General Principles of Toxicology

• Oral > Eye > Skin > Bites/Stings > Inhalation > Aspiration

• 90% poisonings occur in the household (children- most common): cosmetics, cleaning products,

plants, pharmaceuticals, etc)

• Most Deaths: Antidepressants, Analgesics, Stimulants/St. drugs, Alc/glycols, Gases/Fumes, Asthma Rx

• Most frequently involved in Hu Poison Exp: Cleaning substances, Analgesics, Cosmetics, Cough/Cold

preps, Plants

• Priority Toxic Agents for Hu: Alcohols (Etoh, Mtoh, ethylene glycol); Gases/Vapors (CO, H₂S, CN, NO, ozone); Metals (Fe, Lead, Hg); Drugs (Tylenol, deferoxamine, dimercaprol, penicillamine, pesticides, Cl-hydrocarbons, Nitroso compounds, aromatic amines, aminoazo dyes, alkyl agents)

2.  Actions due to physical or chemical properties of toxins

3.  Inhibit enzymes, channels, carrier proteins

4.  Antimetabolites (CN blocks O₂ binding to cyto. oxidase)

• Absorption: lipid solubility & ionization for oral ingestion, SA of stomach/intestine

• Distribution: (Initially) Rate of Bld Flow to organs; (later) redistribution e.g. adipose (DDT) or Bone (lead)

• Biotransformation/Elimination: liver, kidneys; toxic metabolites may be highly toxic and damage these tissues; toxicity (esp. mutagenesis/carcinogenesis) from biotrans and prod of “reactive spp” is almost always due to Phase I biotrans rxns catalyzed by P450 system. Phase II = conjugation by glucuronides.

• Variability in toxic rxns produced by diff individuals b/c genetic diffs in forms of P450s and other enzs and in the diff levels of such enzs due to genetic or environmental diffs. Biotrans => detoxify or form reactive intermediates (may help or hurt!)

• Delayed vs. Immediate Toxicity

• Exp Rate, Elim Rate and Nature of Elim process (1^st Order or Zero order) determines the level of toxin in body => toxic effects

• Special Pop. = neonates/infants (premature/elderly) b/c mech of elim not well devo or maintained.

TI = TD_50/ED_{50          or} TI = LD₅₀/ED₅₀

_{TD or LD  =Toxic/Lethal Dose}

_{ED = Effective Dose}

MOS = TD₁/ED_{99            or} MOS = LD₁/ED₉₉

MOS  > 1 = Very Safe Drug (Drug A)

MOS = NOEL_{(animal studies)} / Hu “Exp Dose”

_{NOEL = No Obs Effect Level (used when tox  for hu unk/unattainable, est. of safety  based on animal data) is  highest dose of a chemical which does NOT produce an obs effect. “Exp. Dose” = (mg/L of toxin) (L/day of exp) / (wt=kg)}

ADI = [NOEL]_{(acute/chronic)} /(10_hv x 10_id x 10)

_{ADI = WHO defines “daily intake of chem which during the entire lifetime appears to be w/o appreciable risk on the basis of all known facts at the time.”  Based on NOEL and uncertainty factors (hu variability, interspecies var, lack of chronic data}

• TLV = “safe” concentration in ambient air in the workplace for many common industrial chemicals.

• TLVs est. by occupational hygienists and published on periodic basis

• Approx. 90% of environmental toxicants that cause genotoxicity do so by the generation of reactive metabolites of the parent compound, reactive oxygen spp, free rads, etc.

• “reactive metabolites” capable of forming covalent bonds w/ proteins, nucleic acids, lipids => loss enz fxn; gen of haptens => Ab production; formation of DNA adducts => mutagenesis, damage membranes integrity/fxn.

• Production of Reactive Metabolites:

1.  Phase I (P450 or PGH synthase catalyzed biotrans) => “Toxication” processes

2.  Phase II (sulfate or glucuronide conjugation) => “inactivation” and elimination

• Bioactivation forms electrophiles (e-deficient atom w/ full or partial pos. chg) or free rads (molecule w/ unpaired e(s) in its outer orbital)

• Reactive Oxygen Species:

1.  O₂^* (Superoxide anion radical) via toxin + O₂ or Mac/Granulocytic O₂ resp burst by membrane bound NADPH:

e.g.  paraquat, doxorubicin, nitrofurantoin

2.  H₂O₂ (Hydrogen peroxide) via SOD or spontaneously

3.  HO^* (Hydroxyl radical) via “Fenton Rxn” (FeII, CuI, MnII, CrV, NiII)

• Glutathione peroxidase (GPO), Superoxide dismutase (SOD), and Catalase (CAT) play a central role in detoxication mechanisms!

