prn8099 - Number 22, April 1999

Japanese encephalitis (JE) was initially dubbed as a "mysterious" disease when it attacked some five victims in October 1998. Now about 6 months later it seems we are back into the realm of mystery with the discovery of a new virus, allegedly Hendra-like. What would have been regarded as a seasonal episode has turn into a full-scale nightmare!

On hindsight, it is probably easier to say that JE is not a new problem in this country. It is known to be endemic in many countries, and for the last 25 years cases were reported periodically to occur in Malaysia. In 1974, 1988 and 1992 sporadic outbreaks were documented. Despite such occurrences the situation was carefully kept under control. But this is not to be any longer. Towards the last quarter of 1998 the situation became more worrying affecting mainly pig-farm workers and the neighbouring residents.

The rude awakening came when it was brought to light that the pig-farming industry is still in a very primitive state. Reports of several on-site visits during the crisis period came out very clearly suggesting that the industry has not live up to the standard of hygiene and cleanliness expected of a food supply industry. This point was illustrated time and time again when authorities came across what literally looks like the proverbial pigsties.

It is indeed shocking to know that when the country is implementing various quality standards in the food sectors nationwide, the pig-rearing activities are lagging behind. While numerous eating outlets would have been forced to close down due to non-compliance to such standards, it seems that no pig-farms have faced similar fate despite its falling way behind the desired standards of cleanliness.

This comes to even greater shock considering that pig-farming garners substantial economic returns for the country. In fact, one of the largest pig-farms in this region was said to be located in Malaysia, perhaps needless to say it is also the dirtiest.

That the pig-farming hygienic standards are in a dire state have long left trails of pollution in our air and waterways. Evidences of these have been staring at our faces all along. Most of us however are pig-in-the-middle, thinking that unkempt piggery can never lashed out any form of disasters in the dimension that we see today. Others insisted that it is not serious enough to threaten public health order. Fewer still are willing to upset the lucrative pig-rearing business in trying to address the long-standing problem. Consequently, it is left relatively untouched while those affected continued to suffer in silent.

It takes the JE-related outbreak to bring the nation to its senses, albeit in an abrupt and tragic manner. With the number of deaths due to viral encephalitis climbs quickly into three-digit figures, ultimately it dawns on us that something is fundamentally wrong. Though there have been many wild accusations including sabotage involving foreign agents, the stark truth remains - namely, the pig-farming industry has been left unregulated for far too long.

The crisis situation has forced us to admit that there are still many unlicensed and illegal pig-rearing and slaughtering activities being carried out without concern for health and the environment. Otherwise generally the situation is not much better either. In short, there is a blatant disregard for health requirements all round.

There is no wonder then we continue to hear voices lamenting about the apathetic attitude of our people when it comes to enforcing or complying with the existing laws, for instance, to check the spread of mosquitoe-borne diseases. Or controlling pollution for that matter. This is indeed a real sad state of affairs because in the last five years we have had more than our fair share of national disasters annually. The present viral outbreak is by no means an isolated national tragedy.

In 1995, the dumping of more than 40 drums of cyanide in a resort island off the coast of Perak could have easily turned ugly killing almost instantly millions of Malaysians; in 1996, cholera outbreak affect more than 1000 people nationwide and; in 1997, we experienced the worst haze in the history of the world; then the viral myocarditis outbreak beginning in Sarawak. In turn 1998 saw the emergence of chikungnya joined by the viral encephalitis foray at its tail end. And of course, in 1999 a full-blown JE-related disaster.

All these events are preventable if only we inculcate the right attitude of mind towards health and the environment.

Unfortunately, this is not to be. Thus in almost all of these cases we can point a finger to the care-free, unreasonable and stubborn attitude of the parties concern. An attitude best described as pig-headedness! An attitude that has cost us not only of love ones, but our image as a health conscious nation and people.

