TOXICOLOGY II. Toxic compounds in cases of intoxication at present

1. TOXICOLOGYII. Toxic compounds in cases of intoxication at present M. Balíková

2. Toxicological cases in laboratory • Clinical – examination from reasons: • Diagnostics • Therapy controls • Prevention b)Clinical – forensic development c) Forensic • Autopsies (suicides, homicides…) • Traffic accidents • Occupational injuries • Violence associated with roberies, rapes, injuries… • Others M. Balíková: Toxic compounds

3. CLINICAL TOXICOLOGY - SYMPTOMS Importance of anamnestic data, symptoms Differential diagnosis – Is it poisoning? Preliminary results – therapeutic action BUT nonspecific symptoms of intoxication • Gastrointestinal problems • Cramps (strychnin, cyanides, antidepressants, cocaine… • Hallucinations (LSD, psilocybine, MDMA, cannabis….) • Mydriasis / Miosis M. Balíková: Toxic compounds

4. Acute intoxications • Intentional (suicides, homicides, associated with violence to others) • Drug abuse • Nonintentional (small children, accidental ingestion, expositions) M. Balíková: Toxic compounds

5. FORENSIC TOXICOLOGY Careful individual attitude Examination in series not common Individual optimalization of examination Principle in toxicology: results confirmation by another independent and specific method – if available The final toxicological evidence – defensible scientifically and legally M. Balíková: Toxic compounds

6. Frequent toxic compoundsin acute intoxications • Ethanol • Pharmaceuticals • Drugs of abuse • Carbon oxide • Volatiles • Glycols • Mushrooms, herbal toxins M. Balíková: Toxic compounds

7. Ethylalcohol • Hydrophilic compound, rapid resorption, in blood distributed in favour of plasma • Pharmacokinetics: • rate of resorption > rate of elimination • elimination with zero order rate (0.12-0.2 g/kg/h) • Metabolism: 70% alcoholdehydrogenase, 25% MEOS, 5% excreted in parent form • Effects: Narcotic – fat solubility – CNS depressant • Endogenous bacterial production (0,001 –0,002 g/kg) • Postmortem production (ethanol and other alcohols) M. Balíková: Toxic compounds

8. Ethanol blood level and methods • Breathanalysers – indirect test • Gas chromatography – direct alcohol measurement in venous blood, specific forensic method • Enzymatic method – clinical cases O. K., but potentional interferences (lactate) • Widmark method – nonspecific (based on reduction of bichromate) M. Balíková: Toxic compounds

9. Ethanol and driving Two general types of legislation in the world: 1) Impairment 2) Perse In Czech Rep. – Impairment type Jurisdiction: • 0.2 g/kg cut off value • 0.5 g/kg – impairment very probable, administrative sanctions • 1.0 g/kg – unfit for driving, dangerous, penal proceedings at court M. Balíková: Toxic compounds

10. Methanol • Lethal doses 5 –100 ml • Metabolites: formaldehyde, formic acid • Very slow oxidation, max level of formic acid – 2 days after ingestion • Dangerous delayed effects: at first – narcotic later – metabolic acidosis , retina damage, blindness, death M. Balíková: Toxic compounds

11. Methanol poisoning • Antidotum ethanol • Competitive alcohols oxidation (long term ETOH infusion – blood level maintenance 1.5 g/kg) protection from methanol oxidation • Haemodialysis • NaHCO3 infusion – correction of pH M. Balíková: Toxic compounds

12. Glycols - Diols • Intoxications – intentional ,accidental • Antifreezers – FRIDEX • Solvents, also vehiculum in some pharmaceutical products (injections) Ethanediol and dimers, trimers, polymers Propanediol 1,2 and 1,3 isomers Butanediol- precursor of GHB Glycol monoalkyl ethers – brake liquids (celosolve, carbitols) M. Balíková: Toxic compounds

13. Ethylene-glycol Toxic oxidative metabolites: glycolaldehyde, glycolic acid, glyoxylic acid, oxalic acid Toxic effects: • narcotic (alcohol) • gradual development of acidosis • renal failure, anuria Therapy as soon as possible – as in methanol poisoning- ethanol as antidotum, haemodialysis, natrium bicarbonate M. Balíková: Toxic compounds

14. Volatiles – CNS depressants Hydrocarbons a) gaseous (propane, butane…) b) liquid (toluene, chloroform…) Fuels Various solvents Aenesthetics (ether, halothane…) Intentional or accidental intoxications Drug abuse by inhalation, euphoria, hallucinations Dangerous overdoses, fatal intoxications M. Balíková: Toxic compounds

15. Volatiles abuse Chronic abuse: • psychical addiction • hepatorenal toxicity • neurotoxicity • cardiotoxicity Overdose: agitation, cramps, coma, cardiac failure, death M. Balíková: Toxic compounds

