Antodots and treatment of intoxications
PharmDr. Milan Juhás


...before we begin
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}Toxicology information centre in Prague
}224 919 283, 224 914 570
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}Snake poisoning consult centre in General University Hospital in Prague
}224 962 244
}
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paracelsus.jpg

Philippus Aureolus Theophrastus Bombastus von Hohenheim (1493 – 1541)  - The difference between
drug and poison is only a matter of dose.

Intoxication
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Intoxication – administration of a substance (drug), which alters basic physiological functions
(breathing, blood circulation, cognition)

Basic algorythm of treatment of intoxications



Necessary definitons
}What exactly are „Antidots“ ?
}Drug or substance with opposite effect to poison or venom, which administration is expected with
improvement of vital functions impaired by intoxication
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}

Antidots – are drugs, which bind or in other way inactivate poison or are antagonists to its toxic
effect !

Antidots available in Czech republic
Amanita Phalloides toxin
Silymarin, hepatoprotectives
Morphin and morphinomimetics (Narcotics)
Naloxone, Naltrexone
Atropin, anticholinergics
Physostigmine
Benzodiazepines
Flumazenil
Digitalis
Digitalis Antitoxin
Glycoles (polyoles)
Etanol
Warfarin and Coumarines
Vitamin K1,
Cyanides
Amylum nitrosum, Hydroxycobalamine
Methemoglobinizing agents
Toluidine blue
Methanol
Etanol, Folic Acid
Lead
Succimer
Organophosphates
Atropin, obidoxime (AchE reactivators)
Paracetamol (Acetaminophen)
N-Acetylcysteine
Mercury
Unithiol
Viper venom
Viper Venom Antitoxin ®
Iron
Desferioxamin
Universal Antidot - Carbo activatus

Opiates and narcotics
D:\Farma\ANTIDOTS AND TREATMENT OF INTOXICATIONS\200px-Morphin_-_Morphine.svg.png D:\Farma\ANTIDOTS
AND TREATMENT OF INTOXICATIONS\332px-Heroin_-_Heroine.svg.png D:\Farma\ANTIDOTS AND TREATMENT OF
INTOXICATIONS\fentanyl.gif

Morphin, Heroine, Fentanyl

Opiates and narcotics
}Symptoms
}Somnolence, miosis, nausea, vomitus
}Euphoria is strongest after Heroin
}Intestinal hypomotility and constipation (chronic use)
}Selective antidots
}Naloxone
}Naltrexone
}Necessary to administer until is secured hepatal elimination of narcotic
}
}Route of administration is crucial for proper pain management and minimazing risk of intoxication
}(from the patient point of view) – i.v., per os, nasal

Naloxone and Naltrexone are used in small doses to prevent adverse effects of opiates in chronic
pain management (Suboxone®)

Management of withdrawal syndrome
}Heroin addiction and overdose
}Opioid antagonist (NLX, NTX)
}
}Spasms and anxiety
}Diazepam
}Haloperidol
}Tiaprid
}

Atropin, Scopolamine, L-Hyocyamine
(Tropan alcaloids)
} naturally occurence in Datura stramonium, Atropa belladona
}
}Direct antagonists of Ach in parasympatikus
}Skin erubescence,  mucose dryness (severe xerostomia), tachycardia, mydriasis, misorientation,
urine retention, coma
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}

Atropin, Scopolamine, L-Hyocyamine (Tropan alcaloids)
}Causal therapy
}Administration direct antagonist – physostigmin
}
}Symptomatic therapy
}Beta-blockers (atenolol)
}Carbo activatus and stomach lavage
}

Anticholinergic agents
(1st generation antidepressants)
}Tricyclic antidepressant agents
}Inhibition of serotonine and noradrenaline uptake
}Dosulepin,   Amitriptylin,  Imipramin
}
}Intoxication induces anticholinergic syndrome
}Xerostomia, mydriasis, tachycardia,
}sedation,  expansion of QRS complex
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}Antidote – None
}High dose of carbo activatus
}Symptomatic therapy till improvement

Sedatives and hypnotics
}Anticonvulsant and myorelaxant activity
}Bezodiazepines
}Alprazolam
}Bromazepam
}Diazepam
}Non-BZD hypno-sedatives
}Zolpidem
}Zopiclon
}Symptoms
}Somnolence, ataxia and hypotension
}Escalation of pharmacodynamic effenct on GABA receptor – coma
}Antidot for both BZD and non-BZD hypno-sedatives
}Flumazenil – antagonist on GABA receptor

Flumazenil requires to be administered in cotinual i.v. Infusion, due to shorter elimination
half-time.

