drug from the cannabis plant. C. sativa, C. indica - Δ9-Tetrahydrocannabinol (THC) is the primary psychoactive substance, more than 113 different cannabinoids in the plant - When smoked >2000 compounds may be formed - THC is medically indicated for multiple sclerosis to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms. - The actions of Delta-9-THC result from its partial agonist activity at the cannabinoid receptor CB1 in the CNS. - Mentalandphysicaleffects: • Euphoria; • Altered mental status; • Lack of concentration; • Impaired short-term memory; • Altered sense of time; • Panic, paranoia, CNS depression; • Tachycardia, dyspnoea, nausea, conjunctival congestion, increased appetite; • Balanse and fine psychomotor control. - At high doses, mental effects can include anxiety, delusions (including ideas of reference), hallucinations, panic, paranoia, and psychosis. - Chronic: lung damage, reproductive effects, immunological effects. Psychosis. - Cannabis is suspected of being a potential, and under-reported, contributory factor or direct cause in cases of sudden death, due to the strain it can place on the cardiovascular system, especially when used concomitantly with other drugs of abuse.

Question 27

Inhalants

Answer 27

- DO NOT EVER USE POPPERS AND VIAGRA SIMULTANEOUSLY!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! - SUCH A PROFOUND HYPOTENSION–NO AMOUNT OF RESUSCITATION CAN SAVE YOUR LIFE!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

Question 28

AGRICULTURAL POISONS – OrgPO4

Answer 28

- Organophosphates are a class of synthetic organophosphorus compounds with the general structure O=P(OR)3 , a central phosphate molecule with esters, alkyl, amides, thiols or aromatic substituents. - They can be derived from phosphoric, phosphonic, phosphorothioic or phosphonothioic acids - Parathion, Malathion, Methyl parathion, Chlorpyrifos, Dichlorvos, Phosmet, Fenitrothion, Tetrachlorvinphos, Azamethiphos, Azinphos-methyl. - Ingested, Inhaled, and Absorbed through the skin. - Distinct smell- kerosene base (petrol). - In death- the body can still expose pathologists, flies that alight on the body also die. - Analysis on the post-mortem samples are mainly focused on detecting the parent compound. - Rapidly metabolised to metabolites. - Metabolites are mostly non-specific. - Acetylcholine is the neurotransmitter at the cholinergic synaptic areas - Acetylcholinesterase enzyme hydrolysis acetylcholine to acetic acid and choline, following stimulation of a nerve - Organophosphates are IRREVERSIBLE acetylcholinesterase inhibitors - By binding covalently to the serine residue in the enzyme active site - Form a stable irreversible covalent bond with the enzyme. - Causes pathological accumulation of acetylcholine in the cholinergic synaptic clefts - Results in initial excessive stimulation followed by depression - CHOLINERGIC TOXIDROME - DUMBELLS - If patient still alive, or one of your colleagues get acute OP poisoning in the mortuary - Remove clothes and wash the patient if skin exposure has happened - IV ATROPINE- it is a competitive inhibitor/ antimuscarinic drug - IV PRALIDOXIME - it reactivates the inhibited acetylcholinesterase

Question 29

Novel psychoactive substance

Answer 29

- Newpsychoactivesubstances(NPS)arearangeofdrugsthathave been designed to mimic established illicit drugs, such as cannabis, cocaine, MDMA and LSD. - Manufacturersofthesedrugsdevelopnewchemicalstoreplace those that are banned, which means that the chemical structures of the drugs are constantly changing to try to stay ahead of the law* • Theyarenotsafe. • Theyhavenotbeentestedonhumans. • Thereislimitedinformationontheshortandlong-termhealth effects of novel psychoactive substances. • Wedonotknowthetoxic-orfatalconcentrationsforthese substances.