block 7 PHARM 3

immediate Management of a Poisoned Patient

ABCDE Airway patency Breathing Circulation Disability (CNS function) Examination of toxic syndrome (toxidrome) treat -Enhancement of Elimination -Antidotes

Clinically Relevant Pesticides Acetylcholinesterase inhibitors: Organochlorides (banned or limited use): Pyrethroids (low toxicity, replacing most pesticides): Others (banned):

Acetylcholinesterase inhibitors: •Organophosphates •Carbamates Organochlorides (banned or limited use): •E.g.: DDT, lindane Pyrethroids (low toxicity, replacing most pesticides): •E.g.: Permethrin Others (banned): •E.g.: Rotenone

Mercury - presentation

Acute •Inhalation: Shortness of breath, pneumonitis, and neuropsychiatric disturbances •Oral: Vomiting, hemorrhagic gastroenteritis, and renal failure Chronic •Fine hand tremor, memory loss, fatigue, anorexia, insomnia, mood changes, erethism and gingivostomatitis

Mercury - treatment

Acute •Supportive care •Chelation with dimercaprol (IM) or oral succimer •Hemodialysis may be required for acute renal failure Chronic •Remove exposure •Benefits of succimer are unclear •Do not use dimercaprol for chronic exposure oMay redistribute mercury to the CNS and cause more damage

Lead - presentation

Acute (uncommon today) •Initial: Headache, fatigue, abdominal pain and myalgias •Delayed: Encephalopathy, colic and anemia Chronic •Adult: Anorexia, fatigue, malaise, headache, irritability, depression, abdominal pain, myalgias, and anemia •Developing child: Neurocognitive deficits, growth retardation or developmental delay •Diagnose: Lead blood levels Organolead (very rare today) •Insomnia, delirium, hallucinations, tremor, convulsions and death

Copper - presenation

Acute poisoning •Vomiting, hematemesis, hypotension, black "tarry" feces, coma and jaundice Chronic exposure or Wilson's disease •Liver and kidney disease •Neuropsychiatric disorders •Copper deposits in the eye oKayser-Fleischer rings •Elevated levels of copper found in Alzheimer's patients

Arsenic poisoning - treatment

Acute poisoning: •GI decontamination if appropriate and supportive care •Use a chelating agent (preferably within hours of exposure) oDimercaprol (IM) •Chronic poisoning: •Remove exposure and provide nonspecific supportive care •Short-term use of oral chelating agents for patients with acute symptoms •Succimer

Arsenic poisoning - presentation

Acute poisoning: •Onset: Minutes to hours •Initial: Nausea, vomiting, diarrhea, abdominal pain, capillary damage, hypotension, shock and metabolic acidosis •Delayed: Cardiac dysfunction, pancytopenia and peripheral neuropathy Chronic •Fatigue, weight loss, anemia, GI complaints and peripheral neuropathy •Dermatologic lesions o"Raindrop" pattern ---Hyperpigmentation and hyperkeratosis ---Hands and feet

Enhancement of Elimination: Manipulation of Urinary pH

Alkalization of the urine can: - Facilitate excretion of weak acids, such as salicylates and phenobarbital •IV sodium bicarbonate (1-2 mEq/kg) over a 1-2 h period Ion trapping: •Based on the principle of the Henderson-Hasselbalch equation

Rodenticides - types

(Anticoagulants rodenticides) -Chlorophacinone -Diphacinone -Warfarin (Non-anticoagulant rodenticides) -Bromethalin, -Cholecalciferol -Zinc phosphide

Chemicals differ in their ability to produce death

(LD50)

Biogenic Amine Theory

(aka Monoamine Hypothesis) •Monoamine (NE, 5-HT, DA) deficiency in key brain locations leads to depression • Overproduction/excess = mania ↓ BDNF → ↓ neurotrophic support

Vasopressor Therapy

(dopamine, norepinephrine or phenylephrine)

