classical toxicology rusyniak - acmt · • cox1&2 inhibition! fenamates! acetic acids!...
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• APAP • ASA • NSAIDS
• Methylxanthines (Theophylline, Theobromine, Caffeine) • CO and HBO
• Oldies and Goodies (Placidyl, Quaaludes)
APAP Hx
• The most widely used analgesic in the US
• Central COX2 Inhibition
• Released in 1955 as Tylenol elixir for children
• Metabolite of phenacetin
• 2011 FDA asks to limit acetaminophen in combo products
• 1982 seven people died from deliberate cyanide contamination
Phenacetin/Acetaminophen
Renal Papillary Necrosis
Unchanged in Urine
40-65% Glucuronidation
Sulfation 20-45%
Phase II
5%
CYP2E1, CYP3A4 CYP2E1, 1A2, 3A4
NAPQI
Mercapturic acid (nontoxic)
Glutathione
Necrosis
Biotransformation APAP
Phase I
NAPQI
• Highly reactive • Binds cellular proteins • Necrosis • Liver and kidneys contain the
majority of p450 • Injury occurs when glutathione
<30-50% of baseline
N
O
O
Central
Middle
Peripheral
Central
Middle
Peripheral
HA
PV BD CV
CV
Why centrilobular?
• Increased p450 • Decreased glutathione
Phases of Tox
• Phase I (0.5-24 hour) – nausea, anorexia, malaise
• Phase II (24-72 hour) – “quiescent” phase, LFT’s rise, RUQ pain
• Phase III (72-96 hour) – Hepatic necrosis, jaundice, encephalopathy
• Phase IV (4 days–2 weeks) - recovery
HN
O
HS
O
NH
NH2
HO
O OH
O
O
OH
HN
OHS
Glutathione
N-acetylcysteine
NAC
NAC Dosing • Oral
• 140 mg/kg load
• 70 mg/kg q 4 h x 72h
• IV
• 150 mg/kg load over 60 min
• 50 mg/kg over 4 hrs
• 100 mg/kg over 16 hrs
Keays R, Harrison PM, Wendon JA et al. Intravenous acetylcysteine in paractamol induced fulminant hepatic failure: A prospective controlled trial. BMJ. 1991, 303:1026-9.
50 APAP-Induced Hepatic Failure w/Poor Prognosis Presented 55 h (mean)
Survival 48% Cerebral Edema 40% Inotropic Support 48%
Survival 20% Cerebral Edema 68% Inotropic Support 80%
NAC Placebo
NAC works late
Prognosis
• Treatment within 10 hrs – Mortality <1%
Kings College Criteria
• Ph < 7.30 = Mortality ~80%*
• Encephalopathy + coagulopathic (INR>6.5) + Renal Failure (Cr>3.3) = Mortality ~80%*
Acetaminophen and the Fetus
• APAP crosses the placenta
• Important cause of fetal demise
• Prior to 16 weeks fetus has low p450 activity (protective)
• N-acetylcysteine crosses the placenta
Anaphalactoid reactions
• Dose dependent
• Cutaneous (most common)
• Transient flushing, urticaria, pruritus, edema
• Systemic (rare)
• Hypotension, wheezing
• Highest risk group brittle asthmatics
Uncommon APAP
• Altered mental status & metabolic acidosis – 5—Oxoproline
• Decreased glutathione synthetase activity
• Hemolytic Anemia – G6PD deficiency
• Isolated Renal Failure
• NAC – increases INR
Aspirin • Derived from Willow Bark
• Inhibits cyclooxygenase
http://chemistry.gravitywaves.com/CHE452/images/Aspirin.gif
Mechanism of Action
Increase renal blood flow
Platelet aggregation
Pain sensation
Inflammation
Fever
Increase GI mucous production and decrease acid secretion
Decreased Pain Decreased Fever Decreased inflammation Decreased clotting (MI) Bleeding disorders GI ulcers Renal Failure
Prostaglandins
Oxidative Phosphorylation
NADH
Complex I
e-
Complex IV
H+ H+ H+
H2O
ATPase
ATP
Ψ
Complex III
Complex IV
F1/Fo ATPase
½ O2 + 2H+
NAD+
Q
Cyt. C
Uncoupling
NADH
Complex I
e-
Complex IV
H+ H+ H+
H2O
ATPase
ATP
Ψ
Complex III
Complex IV
F1/Fo ATPase
ASA H+
ASA H+