Such a pig-headed attitude must therefore be culled if we want to avert any more nationwide disasters and retain our self-respect. This must be carried out as urgently as we continue to cull the tens of thousands of pigs today. It must be planned with as much determination as we didn in the culling of the diseased animals. Indeed, like JE, pig-headedness is in itself a disease that Malaysians must voluntarily immunised themselves against if they want to continue to live in a safer and healthier environment. We cannot wait for another disaster to appear and still find that we as pig-headed as we were before.

Let's act today and now. Or must we wait until pigs can fly.

 DATA SHEET: Ribavirin                                                                                                                               Source:USP, Micromedex 1999

Ribavirin (rye-ba-VYE-rin) belongs to the category of antiviral drug. It is a synthetic nucleoside antiviral agent for oral inhalation therapy. It was orginally synthesized in the 1970s and has been shown to be active against many DNA and RNA viruses.

Use: It is used as a primary agent to treat respiratory syncytial virus infections and was approved by the FDA in December 1985 for use as an aerosol in the treatment of this condition. In January 1994, several foreign countries recognized ribavirin as useful in treating herpes zoster and herpes genitalis infections, as well as varicella.

The FDA approved ribavirin oral capsules in combination with interferon-alpha on June 3, 1998 for the treatment of chronic hepatitis C in patients with compensated liver disease who have relapsed following interferon-alpha therapy. Ribavirin monotherapy is not effective for the treatment of chronic hepatitis C.

It is usually used to treat severe virus pneumonia in infants and young children. Although it may also be used for other virus infection as determined by your doctor, it will not work for certain viruses, such as the common cold.

How ribavirin acts is not fully understood, but its action is intracellular, and the drug appears to selectively inhibit viral DNA and RNA synthesis over cellular (e.g. host cell) DNA and RNA, synthesis in viral-infected cells. The antiviral action of ribavirin appears to require the intracellular phosphorylation to the triphosphate and monophosphate forms.

Ribavirin has some cytotoxicity within viral cells but at a much higher concentration than that required to inhibit viral DNA synthesis. Antiviral and cytotoxic effects are reversible following removal of the drug. There also may be an immunologic effect.

The amount of drug absorbed into respiratory tract secretions vary depending on method of delivery, concentration of drug in solution, and length of time of delivery. There is rapid absorption following oral administration, resulting in peak concentrations within 1-2 hours. Most of the drug is excreted in the urine.

Precautions: Before receiving this medicine a few factors should first be consi-dered. These include the following:

Allergies - Find out if your patient has ever had any unusual or allergic reaction to ribavirin tell this to your doctor. Also mention if you or your child is allergic to any other substances, such as foods, preservatives, or dyes.

Pregnancy - Ribavirin is not usually prescribed for teenagers or adults. Although studies have not been done in pregnant human, ribavirin has been shown to cause birth defects and other problems in certain animal studies. Be sure you have discussed this with your patient.

Breast-feeding - Ribavirin is not usually prescribed for teenagers or adults. However, ribavirin passes into the breast milk of animals and has been shown to cause problems in nursing animals and their young.

Children - This medicine has been tested in children, and, when used as it should be and in effective doses, has not been shown to cause serious side effects or problems.

Older adults - Ribavirin is not usually prescribed for use in elderly patients.

Side Effects: Along with its needed effects, a medicine may cause some unwanted effects. The following side effects may go away during treatment as your body adjusts to the medicine. Check if any of the following side-effects continue or are bothersome: Headache; itching, redness, or swelling of eyes; skin rash or irritation.

To date there is little overdose experience with this drug. Clinical studies indicate primary symptoms to be increased in bilirubin and anemia, followed by rebound reticulocytosis.

Additional Information: Once a medicine has been approved for marketing for a certain use, experience may show that it is also useful for other medical problems. Although these uses are not included in product labeling, ribavirin is used in certain patients with the following medical conditions:

• Influenza A and B (given by aerosol inhalation)
• Lassa fever (either given orally or by injection)

Its use for Hendra-like virus is still not yet well-established. However local experts has been quoted as saying that the drug may work for Hendra-like virus. A seven-day regime treatment with the drug is estimated to cost about RM3,000.

