Toxicity : Beta Blockers

• The common feature of beta-blocker toxicity is excessive blockade of the beta-receptors resulting in bradycardia and hypotension.
• goal of antidote is to restore perfusion to critical organ systems by increasing cardiac output.
• accomplished by improving myocardial contractility, increasing heart rate or both.  

Glucagon

• high-dose glucagon is considered the first-line antidote.
• enhance myocardial contractility, heart rate and atrioventricular conduction; many authors consider it the drug of choice for beta blocker toxicity.
• rapid onset of action and a short duration of effect, rarely longer than 15 minutes.
• The endpoints for discontinuing glucagon infusions are not clear; however, it is reasonable that once a patient is hemodynamically stable for a minimum of 6 hours, a slow taper of a single agent at a time can be employed.
• Evidence suggest that once therapy is discontinued, close observation is necessary for a minimum of 12 hours.

Insulin

• High-dose insulin has long been reported to be an inotrope.
• As HIET is particularly effective in improving myocardial contractility, the early administration of HIET may avoid the need for vasopressors or allow the use of lower doses, thereby reducing the potential for ischemic consequences. Insulin therapy may be considered if the patient has failed to respond to the traditional antidotes or if hyperglycemia is present.

DRUG	DOSING & ADMINISTRATION	STABILITY
Glucagon	Initial bolus dose of 50–150 mcg/kg should be administered i.v. over 1 to 2 minutes. The initial dose should be followed by a continuous i.v. infusion at a rate of 2–5 mg/hr (maximum: 10 mg/hr) diluted in 5% dextrose injection (if benefit is seen). If improvement is not seen with the initial bolus dose, consider increasing the initial dose. Reconstitution requires adding 1 mL of sterile diluent to a vial containing 1 mg of the drug, to provide solutions containing 1 mg of glucagon/mL. http://www.ajhp.org/content/ajhp/63/19/1828.full.pdf?sso-checked=true IV bolus of 5-10 mg (adult) or 0.05mg/kg (pediatric) over 1-5 minutes, followed by a continuous infusion of response dose per hour. http://www.mdpoison.com/media/SOP/mdpoisoncom/healthcareprofessionals/antidote-facts/glucagon%20antidote%20facts.pdf	The bolus dose can be administered using the provided diluent or sterile water for injection. The prepared solution should be used immediately after reconstitution but may be kept at 5° C for up to 48 hours if necessary.
Insulin	1U/kg of an insulin bolus followed by continuous infusion of 1-10U/kg /h, but boluses of up to 10U/kg and continous infusions as high as 22U/kg/h has been used with good outcomes and minimal adverse events (Medscape) IV loading dose of 1 U/kg of regular insulin followed by an infusion of 0.5–1 U/kg/hr.The infusion dosage can be increased every 20–30 minutes. Doses of 2.5–3 U/kg/hr have been used depending on the response. http://www.medscape.com/viewarticle/757588_3	4 weeks after opening

REFERENCES

1. http://www.mdpoison.com/media/SOP/mdpoisoncom/healthcareprofessionals/antidote-facts/glucagon%20antidote%20facts.pdf
2. http://www.ajhp.org/content/ajhp/63/19/1828.full.pdf?sso-checked=true
3. http://emedicine.medscape.com/article/813342-treatment
4. http://www.medscape.com/viewarticle/757588_3

Glyophosate Poisoning Management

• Glyphosate is a non-selective herbicide, widely used in agriculture, forestry, industrial weed control and aquatic environments. 

• Proposed mechanisms of glyphosate surfactant herbicide (GlySH) toxicity to mammals include uncoupling of oxidative phosphorylation and glyphosate-or polyethoxethyleneamine (POEA)-mediated direct cardiotoxicity. 

• It can cause a wide range of clinical manifestations in human beings from skin and throat irritation to hypotension and death

The sign and symptom of Glyphosate toxicity

• Gastrointestinal symptoms are the most common manifestations after oral ingestion. It causes erosion of the gastrointestinal tract, difficulty in swallowing and gastrointestinal hemorrhage. Eye and skin irritation have occasionally been reported from dermal exposure. Inhalation of spray mist may cause oral/nasal discomfort, tingling and throat irritation.