Heavy Metals

-Arsenic -Copper -Iron -Lead -Mercury

Organophosphates (OPs) - treatment

1.Maintenance of patient's airways •Endotracheal intubation •Positive-pressure ventilation 2.Decontamination •Gastric lavage and AC if OP was ingested within the past hour •Washing exposed skin (soap and water, alcohol for residual pesticide) 3.Atropine (large doses, blocks acetylcholine receptors)> •Has little effect on muscle paralysis 4.Sodium bicarbonate and magnesium 5.Benzodiazepines: For seizures 6.Pralidoxime [2-PAM]: Regenerates AChE •Initiate within 36-72 hrs.>>(must give to help nicotinic)> REVERSES PARA •Not necessary for carbamate poisoning(just atropine)

Arsenic - MOA

Binds to thiols on enzymes and competes for phosphate binding in biological processes oInterferes with several enzymes, inhibits ATP production and causes oxidative stress •Arsine gas has a hemolytic effect Known carcinogen oAltering gene expression

•Leading cause of poisoning in the US

CO

Margin of Safety

Check notes for answers to the graph

Standard Saftey Margin

Check notes for answers to the graph

Therapeutic Index

Check notes for answers to the graph

Calcium-ethylenediaminetetraacetic acid (Ca-EDTA):

Chelating Agents Route: IV (oral administration would actually increase lead absorption) •Must be given as calcium disodium salt to prevent Ca2+ depletion •Indication: Severe lead poisoning in combination with dimercaprol •AE: Nephrotoxicity (monitor urinary function), zinc depletion

Penicillamine

Chelating Agents •Route: Oral water soluble derivative of penicillin •Indication: Copper and arsenic (after dimercaprol) poisoning •AE: Rash, pruritus, fever, nephrotoxicity and pancytopenia •CI: Penicillin allergy

Antidotes for Metals

Chelating Agents 1. Bind heavy metals forming a complex with the metal •Form covalent bond(s) with the metal 2. Prevents the metals from participating in toxic reactions 3. Enhance the metals excretion •May also redistribute to other tissues such as the brain (dimercaprol) 4. Most effective when given soon after acute intoxication 5. Limited effectiveness for treating chronic exposure

Dimercaprol

Chelating Agents: Antidotes for Metals Route: IM as 10% solution in peanut oil •ADME: Rapidly absorbed, metabolized by liver, and excreted by kidneys in 4-8 hrs. •Indication: Severe lead poisoning (not recommended for treating chronic exposures) •AE: Hypertension, tachycardia, NV, lacrimation, salivation, fever, thrombocytopenia and redistribution to the CNS

•Pit vipers (rattlesnakes, copperheads, and cottonmouths) - presenation and treatment

Crotalidae venom Signs and symptoms: •Local: Severe pain, bruising and swelling •Systemic: N&V, muscle fasciculations, paralysis and coagulopathy Treatment: •Keep calm and seek medical care •Antivenom is 99% effective if administered with 2 hours •Do NOT apply a tourniquet •Antidote: Antivenin (Crotalidae) polyvalent immune Fab (CroFab)

Muscarinic symptoms

DUMBELLS(increased acetylcholine) Diarrhea Urination Miosis Bradycardia Emesis Lacrimation Lethargy Salivation

Chronic radiation syndrome

Exposure over months/years •Low rate, natural repair competes with damage Usually, no overt symptoms •Due to low dose Symptoms proportional to cumulative exposure •Skin problems •Recurrent GI or neurological problems •Increased cancer

give how long for an antidepressant reponse

Give at least 4-8 wks for a response but may take longer to see full response

Descending order of effectiveness for various routes of exposure:

Inhalation > intraperitoneal > subcutaneous > intramuscular > intradermal > oral > dermal

Methanol - presentation

Initial: •CNS depression (similar to ethanol intoxication) and respiratory depression Delayed: •Metabolic acidosis, hyperventilation, altered mental status, blurred vision that can lead to possible blindness (6-30 hours)

Iron - presentation

Initial: •Necrotizing gastroenteritis, vomiting, abdominal pain, diarrhea (1-6 hours) •Shock, lethargy, dyspnea, coma, metabolic acidosis, bloody vomit and bloody diarrhea (6-24 hours) Delayed: •Liver dysfunction and failure (2-5 days)