• SOD: O₂^* + 2H⁺ >O₂ + H₂O₂

• GPO or CAT: H₂O₂ + 2GSH >GSSG + 2H₂O

Summary:  SOD + GPO(or CAT) => O₂^* > 2H₂O

2.  Modifications of Nucleic Acids:  DNA damage/mutagenesis.

a.  Adduct formation- alkyl sulfates, N-nitroso cpds, epoxides, mustards

b.  Loss of Purine or Pyrimidine (­ spont. incidence by adducts formation)

c.  Deamination- nitrous acid

d.  ssDNA breaks- peroxides, oxygen radicals and x-rays

e.  dsDNA breaks- x-rays

f.  Cross-linking- alkylating agents (mustards & nitrosureas)

3.  Lipid Peroxidation:  Membrane damage, loss of function, generation of more free radicals. Major mechanism for OXIDATIVE DAMAGE!!!  Resulting from many chemicals which lead directly or indirectly to the formation of O₂^* or other reactive spp.

2.  Molecular repair

a.  Repair of Damaged Proteins- GSH may reduce S-S linkages in damaged proteins

b.  DNA repair enzymes- alkyl transferases remove alkyl adducts from DNA, base/nct excision repair; post

replication repair; mismatch repair

REPAIR MECHANISMS cont…

c.  Membrane repair by antioxidants-  tocopherol (Vit E) & ascorbic acid (Vit C) convert lipid peroxides OH-FA’s

and replace damaged membrane lipids

• Hazard Identification- potential hazards to which hu (humans) may be exposed. What is the structure-activity of chemical (func groups)? Epidemiogical studies (incidence over demographics/geographics)? In vitro toxicity tests, toxicology studies in animals for acute, subacute, subchronic, chronic studies.

• Risk Characterization- suspected risk. What is potency of agent (LD₅₀), hu exp (exposure) assessment (air, water, diet? Susceptibility based on genetic background, lifestyle, occupation?

• Control of Risks- d/c production of chemical? Info dissemination to public? Less toxic substitutes available?

• Occupational ds include: Interstitial fibrosis, bronchogenic CA, mesothelioma (asbestos); coal miner’s pneumoconsiosis; byssinosis (cotton dust), toluene diisocyanate asthma, Western red cedar, silicosis (hwy construction).

• At risk Pop. for airborne pollutants: infants, elderly, emphysema or COPD, asthma, & smoking hx.

• Gas: solubility determines rate at which gas => resp tract and abs into bldstream

• Particulates: size of particle determines level to which particle moves

• Uptake: particle density, particle size, minute ventilation

• Protection: directional changes within entire resp tree => deposition of particle before it enters alveolar region

• Elimination

Source:  combustion of fossil fuels

Toxic Effects:  bronchospasm, hypertrophy of goblet cells, & mucous glands, & pulmonary edema; may produce sulfuric acid.

Source:  auto exhaust, cig smoke, gas stoves

Toxic Effects:  interstitial edema (penetrates alveoli), epithelial cell prolif, fibrosis & emphysema w/ high exp; may produce nitric & nitrous acids.

Source:  photochemical rxns involving NO₂ + O₂ + UV radiation.

Toxic Effects:  (chronic exp) Inflammation, edema, bronchial constriction, & pulmonary vasc changes. Contributes to ­ incidence of asthma.

“AIR TOXICS”

1.  “volatile organic compounds”

2.  “aldehydes”

3.  “reactive chemicals”

• Include: cig smoke, (indoor) de-gassing of synthetic bldg materials/plastics = “new car smell”

• “Sick Bldg Syndrome”- collection of sx in atleast 20% of those exposed and relieved by removal from exposure.

Symtoms include:  ENT irritation, HA, ¯ attn span, nasal congestion, dyspnea, nausea, dry skin, nose bleeds

• “Bldg-related illnesses”- well-documented conditions w/ defined dx criteria, e.g. Legionnaires’ ds (bacterial pneuno)

• ~toxic material on carbon particles from incomplete combustion; may be organic/inorganic.

CO binds reversibly to Hb w/ affinity 220 times that of O₂

CO can also bind to heme Fe in cellular cytochromes

MOT = Mechanism of Toxicity (like MOA)

• MOT: tissue hypoxia due to:

a.  competes w/ O₂ for Hb binding sites => functional anemia

b.  Left shift of Hb curve => less cooperativity, impairs O₂ unloading to peripheral tissues

• SX: (dept on level % bld sat of COHb and length of exposure)

0-10% COHb => no symtoms

10-20%           => tightness across forehead; slight HA, dilatation of cutanesous bv

20-30%           => HA, throbbing in temples

30-40%           => Severe HA, weakness, dizziness, dimness of vision, N/V, collapse

40-50%          => Cherry red appearance, ­RR, ­HR, collapse or syncope

>> 50%           => Cheyne-Stokes respiration, coma w/ convulsions, cardiac/resp failure, death

• RX: 1) remove from source of CO 2) give O₂ (may need hyperbaric tx) until COHb < 10% 3) support ABC -should expect acidosis from anaerobic metabolism, pos pressure vent may be needed for air transport of pt.