 PRN CONSULT

Review on

Anti-Parkinson's Drug Toxicity

by Mohamad Haniki Nik Mohamed, Pharm.D

Parkinson's disease (PD) is generally considered a disease involving older adults. It is estimated that one of every l00 persons over the age of 60 is affected. In America, up to 1.5 million people are inflicted. The goal of pharmacological treatment is to maintain the patient's functional ability by relieving symptoms and minimi-zing adverse effects. Polypharmacy is common and often necessary in PD patients. Therefore, there is a high potential for overdose and poisoning from antiParkinson's drugs use in this elderly population.

What are the available antiPD agents in Malaysia?

Antiparkinsonism preparations available in Malaysia and their pharmacokinetic (PK) and dosing characteristics are listed in Table 1. All available agents are designed to counteract imbalances in brain neurotransmitters caused by irreversible degeneration of dopaminergic neurons. Additional medications often are required to manage the adverse effects associated with PD treatment.

At what dose will poisoning occur and what are the common symptoms?

Levodopa

Symptoms seen after acute overdose have included nausea, vomiting, sinus tachycardia, postural hypotension, restlessness, insomnia, hypertension and dyskinesias. There have been several case reports of overdose in the literature. A 57-year-old female developed choreiform movements following an ingestion of 15 to 17 tablets of carbidopa-levodopa 10/100 in combination with paracetamol, carisprodol, hydrocodone, and ibuprofen. She also developed tachycardia (110 beats/min) without hypotension for 5 days following the overdose. A case of neuroleptic malignant syndrome was reported in a 60-year-old woman approximately 2 weeks after discontinuation of carbi-dopa-levodopa therapy and 6 days after receiving orphenadrine 150 mg/day. She developed hyperthermia, tachycardia, rigidity, elevated creatine phosphokinase, rhabdomyolysis, myoglo-binuric renal failure, and coma. She died 21 days after the onset. Reutens et al. (1991) described a similar case of fever, tachycardia, confusion, severe rigidity, and stimulus-sensitive myoclonus, which developed 12 hours after discontinuation of 150 mg/day in a 76-year-old man.
Recently, two patients were reported to exhibit levodopa dependence and abuse by increasing their daily dosages from 400-800 mg to 1500 to 2000 mg. They suffered from anorexia, hyperkinesias, hallucinations, and other motor symptoms of levodopa overdose.

Dopamine Agonists

Data reported to the manufacturer revealed ingestions of up to 32.5 milligrams bromocriptine in children, with vomiting and drowsiness as the most common findings. Hypotension and tachycardia were reported in one 2-year-old child (of 18 cases). Ingestion of as little as 7.5 milligrams (three bromo-criptine tablets) in two young children resulted in lethargy. Another 2-year-old child who ingested 25 milligrams bromocriptine developed vomiting, drowsiness, hypotension, mydriasis and hyperreflexia, but had a complete recovery. A young adult developed vomiting, hypotension and agitation following an intentional pergolide overdose of 60 milligrams. A case of unintentional pergolide overdose of 7 milligrams in an adult resulted in palpitations, hypotension and ventricular extrasystoles. One patient took 14 mg/day for 23 days instead of her prescribed pergolide dose of 1.4 mg/day. She experienced severe involuntary movements and tingling in her arms and legs. Generally, spontaneous vomiting, hypotension, sweating, nausea, dizziness, agitation and hallucinations have been reported as symptoms. Of these, orthostatic hypotension is common and may be prolonged. Hypothermia and hypertension (in postpartum women) have also been reported. Seizures and CNS stimulation have occurred in animal toxicity studies, and may occur following overdoses in humans.

