PHARMACEUTICAL

TOXICITIES

DOC CALDERON
 CHELATORS
• MECHANISM OF ACTION OF CHELATING AGENTS:
• PREVENT OR REVERSE THE TOXIC EFFECTS OF A HEAVY METAL ON AN ENZYME
OR OTHER CELLULAR TARGET,
• ACCELERATE THE ELIMINATION OF THE METAL FROM THE BODY.
• BY FORMING A COMPLEX WITH THE HEAVY METAL,
• RENDERS THE METAL UNAVAILABLE FOR TOXIC INTERACTIONS WITH
FUNCTIONAL GROUPS OF ENZYMES OR OTHER PROTEINS, COENZYMES,
CELLULAR NUCLEOPHILES, AND MEMBRANES.
• CHELATING AGENTS CONTAIN ONE OR MORE COORDINATING ATOMS,
USUALLY OXYGEN, SULFUR, OR NITROGEN, WHICH DONATE A PAIR OF
ELECTRONS TO A CATIONIC METAL ION TO FORM ONE OR MORE
COORDINATE-COVALENT BONDS.
 ACETAMINOPHEN

• ACETAMINOPHEN PRODUCES TOXICITY WHEN

NORMAL METABOLIC PATHWAYS BECOME
SATURATED, LEADING TO THE PRODUCTION OF A
HEPATOTOXIC METABOLITE (N-ACETYL-P-
BENZOQUINONE IMINE, NAPQI)
• AFTER THERAPEUTIC DOSES OF ACETAMINOPHEN,
THE LIVER GENERATES GLUTATHIONE, WHICH
DETOXIFIES NAPQI.
• IN OVERDOSE, GLUTATHIONE IS DEPLETED, LEAVING
THE METABOLITE TO PRODUCE TOXICITY
 PHASES OF
ACETAMINOPHEN
TOXICITY
 N-ACETYLCYSTEINE

• THE ANTIDOTE FOR ACETAMINOPHEN TOXICITY

• WORKS AS A GLUTATHIONE PRECURSOR AND GLUTATHIONE SUBSTITUTE, AND ASSISTS WITH
SULFATION.
• NAC MAY ALSO FUNCTION AS AN ANTIOXIDANT TO AID IN RECOVERY.
• NAC IS MOST EFFECTIVE WHEN INITIATED WITHIN 8 TO 10 HOURS OF INGESTION.
 ALCOHOLS:
METHANOL AND ETHYLENE GLYCOL
• METHANOL IS FOUND IN PRODUCTS LIKE WINDSHIELD WASHER FLUID AND MODEL AIRPLANE
FUEL.
• ETHYLENE GLYCOL IS MOST COMMONLY FOUND IN RADIATOR ANTIFREEZE.
• THESE PRIMARY ALCOHOLS ARE RELATIVELY NONTOXIC AND MAINLY CAUSE CENTRAL NERVOUS
SYSTEM (CNS) DEPRESSION.
• METHANOL AND ETHYLENE GLYCOL ARE OXIDIZED TO TOXIC PRODUCTS:
• FORMIC ACID IN THE CASE OF METHANOL,
• GLYCOLIC, GLYOXYLIC, AND OXALIC ACIDS IN THE CASE OF ETHYLENE GLYCOL.
• FOMEPIZOLE INHIBITS THIS OXIDATIVE PATHWAY BY BLOCKING ALCOHOL DEHYDROGENASE.
• IT PREVENTS THE FORMATION OF TOXIC METABOLITES AND ALLOWS THE PARENT ALCOHOLS TO BE
EXCRETED BY THE KIDNEY
METABOLISM OF METHANOL AND ETHYLENE GLYCOL
 MANAGEMENT

• HEMODIALYSIS IS OFTEN UTILIZED TO REMOVE THE TOXIC ACIDS THAT ARE ALREADY
PRODUCED.
• COFACTORS ARE ADMINISTERED TO ENCOURAGE METABOLISM TO NONTOXIC
METABOLITES
• FOLATE FOR METHANOL,
• THIAMINE AND PYRIDOXINE FOR ETHYLENE GLYCOL
• IF UNTREATED:
• METHANOL INGESTION MAY PRODUCE BLINDNESS, METABOLIC ACIDOSIS, SEIZURES,
AND COMA.
• ETHYLENE GLYCOL INGESTION MAY LEAD TO RENAL FAILURE, HYPOCALCEMIA,
METABOLIC ACIDOSIS, AND HEART FAILURE.
 ALCOHOLS:
ISOPROPANOL

• RUBBING ALCOHOL, ISOPROPYL ALCOHOL

• A SECONDARY ALCOHOL, METABOLIZED TO ACETONE VIA ALCOHOL DEHYDROGENASE.
• ACETONE CANNOT BE FURTHER OXIDIZED TO CARBOXYLIC ACIDS,
• ACIDEMIA DOES NOT OCCUR.

