General principles of poisoning management. Specific antidotes in poisoning therapy. General principles of drug addiction Department of Pharmacology FM MU Pharmacology vs. Toxicology • •Interconnection of both disciplines •They study the effects of chemicals on biological systems • •Pharmacology - therapeutically useful effects, drugs • •Toxicology - adverse, harmful (toxic) effects, poisons and toxins • •Paracelsus (1493-1548): •“All substances are poisonous; there is none which is not a poison. The right dose differentiates a poison and a remedy” Causes of poisoning •1. drugs - 52% •2. industrial products - 30% (chemicals for cleaning, organic solvents, cosmetics...) •3. plants - 8% •4. pure bulk chemicals -5% •5. funghi - 2% •6. animal poisons (snakebite) -1% •7. others -1% • • General principles of acute poisoning treatment • •Treatment has to be provided as quickly as possible but always with judgment so that therapeutical procedures do not cause worsening of the patient´s state or even death !!! General principles of poisoning treatment: •eliminate the substance from organism as quickly as possible (= decontamination) •antidote (rapid counteraction for poison by means of specific actions); • „a drug, chelating substance, or a chemical that counteracts (neutralizes) the effects of another drug or a poison“ •vital functions + symptomatic treatment • • 1. Elimination of unabsorbed toxic substances from organism •Gastric lavage and administration of emetic, preferably within 1 hour of intoxication (the first treatments should be done prior to transportation to the hospital) • •An average patient arrives only after 3 hours 1. Elimination of unabsorbed toxic substances from organism •Induced vomiting •in p.o. poisoning within 4 hours •within 8 hours after anticholinergic agents • within 12 hours of pylorospasm inducing agents (eg, salicylates) •the patient is conscious, without spasms •Syrup of ipeca (emetin)- non-reg., apomorphine (s.c.) •mechanic stimulation of pharynx •(red-eyed treefrog secretion) • Can not evacuate whole stomach content (max 30-50%) ! • •DO NOT INDUCE VOMITING IF ACIDS OR ALKALI WERE INGESTED • • OTHER CONTRAINDICATIONS OF INDUCED VOMITING: • •Somnolence and loss of consciousness •Intoxication with foaming agents •Intoxication with hydrocarbons •Attacks of spasms •Alimentary intoxications in small infants • • 1. Elimination of unabsorbed toxic substances from organism •Adsorbents •With poisons ingested p.o. •Charcoal (adsorbing carbon = Carbo adsorbens) / diosmectit ® large active surface •50 – 100 g in 5 – 10% suspension, possibly with stomach tube, then repeatedly 50 g per 4 hours •Up to 2.5 g/kg • •+: paracetamol, salicylic acid, diazepam, amphetamine •– methyl/ethylalcohol, Li, strong acids and alkali Toxic substances that are poorly adsorbable by Charcoal •acids •alkali •chlorates •chlorids •cyanides •nitrates •ethanol •ethylenglycol •isopropanol •methanol •fluorides •iron •ferrous sulphate •potassium •sodium •detergents • 1. Elimination of unabsorbed toxic substances from organism •Gastric lavage •In p.o. intoxications within 4 hours •The patient is conscious, without spasms •when unconscious, ONLY in lying position and intubated •warm water (37°C), saline(preparation: 2 teaspoons of salt per 1 litre water), 300 ml •Sample for toxicological analysis •In the end (the last lavage) add adsorbent (30 g of activated carbon) or a laxative (Na2SO4) 1. Elimination of unabsorbed toxic substances from organism - PEG - laxative , GIT dialysis • •• PEG - polyethylene glycol in ionic solutions • • 4 liters / 2 hours •until the evacuated rectal content is clear •Indications (toxic and lethal doses): •• rugs bound poorly by charcoal: iron, lithium •Retarded tablets: theophylline, calcium blockers -verapamil, diltiazem! 1. Elimination of unabsorbed toxic substances from organism •Increasing the intestinal passage •The patient is conscious, with no spasms •Administration of big doses of strong and quick-acting laxatives •Sodium sulphate (20 – 30 g with a large volume of water) •Mannitol (ca 50g per 1 litre water; 0.5 – 1 litre is administered p.o.) •Castor oil (20 – 30 ml) • • •CI in poisons soluble in fats!!! (castor oil bile secretion and resorption of fats) 1. Elimination of unabsorbed toxic substances from organism •Total intestinal lavage •Large-volume solution (25 ml/kg) •Through stomach tube, until clean solution flows off •Without resorption, does not cause diarrhoea •It only rinses the intestine •polyethylenglycol + NaSO4, NaCl • • 1. Elimination of absorbed toxic substances from organism •Forced osmotic diuresis •Infusion of saccharide solutions (20% mannitol; possible combination with furosemide), physiological solution •Up to several litres / day •CI: brain and lung oedema, heart failure, anuria • 1. Elimination of absorbed toxic substances from organism •Forced alkali diuresis •Speeds up elimination of slightly acidic poisons •Alkalinisation of urine and blood (pH 7.5 – 9.0) •NaHCO3 solutions •I: salicylates, barbiturates, sulphonamides, antipsychotic drugs,... •CI: pulmonary oedema, shock, serious impairment of kidneys • 1. Elimination of absorbed toxic substances from organism •Forced acidic diuresis •Speeds up elimination of slightly alkalinic poisons •Acidification of blood and urine •5% Glc solutions with