Anticholinergics

Toxicity are due to both central and peripheral anticholinergic effects. The central nervous system manifestations include excitement, confusion, restlessness, paranoid ideation and euphoria. Vivid visual, auditory and tactile hallucinations have also been described. These features are sometimes referred to as central anticholinergic syndrome. The anticholinergic syndrome has a rapid onset and easily recognizable symptomatology. The peripheral features of overdose include nausea, dizziness, blurred vision, dry mouth and skin, distended bladder and urinary retention, hyperpyrexia, dilated pupils, flushed faces and tachycardia. A case of benztropine poisoning exhibiting acute dystonia had been reported following benztropine ingestion by a 20-month-old boy. Benztropine overdose was also reported in a 38-year-old man who had a peak serum benztropine level of 100 micrograms/litre approximately 24 hours after ingesting an unknown amount of benztropine mesylate 1 milligram tablets. Symptoms of intoxication persisted until serum benztropine concentrations had decreased to 9 micrograms/litre. A 30-year-old male ingesting a handful of benztropine tablets expired 1.5 hours after ingestion. A 48-year-old male was found dead next to partially used containers of trihexy-phenidyl hydrochloride, erythromycin, terbutaline elixir, nystatin lozenges, and salbutamol rotocaps. Toxicological analysis revealed only significant levels of trihexyphenidyl in the blood, liver and gastric contents. Femoral artery blood concentration was 0.12 milligram per liter.

Amantadine

Anticholinergic symptoms described earlier including dry mouth, dilated pupils, tachycardia and difficulty in focusing are often observed. The two most serious toxicities are cardiac arrhythmias and CNS stimulation. Tachyarrhythmias, ventricular ectopy, ventricular fibrillation and cardiopulmonary arrest were reported after an ingestion of 2.5 g. Initially CNS depression is seen, followed by CNS stimulation. Drowsiness, weakness, confusion, jitteriness, hallucinations, nightmares and apprehension have been reported as has aggressive behavior and seizures after a single 800 mg dose. A 2.5-year-old child ingested 600 milligrams (60 milligrams/kilogram) resulted in hallucinations, agitation, and dystonic posturing. Ingestion of 2,800 milligrams by a 61-year-old man resulted in an acute toxic psychosis with disorientation, visual hallucinations, aggression, urinary retention, and dilated pupils. Another patient ingested 1,300 mg and deve-loped altered mental status and complex ventricular arrhythmias. Ingestion of 100 milligrams every two hours for 24 hours (total dose 1,200 milligrams) in combination with diphenhydramine 25 milligrams four times a day, resulted in acute psychosis a 35-year-old woman. Plasma levels of 4.4 micrograms/millilitre produced bizarre central nervous system symptoms of hallucinations, nightmares, and agitation. CNS toxicity has been associated with amantadine plasma concentrations of 1000 nanograms/millilitre. The admission serum amantadine level in one fatal case was 23.4 micrograms/millilitre. In another fatal case the postmortem plasma level was 48 micrograms/millilitre.

Selegiline

Some individuals exposed to doses of 600 mg suffered hypotension and psychomotor agitation. Acute overdose effects include anxiety, flushing, tremors, sweating, nausea, agitation, tachypnea and tachycardia. This may progress to muscle rigidity, hypertension, hallucinations, hyperthermia, trismus, and opisthotonus. In severe cases, hypotension, bradycardia, seizures, severe hyperthermia, respiratory depression, and cardiac arrest may develop. The onset of symptoms following acute overdose may be delayed up to 24 hours after ingestion, but usually begins between 6 to 12 hours. Effects may last for 3 to 4 days. Mild overdose or the early phase of severe toxicity may manifest hypertension, tachycardia, flushing and palpitations. Profound hypotension, bradycardia, cardiovascular collapse and asystolic arrest may be noted following overdose of MAO inhibitors alone. Severe hypertensive crisis may be noted with combined use of MAO inhibitors and oral sympathomimetic amines since selegiline poisoning may also involve drug and food interactions. Serotonin syndrome, characterized by mental status changes, hyperthermia, hypertension, muscle rigidity and tremor may develop in patients taking MAOIs and clomipramine, fluoxetine, lithium, meperidine, tricyclic antidepressants, or selective serotonin reuptake inhibitors. Signs and symptoms of the MAOI-tyramine interaction include hypertension, headaches, palpitations, flushing, perspiration, and in severe cases, hyperthermia, seizures, mental confusion, and cerebrovascular accidents.