REMEMBER!  Simple pO₂ no longer predicts O₂ carrying capacity.  Co-oximetry is needed!!  Pulse oximetry values will be falsely elevated in setting of CO poisoning.

At Risk populations:  smokers, Ischemic HD, anemia, elderly, unborn infants in utero and fire exposure victims.

• Inorganic/organic compounds that enter via resp or GI routes.

• MOT: Oxidation of Fe⁺⁺ => Fe⁺⁺⁺ in Hb => Met-Hb

Met-Hb => ¯ O₂ binding to Hb (like CO) and Hb curve shifts to LEFT => umpaired Unloading => tissue hypoxia

• RX: Methylene blue (1-2 mg/kg) augments Met-Hb reductase in RBCs and spontaneously reverses rxn-

met-Hb®Hb.

**NOTE:  methylene blue => false, transient, decrease in O₂ saturation by measured by pulse Ox.

CN (Cyanide)

MOT:  Binds strongly to & inhibits cytochrome oxidase => blocks e-transport in oxphos pathway

SX: BRIGHT RED VENOUS BLD & “ALMOND” ODOR

RX:  MUST BE FAST!!  3 Steps:

1.  Transient production of met-Hb w/ nitrites (amyl nitrite via inhalation) + sodium nitrite (IV)

-met-Hb competes w/ cyto. oxidase for CN ion (e-transport is repaired) b/c Met-Hb binds all CN.

2.  Sodium thiosulfate: CN >SCN (thiocyanate)

3.  Methylene blue used to treat met-Hb-emia

MOT:  Potent inhibitor of cytochrome oxidase (same effects as CN poisoning)

RX:  nitrite-induced met-Hb formation which reacts w/ H₂S to form sulfmet-Hb.  Thiosulfate has little or no role.  O₂ recommended for hypoxemic pt.

I.  ORGANOCHLORINE:  DDT, Methoxychlor, Aldrin, Dieldrin, Lindane…

-low cost, low volatility, lipid sol, chem stable.

-accumulate in fat depots (very lipophilic)

-induce P450s

-Three structural types:

a.  DDT & methoxychlor-  breast milk is major source exp in U.S.

b.  Chlorinated Cyclodienes (Aldrin, Dieldrin, Heptachlor, Chlordane)-  very high dermal abs. w/ potential for severe

acute toxicity, incl. Death

c.  Other (Lindane, Kepone, Mirex, Chlordecone, Toxaphene)-  Kwell (Lindane shampoo) used against lice.

MOT:  (axonal cyto.)  interferes w/ nerve conduction by inhibiting repolarization (prolong falling phase of AP) =>

­ sensitivity to very small stimuli that would not normally elicit a response.

SX:  Paresthesias (esp CNV distribution), apprehension, irritability, tremors, ventilatory failure & motor seizures.

RX:  ABC (acute care); BZD or barbs (seizures); Cholestyramine (po) => fecal excreation of compounds

II.  ACETYLCHOLINESTERASE INHIBITORS (AChEI):  Organophosphorus & Carbamate esters

-Two types:

a.  Organophosphate Insecticides (malathion, parathion, diasinon)-

b.  Carbamates (carbaryl, aldicarb)-  usually reversible by hydrolysis

MOT:  (synapse) inactivates AchE enzyme

SX:  Muscarinic storm (meiosis, cramps, ­ secretions, bronchospasm, diarrhea, urinary incontinence, brady =>

Asystole); Nicotinic-R stimulation then blockade (HTN, muscle fasciculations, tremors, then weakness w/ possible

paralysis); and CNS effects (restlessness, ataxia, mental confusion, seizures, coma, and death).

RX:  ABCs if necessary.  Adm of atropine => muscarinic storm & pralidoxime (reactivates the cholinesterases)

NOTE:  Atropine (high doses) => central anticholinergic syndrome => mental confusion, seizures, and death.

Pralidoxime (high doses) => bind Ca => muscle spasms.

III. PYRETHROIDS:  pyrethrin, cypermethrin, deltamethrin

-Acute toxicity relatively low in hu/mammals, but compounds persist in environment longer than organophosphates.

MOT:  (axonal cyto.) interfere w/ neurotransmission by variety of mechanisms (Na channels, GABA-R’s, effects on

Ca levels).

