prn8099 - Number 9, August 1996

What's in a name? A decade ago it was Narcotics. Now it's Ecstasy! Such drug related names were once alien to our culture, but somehow today has become embedded in it. And like the drug effects themselves, they tend to linger on forever. One can't help but to wonder what will be next and when will all these ends.

Although mind-altering substances have been used in many cultures, this seems not to be the case for Malaysia. If we take a look at our own history, there were not many substances of abuse that make part of our tradition. Malaysia too has never had the tragedy of dimensions like that of the opium war in China, or even neighbouring Golden Triangle. Indeed Ganja seems to surface only quite recently as a social menace. There is of course Daun Biak, but again its use is rather isolated that until today it has not been of grave concern. The immediate threat is of course the "imported stuff" as a result of illicit trafficking that is indeed a lucrative trade. It is said to be only second to armaments in terms of monetary value worldwide, that is about 10 per cent of all international trade. The United Nations International Drug Control Programme estimated that the turnover was as high as USD400 to USD500 billion (about RM1 to RM1.25 trillion) annually.

So today when we talk about substance of abuse we are talking about scourge and epidemic proportions. The government and the public at large have been greatly disturbed, and often times a panic apprehension developed. We have even coined a special word "dadah" that serves to keep the issue in focus, while declaring it as the nation's number one enemy. Many resources have gone into containing it so much so that various efforts have been institutionalised nationwide, albeit modeled on Western concept. Seminars after seminars were held. Various programmes were implemented. But true to their nature these substances kept reminding us of their presence through countless sufferings and miseries, sometimes taking extra dimensions like crimes and prostitutions, and more recently demonstrations and riots.

Our records in the dadah war have of course been laudable. Malaysia has always stood firm in dealing with this issue even when other countries seemed fit to label our drug laws 'barbaric' at one time. Malaysia has repeatedly called for a global war against dadah trafficking at various international forums. But at the end of it all the verdict is pronounced and we are rudely awakened by the statement that "our dadah programme have failed." This is a fact recognised even by the highest office in the country. It is a harsh sentence, but kind of sobering because admitting of our own failures will give us a new lease of life in battling with the problem. Much like the addicts themselves, recognising and admitting the problem forms part of the long-term solution.

Consequently, its time for us to contemplate on a new strategy more effectively. After all dadah abuse has left in its wake more than 200,000 addicts and a rising demand for drugs. Last year for example Malaysia registered about 13,140 new drug addicts (compared to 11,672 in 1994); translating that to a shocking 1,095 new addicts a day. In the first three months of this year alone, 3,518 new addicts were picked up, a rise of 38 per cent over the same period last year. And what with the high rate of relapse of ex-inmates, for example 20,964 in 1995 (3,860 more than 1994). The 1995 Dadah Report issued by the Anti-Dadah Task Force under the Prime Minister's Department confirmed that these figures were the highest since 1988. It humbly submits that this shows that "the preventive measures taken were still ineffective."

Such drastic redemption is perhaps timely because for the last 20 years, anti-drug activities had been handled by many agencies under different ministries. Foremost is the Anti-Dadah Task Force under the National Security Council, and the Rehabilitation and Treatment Department under the Home Ministry. This is not taking into account other non-governmental as well as voluntary organisations that have contributed in their own ways to cope with the problems. Despite these, drugs continue to plague the country and newer ones are making their grand entrance. Thus, though the effort has been substantial and varied, it is also indicative of some rooms for improvement for greater and better participation. To quote the Deputy Home Minister recently: "We want to open's everybody's eyes to show that all is not well and that it is not only the Government's problem but everybody's."

With the setting up of the National Narcotics Agency under the Home Ministry there seem to be a renewed attempt to 'put the house in order' as suggested by its newly appointed director-general. This new set-up is under the National Narcotics Council chaired by the Prime Minister. Expectations are of course very high, not least because the problem has been dragging on for far too long and consuming too many lives. Moreover, we are much wiser now given more than two decades of experience in fighting the dadah problem. It also means that we need to discard old mindsets and to undergo a process of rehabilitation ourselves so that we can be more assured of success this time around. The narrow political platform, as well as self-serving and empire-building tendencies must be dropped immediately in the interest of the nation. We must rise above individual needs and together focus in a concerted way the need of saving precious lives plagued by these insidious substances.