How is poisoning from antiPD drugs confirmed?

The presence of the signs and symptoms of overdose for each antiPD agent previously described are the most important tool in diagnosis. For most of these agents, monitoring of drug levels are not clinically useful. Analyses of serum and urine for dopa and its metabolites may be used to confirm the overdose. Otherwise, no other specific laboratory determinations are required. Blood pressure, ECG, creatine phosphokinase and alkaline phosphatase, signs of dyskinesias or seizures are useful in the diagnosing dopamine agonists poisoning. For anticholinergics, monitoring of drug level is also not particularly useful since the range of toxicity is variable and unpredictable. Amantadine can be identified by a specific gas chromatographic method in the case of suspected poisoning. However, serum levels are not readily available. Serum levels above 1.5 mg/L have been associated with toxicity. For selegiline, assay procedures and toxic levels of MAOI have not been well-defined and the diagnosis must ultimately be made clinically. MAOI activity in man can be measured indirectly by measuring MAO substrates and their metabolites, such as plasma serotonin, norepinephrine, methoxy-4-hydroxymandelic acid (VMA), and urinary 5-hydroxyin-doleacetic acid (5-HIAA). Abbott TDXâ can detect the l-metham-phetemine and l-amphetamine metabolites of selegiline in urine. Roche Abuscreenâ did not detect l-metham phetamine or l-amphetamine in urine or blood; it is specific for d-methamphe-tamine with very little cross reactivity.

Clearly, clinical judgment is more important than attempting to determine the amount ingested or injected.

How do we manage antiPD drugs toxicity?

Levodopa

As in most poisoning cases, respiratory and cardiovascular function support must be provided first. To prevent absorption due to oral exposure, emesis may be induced. The decision to induce or not to induce emesis in ingestion is often controversial, is not automatic, and must be carefully considered. Emesis may be indicated in substantial recent ingestions, and is most effective if initiated within 30 minutes of ingestion Contraindications to emesis induction include signs of oral, pharyngeal, or esophageal irritation; a depressed gag reflex; or central nervous system excitation or depression.

Syrup Ipecac may be administered orally at the dose of 30 milliliters to an adult or a child over 40 to 45 kilograms, 15 milliliters in a child 1 to 12 years old and 5 to 10 millilitres in a child 6 to 12 months (consider administration in a health care facility).

After the dose is given, encourage clear fluids, 6 to 8 ounces in adults and 4 to 6 ounces in a child. The dose may be repeated once if emesis does not occur within 30 minutes. If emesis is unsuccessful following 2 doses of ipecac, the decision to lavage or otherwise attempt to decontaminate the gut should be made on an individual basis. Two doses of ipecac pose little inherent toxicity.

Gastric lavage is performed only after control of any seizures present. Gastric lavage with a large-bore orogastric tube (adult: 36 to 42 French; child: 24 to 32 French) may be indicated if performed soon (1-2 hour) after ingestion, or in patients who are comatose or at risk of convulsing. Protect airway by placement in Trendelenburg and left lateral decubitus position or by cuffed endotracheal intubation. Lavage with 150 to 200 millilitres lukewarm tap water or saline per wash (in children over 5 or adults) and 50 to 100 millilitres of normal saline per wash in young children.

Continue until lavage return is clear. Volume of lavage return should approximate fluid given to avoid fluid-electrolyte imbalance. Complications of gastric lavage have included esophageal perforation, charcoal empyema, laryngospasm, EKG changes, dysrhythmias, and fall in mean PO₂.