-kills broad leaf weeds/plants by antagonizing plant hormones

-chloroacne, & other dermatitis reported in production workers

-component in “Agent Orange” a defoliant used in Vietnam

MOT:  thought to be due to TCDD, a contaminant from the production process

II.  BIPYRIDYL COMPOUNDS (paraquat)

-most serious toxicity is pulmonary fibrosis (probably from generation of free rads, and O₂ adm ­ toxicity)

I.  ALIPHATIC HYDROCARBONS:  Methane, ethane, propane, butane, hexane…

-”asphyxiants”

-”glue sniffing” or hexane => progressive sensorimotor distal axonopathy

MOT:  toxin targets neurofilaments in cytoskeleton of axon => neurofilament aggregates => massive swellings of distal, subterminal axon => demyelination => clinical peripheral neuropathy => “stocking & glove” distribution of sensory loss.

SX:  CNS depression, polyneuropathy

II.  ALIPHATIC ALCOHOLS & GLYCOLS: Methanol, ethylene glycol

a.  Methanol

MOT:  formation of formaldehyde + formic acid by AlcDH

SX:  systemic acidosis (formic acid), blindness- “blind drunk”

RX:  EtOH (IV load 0.6g/kg, MD = 150mg/kg/hr); Hemodialysis

b.  Glycols & glycol ethers

Source:  antifreeze (ethylene glycol), fingernail polish, propylene glycol (foods, cosmetics, meds) are all considered “GRAS” or Generally Recognized As Safe by FDA.

SX (ethylene glycol):  CNS depression, nephrotoxicity (oxalate stones), metabolic acidosis (formic, glycolic, oxalic acids)

III.  HALOGENATED ALIPHATIC HYDROCARBONS:  dichloromethane, chloroform, CCl₄

-solvents, cleaning compounds

-cause generalized CNS depression

Toxicities:  hepatic (+P450 rxns => free rads), renal, heart (arrhythmias)

MOT:  sensitizes P450 rxns

IV.  AROMATIC HYDROCARBONS: Benzene, toluene

-solvents in many chemical production syntheses

-Acute Tox => CNS

-Long-term Tox of Benzene (not toluene) => ­ risk of leukemia and aplastic anemia

MOT:  free rads & highly reactive intermediates form DNA-adducts

-extensively produced in US

-extremely resistant to degradation

II. BY-PRODUCTS of PCB production

-include PCDDs (polychlorinated dibenzo-dioxins) and PCDFs (polychlorinated dibenzo-furans)

III.  TCDD = “Dioxin” or Dioxin-R

-potent inducer of aryl hydrocarbon hydroxylase, P450 dept. Mono-oxygenase

-Ah locus codes for “receptor” for TCDD = nuclear protein which increases transcription of specific P450 genes

(CYP1A1, CYP1A2), UDP-glucuronyltransferase, and one form of glutathione-S-transferase)

-hu Ah-Receptor likely to exist and predicts individual sensitivity to certain classes of drugs and toxicants.

IV.  TOXICITIES

­-Death:   TCDD is one of the most lethal chemicals known in certain species e.g. GUINEA PIG KILLER!

-Hu toxicities:  chloracne, porphyria, psychiatric disturbances, gen CNS effects (acute); leukemias and soft

tissue sarcomas (long term).

-reports of increased thyroid CA

-PCBs and PBBs => neurotoxicity, immunotoxicity, and reproductive toxicity in experimental animals.

Toxicity:  important functional groups (O, S, N, -SH) on proteins serve as ligands for metals; every organ contains proteins w/ these func groups therefore sx are general/non-specific, and multiple organ systems are affected esp.  CNS, resp, GI, Kidney, and immune.

Protection:  Metallothionien (induced by low levels of some metals) in liver and kidney may prevent toxicity to higher levels of metals b/c of its high capacity to bind many molecules of metal per molecule of protein.

TREATMENT of Metal Poisonings:

1.  Removal of exposure source or decontamination, elimination of metal from body.

2.  Supportive treatment for sx (correct lytes, prevent seizures, ABCs)

3.  Chelating agents- remove or prevent the binding of metals to the endogenous “ligand” sites where they produce toxicity, NOT to prevent binding to important molecules (Fe to Hb); chelator-metal complexes are elim in urine, so may accum. in case of renal insuff.

MAJOR CHELATORS:  Dimercaprol (Hg & Ar); EDTA (Pb); Deferoxamine (Fe); Penicillamine (primary for Cu; adjunct for Pb & Hg); Succimer (Pb in children)

• EXPOSURE: old house paints, leaded gasoline; food, contaminated water, and air, pottery & jewelry making, sandblasters; CDC considers 10 mg/dL => some adverse effects can be observed in hu’s

• ABSORPTION: GI & Resp Tract => circulation (in RBCs) => Pb binds to Hb; little free Pb in bld => ­ conc in soft tissues w/ good perfusion (esp. liver, kidney), eventually sequestered in bone; elim from body very slow.

