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