prn8099 - Number 18, June 1998

The Thirst for Safe, Clean Water

Water has been the subject of concern nationally for some time now. Although of late the focus has been on shortages and unscheduled interruptions, statements of concern about the quality of water sources found in this country have been expressed long before this. For example, way back in 1989, the World Resources Institute has been quoted as saying that in Malaysia, palm oil and rubber effluents, in addition to other industrial wastes and sewage, have caused 42 rivers to be officially labelled as ‘dead.’ Still other figures seem to indicate more rivers are being badly polluted between 1992 and 1993 with the number rising from 6 to almost double (11) a year later. An official report of the state of the river for the period 1987-1993 mentioned that the quality of water deteriorated at the rate of 1.19 percent per year. The seven-year trend showed that overall, 67 of 87 rivers monitored (77%), had suffered the onslaught of increased pollutant loads from industrial and domestic effluents, sewage and animal waste, and silt. Of the 116 rivers monitored in 1993, 35 rivers remained filthy with sewage and animal waste. In 1992, "Love Your River Campaign" was launched nationwide.

However, the 1995 Air and Water Quality Index continues to reveal that agricultural activities, land clearing and discharge of industrial waste have worsened the water quality of rivers, notably in Perak. This time ammoniacal nitrogen discharged by the rubber estate and latex-based factories were identified as the main pollutants of the rivers. Electroplating and textile industries were also implicated. Similar observations were made in 1996 as exemplified by the following reports.

Further, in 1997 just barely a month into the year, the death of an estimated 50,000 fishes - keli, lampam, putih - in Sungai Semberong, Kluang made the front page of a national daily; again water pollution was implicated as the probable cause. Unfortunately this is not an isolated case.

Sometimes, it is not just the factories that are culpable. In May, DOE expressed concern that untreated effluent discharge from resorts and residential areas in Tioman and Kuantan has polluted the rivers and seas to a worrying level. The bacteria E. coli suspected from sewage has been isolated.

The same trend is observed so far for the first half of 1998.

The significance of all these is becoming more and more apparent especially in times where not only the quality but also the quantity of our water sources are depleting fast. Our taps are running dry and people have very little choice. Many are focusing on natural sources. With so many of our rivers are in an ailing state, if not ‘dead’ like those declared by the World Resources Institute, groundwater is now seen as an alternative. Here too the situation is not ‘watertight’.

The slipping groundwater

Forests, being part of the hydrologic cycle has always been regarded as integral to water conservation. Unfortunately rapid economic growth, especially when it involved deforestation has also put pressure on the sources of groundwater. In times of dry spell for example, rivers will continue to flow so long as forests are able to absorb and store enough water during wet seasons through their root systems. The stored water will in turn be released into the groundwater system which is said to be the main source of base flows for rivers, lakes and wetlands. But it too is also being threatened by increasing use of agrochemicals and, inappropriate soil and water management. According to the United Nations in conjunction with the 1998 World Water Day, many groundwater sources are being polluted by the dumping of toxic wastes and by slow seepage of agrochemicals through the soil. Untreated human waste can also be a threat to groundwater as a result of diffuse pollution and leaks in the sewage system. Shallow wells and stagnant pools are more easily contaminated with animal waste. Going by the past, it is also shocking to find out how vulnerable our water catchment areas are to being contaminated.

As such groundwater can no longer be wholly relied upon as safe water sources. Instead it may well be the source of waterborne diseases like cholera.

Thus, given the unprecedented demand on water supplies - that are today already sporadic and of poor quality - combined with periodic droughts and floods, and unregulated industrial pollution, almost half of the available resources will be depleted by the turn of the century, according to a book entitled Water: Asia’s Environmental Imperative. Ironically this will in turn impinge on the nation’s economic development and in addition erode the quality of life due to various health problems. More strains are then added to the nation’s already shrinking expenditures.

Now, it is therefore up to us to conserve and manage our water sources judiciously in order to arrive at a prospect of sustainable use of whatever water sources left.

We should have paid more serious attention to a 1989 report - Water for Agriculture: Facing the Limits - published by the Worldwatch Institute and partly supported by the United Nations, which predicted that changes in the world temperature are nearly certain to change patterns of rain and of water supply for several decades.This is in addition to factors like overconsumption, poor management and - most important - rapid population growth in the Third World that will lead to water shortage.