• ACUTE (rare): CNS (paresthesia), muscle weakness/fatigue, gen pain. Hemolysis => anemia & hemoglobinuria => kidney damage.

• CHRONIC: CNS toxicities MOST SERIOUS! = “Pb encephalopathy”

RX:  1) ABC Support;  2) Diazepam for seizures; 3) Chelate q1wk EDTA and dimercaprol (IV); penicillamine/succimer (po) esp good for children.

• EXPOSURE: Occupational/industrial pollution (mercuric salts in water or mercury vapor); agricultural uses of organoHg; Hg vapor from deposition of earth’s crust (main source of Hg in environment) which is then => Hg salts or organoHg primarily by anaerobic bacteria in oceans => ingested by small crustaceans => food chain => humans.

• MAJOR SOURCE: eating large amts highly contaminated food!!

• MOT: thought to bind thiol groups in enz and other protein structures.

• ABSORPTION:

a.  Elemental Hg:  vapor => lungs =>crosses BBB to brain & membranes within CNS => some Hg converted to Hg II by catalase in RBCs.

Note:  liquid form of elemental Hg rarely ingested & relatively non-toxic if it is b/c not abs well from GI.

b.  Inorganic Hg salts:  oral route => circulation => conc in Kidney; Note:  long t_1/2 = 60 days in body;  NO CNS effects b/c charged and can’t cross BBB.

c.  OrganoHg compounds (CH₃Hg) :  GI abs => (very lipophilic) enterohepatic recycling => cleared from the body

VERY SLOWLY t_1/2 = 50-100 days .  CH₃Hg can covalently bind cysteine => ~met => can traverse capillaries =>

CNS/placenta => SEVERE NEUROLOGICAL TOXICITIES in both ADULTS & IN UTERO!!

MERCURY cont…

a.  Elemental/OrganoHg => NEUROLOGICAL (visual) & BEHAVIORAL = “mad as a Hatter”  (MOST  COMMON); Remember Triad:  1) excitability 2) tremors 3) gingivitis.

b.  Hg Salts (corrosive to mucosa of mouth, pharynx, intestine) => intense pain/vomiting => loss of bld/fluids in stool => hypovolemic shock in severe exposures

c.  Hg vapor => severe interstitial pneumonitis & ¯¯ resp fxn (may have residual interstitial lung fibrosis even after recovery

NOTE:  GI tract & Kidney are major sites of toxicity.

RX:

1.  Removal of/from source of exp (decontamination)

2.  Chelation therapy:

a.  Elemental Hg or Hg salts:  use dimercaprol (IV) or penicillamine (po)- NOT effective in OrganoHg;

Penicillamine-Hg chelate => urine only  (caution w/ ¯ renal fxn); Dimercaprol-Hg chelate => bile & urine.

b.  OrganoHg (methylHg):  use non-abs polythiol resin => excreted in bile => feces- Hemodialysis NOT helful for organoHg b/c Hg compound inside RBCs!

ARSENIC

ABSORPTION:  Resp tract & GI tract

MOT (two mechanisms):

1.  Arsenate (AsO₄) substitutes for P_i in ox-phos (mitochondria) => unstable AsO₄-ADP => ADP + AsO₄ + wasted energy

2.  Arsenite (As⁺⁺⁺) binds proteins w/ -SH groups; also interacts w/ lipoic acid (cofactor for Pyruvate-DH rxn)

SX:

• GI, CV, CNS => generalized or nonspecific sx includes mucosal damage => GI bld/diarrhea => hypovolemic shock.

• Triad of As Gas (rare, but potentially fatal): 1) massive hemolysis 2) abd pain 3) hematuria => kidney damage due to ­ degraded Hg in plasma

RX:  1) decontamination 2) dimercaprol (IM) followed by longer times of 3) penicillamine (po)

Remember to watch for hypovolemic shock.

a.  Industrial:  mining & smelting operations

b.  Food ingestion (shellfish conc Cd from water)

c.  Cigarette smoke (Cd in leaves of tobacco plants)

Intake:  Resp Tract > GI tract

MOT:

a.  Resp Tract:  (chronic) bronchitis => fibrosis in lower airways => alveolar damage = alveolar macs release lytic enz and  ¯¯ alpha -1-AT activity that normally counteracts lytic enz => emphysema.  Acute effects: chemical pneumonitis and pulmonary edema which can be severe if exposures are high.

b.  Kidney:  protein metallothionien (usually protectant against metal tox) complexes with Cd in liver => enter

circ => taken up by renal tubule cells => metallothionien-Cd complex degraded in lysosomes releasing Cd in cell => renal tubular necrosis

c.  GI tract: (usually due to acute exposures):  N/V, abd pain, usually reversible.