Ethylene glycol - presentation

Initial: •Transient excitation followed by CNS depression, similar to ethanol intoxication Delayed: •Metabolic acidosis (4-12 hours); renal failure (>6 hours) •Oxalate crystals in the urine

Iron - MOA

Local effect on GI tract •Irritation causes hemorrhage Systemic effect of excessive iron load •Mitochondrial toxicity oDisrupt electron transport system oReduction in oxidative phosphorylation

Decontamination: Activated Charcoal (AC)

Most effective when administered within the first few hours (ideally within the 1st hour) Dosage: •Children 1-12 years old: 25-50 gms. •Adults: 25-100 gms Contraindications: •GI tract in not intact •GI obstruction •Airway is not protected (loss of gag reflex)

what is the toxic metabolite for Acteomenophine

N-acetyl-para-benzoquinone imine (NAPQI)

Cyanide (CN-) - treatment

NITRATES 1st line 1. Cyanide antidote kit: Amyl nitrite (inhalant), sodium nitrite (IV) and sodium thiosulfate (IV) •MOA: oHigh doses of nitrites convert hemoglobin to methemoglobin; which pulls the CN- off cytochrome oxidase to form cyanmethemoglobin oAdministration of sodium thiosulfate converts the cyanmethemoglobin to thiocyanate ion (SCN-); a less toxic product that can be excreted 2.Hydroxocobalamin (IV) is an alternative antidote: •MOA: Directly binds with CN- to form cyanocobalamin •Limited availability Cost ( <$1000)

Modafinil, Armodafinil

Narcolepsy-related EDS in adult patients •stimulation of hypocretin-containing neurons in the hypothalamus or through inhibition of dopamine reuptake; can increase levels of dopamine in the nucleus accumbens

No Observed Adverse Effect Level (NOAEL): vs Lowest Observed Adverse Effect Level (LOAEL):

No Observed Adverse Effect Level (NOAEL): •Highest dose with NO statistically significant increase in negative health outcomes Lowest Observed Adverse Effect Level (LOAEL): •Lowest dose that results in a statistically significant increase in toxicity

Decontamination: Activated Charcoal (AC) - not reccomended

Not recommended: Iron, lead, lithium, simple alcohols, corrosives, and hydrocarbons Contraindications: •GI tract in not intact •GI obstruction •Airway is not protected (loss of gag reflex)

Fluvoxamine - indication

OCD only

Garlic like odor is characteristic

Organophosphate Poisoning

acetaminophen - MOA

Oxidation by CYP2E1 forms N-acetyl-p-benzoquinoneimine (NAPQI) oGlutathione depletion oMitochondrial damage •Chronic alcohol use will increase the toxicity by inducing CYP2E1

Decontamination: Whole Bowel Irrigation

Polyethylene glycol (PEG) electrolyte solutions can be used to decontaminate the GI tract of ingested toxins Used for acute poisoning by •Drugs ingested several hours ago ---Drug smugglers •Sustained-release or enteric coated drugs •Toxic ingestion of heavy metals that are not readily adsorbed by AC •Iron, lithium, and potassium Contraindications: •Perforated bowel •GI obstruction •GI bleeding

•1st line for mild-moderate depression

Psychotherapy •Usually provided over 2-4 months •Effects additive with pharmacotherapy

Cyanide (CN-) - presentation

Shortness of breath, agitation, tachycardia, seizures, coma and hypotension - Cytpchrome C

jellyfish - presentation and treatment

Toxin: Cnidarian venom Signs and symptoms: •Erythema, burning pain, hypersensitivity and inflammation Treatment: •Rinse area with sea water or vinegar •Soak in hot water or use ice packs •Use hydrocortisone or diphenhydramine for itching --- SAME as lion fish

Black widow - presentation and treatment

Toxin: Latrotoxin - causes pore formation in presynaptic nerve terminals increasing intracellular Ca2+ and neurotransmitter release Signs and symptoms: •Muscle pain, muscle spasms, sweating, tachycardia, and abdominal pains Treatment: •Supportive care (anti-inflammatory, analgesics and antispasmodics) •Antidote: Black widow antivenin