ammonium chloride in i.v. infusion •I: amphetamines, quinine, quinidine, nicotine, morphine,... •CI: serious impairment of kidneys 1. Elimination of absorbed toxic substances from organism •Peritoneal dialysis • •Haemodialysis • •Haemoperfusion • 2. Neutralization of poison through administration of antidote •Antidote – a substance that neutralises the effect of poison •specific (using antagonistic effects of pharmaceuticals – antidotes that can counteract the effects of poison either partly or completely) • •Non-specific (adsorption – activated – medicinal carbon = carbo adsorbens – carbo activatus – carbo medicinalis) • RATIO OF CARBON : TOXIC SUBSTANCE = 10 : 1 • (usually 50g / 3 – 4h; most often intoxications with medicines, chemicals) • •It is necessary to administer antidote as quickly as possible • •Dosage according to plasmatic level of toxin • • https://www.annemergmed.com/article/S0196-0644(17)30657-1/fulltext Specific Antidotes 3. Symptomatic treatment •Check vital signs •Intubation •Entry into bloodstream •Support of CVS (inotropics, vasopressors) •Therapy of spasms • • Website of the Toxikologické informační střediskoTIS). Acute poisoning - what to do? Dial +420 224 91 92 93 or 224 91 54 02 To receive advice on first aid and what to do next. Prepare: • precise information on the accident • full name • birth identification number • health insurance company • healthcare professional also their IČP (organization identification number) In order to facilitate the consultation, the doctors are asked to calculate (provided it can be ascertained) the quantity of medication (active substance) that intoxicated the patient. Also please try to estimate or find out the body weight of the patient. Toxicological Information Centre Toxicological Information Centre •A 24/7 nationwide telephone medical information service to consult cases of acute human and animal intoxications • •For both laypersons and doctors • •The goal of the TIS is to decrease the number and severity of intoxications and to favourably effect the course of accidents. The Centre provides information on the chemical composition of commercial products and on the therapy of acute intoxications with these products • •It does not deal with: • the influence of chemical compounds on foetus • cancerogeneity • adverse effects of medicinal drugs • impact of chemical compounds on the environment Intoxication with medicines Intoxication with medicines •Most often: sedatives, hypnotics, analgesics • •Causes of death: •Injury to CNS – psychotropics •Injury to CVS – cardioglycosides antiasthmatic drugs •Liver injury – paracetamol, nimesulide, protease inhibitors, General principles of drug addiction Addiction = compulsive drug use despite harmful consequences is characterized by an inability to stop using a drug (failure to meet work, social, or family obligations; tolerance and withdrawal). accompanied by unnatural cravings that prompt the compulsive behaviors. It is a primary, chronic, neurobiologic disease with genetic, psychosocial and environmental factors that influence its development and manifestations. It is characterized by behaviours that include one or more of the following: loss of control over drug use continued use despite harm compulsive use and craving International Statistical Classification of Diseases and Related Health Problems 10th Revision: Mental and behavioural disorders due to psychoactive substance use (F10-F19) F10: Mental and behavioural disorders due to use of alcohol F11: Mental and behavioural disorders due to use of opioids F12: Mental and behavioural disorders due to use of cannabinoids F13: Mental and behavioural disorders due to use of sedatives or hypnotics F14: Mental and behavioural disorders due to use of cocaine F15: Mental and behavioural disorders due to use of other stimulants, including caffeine F16: Mental and behavioural disorders due to use of hallucinogens F17: Mental and behavioural disorders due to use of tobacco F18: Mental and behavioural disorders due to use of volatile solvents F19: Mental and behavioural disorders due to multiple drug use and use of other psychoactive substances International Statistical Classification of Diseases and Related Health Problems 10th Revision: Historic context of drug use Opium known already in neolithic age (8 000 – 5 000 years B.C.) Coca and resin from hemp – known thousands years Drugs were first used for their therapeutic purposes, secondary for they narcotic purposes Isolation of morphine (1805), caffeine (1820), nicotine (1828), cocaine (1859), ephedrine (1887) cannabinoids (hemp drugs) Summary of frequently abused substances opioids „classical“ psychostimulant drugs „new“ synthetic substances hallucinogens benzodiazepines nicotine alcohol MDMA (exctasy) 19th century: beginning of commercial narcotics production (e.g. morphine since 1828, cocaine 1862, heroine 1898) Legal consumption of drugs was ended by opium conventions: 1909 Shanghai, 1912 Haag 1925 Geneva Illegal way: French Connection (France), Cosa Nostra (USA) After WWII: Single Convention on Narcotic Drugs of 1961 - an international treaty to prohibit production and supply of specific (nominally narcotic) drugs and of drugs with similar effects Council of the Government for Drug Policy Coordination - Annual registr (2012): CZ – the