RX:

1)  Decontamination 2) ABC esp respiratory support 3)  EDTA (not clear how effective)

a.  Young Children (1-2 yrs):  Household Fe supplements for anemic family members; 0.5 g = serious tox; 2g may be fatal.  OTC preps = 250 mg tabs therefore 10-20 tabs => serious poisoning!!  Children also have >> capacity for Fe abs.

b.  Adults:  chronic poisoning due to: 1) repeated transfusions (thalassemia) or 2) inherited d/o’s

(hemochromatosis); also, miners/steel workers may inhale particulates w/ iron oxide => form deposits in lungs.

MOT:  Destruction of mucosal GI tract => Fe damages endothelial cells (esp. liver & kidney)

SX:  severe gastroenteritis, vomiting, bloody diarrhea, abd. pain, can be followed by => shock, metabolic acidosis, coma, CV collapse, death.

RX:

a.  Early Acute:  1) gastric lavage  2)  carbonate salts to form insol Fe complexes => feces 3) deferoxamine (esp in acute children)

b.  Chronic toxicity: 1) recurrent phlebotomy (esp. hemochromatosis) 2) deferoxamine at time of transfusions in thalassemia pts.

Note:  deferoxamine does not remove Fe from Hg, Mg or cytochromes and only removes it to a ltd extent from transferrin; hypocalcemia not a concern.  Complex excreted in urine & feces.  May cause allergic rxn, pain at injection site. Rare hTN and tachy w/ rapid IV infusion.

TREATMENT:  COMMONLY USED CHELATORS

DIMERCAPROL (IV only)

a.  Primary agent => Hg & Ar poisoning

b.  Adjunct + EDTA => Pb poisoning

CAUTION!  NOT for Fe or Cd poisonings b/c ­ nephrotoxicity with drug-metal complexes; NOT for methylHg poisoning b/c drug actually ­ amt Hg in CNS.

a.  Fe poisoning (binds ferric Fe⁺⁺⁺)

b.  Aluminum poisoning

CAUTION! Use in children for Acute Fe poisoning only, NOT chronic b/c => auditory & ocular probs esp. w/ ¯ renal fxn

a.  Primary agent for Pb poisoning

-If used chronically give “on”/”off” to allow Pb to redist. out of bone stores during “off” times.

-May ¯ duration of action of insulin-Zn preps b/c it chelates Zn well.

a.  Primary for Cu in Wilson’s ds

b.  Adjunct for Pb, Hg, Ar toxicity

c.  Some cases of RA

SE:  allergic rxns (x-sens w/ penicillin), stomatitis w/ ulcers, sores, and gingivitis (leukopenia & thrombocytopenia)

a.  Pb poisoning in Young Children

b.  Adjunct for Hg and Ar

SE:  GI (n/v/d) & rash (sens rxns)

• ~2.5 million hu exp/yr in US

• 400,000 referred for med tx, 25% admitted

• 0.03% fatality rate (1998)

• Over 50% of 2.5 miollion are < 6 yrs old

MOST COMMON EXPOSURES & CAUSES OF DEATHS

Exposure: Cosmetics, cleaning products, analgesics, plants, cough/cold preps

Deaths:  CO (most common across all toxicants and ages!!), Analgesics, Fe, cleaning products, CV drugs,

antidepressants, pesticides

ADOLESCENT (Age 13-17)

Exposure:  Analgesics, cough/cold preps, cleaning products, envenomations

Deaths:  Hydrocarbons, antidepressants, analgesics, CV drugs

ADULT

Exposure:  analgesics, cleaning products, bites/envenomations, sedative-hypnotics, antipsychotics, antidepressants

Deaths:  Analgesics, antidepressants, stimulants/st drugs, CV drugs, sedative-hypnotics, antipsychotics, alcohols,

chemicals

• Interview family, sibs, friends, EMS? What meds is pt taking? Family? What does pt have access to?

• CAUTION: possible false hx due to hidden motives.

• Goal of a History:

1) exact ID of toxin-container & poisondex

2) time of exposure

3) conc of liq or # pills

4) Vomit? Other symptoms?

5) Any treatment initiated?

EXAM

• V/S often have vital clues!!

• Examine Head-toe

• Do serial Mental Status checks

• Many toxins affect ANS!!