• ISOPROPYL ALCOHOL IS NOT METABOLIZED TO A TOXIC METABOLITE - NO ANTIDOTE IS NECESSARY

TO TREAT AN ISOPROPYL ALCOHOL INGESTION.
• ISOPROPANOL IS A KNOWN CNS DEPRESSANT (APPROXIMATELY TWICE AS INTOXICATING AS
ETHANOL) AND GI IRRITANT.
• TREATMENT CENTERS ON SUPPORTIVE CARE.
 CARBON MONOXIDE

• IT IS A COLORLESS, ODORLESS, AND TASTELESS GAS.

• IT IS A NATURAL BY-PRODUCT OF THE COMBUSTION OF CARBONACEOUS
MATERIALS
• COMMON SOURCES OF THIS GAS INCLUDE AUTOMOBILES, POORLY VENTED
FURNACES, FIREPLACES, WOOD-BURNING STOVES, KEROSENE SPACE HEATERS,
HOUSE FIRES, CHARCOAL GRILLS, AND GENERATORS.
 EFFECT OF CARBON MONOXIDE ON THE
OXYGEN AFFINITY OF HEMOGLOBIN.
CO-HB = CARBOXYHEMOGLOBIN.

• CARBON MONOXIDE RAPIDLY BINDS TO HEMOGLOBIN TO

PRODUCE CARBOXYHEMOGLOBIN. THE BINDING AFFINITY OF
CARBON MONOXIDE TO HEMOGLOBIN IS 230 TO 270 TIMES
GREATER THAN THAT OF OXYGEN.
• THIS HIGH-AFFINITY BINDING OF OXYGEN PREVENTS THE
UNLOADING OF OXYGEN AT THE TISSUES, FURTHER
REDUCING OXYGEN DELIVERY
• BOUND CARBON MONOXIDE INCREASES HEMOGLOBIN
AFFINITY FOR OXYGEN AT THE OTHER OXYGEN-BINDING
SITES.
 CARBON MONOXIDE

• MAY PRODUCE “CHERRY RED” SKIN – INDICATING HIGHLY OXYGENATED BLOOD CARBON MONOXIDE
TOXICITY
• CAN ALSO OCCUR FOLLOWING INHALATION OR INGESTION OF METHYLENE CHLORIDE FOUND IN PAINT
STRIPPERS.
• ONCE ABSORBED, METHYLENE CHLORIDE IS METABOLIZED TO CARBON MONOXIDE THROUGH THE
HEPATIC CYTOCHROME P450 PATHWAY.
• THE SYMPTOMS OF CARBON MONOXIDE INTOXICATION ARE CONSISTENT WITH HYPOXIA, INCLUDING
HEADACHE, DYSPNEA, LETHARGY, CONFUSION, AND DROWSINESS.
• HIGHER EXPOSURE LEVELS CAN LEAD TO SEIZURES, COMA, AND DEATH.
 TREATMENT

• THE MANAGEMENT OF A CARBON MONOXIDE POISONING:

• PROMPT REMOVAL FROM THE SOURCE OF CARBON MONOXIDE,
• INSTITUTION OF 100% OXYGEN BY NONREBREATHING FACE MASK OR
ENDOTRACHEAL TUBE.
• IN PATIENTS WITH SEVERE INTOXICATION, OXYGENATION IN A HYPERBARIC
CHAMBER IS RECOMMENDED.
 CYANIDE

• CYANIDE IS ONE OF THE TOXIC PRODUCTS OF COMBUSTION PRODUCED DURING HOUSE FIRES
• ITS PRINCIPAL TOXICITY OCCURS AS A RESULT OF THE INACTIVATION OF THE ENZYME
CYTOCHROME OXIDASE (CYTOCHROME A3), LEADING TO THE INHIBITION OF CELLULAR
RESPIRATION.
• TISSUES WITH A HIGH OXYGEN DEMAND SUCH AS THE BRAIN AND HEART ARE ADVERSELY
AFFECTED EVEN IF THERE IS OXYGEN
• DEATH CAN OCCUR QUICKLY DUE TO ARREST OF OXIDATIVE PHOSPHORYLATION AND
PRODUCTION OF ADENOSINE TRIPHOSPHATE.
 ANTIDOTE