16. Volatiles metabolism • Partly expired in parent form • Only some produce known metabolites into urine (toluene 80-90% hippuric acid, butane only 1% as 2-butanol) • Only some can appear in urine in parent form (aromates) • Some metabolites expired into air (dichloromethane – 50% CO metabolite) • Useful sample for toxicology – blood • Method : gas chromatography M. Balíková: Toxic compounds

17. Carbon oxide • Burning of organic compounds at insuffient access of air • Strong affinity to haemoglobin - in the same molar ratio as oxygen but 220 times stronger, competition for binding – even low traces in air can be gradually bound • Degree of poisoning correlates with time of exposition, physical activities M. Balíková: Toxic compounds

18. Carbon oxide cont. Toxic effects: reduction of oxygen transport in blood, neurotoxicity, potentional development of Parkinsonism in chronic exposition Endogenous levels COHb < 0.5 % Smokers up to 10 % Light intoxication 10-20 % COHb Severe intoxication – 30-40% COHb Coma, respiratory failure 40 –50% COHb Fatal 50 –70% COHb M. Balíková: Toxic compounds

19. Cyanides Hydrogen cyanide, HCN, boiling point 26° C, bitter almond like odor, colorless, very toxic gas or liquid (hydrocyanic acid) NaCN, KCN unstable in acidic media, hydrolysis to toxic HCN, unstable in air – carbonates HCN present in exhaust gases, in tobacco and wood smoke, in smoke from burning nitrogen containing plastics HCN in air300 p.p.b. will kill a human in a few min LD50 in humans very individual (0.005 – 1 g) M. Balíková: Toxic compounds

20. Cyanides cont. Biotransformation in the liver : thiocyanates Toxic mechanism: Inhibition of cytochromoxidase, cells can not accept oxygen, tissues hypoxia Therapy: • administration of compounds with Co or Fe(III) • Amylnitrite, natrium nitrite as antidotum –cyanomethaemoglobine production, enzyme block releasing • Thiosulphate infusion – metabolites SCN • Oxygen ventilation M. Balíková: Toxic compounds

21. Mercury • Metallic form – water insoluble • Salts – water soluble, partial resorption p. o. • Fine particles in air – dangerous entrance via lungs into blood, subsequent oxidation, cumulation in the brain, kidney – potentional neurotoxicity, nefrotoxicity • Elimination into urine – very slow • Organic mercury –lipophilic, molecular effects, accumulation in CNS, embryotoxic • Mercury in water sediments – bacteria transformation into organic mercury- contamination of fish meat - dangerous M. Balíková: Toxic compounds

22. Insecticides Herbicides Fungicides Rhodenticides Pesticides-1 Organic compounds of various structures, various toxic mechanisms, various symptoms of intoxication, various effects Human acute intoxications in EUROPE at present not frequent • ORGANOPHOSPHATES (sarin, parathion, malathion...) • CARBAMATES (aldicarb, carbofuran...) • CHLORINATED HYDROCARBONS (chlophenothane=DDT, lindan, aldrin...) • BIPYRIDINE DERIVATIVES (paraquat, diquat...) • ANTICOAGULANS (warfarin, diolan...) M. Balíková: Toxic compounds

23. Pesticides - 2 Organophosphates: irreversible potent acetylcholinesterase inhibition, respiratory difficulties, salivation, miosis, nausea, paralysis... antidotum atropine p-nitrophenol in urine – marker of exposure to parathion Carbamates: derivatives of methylcarbamic acid reversible inhibition of acetylcholinesterase antidotum atropine Polychlorinated hydrocarbons: free radicals by biotransformation convulsions, nausea; chronic neurotoxicity, hepato and nefrotoxicity Bipyridine derivatives: paraquat, diquat (GRAMOXONE, ATRAZINE) contact toxicity, inflamation, bleeding, local necrosis, muscle stiffness, blurred vision, pulmonary fibrosis Anticoagulants: warfarin, diolan (KUMATOX, TALON-G) M. Balíková: Toxic compounds

24. Pharmaceuticals Accidental and intentional overdoses, suicides Combination with alcohol, mixtures of drugs Drug abuse – narcotic and psychotropic substances Mostly organic substances with low molecular mass up to 400 Daltons Classification: 1) Structure – important for analytical toxicology, laboratory attitude 2) ATC system (WHO) – Anatomical-Therapeutical-Chemical : A – Gastrointestinal tract (spasmolytics, anticholinergics….) B – Blood system C – Cardiovascular system (cardiotonica, , antihypertensiva……) D, G, H – Dermatologica, urologica, gynekologica, hormones J, L – Antibacterials, antivirotics, antimycotica, cytostatica M – Muscle-sceletal system (antirevmatica, antiphlogistica, myorelaxancia) N – Neurological system (anestetica,analgesica,antiepileptica,psycholeptica) P – Antiparasitica R – Respiratory system (antiasthmatica, antitusica, antihistaminica…..) S, V – Varia A C M N R – significant participation in drug overdose cases M. Balíková: Toxic compounds