• Goal of an exam are the findings:

Eye:  pupillary changes

Skin/mucosal:  changes? discoloration of skin/nails? Cyanosis? (met-hemoglobinemia => cherry red) caustic burns? Soot? unusual odors? Vesicles?

Lung:  bronchospasm (beta-blockers); ­ secretions, carbamates; pulmonary edema (salicylates, opioids, beta-blockers, Ca-channel blockers)

Abd:  Tender, hepatomegaly (APAP–delayed); Bowel sounds (cholinergic vs. anticholinergic, opioids); Bladder distension (anticholinergics).

RADIOGRAPHS (CHIPES = Radiopaque ingestions)

• Calcium, chloral hydrate cocaine body packs

• Heavy metals, halogenated hydrocarbons

• Fe and Iodine

• Psychotropics (phenothiazines), potassium, phosphates,

• Enteric coated preps

• Slow release prep

ANTICHOLINERGIC/CHOLINERGIC— TOXIDROMES

• Red as a beet (vasodilation) Salivation,Lacrimation,Urination,Defecation,Sweat

• Hot as a hare (hyperthermia)

• Mad as a hatter (delirious)

• Dry as a bone (no sweat)

• Blind as a bat (mydriasis)

• ANS => bowel & bladder lose tone; Brady in the heart

CHOLINERGIC (dumbels)

• Diarrhea

• Urination

• Miosis

• Bradycard/bronchorr

• Emesis

• Lacrimation

• Salivation

• “High & M-A-D on drugs” (cocaine, amphetamines, decongestants)

• “High” = ­ HR (Tachycardia w/ reflex brady), ­ BP (HTN), ­ Tm (Hyperthermia)

• Mydriasis

• Agitation & seizures

• Diaphoresis

• ABC-D: Airway, Breathing, Circulation, D: decontamination, D-stick (glucose), Dextrose (1mg/kg IV)

• COMA protocol: ABC-D plus thiamine (alc), narcan (naloxone if opioid OD); r/o “IT’S COMA!” p.335 First Aid

• DECONTAMINATION:

a.  IPECAC

USE:  home therapy, recent exposure, charcoal ineffective, prolonged transports, “chunky materials” like berries & large pills

NOT IF:  caustics, hydrocarbons, unprotected airway, bleeding d/o, seizures & altered MS, age < 6 months, pt already vomiting

b.  GASTRIC LAVAGE

USE:  recent (1-2hr ) & potentially life threatening ingestion; delayed gastric emptying; agent not bound by Charcoal (Fe, Li)

NOT IF:  low tox hydrocarbons, alkaline caustics

HOW:  secure airway, use large bore orogastric tube, pt on Left Lat Decub Head Dn position, use water or NS in 50-200 ml aliquots until clear ~2 liters

c.  ACTIVATED CHARCOAL

Most efficacious agent (OTC available)

INITIAL DOSE:  1 gm/kg

USE:  first-line for many toxicants; pt must have normal GI fxn; can be used after lavage

NOT IF:  highly ionized or polar toxins (caustics, Fe, Li, alcohols)

d.  CHARCOAL w/ SORBITOL

Sorbital (non-abs sugar) speeds GI transit & stooling

Can cause dehydration and lytes imbalance

NOT IF: age < 5

e. MULTI-DOSE ACTIVATED CHARCOAL (MDAC)

Works by enterohepatic circulation or gut “dialysis”

USE:  many toxins:  carbamazepine, theophylline, phenobarb, ASA, TCA

DOSE:  1g/kg q 6h or continuous NG infusion (must f/u bowel sounds & function closely)

f.  WHOLE BOWEL IRRIGATION (WBI)

Polyethylene glycol/electrolyte soln (PEG/ELS)

USE:  when charcoal is not effective; Fe, sustained release drugs like Li; body packers

NOT IF:  GI dysfxn

DOSE:  Child: 0.5 L qh oral for kids; Adult: 2.0 L qh x 6h till rectal effluent is clear

**A tip:  when using WBI, place first 250-500 ml then listen for pyloric opening

g.  SKIN & EYES

USE:  acids, alkalis, organophosphates, methylene chloride (CO), trichloroethylene, many other solvents and organometallics, that require immediate removal

HOW:  Copious irrigation of eyes w/ NS, copious soap/water for skin

ELIMINATION

a.  URINE ALKYLINIZATION (Acetazolamide = bicarbonate)

Theory:  drugs are filtered, secreted, then reabs by kidney, if drug gets polarized or ionized once secreted into lumen–drugs get trapped in the urine & can’t be reabs back into circ ; weakly acidic drugs are ionized in alkaline urine => favoring excretion.