• THE ANTIDOTE, HYDROXOCOBALAMIN (VITAMIN B12A), IS ADMINISTERED INTRAVENOUSLY

• TO BIND THE CYANIDE AND PRODUCE CYANOCOBALAMIN (VITAMIN B12) WITHOUT THE ADVERSE
EFFECTS OF HYPOTENSION OR METHEMOGLOBIN PRODUCTION SEEN WITH OLDER ANTIDOTES.

• THE OLDER CYANIDE ANTIDOTE KIT CONSISTS OF SODIUM NITRITE TO FORM

CYANOMETHEMOGLOBIN AND SODIUM THIOSULFATE TO ACCELERATE THE PRODUCTION OF
THIOCYANATE, WHICH IS MUCH LESS TOXIC THAN CYANIDE AND IS QUICKLY EXCRETED IN URINE.
• TO AVOID THE OXYGEN CARRYING CAPACITY BECOMING TOO LOW IN PATIENTS WITH SMOKE
INHALATION AND CYANIDE TOXICITY, THE INDUCTION OF METHEMOGLOBIN WITH SODIUM NITRITE
SHOULD BE AVOIDED UNLESS THE CARBOXYHEMOGLOBIN CONCENTRATION IS LESS THAN 10%.
 IRON

• IRON IS RADIOPAQUE AND MAY SHOW UP ON AN ABDOMINAL RADIOGRAPH IF THE

PRODUCT CONTAINS A SUFFICIENT CONCENTRATION OF ELEMENTAL IRON.
• TOXIC EFFECTS CAN BE EXPECTED WITH INGESTIONS AS LITTLE AS 20 MG/KG OF ELEMENTAL
IRON, AND DOSES OF 60 MG/KG MAY BE LETHAL.
• EACH IRON SALT CONTAINS A DIFFERENT CONCENTRATION OF ELEMENTAL IRON
ELEMENTAL IRON CONTAINED IN VARIOUS IRON
PREPARATIONS.
 IRON

• A SERUM IRON LEVEL SHOULD BE OBTAINED,

• LEVELS BETWEEN 500 AND 1000 ΜG/DL HAVE BEEN ASSOCIATED WITH SHOCK
• LEVELS HIGHER THAN 1000 ΜG/DL WITH DEATH.

• PATIENTS WITH IRON TOXICITY USUALLY PRESENT WITH NAUSEA, VOMITING, AND ABDOMINAL
PAIN.
• DEPENDING ON THE AMOUNT OF ELEMENTAL IRON INGESTED - THE PATIENT MAY EXPERIENCE A
LATENT PERIOD OR MAY PROGRESS QUICKLY TO HYPOVOLEMIA, METABOLIC ACIDOSIS,
HYPOTENSION, AND COAGULOPATHY, HEPATIC FAILURE AND MULTISYSTEM FAILURE, COMA, AND
DEATH MAY OCCUR.
 ANTIDOTE

• DEFEROXAMINE , AN IRON-SPECIFIC CHELATOR, BINDS FREE IRON, CREATING FERRIOXAMINE,

WHICH IS EXCRETED IN THE URINE.
• HYPOTENSION MAY OCCUR IF RAPID INTRAVENOUS BOLUSES OF DEFEROXAMINE ARE
ADMINISTERED INSTEAD OF A CONTINUOUS INFUSION.
 LEAD
• SOURCES OF EXPOSURE INCLUDING OLD PAINT, DRINKING WATER, INDUSTRIAL POLLUTION,
FOOD, AND CONTAMINATED DUST.
• MOST CHRONIC EXPOSURE TO LEAD OCCURS WITH INORGANIC LEAD SALTS, SUCH AS
THOSE IN PAINT USED IN HOUSING CONSTRUCTED PRIOR TO 1978.
• ADULTS ABSORB ABOUT 10% OF INGESTED LEAD, WHEREAS CHILDREN ABSORB ABOUT 40%.
• INORGANIC FORMS OF LEAD ARE INITIALLY DISTRIBUTED TO THE SOFT TISSUES AND MORE
SLOWLY REDISTRIBUTE TO BONE, TEETH, AND HAIR.
• LEAD IMPAIRS BONE FORMATION AND CAUSES INCREASED CALCIUM DEPOSITION IN LONG
BONES
• INGESTED LEAD IS RADIOPAQUE AND MAY APPEAR ON AN ABDOMINAL RADIOGRAPH IF
PRESENT IN THE GI TRACT.
• LEAD HAS AN APPARENT BLOOD HALF-LIFE OF ABOUT 1 TO 2 MONTHS,
• ITS HALF-LIFE IN THE BONE IS 20 TO 30 YEARS.
• CHRONIC EXPOSURE TO LEAD CAN HAVE SERIOUS EFFECTS ON
SEVERAL TISSUES

