classical toxicology rusyniak - acmt · • cox1&2 inhibition! fenamates! acetic acids!...

Classic Toxicology Dan Rusyniak

drusynia@iu.edu

You know this already

•  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