Activated charcoal may be administered as slurry; charcoal slurry may be aqueous, or as a mixture of charcoal with saline cathartic or sorbitol. The FDA suggests a minimum of 240 milliliters of diluent per 30 grams charcoal. Optimum dose of charcoal is not established; usual dose is 30 to 100 grams in adults and 15 to 30 grams in children; some suggest using 1 to 2 grams per kilogram as a rough guideline, particularly in infants.

Administer one dose of a cathartic, which may be mixed with charcoal or given separately. Cathartics should not be used in patients who have an ileus. Saline cathartics should not be used in patients with impaired renal function. A dose of 20 to 30 grams (250 milligrams per kilogram in pediatrics) of magnesium sulfate or sodium sulfate, or magnesium citrate 4 millilitres per kilogram per dose up to 300 millilitres per dose, may be administered orally.

Sorbitol may also be given orally at the dose of 1 to 2 grams per kilogram per dose to a maximum of 150 grams per dose in adults, and 1 to 1.5 grams per kilogram per dose as a 35 percent solution to a maximum of 50 grams per dose, to children over 1 year of age. Cathartics need to be administered in a health care facility with close monitoring of fluids and electrolytes, especially in children. The safety of more than one dose of a cathartic has not been established. Repeated cathartic dosing should be done with extreme caution, if at all. Hypermagnesemia has been reported after repeated administration of magnesium containing cathartics in overdose patients with normal renal function. Administration of cathartics should be stopped when a charcoal stool appears.

Pyridoxine (Vitamin B6) 50 mg given orally three times daily functions as a co-factor for dopa-decarboxylase (the enzyme responsible  for peripheral metabolism of levodopa), and reverses the neurotoxicity of levodopa by increasing its peripheral decarboxylation. Themanagement of an acute poisoning of levodopa with carbidopa or benserazide is as for levodopa alone. However, pyridoxine should not be used since dopa-decarboxylase is already inhibited by both carbidopa and benserazide.

Dopamine Agonists

At present, the dangers of overdose with these agents seem minimal and treatable with supportive care. Ipecac induced emesis is generally not recommended due to the potential for CNS stimulation or seizures, especially following pergolide overdoses. Due to the mechanism of action of dopamine D2 receptor agonists, spontaneous emesis may be expected following an overdose.

Gastric lavage and activated charcoal may be administered as previously described. Gastric lavage would not be expected to be helpful unless a large number of tablets were ingested within 1-2 hour. An antiemetic may be used if vomiting is recurrent and persistent. Administer diazepam IV bolus 5 to 10 mg initially, repeat every 10 to 15 mi-nutes as needed (adults) or 0.2 to 0.5 mg/kg initially, repeat every 5 minutes as needed (children) or lorazepam IV bolus 4 to 8 mg (adults) or 0.05 to 0.1 mg/kg (children) to treat any seizures present. Dystonias and dyskinetic movements may also respond to diazepam. Monitor for hypotension, respiratory depression and the need for endotracheal intubation. Consider phenobarbital and/or phenytoin if seizures are uncontrollable or recur after diazepam 30 mg (adults) or 10 mg (children > 5 years). If hypotension occurs, administer IV fluids and place the patient in Trendelenburg position. If the patient is unresponsive to these measures, administer dopamine 2 to 5 mcg/kg/min (first choice) or norepinephrine 0.1 to 0.2 mcg/kg/min and titrate as needed, monitoring for possible exa-ggerated response. Since blood level are negligible and tissue distribution is significant, hemodialysis and hemoper-fusion are ineffective.

Anticholinergics

Treatment is primarily supportive and includes monitoring for the development of seizures, hypertension, rhabdomyolysis, and arrhythmias. Prevention of absorption may be accomplished by gastric lavage followed by activated charcoal/cathartic.