• EARLY SYMPTOMS OF LEAD TOXICITY CAN INCLUDE DISCOMFORT

AND CONSTIPATION (AND, OCCASIONALLY, DIARRHEA),

• WHEREAS HIGHER EXPOSURES CAN PRODUCE PAINFUL INTESTINAL

SPASMS.

• CNS EFFECTS FROM LEAD INCLUDE HEADACHES, CONFUSION,

CLUMSINESS, INSOMNIA, FATIGUE, AND IMPAIRED CONCENTRATION.

• AS THE DISEASE PROGRESSES, CLONIC CONVULSIONS AND COMA

CAN OCCUR.

• DEATH IS RARE, GIVEN THE ABILITY TO TREAT LEAD INTOXICATION

WITH CHELATION THERAPY.
• BLOOD LEVELS OF 5 TO 20 ΜG/DL IN
CHILDREN HAVE BEEN SHOWN TO LOWER IQ
IN THE ABSENCE OF OTHER SYMPTOMS.
• HYPOCHROMIC, MICROCYTIC ANEMIA AS A
RESULT OF A SHORTENED ERYTHROCYTE LIFE
SPAN AND DISRUPTION OF HEME SYNTHESIS.
 TREATMENT

• MULTIPLE CHELATORS CAN BE UTILIZED IN THE TREATMENT OF LEAD TOXICITY.

• SUCCIMER (DIMERCAPTOSUCCINIC ACID [DMSA] – AN ORAL CHELATOR IS THE
TREATMENT OF CHOICE WHEN LEVELS ARE GREATER THAN 45 ΜG/DL, BUT LESS THAN
70 ΜG/DL IN CHILDREN,
• DUAL PARENTERAL THERAPY OF DIMERCAPROL AND CALCIUM DISODIUM EDETATE
(EDTA), WITH LEAD LEVELS GREATER THAN 70 ΜG/DL OR IF ENCEPHALOPATHY IS
PRESENT,
• PARENTERAL THERAPY WITH DIMERCAPROL GIVEN INTRAMUSCULARLY AND
CALCIUM DISODIUM EDETATE GIVEN INTRAVENOUSLY.
• DIMERCAPROL IS SUSPENDED IN PEANUT OIL AND SHOULD NOT BE GIVEN TO THOSE
WITH A PEANUT ALLERGY.
**DIMERCAPROL - Oily, clear (colorless), Mercapturic Smell!!**
POISON ANTIDOTE 9S0

Acetaminophen N-acetylcysteine

Anticholinergic agents (antihistamines, etc) Physostigmine

Arsenic Dimercaprol succimer

Benzodiazepines Flumazenil

Carbon monoxide Oxygen (±ℎ𝑦𝑝𝑒𝑟𝑏𝑎𝑟𝑖𝑐 𝑐ℎ𝑎𝑚𝑏𝑒𝑟)

Cyanide Hydroxocobalamin, sodium nitrite and sodium

thiosulfates

Dabigatran Idarucizumab

Digitalis Digoxin-immune Fab

Heparin Protamine sulfate

Hydrofluoric acid Calcium

Iron Deferoxamine

Isoniazid and Gyromitra mushrooms Pyridoxine

POISON ANTIDOTE 9S0

Lead Calcium disodium edetate (EDTA), Dimercaprol succimer

Methanol and ethylene glycol Fomipizole

Methemoglobinemia Methylene blue

Benzodiazepines Flumazenil

Opiates, Clonidine Naloxone

Organophosphates, nerve gas Atropine, Pralidoxime

Watrfarin Vitamin K1 (Phytonadione)

THANK YOU