The situation is made even more critical now that there is a constant threat of AIDS associated with dadah users, another on-going and desperate war. Injecting drug users (IDU) are said to make up more that 75 per cent of the 15,471 people known to have HIV, the virus that causes the deadly disease. All in all it is a pervasive problem that cuts across geographical and sociocultural boundaries making it even more difficult to dislodge. Meanwhile, the numbers in the various categories grow steadily day by day.

Nicotine addiction - The Missing Link

Verily the dadah war is not just about substances as being emphasised in the more traditional moral-legal sense, where drugs are usually classified as either 'safe' or 'dangerous'. All drugs of abuse belong to the latter which follows that some are illicit and therefore illegal. Nevertheless, when it comes to the question of addiction this dichotomy in itself poses a problem, since there are a number of substances that are addictive and dangerous but are considered legal. Tobacco and alcohol for example are just two cases in point and due to this very reason they have never been targeted in the dadah war previously. Yet they are known to give rise to serious problem of addiction, and are quite frequently abused by millions everyday. In other words, our framework in combating dadah has fallen short despite the millions spent each year.

Tobacco in particular continues to enjoy widespread publicity sometimes to the point of being promotional. "Peddling" cigarettes is still allowable under the law and largely condoned under various disguises. Efforts to curb its use has not been comprehensive enough. What's more frightening is that a good majority seems oblivious that tobacco contains an addictive substance called 'nicotine' and that some are themselves addicts - nicotine addicts. While there are attempts to limit the use of tobacco in the country there have been conflicting viewpoints in support of the tobacco companies apparently because of their massive financial support. As such the mass media's occasional public education messages about the harmful effects of tobacco-smoking are over shadowed by the much more beguiling advertisements of the so-called indirect tobacco promotion. On occasions decision-makers and policy-planners have been quoted as saying that tobacco-sponsored advertisements are generous sources of income, without the slightest mentioned of the long-term health and social consequences of smoking. This is in a way ironic because other addictive drugs too can bring an even fatter revenue if only they are allowed to be promoted like that of tobacco. However fortunately this is not to be for very obvious reasons - medical, health and social. Why this same argument is not applicable to tobacco is really beyond comprehension.

Notwithstanding this, it must be categorically stated that tobacco use has been implicated in one way or another to the question of illicit drug use. According to the Director-General of the World Health Organization (WHO): "The problems no longer relate to the use of only one or a few drugs. More often, users move from one drug to another and use combinations of different substances. In many societies, habit-forming exposure to tobacco, alcohol and drugs can start at a very early age, with grave consequences for health in later life." In fact as far back as 1990, WHO established the Programme on Substance Abuse that addresses problems, both on health and social aspects, of the use of various forms of psychoactive substances, including alcohol, tobacco, pharmaceuticals, illicit drugs, indigenous plants and inhalants. In other words, the complexities and scope of the dadah problems today requires a total and comprehensive approach than what was attempted before.

This is imperative because as discussed in an article in a WHO-sponsored bulletin, World Health, (July-August 1995): "The new concept that smoking induces nicotine dependence means that this is considered an addictive drug. This fact is gaining support from international scientific agencies. Many studies, including some which have been concealed by the tobacco industry, show that nicotine does produce chemical reactions in the body similar to those produced by heroin and cocaine." "The relapse rates of dependent persons trying to quit using nicotine, alcohol, cocaine and heroin are roughly the same; many even report that it is harder to quit tobacco than various illegal drugs." In fact, a recent study by the Center on Addiction and Substance Abuse at the Columbia University in US confirm that nicotine is a "gateway drug" which is associated with the use of illicit substances. According to the study, adults who started to smoke before the age of 15 are three times as more likely to be regular hard drug (including "narcotics") users and more than twice as likely to be regular cocaine users than those who started smoking at 18 or older. Children who smoke daily are 13 times more likely to use heroin than children who smoke less often. All these new scientific findings and information should be seriously considered in conceptualising and developing a new and bold approach to deal with the enlarging dadah problem.