ASA H+ ½ O2 + 2H+
NAD+
Q
Cyt. C
Michaelis-Menten Kinetics
For more pharmacokine0cs go to h4p://www.boomer.org/
Symptoms ASA concentrations 150 – Death/dL
100 – CNS, CV collapse, Non cardiogenic pulmonary edema
75 – Lethargy, worsening acidosis, fever
50 – Tinnitus, hyperventilation, metabolic acidosis
10 mg/dl – Antiplatelet, antipyretic
30 mg/dl – Anti-inflammatory, mild tinnitus, nausea
Chronic Salicylism
• Elderly • chronic pain
• More likely to present with fever, altered mental status, and pulmonary edema
• Poor correlation between levels and toxicity
Unrecognized Adult Salicylate Intoxication ���Anderson R, et al Annals of Internal Medicine 1976; 85:745
73 ASA Poisoned Adults
Group I N = 53 Inten0onal Inges0on Mean Age 32 Mortality 2%
Group II N= 20 Uninten0onal Mean age 53.4 Delayed Diagnosis 6-‐72 h Mortality 25%
Treatment • Alkalinization
• Increases urinary elimination/decrease tissue levels
• Elevated level (>35 mg/dL)
• Symptomatic
• Metabolic acidosis
• Renal clearance increased 20 fold at urine pH 8.0 vs pH 5.0
Rationale for alkalinization
Acidic condi0ons
Alkaline condi0ons
Salicylate pKa = 3.0 so it tends toward a HA (non-ionized) form under acidic conditions and in A-(ionized) form in alkaline conditions
HA
HA
HA
H+ + A-‐
H+ + A-‐
H+ + A-‐
Ion trapping
Renal tubular cell (pH 7.4) Urine pH 8.0
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
A-‐
HA H+
H+
H+ Buffered in alkaline environment
Unable to cross back into body
Dialysis
• Level > 80 mg/dL • Pulmonary edema • Neurologic deficits • Hemodynamic instability • Persistent acidosis
Uncommon ASA
• Coagulopathy
• Non-cardiogenic pulmonary edema
• Hyperglycemia followed by hypoglycemia
• Rhabdomyolysis
• Seizures
NSAIDS
• COX1&2 inhibition
Fenamates Acetic acids Propionic acids Oxicams COX-2 spec Mefenamic acid Indomethacin Ibuprofen Peroxicam Celecoxib
Ketorolac Naproxen Diclofenac Ketoprofen
Mechanism of Action Cell membrane Phospholipids
Arachadonic acid
Prostaglandins
Cyclo-oxygenase NSAID-reversible ASA-irreversible
Vasodilatation, erythema, edema, pain, fever, smooth muscle contraction, GI cytoprotection
Effect of Renal PG’s • Dilate afferent renal arterioles
• Increase GFR in low flow states • Release renin= aldosterone release
• K+ secretion into DT • Inhibit ADH effects on DT
• H2O diuresis • Inhibit Na+ resorption in LOH
• Natriuresis
General Toxicity
• GI (N/V) • Metabolic acidosis • CNS depression • Renal
• Dehydration + NSAID = Renal insufficiency • Hyperkalemia
NSAID Unique Toxicity
• Seizures – Proprionic acids, mefenamic acid
• Prolongation of PT – Proprionic acids, mefanamic, indomethacin
• Hepatitis – mefanamic acid, naproxen
Carbon Monoxide
• Number one cause of poisoning deaths
• Produced during incomplete combustion
• Endogenous (heme breakdown)
• 2nd messenger increases cGMP
CO physiology
• CO binds tightly with iron complex of Hemoglobin
• Binds similar to O2
• Dissociates 200 – 300 less readily
• Decrease arterial O2 content
Left – Leaves O2
Right – Releases O2
Clinical Effects Severity Neurologic Cardiac
Headache (releases NO)
Mild Nausea/Vomiting
Dizziness Tachycardia
Cognitive dysfunction Chest Pain
Somnolence Dyspnea/Tachypnea
Moderate Ataxia Tachycardia
Seizures Chest Pain/MI
Coma Arrhythmias
Severe CVA Hypotension
Death Cardiac collapse
Basal Ganglia Infarcts
Coric V, J Neurol Neurosurg Psychiatry. Aug 1998; 65(2): 245–247.