The use of gastric lavage and activated charcoal/cathartic is as previously described. Gastric emptying may be successful even if delayed. No data are available on the ability of multiple dose activated charcoal to adsorb anticholinergic agents. Additional studies are needed to establish efficacy of multiple dose activated charcoal in the treatment of anticholinergic toxicity.

Physostigmine is rarely used except in cases of otherwise refractory life-threatening emergencies and as a diagnostic challenge. In the presence of severe, life-threatening, intractable anticholinergic effects (such as hypertension, seizures, and arrhythmias) unresponsive to other agents, a therapeutic trial dose of physostigmine may be useful. Although coma may be reversed dramatically in some cases, physostigmine should not be used just to keep a patient awake. The anticholinergic effects can be reversed by slow intravenous injection of 2 mg physostigmine. The use of physostigmine has fallen into disfavour or abandoned due to its ability to cause an increase bronchial secretions, bronchospasm and convulsions. Bethanechol has been used to alleviate peripheral anticholinergic side effects. Alkaline diuresis and mannitol may be used to treat rhabdomyolysis. Induction of emesis is not recommended because of the potential for CNS depression and seizures. Diazepam is the drug of choice to be used if sedation is required. Hemodialysis, hemoperfusion and peritoneal dialysis are ineffective in removing these agents.

Amantadine

Treatment should be directed at maintaining cardiovascular function and reducing CNS stimulation. Amantadine may produce cardiac arrhythmias for many hours after an ingestion.

Gastric lavage and activated charcoal may be administered as previously described.

Activated charcoal should be the first agent given in a large ingestion because of seizure risk. The efficacy of multiple dose charcoal in amantadine overdose has not been established. Emesis is not recommended due to potential for seizures and CNS depression. Similar treatment as described earlier are recommended for the management of seizures and hypotension. Treatment of premature ventricular contractions (PVCs) may include lidocaine, propranolol, phenytoin, or overdrive trans-venous pacing. Atropine may be used when severe bradycardia is present and PVCs are thought to represent an escape complex. If there is evidence of torsade de pointes, hemodynamically unstable patients require electrical cardioversion. Emergent treatment with magnesium, isoproterenol, or atrial overdrive pacing is indicated. The dosage regimen of magnesium sulfate is 2 g IV over 1 to 2 minutes, followed by a second 2 g bolus and infusion of 3 to 20 mg/minute in patients not responding to the initial bolus or with recurrence of arrhythmias (adults) or 25 to 50 mg/kg diluted to 10 mg/mL for IV infusion over 5 to 15 minutes (children). For isoproterenol, give 2 to 10 mcg/minute (adults) or 0.1 to 1 mcg/kg/minute (children) by continuous monitored IV infusion; titrate to heart rate and rhythm response. A 2-mcg/mL solution may be prepared by mixing 1 mg isoproterenol hydrochloride in 500 mL of D5W. Hypovolemia must be corrected first before using isoproterenol. Institute overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Avoid class Ia antiarrhythmics (quinidine, disopyra-mide, procainamide, aprindine) and most class III antiarrhythmics (N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with torsade de pointes. If there is manifestation of CNS stimulation such as bizarre, psychotic behaviour that cannot be controlled, diazepam 10 to 20 mg orally to adults or 0.1 mg/kg in children, may be tried. Hemodialysis is not expected to increase drug elimination since amantadine has a large volume of distribution (5 L/kg), but may be an appropriate method to remove the drug in a patient with no renal function.

Selegiline

Induction of emesis is not recommended because of the potential for CNS depression and seizures.

Gastric lavage and activated charcoal/cathartic may be administered as previously described. For severe CNS excitation, small incremental doses of IV diazepam 2 to 10 mg (adult) or 0.1 mg/kg (child) may be administered slowly, and repeat if necessary.

Administer diazepam IV as stated earlier to treat any seizures present. If symptomatic hypertension is evident, phentolamine 2.5 to 5 mg every 5 minutes until hypertension is controlled, then every 2 to 4 hours as needed (adult) or 0.05 to 0.1 mg/kg/dose every 5 minutes until hypertension is controlled, then every 1 to 4 hours as needed (child), or IV nitroprusside 1 mcg/kg/min IV infusion (adult and child). Close monitoring of vital signs and EKG are required with the use of these agents.