In short, we clearly need to rethink our new strategies in the continued fight against dadah, to encompass that of tobacco and alcohol abuse. This is so important in order to avoid the pitfalls of the yesteryears. The task ahead will not be an easy one. So-called socially accepted forms of drug use, including intoxication on specified festive occasions, have always been strongly defended when even governments tried to ban them. It is precisely because of this that a clear and definite policy statement is badly needed as part of the new battle plan. Similarly it is incumbent therefore that the National Narcotics Agency interprets its responsibility beyond that of the traditional moral-legal definition of the word "narcotics." The problem of tobacco addiction can no longer be glossed over if Malaysia is serious about realising its own vision by the year 2020. In fact, it has been estimated that by the 2020s, of the 10 million global annual tobacco death toll, about 7 million death will involve population of the developing countries, including Malaysia; while millions more will pick up the addictive habits making our chance in winning the dadah war a near impossible task.

We are indeed at crossroads. We must decide on not only doing the things right; equally important doing the right things as well. Otherwise as remarked by Dr. Judith Mackay, the Director of the Asian Consultancy on Tobacco Control: "History will look back and ask why it took us so long to ban tobacco advertising. Future generations will have difficulty in comprehending why glamorous and seductive promotions were allowed of a product which, over 30 years, was known to be dangerous and addictive - killing one in two of its lifelong users." It is therefore important for all of us to join forces in smoking out all types of substance abuse from our society. 

PRN CONSULT          

Review of GLYPHOSATE Poisoning 
Mohd. Isa Abdul Majid, Ph.D. 

Glyphosate is a broad-spectrum, non-selective systemic herbicide. It is useful on essentially all annual and perennial plants including grasses, sedges, broad-leaved weeds and woody plants. It can be used on non-cropland and among variety of crops. Glyphosate is a non-selective post-emergent herbicide that is translocated to all parts of the plant. It inhibits the shikimic acid pathway in the plant's production of aromatic amino acids, chlorophyll and carotenoids. With these processes inhibited, the plant slowly withers and dies with effects being seen within 2-7 days. Animals do not have the shikimic acid pathway and no direct action in mammalian systems has been demonstrated.

The chemical name of glyphosate is N-(phosphonomethyl) glycine. While it can be described as an organophosphorus compound, glyphosate is not an organophosphate ester and it does not inhibit cholinesterase activity. The presence of a phosphono-group in the structure has been incorrectly interpreted as an organophosphate which suggests cholinesterase inhibition in such poisoning cases. Retrospective studies on glyphosate poisoning have shown atropine and pralidoxime been mistakenly administered to such poisoning cases.

What are the available pesticide products containing glyphosate and the content of glyphosate in each product?

Based on the approved pesticide listing in Malaysia , there are 172 herbicide products which contain glyphosate. Table 1 shows the various products that contain glyphosate and their contents. These products can be classified into two main groups based on the supplied concentrations.

Technical glyphosate is normally supplied as a white solid material which is poorly soluble in water. The concentration range for the technical grade is usually between 70-95%. Besides, the technical grade that is normally supplied to large plantations, the commercial products being supplied to small scale plantations and farmers are in the concentration range of 13-41% w/w and require dilution with water before application. The majority of the glyphosate containing herbicides are supplied as the isopropylamine salt in combination with various surfactants including the polyethoxylated amine non-ionic surfactant that allows the herbicide to spread over the plant leaves. In some reports, the toxicity arising from glyphosate products is said to be caused by the surfactant incorporated into the formulation rather than the active ingredient. Besides the isopropylamine salt, other glyphosate salts commonly found in Malaysia are the monoammonium, sodium and trimesium salts. Glyphosate is also available as a combination product in formulation with other herbicides. The active ingredients used in combination with glyphosate include picloram and terbuthylazine.

Besides the active ingredient and the surfactant which are thought to cause the clinical effects seen in a poisoning exposure, the by-products that are found in glyphosate formulations are also responsible for some clinical effects. These identified by-products include ethylene glycol that may be found with the surfactant in the formulation and isopropylamine which is a by-product of the herbicide manufacturing process. The final concentrations of these by-products in the commercial products are expected to be very low. If these products are further diluted for regular use, the minute concentrations of these by-products are probably not significant.