• Cardiovascular, respiratory and renal systems may be affected; and signs and symptoms include tachypnea, dysrhythmias, hypotension, non-cardiogenic pulmonary edema, hypovolemic shock, oliguria and respiratory failure

• Seizures and depressed level of consciousness may also occur. 

• Death was often caused by severe hypotension and respiratory failure.

• Hyperkalemia may occur as a complication of renal failure.

Confirmation of Poisoning

• Glyphosate can be measured in the plasma, with levels above 734 µg/mL being measured in fatal cases

Severity

• The assessment of severity of toxicity is determined by dose ingested and clinical grading of toxicity.
• ingested dose- The ingestions of 5-50 mL may result in no symptoms or minor gastrointestinal symptoms only. 
• Moderate symptoms occur with 50-100 mL of the concentrate and severe symptoms are likely when 100 mL or more of the concentrate are ingested.

Clinical Grading of Toxicity

Asymptomatic

No abnormalities on physical or laboratory examination

Mild	Predominantly gastrointestinal symptoms with stable vital signs and no other organ involvement

Moderate

Gastrointestinal symptoms lasting longer than 24 hours Hypotension, responsive to intravenous fluids Pulmonary dysfunction not requiring intubation Acid base disturbance Evidence of transient hepatic renal damage or temporary oliguria

Severe

Pulmonary dysfunction requiring intubation Renal failure requiring dialysis Hypotension requiring pressor amines Cardiac arrest Coma Repeated seizures Death

Management of Glyphosate Toxicity

• There is no antidote for Glyphosate toicity and treatment is supportive.

• The mainstay of treatment for systemic toxicity is decontamination and aggressive supportive therapy. 

• <1 h after ingestion and who have no evidence of buccal irritation or burns - Gastric lavage or activated charcoal can be administered .

• If the ingestion occurs more than 1 hour, the monitoring should be done as follow:

Supportive 

• Hypotension may develop several hours after ingestion. 
• Cardiac monitoring should be available. 
• Hypotension should be treated initially with intravenous fluids and if unresponsive with pressor amines. 
• There is a risk of pulmonary oedema so aggressive fluid resuscitation is inadvisable. 
• Hyperkalaemia should be corrected.

Respiratory dysfunction

• Respiratory function should be monitored closely, oxygenation assured and intubation with assisted ventilation may be required. 
• If pulmonary oedema occurs positive respiratory pressure may be of value. 
• Urine output should be monitored and prevention of hypovolaemia and hypotension should be a priority. 
• Acidosis usually responds to bicarbonate therapy but may on occasion be resistant.
  

Elimination enhancement 

• Haemodialysis may be of value for renal failure or acidosis which does not respond to bicarbonate.

Severe systemic toxicity 

• The mechanism of action of intravenous fat emulsion (IFE) may be due to the lowering of serum concentration of the free surfactant glyphosate-or polyethoxethyleneamine (POEA)-mediated component of Glyphosate (which are more lipophilic) by dragging into the lipid sink formed by the IFE, thereby blunting its cardiovascular toxicity.

2nd Gen Antipsychotic : Management of EPS in Children

table obtained from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3223903/ 
Treatment recommendations for extrapyramidal side effects associated with second-generation antipsychotic use in children and youth. Paediatr Child Health. 2011 Nov; 16(9): 590–598.

Acute Dystonic Reaction : Treatment

• An acute dystonic reaction, usually transient, is a recognized complication of the dopamine receptor-blocking drugs, such as the antipsychotics (eg, haloperidol, chlorpromazine) and antiemetics (eg, phenothiazines, metoclopramide)
• Dystonic reactions also can occur with levodopa, anticonvulsants, antidepressants (eg, selective serotonin reuptake inhibitors), and ergots.

