Clinically relevant Clinically relevant drug intoxications drug intoxications and their therapy and their therapy

Anton KohútAnton Kohút

Toxic effects of drugsToxic effects of drugsAntidotesAntidotes

Harmful effects of drugsHarmful effects of drugs

Toxic effectsToxic effects

--effects unrelated effects unrelated to the principal to the principal pharmacological pharmacological action of the action of the drugdrug

Overdosis – Overdosis – intoxicationintoxication

- these effects are - these effects are closely closely associated with associated with the the pharmacodynamipharmacodynamic action for c action for which the drug is which the drug is being used.being used.

GENERAL MECHANISMS OF CELL GENERAL MECHANISMS OF CELL DAMAGE AND CELL DEATHDAMAGE AND CELL DEATH

In most cases it is caused by In most cases it is caused by interaction between reactive interaction between reactive compounds formed during compounds formed during metabolism and cell constituents metabolism and cell constituents (lipids, proteins, DNA)(lipids, proteins, DNA)

1.1. non non--covalent boundcovalent bound 2. 2. covalent boundcovalent bound

GENERAL MECHANISMSGENERAL MECHANISMS

1.1. non non--covalent boundcovalent bound lipid peroxidationlipid peroxidation generation of toxic generation of toxic

oxygen speciesoxygen species alteration alteration

(depletion) of GSH(depletion) of GSH concentrationconcentration

modification of modification of SH-SH- groupsgroups

2. 2. covalent boundcovalent bound Targets are: Targets are: DNA,DNA,

proteins/peptides, proteins/peptides, lipids, carbohydrateslipids, carbohydrates binding to proteinbinding to protein

can produce an can produce an immunogenimmunogen

binding binding to DNAto DNA can cause can cause

carcinogenesis, carcinogenesis, mutagenesis or mutagenesis or

teratogenesisteratogenesis

Toxic effectsToxic effects

HepatotoxicityHepatotoxicity Paracetamol, Paracetamol,

isoniazid (INH), isoniazid (INH), iproniazid, iproniazid, halothane, halothane, methotrexate, methotrexate, chlorpromazinechlorpromazine

NephrotoxicityNephrotoxicity

NSAIDs, ACEI, NSAIDs, ACEI,

Phenacetin, Phenacetin, paracetamol, paracetamol, cyclosporincyclosporin

Toxic and allergic reactionsToxic and allergic reactions

HOW TO MINIMIZE THE SEVERITY OF HOW TO MINIMIZE THE SEVERITY OF TOXIC REACTIONSTOXIC REACTIONS

Individualize drug therapyIndividualize drug therapy Refer to the literature for Refer to the literature for

information on drug interactionsinformation on drug interactions Anticipate that after prolonged Anticipate that after prolonged

therapy patients are most likely to therapy patients are most likely to react adversely when new therapy is react adversely when new therapy is initiated or terminatedinitiated or terminated

Teach patients to identify early signs Teach patients to identify early signs of adverse reactionsof adverse reactions

Optimize the therapyOptimize the therapy

DRUG POISONING-DRUG POISONING-

TREATMENTTREATMENT General managementGeneral management1. Observe vital function1. Observe vital function2. Obtain history2. Obtain history3. Perform a toxicologicaly oriented physical 3. Perform a toxicologicaly oriented physical

examinationexamination SymptomsSymptoms Extensions of pharmacological properties of Extensions of pharmacological properties of

drugs.drugs. Common causes of death include: CNS Common causes of death include: CNS

deppression, deppression, respiratory arrest, cellular hypoxia, respiratory arrest, cellular hypoxia, hypothermia, hypotension and arrhytmias hypothermia, hypotension and arrhytmias. .

DRUG POISONING-TREATMENT - DRUG POISONING-TREATMENT - cont.cont.

TreatmentTreatmenta. Vital funcion supporta. Vital funcion support (ventilation, blood pressure, electrolyte (ventilation, blood pressure, electrolyte

balance)balance)b. Prevention of drug absorbtion:b. Prevention of drug absorbtion: -emetics (apomorphine), gastric lavage-emetics (apomorphine), gastric lavage - chemical absorbtion with activated charcoal- chemical absorbtion with activated charcoalc. Promotion of elimination:c. Promotion of elimination: - chemically enhancing urinary excretion, - chemically enhancing urinary excretion,

sodium bicarbonate-raises pH, ammonium sodium bicarbonate-raises pH, ammonium chloride- decreases urinary pH)chloride- decreases urinary pH)

d. Hemodialysisd. Hemodialysise.e. AntidotesAntidotes

AntidotesAntidotes

Antidotes (contin.)Antidotes (contin.)