General Principles of Toxicology
|Scope of Medical Toxicology: Occupational (Chemicals), Environmental (agricultural/air), Clinical (drug toxicity, accidental, intentional)
plants, pharmaceuticals, etc)
|MECHANISMS OF TOXICITY|
|1. Receptor Interactions
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)
|Routes of exposure: Oral, inhalation, dermal (fastest-slowest)
|DOSE EFFECTS & MEASURES OF TOXICITY|
TI = TD50/ED50 or TI = LD50/ED50
TD or LD =Toxic/Lethal Dose
ED = Effective Dose
|Margin of Safety:
MOS = TD1/ED99 or MOS = LD1/ED99
MOS > 1 = Very Safe Drug (Drug A)
|NOELs & MOS for Non-Drugs:
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)
|Acceptable Daily Intake:
ADI = [NOEL](acute/chronic) /(10hv x 10id 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
|Threshold Limit Values:
|TOXICATION or ACTIVATION MECHANISMS|
1. Phase I (P450 or PGH synthase catalyzed biotrans) => “Toxication” processes
2. Phase II (sulfate or glucuronide conjugation) => “inactivation” and elimination
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)
|DETOXICATION of REACTIVE OXYGEN & FREE RADICALS|
Summary: SOD + GPO(or CAT) => O2* > 2H2O
|1. Covalent Modification of proteins: loss of enz or protein fxn, hapten formation
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.
|1. Tissue repair
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
|RISK ASSESSMENT & MGMT|
|INTRODUCTION: Air Pollutants, Gases, Vapors|
|Five Major Pollutants: CO (52%), sulfur oxides, volatile hydrocarbons, particulate matter, nitrogen oxides.
|RESPIRATORY TRACT EXPOSURES|
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” are ~ 200 chemicals by EPA => pollutants (3 major classes)
1. “volatile organic compounds”
3. “reactive chemicals”
Symtoms include: ENT irritation, HA, ¯ attn span, nasal congestion, dyspnea, nausea, dry skin, nose bleeds
|MOST FREQUENT CAUSE OF DEATH FROM POISONING
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)
a. competes w/ O2 for Hb binding sites => functional anemia
b. Left shift of Hb curve => less cooperativity, impairs O2 unloading to peripheral tissues
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
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.
Met-Hb => ¯ O2 binding to Hb (like CO) and Hb curve shifts to LEFT => umpaired Unloading => tissue hypoxia
**NOTE: methylene blue => false, transient, decrease in O2 saturation by measured by pulse Ox.
|Source: electroplating/metal processing industries; byproduct of nitroprusside (vasodilator in OR/ICU) metabolism; combustion of plastics containing nitrogen.
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
|H2S (Hydrogen Sulfide)|
|Source: natural sources & petrochemical industry.
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.
PESTICIDES, SOLVENTS, INDUSTRIAL CHEMICALS
|All toxic to insects, hu, other animals by interfering w/ Neurotransmission.
I. ORGANOCHLORINE: DDT, Methoxychlor, Aldrin, Dieldrin, Lindane…
-low cost, low volatility, lipid sol, chem stable.
-accumulate in fat depots (very lipophilic)
-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
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
|I. CHLOROPHENOXY COMPOUNDS (2,4-D; 2,4,5-T)
-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)
|COMMON SOLVENTS & VAPORS|
|I. ALIPHATIC HYDROCARBONS: Methane, ethane, propane, butane, hexane…
-“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
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
|POLY-CHLORINATED & POLY-HYDROXYLATED AROMATIC HYDROCARBONS|
|I. POLYCHLORINATED & POLYBROMINATED BIPHENYLS: PCB, PBB
-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.
-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.
HEAVY METALS & CHELATORS
|Exposures: acute or chronic
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)
|Lead has no est. physiological function in hu or animals => All actions considered TOXIC!!