Treatment

• The offending drug should be discontinued.
• Treatment of acute dystonia with antihistamine or anticholinergic medications is usually rapidly effective

Diphenhydramine

• IV diphenhydramine (1 to 2 mg/kg per dose, maximum dose 50 mg) is used most frequently
• Diphenhydramine may also be given intramuscularly but the onset of action is delayed compared with intravonicenous administration.
• Typically results in resolution of an acute dystonic reaction within minutes.
• Muscle relaxation begins within 30 minutes and but may not complete for 90 minutes when the antidote is given as IM or Oral
• Intravenous administration is preferred over oral administration for initiation of treatment because patients may have difficulty swallowing.
• Parenteral administration is required for life-threatening dystonia with associated laryngospasm or stridor
• Once the acute dystonic reaction is treated, diphenhydramine is given orally (1.25 mg/kg per dose) every six hours for one to two days to prevent recurrence or 12.5-50mg TDS-QID for 3 days
• In some cases, however, a single dose of oral diphenhydramine or trihexyphenidyl suffices.

Benzodiazepams

• Some recommend using diazepam for patients with dystonic reactions refractory to anticholinergic therapy or when such therapy is contraindicated
• Diazepam and lorazepam are favoured because of their longer duration of action
• IV diazepam can be given in 5-mg increment every 5 minutes as needed for reversal
• lorazepam 1 to 2 mg IV in adults; 0.05 mg/kg IV in children or 2mg every 5 minute as needed

Others

• Antihistamine, benzodiazepines, beta-adrenergic antagonists (propranolol), beta-adrenergic agonists (clonidine), or dopamine agonists (amantadine) may also be used
• amantadine (100 mg orally twice or three times daily in adults), or biperiden (2 mg orally in adults). At least two controlled studies have shown amantadine to be as effective as anticholinergic therapy, with fewer side effects
• Propranolol (20 to 40 mg initial dose) reduces involuntary movements in akathisia, but does not reduce anxiety
• A randomized trial of 13 patients with acute akathisia from antipsychotic medications reported a benefit from trazodone (100 mg/day orally in adults)
• Patients treated with dopamine receptor-blocking agents occasionally develop persistent tardive dystonia after the offending drug is stopped.
• If no spontaneous improvement occurs, they may respond to trials of muscle relaxants, anticholinergic drugs, and tetrabenazine

References:

1. www.uptodate.com
2. www.lexicomp.com
3. Harwood-Nuss' Clinical Practice of Emergency Medicine
4. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3460160/
5. http://emedicine.medscape.com/article/814632-medication

Bleach Poisoning

 Bleach, Clorox & Sodium Hypochloride

• Based on American Association of Poison Control Centers (AAPCC) data, household bleach is the most common alkaline substance people are exposed to, accounting for more than 49,000  exposures per year.
• The most common household alkali is bleach, a 3%-6% sodium hypochlorite solution with a pH of approximately.
• Chlorox is liquid chlorine bleach containing sodium hypochlorite 5%.
• Chlorox Fresh Mint Concentrated contains 3.985% sodium hypochlorite. 

Route of Exposure

• Toxic effects of hypochloride are primarily due to corrosive properties of the hypochloride moiety.
• Hypochloride is toxic by oral, dermal and inhalation routes.

Inhalation

• Hypochloride solution can deliberate gasses such as chlorine.
• At low concentration inhalation of gases may cause eye and nasal irritation, sore throat, and coughing.
• At higher concentrations can lead to respiratory distress with airway constriction and accumulation of fluid in the lungs (pulmonary edema).
• Patients may exhibit immediate onset of rapid breathing, cyanosis, wheezing, rales, or hemoptysis. 

Skin/eye contact

• Direct contact with hypochlorite solutions, powder, or concentrated vapor causes severe chemical burns, leading to cell death and ulceration.
• Following acute exposure it may irritate the skin and cause burning pain, inflammation and blister.
• Contact with low concentrations of household bleach causes mild and transitory irritation if the eyes are rinsed. 

Ingestion

• Ingestion of hypochlorite solutions causes vomiting and corrosive injury to thegastrointestinal  tract. 
• Household bleaches (3 to 6% sodium hypochlorite) usually cause esophageal irritation, but rarely cause strictures or serious injury such as perforation. 
• Commercial bleaches may contain higher concentrations of sodium hypochlorite and are more likely to cause serious injury. 
• Metabolic acidosis and pulmonary complications may also be seen after ingestion although relatively rare.

