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====== Propanil ======

Dr Darren Roberts

===== SUBSTANCES INCLUDED =====

Propanil (3,4-dichloropropioanilide) is a selective acylanilide herbicide used in Paddy cultivation in parts of Asia and the Americas. Commercial products contain 36-48% propanil. It is co-formulated with surfactants and contains some impurities which may contribute to the toxicity.

===== OVERVIEW =====

There is limited information about the clinical toxicology of propanil. [[:wikitox:methaemoglobinaemia|Methaemoglobinaemia]] (metHb) appears to be the most important manifestation with acute poisoning. This produces central nervous system depression, hypotension, respiratory distress, metabolic acidosis and death. MetHb from severe propanil poisoning is usually treated with oxygen and methylene blue and/or exchange transfusion. N-acetylcysteine, ascorbic acid and other antioxidants may be trialled in cases of severe toxicity, particularly if unresponsive to standard treatments, although there is no clinical data to support these treatments.

===== MECHANISM OF TOXIC EFFECTS =====

Propanil (3,4-dichloropropioanilide) is hydrolysed //in vivo// to 3,4-dichloroaniline which is then metabolised to other compounds, including 3,4-dichlorophenylhydroxylamine. //In vitro// data suggest that toxicity is induced primarily by the 3,4-dichlorophenylhydroxylamine metabolite. This compound induces cellular dysfunction through formation of free radicals and depletion of intracellular glutathione stores. Interspecies differences in toxicity to propanil are probably due to variability in the activity of bioactivation and detoxification enzymes.

The major apparent biochemical effect is the production of metHb by oxidation of the ferrous haem (Fe<sup>2+</sup> ) in erythrocytes to the ferric state (Fe<sup>3+</sup> ). The effect of inherited disorders of erythrocytes (eg. glucose-6-phosphate dehydrogenase deficiency (G6PD)) predisposing metHb has not been reported. But severe metHb has been reported in acute propanil poisoning where G6PD deficiency was not present.

MetHb is unable to bind and transport oxygen in the vascular system, inducing a relative hypoxia at the tissue level, despite adequate oxygen and ventilation. Clinically the cardiovascular, central nervous and respiratory systems are the main organs affected, although any organ with a high metabolic activity is likely to be susceptible.

Of the few cases of acute propanil poisoning where metHb has been quantified, clinical toxicity was more severe than noted in patients with similar metHb concentrations from other poisons. Therefore, it is possible that propanil may also induce toxicity by mechanisms other than metHb.


===== KINETICS IN OVERDOSE =====

==== Absorption ====

No human data are available, but sufficient propanil is absorbed with oral exposures to produce severe toxicity and death.

==== Distribution ====

No human data are available.

==== Metabolism - Elimination ====

Propanil is hydrolysed to 3,4-dichloroaniline and oxidised predominantly in the liver by CYP450 to toxic metabolites, in particular 3,4-dichlorophenylhydroxylamine. On the basis of clinical observations, propanil or its metabolites appear to have a long plasma half-life given that the clinical effects of metHb are prolonged for a number of days.

===== CLINICAL EFFECTS =====

Clinical effects are generally noted within six hours of ingestion of propanil, the principle effect being metHb. When poisoning is severe there may be an altered level of consciousness, lactic acidosis, hypotension and hypoventilation secondary to tissue hypoxia. Mortality approaches 12% in some series, although this may vary depending on resource availability.

==== Gastrointestinal effects ====

Nausea, vomiting and diarrhoea occur but are not a prominent feature.

==== Pulmonary effects ====

Patients may complain of dyspnoea. Hyperventilation secondary to metabolic acidosis may be noted initially, which is followed by hypoventilation and hypoxaemia with severe poisoning.

==== Cardiac effects ====

Tachycardia, hypotension and ischaemic changes on ECG may occur with severe poisoning.

==== Central nervous system effects ====

Headache, dizziness, syncope, confusion, sedation, coma and seizures may occur.

==== Metabolic effects ====

In seriously poisoned patients a metabolic acidosis with an elevated lactate is frequent.

==== Other effects ====

Data are limited regarding other abnormalities. Patients with mild-moderate poisoning may complain of fatigue. With severe poisoning there is multisystem dysfunction (eg. oliguria, ischaemic hepatitis) due to tissue hypoxia. Anaemia has also been noted, most probably due to haemolysis.

===== DETERMINATION OF SEVERITY =====

The assessment of severity of toxicity is determined by clinical grading of toxicity.

==== Ingested dose ====

No data are available on toxic dose of oral propanil in humans. The reported animal LD50 ~1400mg/kg (rat) suggests low toxicity, although inter-species differences in the degree of propanil-induced metHb production have been noted. The high case fatality ratio in humans (approaching 12%) suggests that all oral ingestions should be treated as potentially severe.