USE:  ASA, phenobarb, MTX

HOW:  Nabicarb 1-2meq/kg q3-4h to keep urine pH > 7.5 (avoid hypokalemia cuz it interferes w/ ion xchg)

b.  HEMODIALYSIS

USE:  drug = low mw < 500 daltons, water sol, low V_d (L/kg), not highly bound to protein, low endogenous clearance <4ml/min/kg:  Li, ASA, MeOH, EtOH, ethylene glycol, chloral hydrate, corrects severe acid-base, lytes/fluid disturbances

c.  CHARCOAL HEMOPERFUSION

USE:  (similar drug criteria as hemodialysis except…)

1.  NOT for alc & metals

2.  Can handle drugs more protein bound

3.  Carbamazepine, phenobarb, theophylline, phenytoin

MOT:  APAP overdose, alcoholics, malnutrition, CYP-450 induced states => overworked glutathione detoxifying mechanisms can’t keep up => accumulation of reactive intermediate NAPQI => free electrophilic attack on sulfur containing aa’s in cell membranes proteins & enz => centrilobular necrosis of liver (similar damage in kidney).

ANTIDOTE:  N-Acetylcysteine (NAC) po or IV following Loading Dose (LD); use if 4h APAP > 140mcg/ml

MOT:  Stimulates central resp cntrs => RESPIRATORY ALKALOSIS, then interferes w/ Kreb cycle, uncouples ox-phos => METABOLIC ACIDOSIS (tachypnea, tinnitus, coma, seizures, pulmo edema => RESPIRATORY ACIDOSIS (compensatory).

ANTIDOTE:  Gastric lavage, MDAC, Bicarb alkalinization of urine, hemodialysis for severe cases.

NOTE:  ASA makes BEZOARS (concretions) => delayed gastric lavage may be useful!

Source:  solvent, windshield washer fluid, de-icers, canned heat

• MOT: metab by alc-DH to formaldehyde and formic acid => formic acid can hurt retina “blind drunk”; anion gap acidosis and +OSMOL GAP

2Na + Glc/18 + BUN/2.8 + EtOH/4.6   (Normal = 270-290 mOsm/L)

GAP b/t measured OSMOL and calc OSMOL suggests presence of osmotically active particles but normal results don’t guarantee that ingestion has not occurred.

• SX: seizures, gastritis, pancreatitis and RETINA damage

• RX:

1.  EtOH- “keeps ADH busy”

-give initial Loading Dose and Maintenance Dose = 100 mg/dl

-sx pts or those w/ MeOH or ethylene glycol levels > 25-50 mg/dl need definitive tx.

2.  Folate- enhances formic acid metabolism

3.  Hemodialysis

4.  4-MP (4-methylpyrazole)- blocks AlcDH

ETHYLENE GLYCOL + ANION GAP ACIDOSIS

• MOT: CNS depression => seizures, acidosis, and RENAL FAILURE

• RX: EtOH, 4-MP, hemodialysis; pyridoxine and thiamine promote non-toxic metabolites

ISOPROPYL ALCOHOL + KETOSIS (better tolerated)

• MOT: Strong CNS depressant => metab to ACETONE => GI distress (no acidosis) => causes ketosis w/ +OSMOL GAP

• RX: Supportive

• MOT: bradycardia, hTN, coma, hypo/hyperglycemia

• RX: ABC-D + WBI for sustained release; fluids, atropine, glucagon–large doses, epinephrine, pacemaker, amrinone,

ballon pump; some dialyzable

CA-CHANNEL BLOCKERS (Verapamil is most dangerous!)

• MOT: bradycardia, hTN, coma, etc…~beta’s

• RX: ABC-D + fluids & atropine, Calcium, glucagon, catecholamines, amrinone

Toxicity:  based on amt of ELEMENTAL IRON:  ferrous gluconate 12%; ferrous sulfate 20%; ferrous fumarate 33%

10-20 mg/kg => GI sx

20-50mg/kg => systemic sx

> 100 mg/kg => FATAL

MOT:  affects enzyme systems => hypovolemia, vasodilation, myocardial depressant => inhibits aerobic metabolism =>     ANION GAP ACIDOSIS

RX:

1.  Ipecac (home)

2.  Gastric lavage & WBI reasonable

Activated charcoal DOES NOT work!

3.  Deferoxamine chelator (6h Fe level 350-500 mcg/dL) causes urine to be rose colored

• MOT: INH inhibits production of activated B6 (essential cofactor in GABA production) => ¯ GABA a major inhibitory NT => seizures/polyneuropathy => shock, hyperthermia, acidosis, hyperglycemia

RX w/ PYRIDOXINE DOSING

• Mass quantities = Gram per gram of INH

• Empiric: 5g or 70 mg/kg or 0.5 g/min (child)