What are the signs and symptoms of glyphosate poisoning?

In cases of glyphosate ingestion, a review on the common signs and symptoms associated with commercial products containing 41% glyphosate (n=246 cases) showed the following features:

On the other hand, it has been suggested that the clinical effects seen in a glyphosate poisoning may be divided into minor to moderate and significant exposures. By having the severity classification, a different treatment strategy could be employed to manage the poisoning cases.

The recommended severity classification is as follows:

Minor to moderate (ingestion up to 130ml of 41% commercial formulation):

• Transient symptoms localized to oral mucous or GI tract
• Duration of GI symptoms for less than 24 hours, endoscopically verified esophagitis, oral ulceration, transient hypotension or oligouria, pulmonary dysfunction not requiring intubation, transient hepatic or renal damage and acid base disturbance

Severe (ingestion of about 200 ml of the 41% commercial formulation):

• Pulmonary dysfunction requiring intubation, renal failure requiring dialysis, hypotension requiring pressor amine treatment, cardiac arrest, coma, repeated seizures, death.

When an exposure to glyphosate occurs locally, the clinical effects seen are usually classified as mild to moderate effects. These local effects include:

• exposure to the skin may result in erythema, piloerection and contact dermatitis. It is expected that the severity of a skin exposure will be significantly decreased with a less concentrated product. As the contact time with the product and the skin is decreased, the severity of a reaction will also be decreased. Also, animal experiments showed that significant absorption through the skin does not occur (0.5% in 24 hours on the shaved abdomens of monkeys).
• eye exposures, corrosive effects would not be expected from the formulated consumer products, especially after dilution. Among the most common effect seen from eye contact with the herbicide is mild conjuctivitis which normally cleared in 1 to 2 days. It is expected that the consequences of an eye exposure will be less severe with a less concentrated product. Rapid removal of the herbicide from the eye by irrigation reduces the likelihood of serious effect. In addition, there have been several cases of prolonged pain after exposure but these were attributed to the presence of a foreign body. In a retrospective review of 223 human eye exposures to a commercial product of glyphosate, 11.2% were judged to have no effect, 73.8% had a minor effect (primarily conjunctival irritation) and 3% had a moderate effect (Grade 1 corneal epithelial injury).

What is the mechanism of glyphosate toxicity?

At present, the mechanism in which glyphosate exert its toxic effect seems to be inconclusive. Although there have been various animal studies done to look into the toxic mechanism, the interpretation of the significant findings to clinical studies have produced conflicting evidence.

Several reports mentioned that the surfactant, non-ionic polyoxyethylene tallow amine being used in a glyphosate product (RoundUp() is responsible for the clinical syndrome following massive ingestion. Animal pharmacological studies indicate that the surfactant produces the hypotensive effect when the surfactant was adminisitered intravenously into dogs. In addition, comparative systemic toxicities between glyphosate and the surfactant in rat supported this theory where the median lethal dose of the surfactant was higher as compared to the glyphosate (oral LD50 5000 mg/kg versus 1200 mg/kg, respectively ). Although a correlation is shown to the effect of the surfactant in animal studies, the interpretation of this data to clinical situation must be done cautiously.

At the cellular level, it has shown that the toxicity of glyphosate in humans and animals was related to the ability of the compound to uncouple the mitochondrial oxidative phosphorylation. However, this effect has not been conclusively proven as the clinical effects normally seen with agents that uncouple oxidative phosphorylation such as tachypnea and tachycardia were not consistently seen with glyphosate poisoning and no cases of significant hyperpyrexia were encountered.

How is glyphosate poisoning managed?

Treatment for minor exposure:

In cases of dermal exposure, the management of such exposure involves removing all contaminated clothing and flooding the skin surface with water. Following this, the exposed skin is then washed with soap and water. A close examination of the skin may be required if pain or irritation exist after decontamination. All contaminated clothing should be laundered before being worn again.

In eye exposures, the exposed eyes should be irrigated with copious amounts of water or saline for at least 15 minutes. Pour the water from a cup or glass held 3 inches from the eye. A close examination of the eyes may be needed if pain or irritation exists after 15 minutes of irrigation with water or saline.