Management

• There is no specific antidote for hypochloride poisoning.
• Treatment are supportive.

Initial   Management	1)       Skin/eye contact Flush exposed skin and hair with copious amounts of plain water.  Irrigate exposed or irritated  eye with saline, Ringer's lactate, or D5W for at least 20 minutes. Remove contact lenses if it can be done without additional trauma to the eye. If a corrosive material is suspected or if pain or injury is evident, continue irrigation.     2)       Ingestion If patient is conscious and able to swallow should be given 4 to 8 ounces of water or milk It is very unlikely to be of any benefit after more than 30 minutes. Dilutants are contraindicated in the presence of shock, upper airway obstruction, or in the presence of perforation.
Specific Management	General Patient’s airway and mental status should be immediately assessed and continually monitored. If possible, it is best to avoid inducing paralysis for intubation because of the risk of anatomical distortion from bleeding and necrosis. If a difficult airway is anticipated, IV ketamine can be used to provide enough sedation to obtain a direct look at the airway. Inhalation Administer supplemental oxygen by mask to patients who have respiratory symptoms. Aerosolized bronchodilator may be used to treat patients who have bronchospasm. Skin Exposure Patients developing dermal hypersensitivity reactions may require treatment with systemic or topical corticosteroids or antihistamines. Eye Exposure Check the pH of the conjunctiva every 30 minutes for 2 hours after irrigation is stopped. If the pH is not neutral an irrigating contact lens should be used to apply continuous irrigation for several hours until the pH of the tissue normalizes. Ingestion Direct visualization of the esophagus/ endoscopy  is of primary importance for determining the extent of injury. All patients who are suspected of having significant ingestion, or those (such as children) for whom there is an unreliable history, must have early endoscopy within 36 to 48 hours of ingestion. Contraindications for endoscopy include: unstable patient, evidence of perforation, upper airway compromise, or more than 48 hours after ingestion. Endoscopy past 48 hours is discouraged because of progressive wall weakening and increased risk of perforation.
Contraindicated Procedures	Use of activated charcoal and anti emetics is contraindicated because vomiting re-exposes the esophagus and the oropharynx to the caustic agent, further aggravating injury. Neutralizing agents (weakly acidic or basic substances) should not be administered because damage is generally instantaneous. Furthermore, neutralization releases heat that adds thermal injury to the ongoing chemical destruction of tissue. Nasogastric intubation to remove any remaining caustic material is contraindicated because it may induce retching and vomiting, which can compound injury and possibly lead to perforation of the weakened esophagus or stomach.
Pharmacological Management	Antibiotics (3rd generation Cephalosporin) Given for patients with Grade 3 (focal necrosis & extensive necrosis) caustic injury or when there is a high suspicion for esophageal perforation.  Proton Pump Inhibitors Can be used to prevent stress ulcers of the stomach. Narcotics Analgesic Can be reduce the pain associated with these ingestions. Steroids Have been a controversial treatment, some studies found no difference in the incidence of stricture formation with the use of steroids while some other claimed otherwise.

 References:

1. http://www.atsdr.cdc.gov/MMG/MMG.asp?id=927&tid=84
2. https://medlineplus.gov/ency/article/002488.htm
3. http://emedicine.medscape.com/article/813772-medication#5
4. http://www.inchem.org/documents/pims/chemical/pim495.htm#SectionTitle:10.1 General principles
5. http://www.uptodate.com.
6. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3096249/
7. Demographic Features of Drug and Chemical Posisoning in Northen Malaysia Retrived from http://www.ncbi.nlm.nih.gov/pubmed/15822759

Paraquat Poisoning : Fuller’s Earth

• Fuller’s Earth is a calcium montmorillonite and it has been used as one of the treatment in Paraquat Poisoning
• The mode of action is by tightly binding paraquat to the clay in the formulation, which takes place in thegastrointestinal tract and facilitates elimination in the feces.
• Dosing and dilution of Fuller’s Earth :
• Dosage form : 30% suspension
• Recommended dose : 100-150 g for adults or 2 g/kg body weight in children
• There is also some evidences showed the difference of concentration of Fuller’s Earth used in paraquat poisoning:
• Dosage form : 15% suspension
• Recommended dose : 100-150 g for adults or 2 g/kg body weight in children

HUSM FORMULARY

• Dosage Form: Suspension 30% Fuller’s Earth
• Recommended Dose: 300 ml of 30% Fuller’s Earth suspension every 2-4 hrs for several days.