25. Barbiturates Barbituráty Psychotropic substances – CNS suppression The first derivative at the market – barbital Common structure of various derivatives - barbiruric acid Acidic character – after p. o. resorption mainly in small intestine Variable effect duration, therapeutic indication: Short time effect – pentobarbital halflife 20-30 h) Long time effect – phenobarbital halflife 2-6 days) Thiobarbital (thiopental) – i. v. anestheticum Thiobarbital, pentobarbital – intracranial pressure reduction Phenobarbital – sedative, antiepileptics Various barbiturates in pharmaceutical composites, analgesics, antiphlogistics (Spasmoveralgin, Alnagon,Bellaspon, Dinyl, Eunalgit……) At present – less prescription due to significant mortality at overdose, replacement by more safe substances M. Balíková: Toxic compounds

26. Benzodiazepines Psychotropic substances with CNS sedation Frequent therapeutical indication Frequent abuse (sometimes with alcohol or illegal drugs) Potential criminal misuse More than 30 various structures with variable therapeutic indication: sedatives (diazepam, alprazolam) hypnotics (nitrazepam, flunitrazepam), antiepileptics (clonazepam) Shortly active – midazolam – introduction into anesthesia (halflife 1-4 h) Long term active – diazepam – sedative (halflife 21-37 h) At overdose – accummulation in tissues, prolonged elimination Extensive biotransformation – metabolites of phase I and II Identification of toxic substance – important for differential diagnosis Plasma level monitoring no correlation to effect Addictive substances at chronic use, development of tolerance Low mortality when related to barbiturates Additive sedation at combination with alcohol and sedative drugs Coma state - antidote flumazenil (ANEXAT), short halflife 40-60 min General danger at coma – vomit aspiration M. Balíková: Toxic compounds

27. Antidepressants TCA – tricyclic antidepressants (amitriptyline, imipramine, trimipramine, clomipramine, dibenzepine…) Tetracyclic antidepressants – maprotiline, mianserine Frequent drugs at suicidal attempts Pacients with psychiatric treatment, endogenous depressions Lipophilic substances with protein bounds, large Vd At overdose – drug accumulation – prolonged effect Normetabolites more potent related to parent drug form Therapeutic effect: CNS sedation, inhibition of neurotransmiters resorption Overdose: cardiotoxicity, neurotoxicity Symptoms of overdose: Cardivascular disturbances (hypotension) Coma, cramps, hyperthermia Respiratory collaps, death Therapy of overdose Symptomatic procedures Hemoelimination, hemoperfusion New types with lower toxicity Selective serotonin reuptake inhibitors fluoxetine, citalopram, sertraline, venlafaxine, paroxetine………. M. Balíková: Toxic compounds

28. Phenothiazines Antihistaminics – promethazine, dithiadene Neuroleptics – chlorpromazine, levopromazine, chlorprothixene, thioridazine…… Treatment of psychoses Frequent substances in overdose cases, suicidal attempts Lipophilic substances bounded to proteins Extensive biotransformation At overdose – accumulation in tissues, prolonged effect Antipsychotic effect, CNS sedation, affinity to neurotransmitters Symptoms of overdose: Delirium and coma Tachycardia, bradycardia, arythmia, hypotonia Breath center suppression Life endargement: circulation and respiratory failure Therapy: symptomatic, sometimes physostigmine recommended M. Balíková: Toxic compounds

29. MAO Inhibitors MAO inhibitors – the first ones among antidepressives Structurally hydrazines, hydrazides, amides, amines Moclobemide (AURORIX) Extenzive oxidation, hydrolysis Effect mechanism: Interaction with catabolism of dopamine, noradrenaline, adrenaline, serotonine – with impact of neurotransmitters accumulation - serotonine syndrom – endargement of hyperpyrexia and shock Potential interaction with other MAO inhibitors – amphetamines,TCA Symptoms of overdose: similar to overdose by amphetamines, cocaine, caffeine ... agitation, confusion, hallucination, convulsions, coma, cardiovascular disturbances – tachycardia, hypertension, renal failure Phentermin(ADIPEX) Treatment of obesite Methamphetamine isomer Addictive potential M. Balíková: Toxic compounds