If an ingestion involves dilute preparation of glyphosate preparations such as 2% w/w preparation, irrigate the mouth with water. Other immediate therapy includes dilution with water or milk if the patient is able to swallow. If this is done, do not exceed 5ml/kg body weight in a child or 250 ml in an adult. Further gastrointestinal decontamination is not needed, even if spontaneous vomiting has not occurred.

Treatment for significant exposures:

There is no available antidote for glyphosate poisoning and treatment is largely symptomatic in nature.

In any significant ingestion exposure, the acute syndrome of glyphosate/surfactant toxicity may occur within the first 24 hours of ingestion and may progress rapidly. These cases of significant ingestion, in particular greater than a mouthful (>0.5ml/kg) of larger than 41% glyphosate concentration should be evaluated by a physician and considered for admission based on the clinical condition of the patient.

Prevention of absorption

Table 1: Registered Pesticides containing Glyphosate

Prevention of absorption

Lavage may be considered if no significant spontaneous vomiting has occurred. Gastric lavage may be very effective if performed within 1-2 hours post ingestion. However, if a co-ingestant has pharmacologic properties that slows gastrointestinal motility, lavage may be indicated, even after a prolonged post-ingestion time. A soft nasogastric or orogastric tube should be inserted by experienced personnel and suction should be performed within 1-2 hours of ingestion. Lavage can be performed with 150-200 ml/wash of at least room temperature water (some advocate warming the lavage fluid) or saline in adults while 50-100 ml/wash or 10 ml/kg/wash of normal saline are used in children. Continue until the return is clear. Lavage return should roughly equal the amount of liquid given.

The general value of induced emesis is controversial at this time. Glyphosate/surfactant products are irritating to the mucosal lining of the gastrointestinal tract (a property that usually contraindicates induced emesis).

Activated charcoal is also given to absorb remaining glyphosate (1-2 gram/kg of charcoal if used). The dose to be given is 15-30 grams for children while for adult 50-100 grams orally or by tube in a charcoal/sorbitol slurry if the patient is awake and the airway is protected.

Cathartics speed gastrointestinal transit time and decrease the time that the drug or chemical is available for absorption. Cathartics also hasten the elimination of the charcoal/drug complex in the GI tract. A point to note in the use of cathartics is that the use of cathartics may exacerbate hypovolemia.

The recommended doses for cathartics are as follows:

Citrate of magnesia:
Children and Adults: 4 ml/kg, up to 300 ml as a single dose.

Sorbitol:
Adults: 1-2 gram/kg/dose up to 150 grams.

Children: The exact dose response is not yet determined. For children over 1 year of age, a dose of 1.0-1.5 gram/kg/dose as a 35% solution to a maximum of 50 gram/dose is usually given.

Enhanced elimination

Forced diuresis

Glyphosate is excreted very well by the kidneys. Adequate urine flow will ensure the rapid elimination of glyphosate. Although this elimination theoretically should be enhanced by force diuresis, there is no clinical evidence that this is necessary. Fluid overload to induce diuresis may precipitate pulmonary edema.

Hemodialysis and hemoperfusion

Haemodialysis and charcoal haemoperfusion are probably effective at removing glyphosate from the blood, but there is no clinical evidence that this is necessary or that it improves clinical outcome. Haemodialysis should be performed in the patient with renal failure.

Blood pressure monitoring

Monitor the patient closely for signs of haemodynamic instability. The insertion of a catheter (Swan Ganz) to monitor pulmonary wedge (left arterial) pressure may be warranted in cases of severe or prolonged hypotension, particularly in the setting of pulmonary edema. (The use of a Swan Ganz catheter may also help in detecting hypoxemia and in preventing fluid overload from transfusion; see below). If the patient is hypotensive, administer IV fluids to assure adequate circulating blood volume. As a precautionary step, care should be taken when administering IV fluids to a patient at risk for developing pulmonary edema. Fluid overload may precipitate pulmonary edema. Monitor the patient's respiratory status closely. If the patient is unresponsive to these measures, administer a vasopressor if needed.