Hyperthermia should be managed with external cooling. Dantrolene has been used with some initial success in treating hyperthermia. Early neuromuscular paralysis, intubation and ventilation in patients with a core temperature of greater than 39⁰C. Other monitoring parameters include liver and renal function, CBC, and fluid and electrolyte balance, creatine phosphokinase levels (especially in patients with muscular hyperactivity).

Conclusion

Parkinson's disease patients are at high risk of poisoning from agents producing either dopaminergic or anticholinergic actions or both. It is vital to provide meticulous supportive care and monitor patients for development of complications of poisoning, including arrhythmias with hemodynamic disorders, seizures and hypotension. Prevention of absorption may be accomplished by gastric lavage followed by activated charcoal/cathartic. Gastric lavage is indicated for substantial ingestion of drugs within 1 to 2 hours of presentation. Emesis can be induced by the use of ipecac syrup in the management of levodpa overdose. Since levodopa is mostly prescribed in combination with a dopa-decarboxylase inhibitor, pyridoxine use as an antidote is not useful. Benzodiazepine agonists such as diazepam should be used to control convulsions and for sedation. The anticholinergic effects can be reversed by physostigmine but problems associated with its use render physostigmine into abandonment. Hemodialysis, hemoperfu-sion and peritoneal dialysis are likely to be ineffective in removing these drugs. Additional agents are required as deemed necessary based on the clinical judgment of the physician to manage other complications present. 

Viagra Arrives on April Fool's Day

This is no April Fool joke Viagra (sildenafil ) is here at last!

It received the approval of the Ministry of Health on April 1, giving April Fool's Day a new meaning for Malaysian: especially the estimated 1.6 million sufferers of erectile dysfunction (ED). It came just a few days after birthday, March 27, and after almost 300 news and reports found their way into our mass media.

Viagra, dubbed as `Pfizer riser' is therefore anxiously waited by many including the non-ED persons. But do not let the little blue pill fooled you. It is not for all men, and works in about 75% of the cases for ED. It is not an aphrodisiac, not a sex enhancer or stimulant. And like all medicines it has side-effects and carry its own risks, particularly when used inappropriately.

To ensure minimum risk, the following facts and guidelines are reiterated to assist patients and doctors in the correct use of the medicine.

• Patients taking nitrates in any form, including nitroglycerin and long-acting nitrates commonly used for chest pain, should not take sildenafil. In addition patients taking Viagra should not be administered nitrates. Large and sudden drop in blood pressure can occurs with the co-administration of these types of drugs.
• Viagra was developed and tested to treat men with ED. Men without ED has no use for the medicine. Similarly, the tablet has not be approved for use in women. Clinical trial testing in women has not given conclusive result.
• Viagra should be considered for use after a clinical evaluation that involves physical examination and medical history to confirm diagnosis of ED and to assess the appropriateness of the ED therapy.
• Since ED is often associated with serious and chronic medical conditions such as diabetes and hypertension, Viagra labeling notes that a medical examination can be important in identifying causes that may themselves require treatment.
• As stated in the label for Viagra, there is some degree of cardiovascular risk associated with sexual activity, particularly among older patients with known cardiovascular disease. Because sexual intercourse increases the heart rate as well as the cardiac work load, patient's cardiovascular status should be medically assessed prior to the resumption of sexual activity or initiation of any treatment for ED.

In December 1998, PRN has launched a special website called `ViagrAlert' (http://prn.usm.my/viagra.html) in anticipation of this day. We believe patients and doctors must be fully informed about the drug before the attempt to use or prescribe it. ViagrAlert is aimed at assisting in this learning process. It provides various level of information through daily news updates, information for consumers and professionals, various articles and readings on the subject, including impotence.