RX: 1) ABC Support; 2) Diazepam for seizures; 3) Chelate q1wk EDTA and dimercaprol (IV); penicillamine/succimer (po) esp good for children.
|Chemistry: Elemental Hg (liq/vapor); Ionized Hg in hu & mammals (Hg II); methylmercury (organic mercurial)-Hu ingest this form of organoHg made by bacteria via diet.
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 t1/2 = 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 t1/2 = 50-100 days . CH3Hg can covalently bind cysteine => ~met => can traverse capillaries =>
CNS/placenta => SEVERE NEUROLOGICAL TOXICITIES in both ADULTS & IN UTERO!!
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.
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!
|EXPOSURE: Natural substance in earth’s crust & groundwater (well water); Industrial & agricultural chemicals (herbicides & insecticides); industrial accidents release arsine gas (AsH3)
ABSORPTION: Resp tract & GI tract
MOT (two mechanisms):
1. Arsenate (AsO4) substitutes for Pi 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)
RX: 1) decontamination 2) dimercaprol (IM) followed by longer times of 3) penicillamine (po)
Remember to watch for hypovolemic shock.
|Exposure: Ni-Cd rechargeable batteries; byproduct of Zn mining
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
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.
1) Decontamination 2) ABC esp respiratory support 3) EDTA (not clear how effective)
|Sources/Exposures: Normal diet (tox uncommon in normal individuals). Special considerations:
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.
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.
|DEFEROXAMINE (IV only)
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
|EDETATE aka Calcium EDTA (IV only)
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)
ACUTE POISONINGS & OVERDOSES
|EPIDEMIOLOGY OF POISONINGS|
|MOST COMMON EXPOSURES & CAUSES OF DEATHS|
|CHILD (Age < 6)
Exposure: Cosmetics, cleaning products, analgesics, plants, cough/cold preps
Deaths: CO (most common across all toxicants and ages!!), Analgesics, Fe, cleaning products, CV drugs,
ADOLESCENT (Age 13-17)
Exposure: Analgesics, cough/cold preps, cleaning products, envenomations
Deaths: Hydrocarbons, antidepressants, analgesics, CV drugs
Exposure: analgesics, cleaning products, bites/envenomations, sedative-hypnotics, antipsychotics, antidepressants
Deaths: Analgesics, antidepressants, stimulants/st drugs, CV drugs, sedative-hypnotics, antipsychotics, alcohols,
|EVALUATION OF POTENTIAL POISONING|
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?
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)
|ANTICHOLINERGIC (…as a…) or SLUDS
|TREATMENT OF POISONS|
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
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)
USE: drug = low mw < 500 daltons, water sol, low Vd (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
|ACETAMINOPHEN (APAP) TOXICITY|
|General: Most common ingestion; APAP metab by sulfation/glucuronidation in liver; 5% Therapeutic dose and in OD dose oxidized by CYP-450 (liver) => reactive intermediate NAPQI => usually conjugated by glutathione and excreted in urine
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
|General: Common ingestion too & in many combination meds; approx. 150 mg/kg acute is toxic; ASA tabs- 65-500mg; Pepto- 8.7 mg/ml salicylate; Oil of Wintergreen-1.4 gm/ml methyl salicylate–VERY TOXIC!!
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!
|METHANOL + ANION GAP ACIDOSIS
Source: solvent, windshield washer fluid, de-icers, canned heat
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.
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
4. 4-MP (4-methylpyrazole)- blocks AlcDH
ETHYLENE GLYCOL + ANION GAP ACIDOSIS
ISOPROPYL ALCOHOL + KETOSIS (better tolerated)
|BETA_BLOCKERS (Propranolol is very DANGEROUS!!)
ballon pump; some dialyzable
CA-CHANNEL BLOCKERS (Verapamil is most dangerous!)
|General: common and mistaken for candy; most tabs = 65 mg ele.Fe
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
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
|INH, PYRIDOXINE, & GABA|
RX w/ PYRIDOXINE DOSING
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