To quote the New Delhi Statement (1990) issued after the Save Water 2000 Conference: Uncontrolled pollution puts further stress on the living environment and aggravates competition for increasingly expensive water sources. Without fundamentally new approaches, the hardship will turn into an unmanageable crisis. We are seeing the beginning of this crisis today and we badly need innovative approaches.

As much as we thirst for development, the thirst for safe, clean water is something that we may not be able to bear for much longer. Human beings can scarcely live four days without water! Like us humans, water is the blood and lymph of the biosphere that must be protected at all cost. Our lives depend on it.N

Why saving water is crucial?

• Industry uses staggering amounts of water: Up to 568,750 litres for a tonne of printing paper; 910,000 litres for a tonne of aluminum; about 2.275 million litres for a tonne of synthetic rubber; 70 litres to refine a litre of petrol; about 30.48 metric tonnes of water to produce a tonne of plastic
• In one year, a typical domestic user contaminates 59,150 litres of clean water to flush away only 750 litres of the body’s wastes
• More than 2 million ch ildren under the age of five in the Third World die every year from drinking polluted water
• 97.4 percent of Mother Earth are covered by oceans. Of the remaining 2.6 percent, which is freshwater, only 0.8 percent is available for drinking and irrigation purposes. The rest is buried deep underground (some beyond human reach), or frozen in icecaps and glaciers.
• To produce 4 litres of milk, a dairy cow needs to drink 16 litres of water
• It takes 16 litres of water to grow a tomato

Source: Water-Asia’s Environmental Imperative, Singapore: AMIC, 1997

 Review on 

Poisoning Involving Barbiturates

by Mohd Baidi Bahari PharmD

Barbiturates are a group of drugs used as hypnotic and sedative agents, for induction of anesthesia, management of epilepsy, status epilepticus and sometimes in the management of hypertension in pregnancy and neonatal hyperbilirubinemia. Barbiturates enjoyed popularity in the early part of this century, but their use has decreased and being replaced by other drugs especially benzodiazepines for the sedative and hypnotic effects. The decrease in the barbiturates use has been associated with the decrease in the incidence of barbiturate poisoning.

What are the types of barbiturate available in Malaysia

In Malaysia, barbiturates are classified as Dangerous Drug Group A available only on prescription. Their use is controlled under the Dangerous Drug and Psychotropic Act 1952. The types of barbiturate available in Malaysia are as listed in Table 1. All barbiturates are derived from barbituric acid and they are differentiated based on its duration of action. This difference is used for the classification of barbiturates into ultra-short, short, intermediate and log acting barbiturates.

Barbiturates are derivatives of barbituric acid, 2,4,6-trioxohexahydropyri-midine, a compound that is without central nervous system activity (Figure 1). Substitution of the R1, R2, or R3 changes the lipid solubility of the barbiturate and confers sedative and hypnotic activities. A high lipid soluble barbiturate (i.e. thiopentone) has a rapid onset and shorter duration of action as compared to a barbiturate with a low lipid solubility (i.e. phenobarbitone). This difference is used for the classification of barbiturates into ultra-short, short, intermediate and long acting barbiturates (Table 1).

At what dose will poisoning occur?

The dose or amount of barbiturates required to cause poisoning is depending on the type of ingested barbiturate. Toxic fatal dose of a long-acting barbiturate such as phenobarbitone is igher (6-10gm) as compared to the short-acting barbiturates such as pentobarbitone and secobarbitone, which is only 2-3gm.

The extent and severity of barbiturate poisoning is influenced by the dose and type of ingested barbiturates. High lipid soluble barbiturate such as thiopentone produces toxicity at relatively lower dose as compared to the water soluble barbiturates such as phenobarbitone. This variation is secondary to the difference in the ability of the drugs to penetrate the CNS. Ingestion of other CNS drugs such as alcohol and benzodiazepines may worsen the severity of CNS toxicity of the barbiturates.

Barbiturate overdose is manifested by the oversuppression of the CNS. The manifestations of CNS suppression is dose dependent. In mild overdose, lethargy, slurred speech, nystagmus and ataxia are common. In severe acute overdose, CNS and respiratory depression may progress to Cheyne-Stokes respiration, areflexia, oliguria, tachycardia, hypotension, hypothermia and deep coma with slight constriction of the pupils. The blood pressure will drop secondary to the direct effect of the drug and hypoxia of the medullary vasomotor centre leading to arteriolar dilation, depression of cardiac contractility and vasomotor smooth muscle. Death may occur as a result of typical shock syndrome indicated by the apnea, circulatory collapse and respiratory arrest. EEG examination may show a "flat" tracing indicating the cessation of the electrical discharge from the brain.