Lionfish - presentation and treatment

Toxin: Pterois venom Signs and symptoms: •Extreme pain, N&V, fever, dizziness, headache, numbness, tingling and sweating Treatment: •Rinse area with sea water or vinegar •Soak in hot water or use ice packs •Use hydrocortisone or diphenhydramine for itching --- SAME as jelly

region of homeostasis

U-Shape Vitamin Dose-Response Curves

Arsenic poisoning - labs

Urine and blood can be tested for arsenic concertation •Spot urine test can be used in an emergency situation Hair and nail testing •Suitable for less than toxic concentrations

most common cause of acute liver failure

acetaminophen

LEAD - MOA

adverse effects on the developing CNS Myriad of adverse biological effects •Inhibits enzymes oEspecially those necessary for heme synthesis Interferes with cation function •Calcium, zinc and iron Interferes with neurotransmitter release •Generates reactive oxygen species •Alters gene expression •Disrupts cell membrane integrity •Interferes with bone and teeth metabolism

In emergency situations, there are no specific timing recommendations; instead, specimens should be collected

as soon as possible.

Hemodialysis

blood filtration across a semipermeable membrane using counter current flow between the blood and the dialysate Severe cases of toxication intoxication is prolonged such as extended release formulation of drugs •Methanol and ethylene glycol poisoning •Lithium •Salicylates •Ethanol •Theophylline Useful for removing water soluble drugs:

Decontamination: Gastric Lavage

considered for potentially life-threatening ingestions when: •Ingestion occurred within the past 1 hour •The substance is not adsorbed by activated charcoal (AC) •Toxicants that remain in the stomach for a long time or that form large bezoars (e.g., bone meal, blood meal, large wads of aspirin, prenatal iron tablets) Not recommended: Corrosive agent (eg; lye, caustics, H2O2) or a hydrocarbon

Acute radiation syndrome - Treatment

decontaminate, then •Supportive, blood transfusions, antibiotics prn, bone marrow transfusion 1. Potassium iodide (KI) - stat post-exposure •Protects thyroid - blocks abs of radioactive iodine 2. Prussian Blue - Chelates radioactive cesium, thallium 3. DTPA - Chelates radioactive plutonium, americium, curium Fractionation of dose (radiotherapy) •Divide larger dose - allow recovery time, less cell death -Mortality rate (days to weeks) 100% with exposures > 8 Gy

Rodenticides MOA

disrupting the normal blood clotting or coagulation process so that dosed individuals or animals suffer from uncontrolled bleeding or hemorrhage.

xenobiotics

drugs •Chemicals: Drugs (xenobiotics), industrial chemicals, pesticides, food additives, household products, and personal care items •Biological agents (toxins): Insect stings, poisonous mushrooms and plants, venomous snakes, and aquatic life •Physical agents: Radiation and noise

Quantal dose-response relationship

effect of various doses of a drug on a population

Decontamination: Cathartics

magnesium citrate and sorbitol •GI elimination of the poison •Elimination of poison-AC complex Rarely used and when used: •They should be administered only once and only when bowel sounds are present

The relationship between side effects (SE), adverse effects (AE), and toxic effects (TE) is dependent on ______________

margin of safety •MOS = LD1/ED99

Hemoperfusion

passing large volumes of blood over an adsorbent substance •Resins •Activated carbon Useful for removing lipid soluble drugs: •Barbiturates •Hypnotics and sedatives •Digitalis

•BW on ALL ANTIDEPRESSANTS:

suicidal thought and behavior •Increased risk in children, adolescents and young adults (<24 yo) in short term studies •Decreased risk in ≥ 65 yo •MONITOR ALL PATIENTS

Antidotes

toxin specific treatments - Acute care hospitals are required to stock 24 antidotes that can be used for treatment of common causes of poisonings --- must identify the toxin

if not doing compressions or ventillating what is the position the pt should be in for poisens

§While awaiting transport, placing the patient on the left side may slow absorption of a drug from the GI tract Highest priority: establish adequate oxygenation and circulation

Toxicodynamics

•"what the toxicant does to the body" the result of the interaction of the biologically effective dose of active form of the toxicant with a molecular target (M)