{{:wikitox:methb_blood_propanil.png}}Clinical evidence of cyanosis, with ‘chocolate brown’ coloured blood on white filter paper is suggestive of severe propanil poisoning. This can be quantiated at the bedside using a simple bedside color chart which can be downloaded at [[:wikitox:methaemoglobinaemia|Methaemoglobinaemia]].

|**Asymptomatic** |No abnormalities on physical or laboratory examination.|
|**Mild** |Mild gastrointestinal symptoms with stable vital signs and no other organ involvement. Normal lactate on arterial blood gases.|
|**Moderate** |MetHb <20% and/or mild acidosis (pH>7.2)Hypotension responsive to intravenous fluids \\ Sedation|
|**Severe** |MetHb>20%Severe metabolic acidosis (pH<7.2)Hypoventilation requiring intubationOliguria \\ Hypotension unresponsive to fluid loading and/or ischaemic changes on ECGCardiac arrest \\ Coma, seizures \\ Death|

\\


===== INVESTIGATIONS =====

==== Biochemistry ====

Arterial blood gases (including metHb and lactate measurements) are the most important investigations for diagnosis and monitoring. In the absence of resources to directly measure metHb concentrations, the diagnosis is suspected when low saturations are noted on pulse oximetry despite a normal or elevated pO2 on arterial blood gas measurements. Elevations in metHb are noted within a few hours of poisoning and may continue to rise beyond 6h.

Once metHb is diagnosed, serial venous lactate measurements may be useful to monitor the course of poisoning (including response to antidotes). Serum electrolytes, creatinine, urea, liver function tests, cardiac enzymes and glucose should also be measured.

==== Pulse oximetry ====

Pulse oximetry is an unreliable investigation for monitoring metHb.

==== ECG ====

All patients with significant metHb or acidaemia should have a baseline ECG to detect silent ischaemia. Ischaemic changes may be focal due to underlying coronary vessel disease, or generalised with ST segment and/or T wave changes.

==== Imaging ====

Chest X-ray should be performed in any patient with abnormal gas exchange or clinical signs of pulmonary involvement. Transfusion-associated Acute Lung Injury (TRALI) may occur following multiple episodes of exchange transfusion (see below –elimination enhancement).

===== TREATMENT =====

==== Supportive ====

Hypotension can develop several hours after ingestion which may be corrected with intravenous fluids. Reversal of significant metHb levels remains a priority and cardiac monitoring should be available. Normoglycaemia should be ensured since adequate glucose concentrations are required by the reducing enzymes present in erythrocytes and the antidote methylene blue.

==== Respiratory function ====

Respiratory function should be monitored closely. Supplemental oxygen should be given to all symptomatic patients. Intubation and assisted ventilation should be performed on patients with significant CNS depression or hypercarbia.

==== Antidotes ====

Although no clinical studies have assessed the efficacy of antidotes in acute propanil poisoning, [[:wikitox:methaemoglobinaemia_teaching_material|methylene blue]] is commonly used first line. //In vitro// studies with metHb by other poisons suggest that N-acetylcysteine (NAC) or ascorbic acid (Vitamin C) may also reverse metHb, although very high doses were required, questioning the clinical practicalities of this treatment. Nevertheless, NAC and/or ascorbic acid may be considered in patients with severe propanil poisoning unresponsive to methylene blue, or where methylene blue is unavailable, in an attempt to preserve the patient’s life.

**Methylene blue (methylthionium chloride)** \\
The standard antidote for reversal of metHb is methylene blue. Methylene blue is currently considered the first line antidote in acute symptomatic propanil poisoning, although there are no controlled studies assessing the efficacy of methylene blue in the treatment of propanil poisoning.

Given that propanil appears to produce prolonged and recurrent MetHb, methylene blue may be more effective if administered as an infusion following the initial bolus. [cross reference to dapsone?]. The following doses are recommended:

__Moderate poisoning__: 1mg/kg methylene blue as a bolus injection over 1 minute. MetHb should be reassessed after one hour, and the methylene blue can be repeated if toxicity persists.\\
__Severe poisoning__: 2mg/kg methylene blue as a bolus injection over 1 minute followed by an infusion of 10 mg/hour for 10 hours. The metHb concentration should be reassessed within one hour of commencement of the infusion. If metHb > 20%, a further bolus injection of 2 mg/kg should be given & the infusion rate increased by 50%. If metHb < 20% then the infusion is maintained at the current rate.