DEPARTMENT Of MEDICAL SCIENCES, MINISTRY OF PUBLIC HEALTH THAILAND, 2005

• Dosage and administration: 200-500ml of 30% Fuller's Earth suspension every 2 hours for 3 doses, in association with 5% w/v magnesium sulphate or mannitol to promote diarrhea and empty the gut.

Reference

1. William N.R.  2007. Environmental and Occupational Medicine 4^th Edition, Wolters Kluwer health /Lippincot Williams & Wilkins, Philadelphia. 1834pp
2. http://www.kck.usm.my/husm/pharmacy/formulary/
3. http://paraquat.com/sites/default/files/PQ%20Booklet%20Rev8%20final%201600212.pdf
4. http://dmsc2.dmsc.moph.go.th/webroot/drug/products/pdf/antidotesComplete.pdf

Baclofen : Poisoning

• centrally acting skeletal muscle relaxant
• an agonist at gamma-aminobutyric acid B (GABAB) receptors.
• It is used primarily to treat severe muscle spasms, secondary to conditions such as multiple sclerosis and spinal cord injuries.
• The mechanism of action has not been fully established.
• proposed that baclofen inhibits the influx of calcium at the spinal cord preventing the transmission of excitatory synaptic reflexes.
• Baclofen is primarily renally excreted; therefore, patients with renal impairment are at risk for developing toxicity at therapeutic doses.
• Overdoses of baclofen may occur due pediatric ingestions, intentional ingestions by adults or due to complications and malfunctions with intrathecal pumps and spinal catheter systems.

Overdose Symptoms

• CNS depression, lethargy, somnolence, hallucinations, agitation, mydriasis, nausea and vomiting.
• Severe toxicity is associated with bradycardia, hypotension or hypertension, respiratory failure, hypothermia, seizures, coma and death.
• Rarely, status epilepticus, rhabdomyolysis, and conduction disturbances may occur.

Pharmacokinetics

• Urine toxicology screens do not routinely test for baclofen and serum concentrations are not readily available or useful.
• After a single therapeutic dose, baclofen is rapidly absorbed from the gastrointestinal tract. Blood levels peak within 2 hours.
• serum half-life is 2–6 hours, which can be significantly prolonged after an overdose.
• majority of this drug is excreted unchanged in the urine
• Clinical effects of baclofen overdose may last four to eight hours.
• While improvement in mental status was shown to parallel the fall in serum concentration in one study, Lipscomb et al., noted that serum elimination half-life may not reflect a slower elimination rate from the central nervous system.
• Delayed diffusion across the blood-brain barrier is thought to account for the lag of a few hours in clinical recovery observed in some people

Treatment

• Treatment of baclofen overdose consists of supportive care (e.g. IV fluids, endotracheal intubation, mechanical ventilation).
• Activated charcoal - may be warranted in acute ingestions.
• Benzodiazepines - may be required for agitation and/or seizures.
• Vasopressors - hypotensive patients may require it
• There are case reports of mild to moderate overdoses being treated with physostigmine with a slight benefit, but evidence to support its use is controversial.
• Hemodialysis increases the clearance of baclofen and shortens the duration of toxicity in patients with or without impaired renal function.
• Most ESRD patients experienced marked improvement in clinical toxicity following haemodialysis, compared with patients who did not receive haemodialysis

References

1. Marryland Poison Centre Weekly Update, Feb 2012.
2. Treatment of baclofen overdose by haemodialysis: a pharmacokinetic study. Nephrol Dial Transplant (2005) 20: 441–443
3. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3229794/
4. http://emj.bmj.com/content/22/9/673.full