Digoxin and cardiac glycosides
}D. Purpurea, D. Lanata,
}Cardiotonicum, antiarrhytmic agent
}
}Atrial fibrilation
}Heart failure
}
}Terapeutic drug monitoring
}

Most common intoxication, range 0,5mmol/l – 1,15 mmol/l in plasma.

Management of digitalis toxicity

Digitalis antitoxin selectivelly binds to digoxin and allows its elimination through kidneys (very
expensive).

Symptoms of digitalis toxicity
}Hypokalemia – increased potassium kidney elimination
}Nausea, vomiting
}Color perception disorder – yellow sight
}dizziness, arrhytmia
}
}Strategy
}Discotinue digoxin administration
}In severe cases apply antitoxin

Management of glycol intoxication
}Glycols
}Carbohydrates with more than one OH functional group
}Hepatal metabolism converts glycolsto oxalic acid and to calcium oxalate
}
}Risk of metabolic (chemical damage) acidosis and renal damage by precipitated calcium oxalate
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}

Calcium Oxalate insoluble in water (urine).

Management of glycol intoxication
}Symptoms
}Renal
}Hematuria , albuminuria,  acute tubular necrosis, anuria
}Non-renal
}Metabolic acidosis, hypocalcemia, spasms,  dysrrhytimias
}
}Ethyleneglycol metabolised by alcoholdehydrogenase
}Antidotum – ethanol
}Ethyleneglycol eliminated by kindeys in unchanged form
}
}During threatment with ethanol, correction of metabolic acidosis and calcium supplementation is
required

Lead poisoning
}Toxicity of Lead
}Ligation to haemoglobin
}Inhibition of haem synthesis ( block of 5-ALA-synthase)
}Accumulation of koproporphyrines
}
}Results to
}Sideroblast anaemia, neuropathy and constipation
}
}Threatment
}Chelation by DMSA (dimercaptosuccunic acid) and elimination through kidneys, EDTA
}Organic forms of lead do not respond to chelation (penicilamine ?)

Anaemia, neuropatia and constipation due to Iron accumulation in plasma

}



Mercury poisoning
}form ion Hg2+ in mercury chloride and mercury nitrate
}Route on intoxication through lungs
}Central neural toxicity (tremor, sleep inversion, eretism)
}
}Threatment with chelation
}Unithiol – dimercaptopropan sulphate
}
}
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}

Only 5 percent of ingested mercury reaches bloodstream, due to minimal GI absorbtion.

Organophosphates poisoning
}Esters of phosphoric acid with carbohydric alcohols (methanol), which cause irreversibile
inhibition of AchE
}Irreversibile inhibition of AchE, which results to its toxicity
}Cumulation of acetylcholine
}Symptoms of parasympatomimetic stimulation
}
}Muscarine
¨salivation, bradycardia, miosis, nausea, vomitus, lacrimation, diarrhoea
}
}Nicotinic
¨Desorientation, spasms, coma

Decrease of AchE activity under 30 percent si limit for presentation of toxicity, decrease of AchE
activity under 20 percent is heavy poisoning.

Organophosphates poisoning

Organophosphate-AchE complex Aging – change in conformation, which makes whole complex stable and
intact to any reactivation.

Carbamate insecticides
}Carbamates
}Competitive inhibitors of AchE
}Poisoning is simillar to Organophosphates
}
}Atropin administered in individual dose according to improvement.
}Management of adverse phenomenon
}Symptomatic therapy
}
}Administration of Oximes is not necessary

Similar symptoms, however not that severe.