BG Infarctions • Watershed area few anastomoses
• Song et al, Acta Neuropathologica, 1983:232-8
• Predicts worse outcome
• Sawada et al, Lancet, April 12, 1980
• Parkinsonian syndrome
• Klawans et al, Arch Neurol,1982, 39:302-304
Delayed Neurologic Sequelae
Delayed Neurologic Sequelae
• 3%-20% of CO poisoned patients • Older age
• Hypotension
• Coma
• Loss of consciousness
Delayed Neurologic Sequelae • 4 days to 4 weeks after acute injury
• Cognitive and emotional deterioration
• Frontal release signs
• Diffuse demyelination of white matter
Autoimmune?
• Regional hypoperfusion
• Free radical formation
• Oxygen Free Radicals
• Changes in Myelin Basic Protein
• Immune Response
HBO for CO
• Hyperoxygenation
• Increased dissolved O2 (Boyle’s Law)
• Increased Elimination
• T1/2 from 300 min (1ATA/21%) – 20 min (2.8 ATA/100%)
• Vasoconstriction/ò Cerebral edema
• Inhibits Leukocyte activation
CO and pregnancy
• Fetal hemoglobin
• Elimination takes 3.5 times longer
• Increases risk of
• Fetal demise
• Lower birth weights
• No clear syndrome of congenital defects
Prolonged CO levels
Methylxanthines
Theophylline Caffeine Theobromine
Methylxanthines • Phosphodiesterase inhibitors
• Asthma, Neonatal apnea, Waking me up in the am
• Increase circulating catecholamines
• Elimination half-life ~8h (CYP1A2)
• Decreased by cimetidine, macrolides, antifungals
• Increased by smoking
• Enterohepatic circulation
• Multidose activated charcoal
Symptoms
• Refractory vomiting • Central
• Gastric Acid secretion
• Hypokalemia • Hypotension
• Beta-2 dilation • Ventricular fibrillation
GI
CV
Seizures • Decrease GABA
• Depress plasma pyridoxal 5'-phosphate
• Adenosine receptor (A1) antagonists
• Refractory
• Mortality 30%
• Acute Treatment: Benzo, Barbs, Pyridoxine
• Prophylaxis: (levels approach 100 mg/l)
• Phenobarb
Treatment
• MDAC
• Phenobarb prophylaxis
• Beta Blocker (?)
• PPI (refractory vomiting)
• Hemodialysis
• Levels ~100 mg/l Gal et al, 1984; JAMA. 251(23)
T1/2 =17 h
T1/2 =6 h
Levels
Acute 100 mg/l threshold for action
Olson et al, 1985; Ann EM, 3, 386-394
The S#*T that killed Elvis • Rx Drugs
• Morphine & Demerol • Methaqualone • Multiple Barbiturates • Valium • Placidyl • Ethinamate • Chlorpheniramine
Dr. Nichopoulus – Rx for 5,300 pills between Jan – Aug 1977
Ethchlorvynol
• Sedative-Hypnotic
• Chlorinated Tertiary alcohol
• Short duration of action
• Hepatically metabolized
• CNS and Cardiac depression
• Noncardiogenic Pulmonary Edema
Ethinamate • Valmid ® • Short acting sedative hypnotic
• Mechanism of action: unknown • CNS depression & coma • Death from respiratory arrest
Methaqualone • Ludes, Lemmons (714)
• Sedative-hypnotic
• CNS depression
• Respiratory arrest