Dopamine

Dilute in normal saline or dextrose/saline to produce a 400 mcg/ml dilution. Administer 2-5mcg/kg/min of dopamine titrating if needed to as high as 20-30mcg/kg/min. Rarely doses up to 50mcg/kg/min have been administered but with levels above 20-30mcg/kg/min renal shutdown and/or ventricular dysrhythmias may occur. Decrease the rate of administration if ventricular dysrhythmias occur or with increasing ectopic beats. Titrate the patient dose to the lowest required dose.

If the patient is unresponsive to dopamine at a rate 20-30 mcg/kg/min, consider an alternative vasopressor such as noradrenaline, adrenaline or phenylephrine.

Noradrenaline

Dilute in 1000ml of normal saline or dextrose/saline to produce a 4mcg/ml dilution. Begin at 0.1-0.2mcg/kg/min and increase as needed.

Adrenaline

Adult: Administer 0.5-1.0mg (usually 5-10ml of 1:10,000 solution) by slow IV injection. This may be repeated every 5 minutes as needed. The initial injection may be followed by 0.3mg of adrenaline subcutaneously or an IV infusion of 1mcg/min, increasing the rate up to 4mcg/min as needed.

Child: Administer 0.01mg/kg (0.1ml/kg of a 1:10,000 solution) slow IV and may be repeated every 5 minutes as needed; also adrenaline can be infused intravenously at a rate of 0.1mcg/kg/min and can be increased in 0.1mcg/kg/min increments as needed up to maximum of 1mcg/kg/min.

Phenylephrine

Dilute in dextrose/saline or normal saline to produce a 1:50,000 (20 mcg/ml) dilution.
Adult: To raise the blood pressure rapidly, start the infusion rate at 100-180mcg/min.

Child: To raise the blood pressure rapidly, administer an IV bolus dose of 5-20 mcg/kg/dose and repeat as needed every 10-15 minutes. When the blood pressure is stabilized at a low normal blood pressure for the individual, one can use a maintenance dose rate of 40-60mcg/min. For children, the maintenance dose is 0.1-0.5 mcg/kg/min.

If a prompt initial vasopressor response is not obtained, additional increments of 10 mg may be added to the infusion bottle. Adjust the flow rate until the desired blood pressure is obtained. Avoid hypertension and check the blood pressure frequently. Headache or bradycardia may indicate hypertension.

Monitor blood gases and obtain x-ray

Consider the use of repeat blood gases and a peripheral pulse oximeter to monitor hypoxemia. Observe closely for acidosis. In all but minor cases, a chest X-ray as early as the patient's condition permits should be taken, if only as a baseline.

Pulmonary edema

Closely monitor arterial blood gases. If PO2 cannot be maintained above 50mm Hg with inspiration of 60% oxygen by face mask or mechanical ventilation, then positive end expiratory pressure (PEEP) or continuous positive airway pressure (CPAP) may be needed. Avoid a positive fluid balance by careful administration of crystalloid solutions. Monitor fluid status through a central venous line or Swan Ganz Catheter.

Routine use of furosemide/frusemide (Lasix() is not recommended. Indications for furosemide use are fluid overload and left ventricular heart failure. Furosemide dose (if needed):

Adults: 20-80mg IV.
Child: 1-2mg/kg/dose IV up to 2-4 mg/kg/day.

Antibiotics should be administered only when there are signs of infection.

Acidosis

Administer sodium bicarbonate to counteract metabolic acidosis (adult dose 1-2mEq/kg every 1-2 hours; children's dose 1 mEq/kg). It may be given more frequently for severe acidosis. The goal of bicarbonate therapy is a partial correction of the pH to 7.2-7.3 and a serum bicarbonate of no more than 15 mEq/1. As a precautionary step, correction to a normal plasma bicarbonate level should not be achieved because hyperventilation will continue after the pH correction and may lead to alkalosis. Bicarbonate use in children especially, must be guided by clinical judgment and experience with careful attention to laboratory results of acid/base balance, such as blood gases and electrolytes.

NOTE: If the patient is in a poor cardiac state and may be requiring pressor or inotropic support, it may become necessary to correct the pH further, based upon clinical judgment, blood gases and other laboratory criteria.

Monitor renal status

Assure adequate urine output. Catheterize severely ill patients. Haemodialysis may be needed in the event of renal failure.