Methemoglobinemia agents
}Aromatic and alifatic organic amines (Aniline, etc.)
}Nitroarenes (nitrobenzene, etc.)
}Industrial substances to prepare explosives, when ingested, causing oxidation of iron in
Haemoglobin
}Fe2+ to Fe3+
}
}15 – 30 % damaged haemoglobine
}Cyanosis, tachycardia, fatigue
}30 – 50 %
}Weakness, dyspnoe, headache
}50 – 70 %
}Cognition impairment, death

Antidotes and treatment
}Chemical reduction of Fe3+  to Fe2+
}  symptoms
}Dyspnoe, fuzziness, chest pain
}Thiazine colours
}Toluidin blue 3 % solution i.v.
}Methylene blue 1% solution i.v.
}Donors of electrone necessary for NADPH- dependent mechanistm of methemoglobin-reductase enzyme
}
}Risk for patients with congenital GLUCOSE-5-PHOSPHATE DEHYDROGENASE deficiency
}
}Indication of Thiazines administration is concentration of methemoglobin above 25 %

Accumulation of non-reduced form of colour and worsening of methemoglobinaemia, due to acido-basic
character of colours.

Inhalation trauma
}First Aid !
}Administration of oxygen
}
}In case of bronchospasm
}Beta2-mimetics (formoterol, salbutamol)
}Inhalation spasmolytic agents (ipratropium bromide)
}
}Inhalation of corticosteroids is obsolent and has no effect

Warfarin
}Anticoagulant widely used in many coagulopathies
}
}Necessary periodic monitoring of INR
}High risk of drug-drug interacions
}3 day latency
}Competitive inhibitor of vitamin K-mediated synthesis of coagulation factors ( II, VII, IX, X)
}
}Antidote – vitamin K
}




Iron intoxication
}GI tract disorder
}Haemorhhagic gastritis, black vomitus and severe stomach pain
}Severe constipation and circulation colaps
}
}Antidotum
}Chelation using deferoxamin
}i.v. , i.m.
}per os with gastric scope
}
}Symptomatic therapy to secure vital functions and prevent shock

Paracetamol (Acetaminophen)



Toxicity of paracetamol
}Toxic dose 140 – 150 mg/kg
}Nausea, vomitus, hepatotoxicity,
}After 24 hrs of no treatment lead to hepatorenal syndrome with hepatal and renal failure
}
}High dose of carbo activatus, hepatoprotectives
}(N-acetylcysteine),
}In case of vomitus (ondansetrone)
}
}Therapy in cursu till normalisation of hepatic markers

Prolongation of PTT, amonium encephalopathy, metabolic acidosis, death.

Methanol intoxication
}Dangerous substitution for ethanol
}Metabolized with same alcoholdehydrogenase to formic acid (toxic metabolite)
}Individual dose due to activity of Alcoholdehydrogenase and capacity of folic acid
}Cummulation of formic acid lead to damage of retina
}
}Early symptoms
}Drunkness, gastritis
}Late symptoms
}blindness (after 30 hrs), spasms, coma, death
}
}Antidote – ethanol
}Formic acid creates with ethanol ester, which is harmlessly eliminated by kidneys

Adjuvant antidotes – folic acid, fomepizol (inhibitor of alcoholdehydrogenase) used without ethanol
!!!

Carbo activatus as universal antidote
}Prepared by pyrolysis of plants
}Characteristic with its high absorption surface            (3700 m2/g)
}
}Mechanism of effect
}Absorption
}Secondary elimination of toxins from bloodstream
}
}Lack of effect with high-polar molecules
}Lithium, glycoles





}Indications
}Poisons with enterohepatal circulation
}Severe intoxications withou dialysis`s perspective
}Slow-release drug forms (repeatedly)
}
}
}Contraindications
}Intoxication with irritative poisons (acid, lye)
}Cognitive impairment and airways blockage
}GI obstruction
}
}Carbo activatus is without any severe adverse effect, in rare cases can cause constipation.

milan.juhas@fnusa.cz