The maximum recommended daily dose of methylene blue is 7mg/kg, but toxicity has also been reported following doses of 4mg/kg. Adverse effects from methylene blue include nausea, vomiting, diaphoresis, burning sensation of the mouth and fingers and abdominal pain. Severe toxicity is also reported, including hypotension, exacerbation of MetHb and haemolysis.

Methylene blue should not be administered to patients with G6PD deficiency because it is minimally effective, may exacerbate the degree of MetHb and also induce haemolysis.

**N-acetylcysteine** \\
N-acetylcysteine (NAC) is an antioxidant which donates sulfhydryl groups, replacing depleted intracellular glutathione stores [cross reference to mechanism of NAC in paracetamol poisoning]. //In vitro// data supports the use of NAC in the management of acute propanil poisoning, although there are no clinical data to support this. Empirically, it is reasonable to trial NAC in patients with moderate to severe propanil poisoning that is refractory to methylene blue, or where methylene blue is unavailable.

In the absence of formal dose-response studies, it is reasonable to administer NAC at a dose similar to that used for [[:wikitox:2.1.1.1_acetaminophen|paracetamol poisoning]]. Given the potential for hypotension and respiratory distress with severe propanil poisoning, it is recommended that the initial loading dose is administered over a longer period, to minimise the effects of a concurrent anaphylactoid reaction, as follows:

  * 150mg/kg NAC over 4h, then
  * 50mg/kg NAC over 4h, then
  * 100mg/kg NAC over 16h. This infusion should be repeated until the patient has recovered.

**Ascorbic acid (Vitamin C)** \\ Ascorbic acid (Vitamin C) is an antioxidant that scavenges free radicals //in vivo//, minimising the formation of metHb. //In vitro//  data supports the use of ascorbic acid in the management of acute propanil poisoning, although there is no clinical data to support this. Oral ascorbic acid has been administered to such patients when methylene blue was unavailable, but it did not appear to be effective on the basis of uncontrolled clinical observations. This may relate to the decrease in bioavailability with increasing doses of oral ascorbic acid.

Empirically, it is reasonable to trial ascorbic acid in patients with moderate to severe propanil poisoning that is refractory to methylene blue. In the absence of formal dose-response studies, intravenous ascorbic acid 2g infused over 24h is associated with limited toxicity and may be trialled.

**Toluidine blue** \\ There is no clinical or laboratory data available on the effect of toluidine blue on acute propanil poisoning. However, toluidine blue has been noted to be superior to methylene blue in the treatment of 4-dimethylaminophenol-induced metHb in volunteers. A bolus dose of 2mg/kg toluidine blue was 80% more effective than methylene blue and without side effects (compared with methylene blue). Administration of a bolus dose of 4mg/kg toluidine blue was even more effective and also without side effects.


==== GI Decontamination ====

Oral [[:wikitox:3.2.2.2.3_activated_charcoal|activated charcoal]] should be given if the patient presents within 1 hour of ingestion.

==== Elimination enhancement ====

Exchange transfusion is used in some countries where methylene blue is unavailable, or in cases poorly responsive to methylene blue, or in severe haemolysis. A regimen which has been used is exchange of one unit of blood every hour until clinical improvement. While efficacy data are not available to support exchange transfusion, it appears to be a reasonable treatment to trial given the apparent long duration of toxicity.

There is no experience with other enhanced elimination techniques for acute propanil poisoning, and no data regarding the pharmacokinetics of propanil to determine the theoretical value for attempting [[:wikitox:3.2.3.1.1_haemodialysis|haemodialysis]] with severe poisoning.

===== DIFFERENTIAL DIAGNOSIS =====

The differential diagnosis should include any Unknown pesticide, dapsone or other chemicals known to induce metHb.

===== LATE COMPLICATIONS, PROGNOSIS - FOLLOW UP =====

Patients who have had severe CNS toxicity (coma or seizures) or [[:wikitox:3.4.3.1_cardiac_arrhythmias_and_cardiac_arrest|cardiac arrest]] should be assessed for hypoxic brain injury. Anaemia has been reported.

