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prn8099 - Number 33, April 2002

Chemical, Biologicals, Wars and Sedentary Lifestyles:
A Threat to Human Health
Lack of physical activity leads to more than 2 million deaths per year and combined with improper diets and tobacco, causes most premature coronary heart diseases
Sarin reminds us of the infamous 1995 terrorist attacks on commuters in the Tokyo subway system, killing 12 and sending 5,500 persons to local hospitals. Being a nerve gas, sarin or GB, is an example of a chemical warfare agent synthesized and deployed for hostile purposes causing massive casualties to civilians.
Meanwhile, following the September 11 attack on the World Trade Centre, New York, biological warfare has been closely associated with bioterrorism. More so when anthrax and its causative pathogens Bacillus antracis is used as a biological weapon. This infective agent is one of thousands of biological agents that has been investigated and finally selected for its potential as a weapon.
Prior to both highly publicised incidents, a long list of other toxic and infective agents has been apparently used as early as 1918 for hostile purposes. These include, to name a few, mustard gas, chlorine, phosgene, agent orange, tabun, and Salmonella enteridis serotype thyphimurium.
Apart from introducing chemical and bi­ological warfare agents as topics of global discussion, September 11 too has resulted in vast physical and economic destruction to the war-torn country of Afghanistan. The war also caused loss of lives and severe morbidity particularly to its weaker population — its women, chil­dren and senior citizens.
This year, International Women's Day celebrated on March 8, focused on the health of Afghan women. The World Health Organization (WHO) has quoted that years of war and instability have left the Afghanistan healthcare system among the poorest in the world and the health of girls and women has been especially compromised.
The World Health Day 2002 (April 7) slogan, 'Move for Health' promotes movement or action as the key to physical activity and public health efforts. WHO defines physical activity as "all movements in everyday life, including work, recreation, exercise and sporting activities". According to Dr. Gro Harlem Brundtland, the Director General of the WHO, "lack of physical activity leads to more than 2 million deaths per year and combined with improper diets and tobacco, causes most premature coronary heart diseases and also increases the risks of several cancers, diabetes, high blood pres­sure, blood lipid disorders, osteoporosis, depression and anxiety".
Whatever the slogans or themes promoted year by year, they must not be diluted and forgotten as new slogans are invent­ed for the forthcoming 'world days'. The efforts and campaigns of health promotion should be sustained and undertaken seriously with full commitment and perseverance by government institutions and non-government organisations globally this is to ensure that the world we live in today is a safer place for us and our future generations. 

Poison Content Toxicity Profile Management

Nail Polish

Toluene, xylene with alcohol


May cause nause, vomiting, diarrrhea, burning sensation of mouth and abdomen, transient CNS depression


May cause fatigue, headache, incoordination, coma, respiratory arrest, cardiac arrythmias, death

Eye/Skin Exposure

May cause transient epithelial eye injury

Skin irritation is rare


Gastric lavage if more than 30-60ml is ingested and if within 30-60 minutes post ingestion

Activated charcoal

Symptomatic and supportive


Symptomatic and supprotive


Irrigate with copious amount of tepid water

Nail Polish Remover

Acetone and/or ethanol

Ingestion (Acetone)

Ingestion of small amount usually does not cause significant toxicity except in young children

Large volume ingestion (>200ml) may cause nausea, vomiting, inflammation and edema of throat, headache, lethargy, CNS depression, seizures in children, acidosis, hyperglycemia.


May produce cough, bronchial irritation, headache, fatigue, coma

Eye/skin Exposure

May cause transient irritation

Prolonged skin contact may cause dryness and erythema


Gastric lavage indicated

Activated charcoal

Symptomatic and supportive

Important to maintain respiration


If respiration is impaired, oxygen and ventilation may be required


Irrigate eyes with copious of water or saline for at least 15 minutes

Wash skin with soap and water.

Review on
Theophylline Poisoning 
by Mohd. Baidi Bahari,
PharmD, Clinical Pharmacy Discipline,
School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800 Penang.
What is theophylline?
Theophylline is a naturally occurring xanthine found in small amount in several plants including tea and coffee. It is used clinically for the management of respiratory disorders such as asthma, chronic obstructive pulmonary disease (COPD), acute and chronic bronchitis, and in neonatal apnea.   Theophylline has a low therapeutic safety margin and levels above the serum therapeutic range are considered toxic. Though theophylline poisoning is not commonly reported in Malaysia, a recent report in Arc. Internal Medicine, May 1999 described that the mortality due to theophylline poisoning is 4.2% of the total theophylline poisoning.
Theophylline is available in various dosage forms and commonly used theophylline preparations are listed in Table 1.