Major Depressive Disorder (MDD) - symptoms

•(SIG E CAPS) •Sleep disorder (increased or decreased) •*Interest deficit (anhedonia) •Guilt (worthlessness, hopelessness, regret) •Energy deficit •Concentration deficit •Appetite disorder (increased or decreased) •Psychomotor retardation or agitation •Suicidality | *Depressed mood

Acetaminophen poisoning - staging

•1. First 24 hours - asymptomatic or have minimal and nonspecific clinical effects of toxicity, such as anorexia, nausea, vomiting, and malaise. •2. Days 2 to 3 - nausea and vomiting improve, develop right upper quadrant pain (hepatotoxicity) and elevated transaminases •3. Days 3 to 4 - fulminant hepatic failure; metabolic acidosis, coagulopathy, renal failure, encephalopathy •4. Next 2 weeks - recovery, with complete resolution after 1 to 3 months

daily upper limit dose for acetaminophen

•< 4g/24 hours

tricyclic antidepressant - lethal does

•>10mg/kg is potentially life threatening

ECT therapy eligibility

•A rapid response is needed (e.g., severe suicidality, nutritional deficiency, catatonic symptoms) •Risks > benefit of other treatments •A history of refractory symptoms with 2 antidepressant trials •History of good response to ECT Patient expresses a preference for ECT

•Acute exposure ? •Subacute exposure ? •Subchronic exposure ? •Chronic exposure ?

•Acute exposure is defined as exposure to a toxicant for less than 24 hours •Subacute exposure refers to repeated exposure to a toxicant for 1 month or less •Subchronic exposure refers to repeated exposure to a toxicant for up to 3 months •Chronic exposure refers to repeated exposure to a toxicant for more than 3 months

Copper - treatment

•Acute: Oral penicillamine Chronic: •Limit copper in the diet and use oral penicillamine •Use the chelating agent trientine as an alternate to penicillamine oMay be less toxic

Acetaminophen Overdose •Adult: single acute ingestion of________ is potentially toxic •Pediatric: single ingestion of ____________ is potentially toxic

•Adult: single acute ingestion of 7.5-10g is potentially toxic •Pediatric: single ingestion of 150-200 mg/kg is potentially toxic

Hemodialysis risks

•Anticoagulation •Loss of blood elements •Fluid/electrolyte disturbances •Infection

Salicylates - MOA toxic

•Aspirin (Acetylsalicylic acid) •Uncoupling of oxidative phosphorylation •First-order kinetics at low doses •Zero-order kinetics at higher doses

Mercury - MOA

•Binds to thiol groups on enzymes inhibiting their function and disrupts cell membrane integrity

Acute radiation syndrome

•Direct whole body exposure to high dose for short duration Prodrome •n/v, HA, fatigue, fever, skin reddening •Usually w/in 24 hrs., may last several months Triad of acute symptoms •GI - n/v •Hematologic - aplastic anemia → pancytopenia → anemia, infection, bleeding; •Neurological - dizziness, HA, decreased consciousness

Decontamination - GI

•Emesis(out of favor) •Gastric lavage •Activated charcoal •Whole bowel irrigation •Cathartics

Salicylates toxic - treatment

•Gastric lavage, AC therapy, and whole bowel irrigation if necessary and appropriate •IV fluids for dehydration •Moderate intoxication: Sodium bicarbonate (IV) to alkalinize the urine •Severe intoxication (severe acidosis, coma): Hemodialysis

Salicylates toxic - presentation

•Initial: Hyperventilation and respiratory alkalosis •Followed by: Metabolic acidosis, hyperthermia, vomiting, dehydration, hypokalemia, seizures and coma

Signs and symptoms of OP poisoning

•Initial: Miosis, salivation, sweating, bronchoconstriction, vomiting, diarrhea, muscle fasciculations, and paralysis •CNS: Cognitive disturbance, seizure, coma •Onset: Usually within 6 hrs. •Fastest with inhalation and slowest with skin contact •Death: Usually occurs due to respiratory failure •Can occur in 5 mins. - 24 hrs. if untreated (depending on the route of exposure)

Organophosphates •Intermediate syndrome ? •Extrapyramidal symptoms ? •Neuropsychiatric effects (? •Delayed chronic neuropathy ?