30. Opiates and opioides Opiates – alkaloides of natural origine and their structural synthetic analogs: morphine, codeine, dihydrocodeine, hydrocodone, oxycodone, pholcodine, ethylmorphine) – phenanthrene structure Opioides – synthetic origine, another structure but similar effect, interaction with opioide CNS receptors: methadone, buprenorphine, tramadol, pethidine, fentanyl.... Narcotics – in therapy part of analgetics, antitussives Abuse – illegal heroin – risk of fatal overdose Chronic abuse: somatic addiction, tolerance Effects: Euphoria and sedation of CNS, miosis, suppressed intestine motility, constipation, respiration center suppression, coma, hypothermia, hypotonia, bradycardia, respiration and circulation collaps, death Symptoms of fatal overdose: lung and brain edema Therapy: Respiratory support, antidote naloxone, short halftime, repeated administration Naloxone – antagonist of opiate receptors – careful dosing – risk of abstinence syndrom M. Balíková: Toxic compounds

31. Acetaminophen - Paracetamol Part of pharmaceutical products (COLDREX, KORYLAN, PANADOL…) Overdose– hepatotoxicity Assessment of hepatotoxic risk: temporal profile of serum level after resorption (4 h after dose) hepatoprotective antidotum – substance with SH groups (N-acetylcysteine) M. Balíková: Toxic compounds

32. Salicylates Salicine –glycoside in willow-tree rind laic treatment of rheumatism Aspirine, Acylpyrine – acetylsalicylic acid Antipyretics, analgetics, antiphlogistics, anticoagulants Metabolism: hydrolysis, conjugation) Effect mechanism: Irreversibile inactivation of cyclooxygenase, local and systemic effects Toxic effects: Mucosal irritation, bleeding in GI, vomitting Stimulation of respiratory center, disturbances in electrolytic and acidobasic balance, metabolic acidosis Rey syndrom in children with virosis: risk of encephalitis and hepatodamage, risk at susceptive asthmatics – abstinence from salicylates application M. Balíková: Toxic compounds

33. Theophylline • Methylxantines: • Theophylline, caffeine – in coffee, tea • Theobromine - cacao • Pharmaceutical products: • Theophylline (1,3-dimethylxanthine) • – antiasthmaticum, bronchodilatator • Aminophylline– theophylline-ethylenediamine • Theophylline- narrow terapeutic window • potential of overdose • Significant plasma level monitoring (TDM) • Adverse effects, overdose, intoxication: • CNS stimulation • cardiovascular disturbances, arythmia (even fatal), convulsions, GI problems, vomiting , nausea M. Balíková: Toxic compounds

34. Cardiotonics Glycosides of digitalis Digoxine (C41H64O13), Digitoxine (C41H64O14) Cardiotonics – lipophilic substances, localized in myocardium, bonded to cardiac receptors, slow excretion. Digoxine excreted rather faster when related to digitoxine In cases of overdose – digoxine level in myocardium much higher than in plasma (100x). No correlation between effect to plasma level TDM: control of therapeutic plasma level Laboratory methods with respect to higher Mr (765, 781) – ICH, HPLC, not GC Toxicita: Vomiting, nausea, confusion, visual disturbances Ion balance disturbance, hypokalemia Cardiac arythmia – life endargement, cardiac failure Digoxine fatal intoxication – death within 24 hours Digitoxine fatal intoxication - dysrythmia prolonged to 5 days, prolonged toxic effects related to digoxine M. Balíková: Toxic compounds

35. Pharmaceticals with cardiovascular effects Drugs affecting heart function directly Heart glycosides Antidysrythmics – amiodarone, propafenol, verapamil, chinidine…. Drugs affecting circulation system Antihypertensiva Cardioselective beta-blocking agents – atenolol, metoprolol, labetalol, pindolol, sotalol, propafenone…. Diuretics – enhanced salts and water excretion– chlorothiazide, furosemide…. Therapeutic indication: heart ischemia, arythmia, heart failure, cardiomyopatia, hypertension Toxic effects: dizziness, nausea, vasoconstriction, bradycardia bronchoconstriction, coronar spasms, hypotension, cardiac and circulatory failure – life endargement, death M. Balíková: Toxic compounds

36. Abuse of addictive substancesPharmaceuticals, illegal drugs • CNS sedative substances, narcotics opiates/opioids, benzodiazepines.... • CNS stimulating substances: amphetamines and derivatives, ephedrine, cocaine.... • Substances affecting perception, psychedelics, hallucinogens: PEA derivatives (MDMA, PMA, DOB, mescaline.....), tryptamine derivatives (harmine, dimethyltryptamine....) ketamine, 9-THC, LSD, psilocybine, muscarine, atropine, scopolamine....... Tribe rituals - shaman leadership– application of natural products New trends – new synthetic drugs (NSD), dancing drugs stimulating and psychedelic effects PEA, tryptamine, piperazine structure analogues, synthetic cannabinoids NSD available via internet, frequent origine – Asia, China Health risk of application of an illegal product – no guarancy of its composition or content M. Balíková: Toxic compounds

37. Correlation of anamnesis and toxicology findings M. Balíková: Toxic compounds