Table 1     Theophylline preparations available in Malaysia

Trade name Dosage form Strength         Recommended dose



50 mg and 125 mg

Adult: 125-150 mg q. 6 hrly

Ped.: 125-200 mg q. 12hrly



50 mg and 125 mg

Adult: 125-200 mg q. 6 hrly

Ped.: 5 mg/kg q. 6hrly


80 mg/15 ml

Ped.: 1 mg/kg up to 25 ml q. 6hrly

Sustained release tablet

125 mg and 250 mg

Adult: 250 mg q. 12 hrly

Ped.: 10 mg/kg q. 12hrly

Retafyllin CR®

Sustained release tablet

200 mg and 300 mg

Adult: 200-300 mg b.d. or 400-800 mg daily

Ped: >40 kg wt, 200 mg b.d.

        >30 kg wt, 150 mg b.d.

        >10 kg wt, 100 mg b.d.


Sustained release tablet

200 mg and 300 mg

Adult: 200-3-- mg b.d.

Ped: adjust based on body weight.


Tablet syrup

125 mg

80 mg/15ml

Adult:120-240 mg t.d.s. to q.i.d

Ped.: 7-12 yr, 90-120 mg t.d.s. to q.i.d

2-6 yr, 60-90 mg t.d.s. to q.i.d

6 mth-2 yr, 4-5 mg/kg t.d.s. to q.i.d

Aminophylline DBL®


25 mg/ of 10 ml

Adult: LD 6 mg

Ped.: MD 0.5 mg/kg/min



100 mg aminophylline

Adult: 3-4 tab daily

Ped.: 2-4 mg/kg t.d.s. to q.i.d

How does theophylline toxicity occur?
Theophylline toxicity is related to the uncontrolled adrenergic stimulation with an increase of catecholamine activity. Catecholamine concentration seems to correlate with patient's serum theophylline concentrations (STCs). About 10-15% of theophylline treated patients with normal STC (suggested therapeutic range for theophylline is 10-20mg/L.) develop some degree of theophylline toxicity. However, in acute overdose cases, about 75% of patients develop minor toxicity at serum level of 25mg/L, and major toxicity such as seizures, hypotension and serious dysarhythmias do not occur until STCs are extremely high that is exceeding 60mg/L. In chronic poisoning, toxic symptoms may appear at lower STCs. Severe dysrhythmias and convulsions may occur at STCs between 40-60mg/L. The onset of toxicity in both cases may appear within 1-2 hours after ingestion of plain tablet but may be delayed up to 6-8 hours with sustained-release preparations.
The elevation of STCs may occur due to excessive theophylline ingestion which normally occurs in children and elderly patients, or due to impairment of theophylline metabolism as a result of drug-theophylline interactions (Table 2)
Table 2 Theophylline-drug interaction


Effect on theophylline serum levels

Prevention / management




Increase STC up to 20%

Avoid concurrent use

Theophylline dosage adjustment

Histamine blockes:



Increase STC up to 30-40%

Avoid concurrent use

Theophylline dosage adjustment


Decrease STC up to 30%

Avoid concurrent use

Theophylline dosage adjustment


Decrease STC up to 30 - 50%

Avoid concurrent use

Theophylline dosage adjustment

Quinolone antibiotics:



Increase STC

Avoid concurrent use

Monitor STC closely

Theophylline dosage adjustment


Increase STC

Monitor STC

Appropriate theophylline dosage adjustment

Tobacco smoking

Decrease STC

Monitor STC

Appropriate theophylline dosage adjustment

Who is at risk of theophylline toxicity?
Children and elderly patients on chronic theophylline therapy are at risk of developing theophylline toxicity commonly due to error in drug administration. So are patients with significant underlying medical condi­tions and patients on multi-drug therapy.
What are the presentations of theophylline toxicity?
The toxicity of theophylline involves multi-organ system. The most com­mon manifestations of theophylline toxicities are:
Gastrointestinal, such as nausea, vomiting, diarrhea, abdominal pain, gastrointestinal ulceration and bleeding.
Cardiovascular system. Theophylline increases cardiac rate and contractility, and peripheral vasodilatation. In a serious theophylline cardiotoxicity, a multitude of tachyarrhythmias and ectopy such as ta­chycardia, atria/ventricular fibrillation, pre­mature atrial/ventricular depolarization and cardiac arrest occur. Tachyarrhythmias and cardiac arrest usually do not happen until the STCs are above 40mg/L when ingested chronically or more than 90mg/L in acute overdose (AO). The incidence of hypotension has been reported in 25% of cases involving AO as compared to only 3% in chronic ingestion (Cl).
Central nervous system. Theophylline may produce generalized CNS stimulation at therapeutic STCs such as decreased fatigue and increased capacity to sustain intellectual effort. In poisoning cases, theophylline causes nervousness, insomnia, central respiratory stimulation, hyperesthesia, focal and generalized seizures and coma. The seizures may progress to status epilepticus in about 25% of cases and are refractory to conventional anticonvulsants. The seizures occurs at STCs more than 40mg/ L in Cl and more than 90mg/L in AO. Under such circumstances, mortality have been reported to be in the range of 25-50%. Most of AO patients experience toxic symptoms prior to the seizures where as following Cl, the seizures may occur without prior toxic symptoms. Hallucination has also been reported in children with theophylline poisoning.
Muscular. Theophylline relaxes smooth muscle except in cerebral vasculature and increases skeletal muscle contractility, including the diaphragm. Acute rhabdomyolysis has been described following theophylline toxicity. This problem normally occurs following AO but not in Cl. 
Metabolic and electrolyte abnormalities.
Acute theophylline toxicity is commonly associated with hypokalemia, hyperglycemia, leukocytosis and elevated serum catecholamine levels. Increase in cat-echolamine activities may also result in hypercalcemia, hypophosphatemia and hypomagnesemia. About 25-50% of cases of acute overdose developed significant hypokalemia but this was not reported in patient who ingested theophylline chronically.
How can we confirm theophylline toxicity?
Diagnosis of theophylline toxicity is usually done in patient with history of theophylline therapy presented with complaints of gastrointestinal, cardiovascular or neurological manifestations and supported by elevation of STCs. Other laboratory findings include significant hypokalemia that inversely correlate with STC. Moderate hyperglycemia, leukocytosis, hypercalcemia, respiratory alkalosis and metabolic acidosis have been reported in cases of theophylline poisoning.
Determination of the STCs may confirm the diagnosis of theophylline poisoning and may also be useful to guide the management of theophylline toxicity. Table 3 shows the correlation of STC and severity of theophylline toxicity. 
How do we manage theophylline toxicity?
Initial evaluation and management begin with rapid assessment and stabilization of the patient's airway, ventilation, and circulation followed by the establishment of intravenous access and cardiac monitoring. Intravenous fluid replacement will usually be necessary, particularly in the presence of severe vomiting and hypovolemia. Hypokalemia should be corrected with intravenous potassium chloride infusion. Hyperglycemia does not usually require correction and will resolve with fluid therapy. However, close monitoring of serum electro­lytes, urea, creatinine and arterial blood gases is very important.
STC should be measured on admis­sion and at intervals thereafter. The timing of these measurements will be determined by the type of product ingested (plain or sustained-release tablet), the clinical condition and the progress of the patient, and the nature of the elimination procedures employed. In severe theophylline toxicity, STCs should ideally be measured every 2 hours to determine the peak level and every 4 hours thereafter until the STCs return to the therapeutic range.
Prevention of absorption
Gastric lavage
Gastric lavage may be indicated in a patient who has ingested a large quantity of theophylline and should be performed within 2-4 hours after plain theophylline ingestion and up to 8-10 hours after ingestion of sustained-release preparation.
Oral activated charcoal (OAC)
OAC administered as slurry is a good adsorbent and its effectiveness depends partly on the ratio of charcoal to theophylline which was suggested to be about 10:1.
Multiple-dose oral activated charcoal
Repeated doses of OAC may reduce the absorption of theophylline, interrupt the enterohepatic circulation of theophylline and promote back-diffusion of theophylline from the blood to the intestine. Multiple-dose OAC has been shown to enhance the elimination of theophylline and to reduce the theophylline half-life by 40-70% of initial values. Current recommended initial dose is 50gm in adults followed by 25gm every 2 hours until STCs fall to therapeutic range. Concomitant use with cathartic is recommended to accelerate the evacuation of charcoal-theophylline complex and unabsorbed sustained-release preparations from the gut.
Whole bowel irrigation
Although not commonly employed, whole bowel irrigation using polyethylene glycol solution may be useful in the management of theophylline poisoning especially when sustained-release preparation is involved.
Enhanced elimination      
In normal healthy individual, the half life of theophylline ranges from 2-12 hours. Patients with high STCs and prolonged half-life may develop potentially fatal events. Therefore, rapid reduction of STCs is important.
Hemoperfusion (HP) may be of benefit in patients presented with life threatening manifestations such as significant dysrhythmias, hypotension, seizures or cardiac arrest; patient with persistent unstable hemodynamic parameters; patients with STCs more than 80-100mg/L following acute overdose; patients with STCs more than 40-60mg/L following Cl and age younger than 3 years or more than 60 years; patients with liver diseases and patients who cannot tolerate OAC. 
Uncoated charcoal is preferred than resin HP and it was reported that charcoal HP increases theophylline clearance by four to six fold than normal. The half-life of theophylline reduces to approximately 2 hours regardless of initial baseline half-life. A 6-8 hours charcoal HP may be sufficient to remove substantial amount of theophylline. HP should be employed early when the symptoms of serious toxicity are present. Studies reported that in most life-threatening theophylline toxicities treated with charcoal HP, clinical improvement occurs within the first two hours.
Although HP is usually well tolerated, patients must be hemodynamically stable and able to tolerate anticoagulation. A 30-50% drop in platelets count have been reported with HP and this usually resolves within few days. Hypoglycemia, anemia and electrolytes disturbances may also occur with HP. Occasionally a rebound increase in theophylline STC which was reported to range between 5-20mg/L may develop following termination of HP and this may result in recurrence of toxicity.
The increase in theophylline clearance during hemodialysis is similar to those achieved with HP and multiple-dose OAC. However peritoneal dialysis does not seem to contribute to the clearance of theophylline. Hemodialysis should be considered in patients who require HP but is unavailable. It is important to continue multiple-dose OAC during these procedures to ensure adequate clearance.
What are other therapy needed in theophylline toxicity?
Antiemetics such as metoclopramide, prochloperazine and ondansetron may be necessary to allow the initiation of OAC and multiple-dose activated charcoal therapy in patients having severe vomiting. Propranolol and esmolol have been administered to correct Supraventricular and ventricular tachycardia.
Diazepam given as IV bolus is the first line of treatment to control convulsion due to theophylline poisoning. In intractable convulsion, phenobarbitone is indicated.
Prompt evaluation and institution of supportive measures are paramount in the management of theophylline toxicity. A focused history should be elicited and laboratory investigations should be carried out to guide the management plan. Gastric evacuation should be performed in patient presented within a few hours of ingestion of sustained-release theophylline preparations if spontaneous vomiting has not occurred. Repeated-dose activated charcoal is the most effective treatment for theophylline toxicity and should be initiated without delay. Charcoal hemoperfusion alone or in combination with hemodialysis may be life saving in cases presented with systemic complications. 