•Intermediate syndrome (1-3 days) •Extrapyramidal symptoms (1-7 days) •Neuropsychiatric effects (starts weeks to months after recovery and last for years) ---confusion, lethargy, memory impairment, headache, depression •Delayed chronic neuropathy (starts 1-5 weeks after recovery and may be permanent) ----muscle weakness •Phosphorylation of neuropathy target esterase •Organophosphate-induced delayed neuropathy (OPIDN)>phospholipase domain-containing protein 6 (PNPLA6)

Hemodialysis - what are the properties of drugs that it removes

•Low molecular weight •Not tightly protein bound, •Not highly distributed to tissue (low Vd)

Enhancement of Elimination

•Multiple-dose AC •Diuresis •Hemoperfusion •Hemodialysis Manipulation of urinary Ph •Alkalization •Acidification

acetaminophen - treatment

•N-acetylcysteine

•Other indications for specific agents •Escitalopram - •Fluoxetine •Fluvoxamine - •Paroxetine - •Sertraline - --- said we dont need to know `

•Other indications for specific agents •Escitalopram - GAD •Fluoxetine - Bulimia nervosa, depressed bipolar disorder (w/ olanzapine)OCD, panic disorder, PMDD •Fluvoxamine - OCD only •Paroxetine - GAD, OCD, panic disorder, PTSD, PMDD, social phobia •Sertraline - OCD, panic disorder, PTSD, PMDD, social phobia

Organophosphates

•Pesticides: dichlorvos, malathion, mevinphos, •parathion, and phosmet •Nerve gas: sarin and VX •Inhalation, oral, and absorption through the skin MOA •OPs target acetylcholinesterase (AChE) •Forms a strong bond which after ageing (72 hrs.) is irreversible> cause accumulation of acetylcholine in synapses throughout the body

tricyclic antidepressant - EKG

•QRS widens due to fast sodium channel blockade •>100ms is predictive of seizures •>160ms is predictive of ventricular tachycardia

Lead - treatment

•Remove from exposure •Supportive care oCorticosteroids, mannitol (cerebral edema) oAntiepileptics (seizures) Chelating agents •Edetate calcium disodium (Ca-EDTA, IV infusion) or ----Dimercaprol (IM) followed by Ca-EDTA and Dimercaprol •Parenteral agents < 5 days convert to oral succimer if needed If asymptomatic - studies have shown no help when treating vs not

Rumack-Matthew Nomogram

•Requires a 4-hour acetaminophen level --- treatment line slightly below> treat them when it hits this line(under this line they do not need external treatment they will clear it themselves)

Deferoxamine:

•Route: Given IV or IM, oral administration may increase iron absorption •MOA: Binds free iron, loosely binds iron bound to transport proteins but has no affinity for binding iron complexed in cytochromes and heme •Turns urine orange-red color •AE: Hypotension, flushing, abdominal discomfort and rash •Acute respiratory distress syndrome (ARDS) may occur with administration > 24 hours --- dont give longer than that???

Succimer

•Route: Oral water soluble analog of dimercaprol •ADME: t1/2 ~ 48 hrs. •Indication: Lead poisoning (less severe), arsenic, and mercury •AE: NV and diarrhea

Reference Dose (RfD):

•Starting point for regulating human exposure •RfD = NOAEL/(10 for each source of uncertainty) •E.g..: Interspecies variability (human to animal) •Interindividual variability (human to human) •RfD = NOAEL/100

Methanol - MOA

•Toxic metabolites: Formic acid and formaldehyde lead to metabolic acidosis, coma and blindness

Iron - treatment

•Whole bowel irrigation •Intravenous deferoxamine (iron-chelating agent) ----Produces a orange-red colored urine ----Use of deferoxamine > 24 hours is associated with an increase in ARDS •Note: activated charcoal will not help

Absorbed dose of radiatioin

•gray (Gy) Health risk/effects = sievert (Sv) •Based on strength of radiation