===== REFERENCES - FURTHER READING =====

==== Propanil: ====

Varathan S. The value of exchange transfusion in severe propanil poisoning. Sri Lankan Journal of Anaesthesiology 2004; 12(2): 107-8. \\ Kurukulasuriya AP, Asokan P, Dissanayake HWW. Direct oxidant damage to red cells associated with propanil ingestion. Ceylon Medical Journal 2003; 48(3): 88-9. \\  \\ [[http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=12507053|Eddleston M, Rajapakshe M, Roberts D, Reginald K, Rezvi Sheriff MH, Dissanayake W et al.]] Severe propanil [N-(3,4-dichlorophenyl) propanamide] pesticide self-poisoning. Journal of Toxicology - Clinical Toxicology 2002;40(7):847-54. \\
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De Silva WAS, Bodinayake CK. Propanil poisoning. Ceylon Medical Journal 1997; 42: 81-4. \\
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Valentovic M, Ball JG, Stoll S, Rankin GO. 3,4-Dichlorophenylhydroxylamine cytotoxicity in renal cortical slices from Fischer 344 rats. Toxicology 2001;162:149-56. \\
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Yamazaki M, Terada M, Kuroki H, Honda K, Matoba R, Mitsukuni Y. Pesticide poisoning initially suspected as a natural death. Journal of Forensic Sciences 2001; 46(1): 165-70. \\
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McMillan DC, Bradshaw TP, McMillan JM, Hinson JA, Jollow DJ. Contribution of 3,4-dichlorophenylhydroxylamine in propanil-induced hemolytic anemia. Advances in Experimental Medicine and Biology 1991; 283: 343-5. \\
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McMillan DC, Bradshaw TP, Hinson JA, Jollow DJ. Role of metabolites in propanil-induced hemolytic anemia. Toxicology and Applied Pharmacology 1991; 110: 70-8. \\
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McMillan DC, McRae TA, Hinson JA. Propanil-induced methemoglobinaemia and hemoglobin binding in the rat. Toxicology and Applied Pharmacology 1990; 105: 503-7. \\
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McMillan DC, Freeman JP, Hinson JA. Metabolism of the arylamide herbicide propanil. I. Microsomal metabolism and //in vitro//  methemoglobinaemia. Toxicology And Applied Pharmacology 1990; 103: 90-101. \\  \\ Chow AYK, Murphy SD. Propanil (3,4-dichloropropionanilide)-induced methemoglobin formation in relation to its metabolism in vitro. Toxicology and Applied Pharmacology 1975; 33: 14-20. \\  \\ Singleton SD, Murphy SD. Propanil (3,4-dichloropropionanilide)-induced methemoglobinaemia in mice in relation to acylamidase activity. Toxicology and Applied Pharmacology 1973;25: 20-9. \\  \\ Ambrose AM, Larson PS, Borzelleca JF, Hennigar GR. Toxicologic studies on 3’,4’-dichloropropionanilide. Toxicology and Applied Pharmacology 1972; 23: 650-659.

==== Methaemoglobinaemia and antidotes: ====

Clifton J, Leikin JB. Methylene blue. American Journal of Therapeutics 2003;10:289-91. \\  \\ Liao YP, Hung DZ, Yang DY. Hemolytic anemia after methylene blue therapy for aniline-induced methemoglobinaemia. Vet Hum Toxicol 2002; 44(1):19-21. \\  \\ Wright RO, Lewander WJ, Woolf AD. Methemoglobinemia: Etiology, pharmacology and clinical management. Annals of Emergency Medicine 1999; 34(5): 646-56. \\  \\ Dötsch J, Demirakça S, Cryer A, Hänze J, Kühl PG, Rascher W. Reduction of NO-induced methemoglobinaemia requires extremely high doses of ascorbic acid //in vitro//. Intensive Care Med 1998; 24: 612-5. \\  \\ Evelo CTA, Spooren AAMG , Bisschops RAG, Baars LGM, Neis JM. Two mechanisms for toxic effects of hydroxylamines in human erythrocytes: involvement of free radicals and risk of potentiation. Blood Cells, Molecules, and Diseases 1998; 24(13): 280–95. \\  \\ Wright RO, Magnani B, Shannon MW, Woolf AD. N-Acetylcysteine reduces methemoglobin //in vitro//. Ann Emerg Med 1996;28:499-503. \\  \\ Dawson AH, Whyte IM. Management of dapsone poisoning complicated by methemoglobinaemia. Medical Toxicology. Adverse Drug Experience,1989: 4(5):387-392. \\  \\ Kiese M, Lörcher W, Weger N, Zierer A. Comparative studies on the effects of toluidine blue and methylene blue on the reduction of ferrihaemoglobin in man and dog. European Journal of Clinical Pharmacology 1972; 4: 115-8. \\  \\ [[http://www3.interscience.wiley.com/cgi-bin/fulltext/113319629/PDFSTART|Umbreit J]]. Methemoglobin–it's not just blue: a concise review. Am J Hematol 2007;82:134-44. \\
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[[http://www.ncbi.nlm.nih.gov/pubmed/14579544?ordinalpos=11&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum|Bradberry SM]]. Occupational Methaemoglobinaemia: Mechanisms of Production, Features, Diagnosis and Management Including the Use of Methylene Blue. Toxicol Rev. 2003;22;13-27.

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