Clinical Updates
High-Flux Hemodialysis Without Hemoperfusion Is Effective in Acute Valproic Acid Overdose
Author(s): KaneSLet.al.
Source: Ann. Pharmacotherapy, Vol 34, Iss 10, Pg  1146-1151, Yr2000
Abstract: This is a case report of a 25 year-old lady who became comatose,and developed hypotension and lactic acidosis after ingesting an unknown amount of valproic acid. High-flux hemodialysis was performed and toxic concentrations of valproic acid was effectively reduced without the addition of charcoal hemoperfusion and its attendant risks. 
Acute Hepatic Steatosis Complicating Massive Insulin Overdose and Excessive Glucose Administration  
Author(s): Jolliet P et.al.
Source: Intensive Care Med, Vol 27, Iss 1, Pg 313-316, Yr 2001 
Abstract: A description of a case of acute hepatic steatosis due to excessive administration of glucose after massive insulin overdose, a complication which resolved rapidly and completely after rapidly tapering glucose infusion. 
Metabolic Acidosis and Coma Following A Severe Acetaminophen Overdose 
Author(s): Koulouris Z et.al. 
Source: Ann Pharmacotherapy, Vol 33, Iss 11, Pg 1191-1194, Yr 1999 
Abstract: A case report of a lady being admitted to the emergency department with a diminished level of consciousness and metabolic acidosis, after a severe acetaminophen overdose without manifesting signs of hepatotoxicity. 
Risk Factors in the Development of Adverse Reactions to N-Acetylcysteine(NAC) in Patients with Paracetamol Poisoning 
Author(s): Schmidt LE, Dalhoff K
Source: Br J Clin Pharmacol, Vol 51, Iss 1, Pg 87-91, Yr 2001
Abstract: A retrospective study in 529 patients with paracetamol poisoning and treated with NAC to identify risk factors in the development of side-effects to NAC. It was found out that asthmatic patients were 2.9 times more likely to develop side effects than non-asthmatics. Severity of side effects were similar in both group of patients, and easily managed. As such, there is no reason to withhold NAC from any patient with paracetamol poisoning and paracetamol itself seems to offer some protection against the development of side effects to NAC.


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