most frequently abused drugs: Psychostimulant drugs (particularly methamphetamine, syn. pervitin) Hemp drugs (particularly tetrahydrocannabinol – THC). Tolerance x Dependence x Sensitization Tolerance: a decrease in the effect of a drug as a consequence of repeated exposure (the effectiveness can decrease with continued use). Mechanisms of Tolerance: Pharmacokinetic Tolerance (enzyme induction effect) It occurs because of a decreased quantity of the substance reaching the site it affects. This may be caused by an increase in induction of the enzymes required for degradation of the drug e.g. CYP450 enzymes. This is most commonly seen with substances such as ethanol. This type of tolerance is most evident with oral ingestion, because other routes of drug administration bypass first-pass metabolism. •Tolerance x Dependence x Sensitization • • Pharmacodynamic Tolerance (NT depletion, receptor plasticity) •It occurs when the cellular response to a substance is reduced with repeated use. •This may be caused by a reduced receptor response to receptor agonists (receptor desensitization), a reduction in receptor density (usually associated with receptor agonists), or other mechanisms leading to changes in action potential firing rate. • • • Dependence: a maladaptive pattern of substance use, leading to clinically significant tolerance, impairment, or distress; an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake). • • • • • Tolerance x Dependence x Sensitization Dependence develops when the neurons adapt to the repeated drug exposure and only function normally in the presence of the drug. When the drug is withdrawn, several physiologic reactions occur. These can be mild (caffeine) or even life threatening (alcohol). This is known as the withdrawal syndrome. 1) 1) Tolerance x Dependence x Sensitization Physical dependence x psychological dependence Physical dependence (physiologic dependence) referrers to the adverse physical symptoms and signs that result from the withdrawal of the drug. It results from many of the same mechanisms that produce tolerance. As with tolerance, homeostatic set-points are altered to compensate for the presence of the drug. If drug use is discontinued, the altered set-points produce effects opposite to those manifested in the presence of the drug. Tolerance x Dependence x Sensitization Physical dependence x psychological dependence Psychological dependence Psychological dependence is a change in emotional state that occurs after using a substance or engaging in a behaviour over a period of time. i.e. dependency on specific psychological phenomena provoked by the drug (e.g. euphoria) This change in emotional state is a result of changes in brain chemicals. It can cause craving, motivation to seek out the substance or behavior, irritability, anxiety, or general dissatisfaction when withdrawing from the substance or activity. •Increased response following repeated drug administration • Decreased response to substance effects. A higher dose is required to achieve the same effect. Intermitent drug administration Substance is usually given in shorter intervals or continuously Tolerance Senzitization (Robinson & Berridge, 1993) Dependence producing substances vfu-color Inverse tolerance (sensitization): the drug becomes more effective with repeated doses. Inverse tolerance (sensitization): There are two hypothesis to explain mechanism of sensitization to psychostimulants: 1)Intermittent exposure to a drug will cause intermittent dopamine release. This will lead to decreased sensitivity or density of pre-synaptic dopamine autoreceptors. 2) These receptors are responsible for negative feed back → increased dopamine release → increase stimulatory effects of dopamine. Important rather for development of sensitization than expression. 2) Long-term intermittent exposure to a drug provokes intermittent release of high amounts of dopamine → gradual depletion of dopamine in cytoplasm. This results in increased sensitivity of D1 postsynaptic receptor (because they are not stimulated by their natural ligand). Thus, after challenge dose administration (that acts through activation of the same postsynaptic receptors), an augmented behavioural response can be expected. Exposure to alcohol and other drugs (AODs): Plastic changes associated with AOD use - release of the neurotransmitter dopamine from cells in ventral tegmental area (VTA) induced by addictive drugs. The VTA is one of the components of the mesolimbic dopamine system – REWARD PATHWAY. Neurons whose cell bodies are located in the VTA, extend long axons most prominently to the nucleus accumbens (NAc) and the prefrontal cortex Dopamine release in the mesolimbic system is critical for the drive to ingest AODs. The mesocorticolimbic dopamine system as an initial target of addictive drugs. The VTA, at the origin of the mesocorticolimbic system, is composed of dopamine projection neurons that are under inhibitory control of GABA interneurons The main targets are the NAc and the mPFC. Addictive drugs cause an increase in mesocorticolimbic dopamine through: 1)direct activation of dopamine neurons (e.g., nicotine); 2) 2) indirect disinhibition of dopamine neurons (opioids, cannabinoids, benzodiazepines); 3) interference with dopamine reuptake (cocaine, ecstasy, and amphetamines).