Acute overdose of intravenous (IV) barbiturate especially if administered too rapidly may lead to severe respiratory depression, apnea, laryngospasm, bronchospasm and hypertension. This symptoms are reversible with the discontinuation or reduction of the rate of IV administration.

Barbiturates may also cause necrosis of the sweat gland and bullous cutaneous lesion which is not related to hypersensitivity reaction. This lesion, if occur will heal slowly but may require few weeks to achieve a complete resolution.

How do you confirm a possible case of barbiturate poisoning?

The diagnosis of barbiturate poisoning is done based on the presence of the above manifestations confirmed by the elevated serum levels of barbiturate. The serum levels of barbiturate may not necessarily correlate well with the outcome of the therapy especially in those patients who consume barbiturate together with other CNS drugs. The potential fatal levels of barbiturates is 1mcg/ml with the short-acting barbiturates and up to 290 mcg/ml with the long-acting barbiturates.

How do we manage barbiturate poisoning?

The main objective of barbiturate poisoning management is to prevent cardiorespiratory collapse and death. This could be achieved by limiting the amount of the barbiturate absorbed and expediting its elimination. Appropriate cardiorespiratory support should be instituted if the patient develops signs and symptoms of respiratory and cardiovascular depression. Therefore, the evaluation of the patient’s level of consciousness should be carried out before other modes of therapy are instituted. Intubation should be done in all unconscious patients Stage III coma (Table 2) and to provide respiratory support and prevent aspiration. Appropriate fluid and electrolytes replacement should be given in patients who develop hypotension.

There is no antidote available for the barbiturate poisoning. The management is therefore to limit the absorption and increase the elimination of barbiturates.

Induction of emesis and gastric lavage should be employed to reduce the amount of drug absorbed in all patients who remained conscious on admission. Since most barbiturates are rapidly absorbed, emesis and gastric lavage are recommended in all patients who are seen within 4 hours post-ingestion. However there are reports of delayed gastric emptying and gastrointestinal hypomotility after barbiturate poisoning suggesting that emesis and gastric lavage might still be useful up to 8 hours post-ingestion. In unconscious patients, great care should be taken to prevent aspiration of the vomitus and other gastric contents. Intubation is recommended in all unconscious patients with Stage III coma according to the Reed’s classification of coma before the induction of emesis or gastric lavage are carried out.

The absorption of barbiturates from the gastrointestinal tract can be reduced by the administration of activated charcoal. The administration of activated charcoal within 4 hours after the barbiturate ingestion reduces the plasma drug concentration of barbiturate significantly. Activated charcoal acts by adsorbing the remaining of the barbiturates present in the gastrointestinal tract after emesis or lavage. The dose of activated charcoal needed to provide optimum effect should be ten times higher than the dose of barbiturate ingested .

There are studies and reports on the use of repeated activated charcoal administration in barbiturate overdose and poisoning. Repeated activated charcoal administration increases the rate of barbiturate removal and reduces the duration of barbiturate intoxication. Beside reducing the absorption of barbiturate from the gastrointestinal tract, repeated administration of activated charcoal will also adsorb the conjugated barbiturate metabolites secreted through the biliary system. This adsorption will interrupt the enterohepatic recirculation of barbiturates and provide a mechanism of gastrointestinal dialysis. The initial dose of 75gm to 100gm (1g/kg) followed by 50gm (0.5g/kg) every four hourly. The dose should be continued until recovery. Activated charcoal is prepared in 200ml of water and the suspension could be administered through the nasogastric tube. To provide optimal effect, the administration of activated charcoal should be followed by the administration of cathartic to avoid gastrointestinal stasis.

The elimination of barbiturates especially long acting or low lipid soluble barbiturates can be increased by the utilization of forced alkaline diuresis. NaHCO3 is used to maintain a pH of 7.5 to 8.0. Forced alkaline diuresis is unable to increase the elimination of short or lipid soluble barbiturates as most of these barbiturates are bound to serum protein. Furthermore, these barbiturates have high dissociation constants (pKa) and is not amendable with alkalization of urine. Renal clearance increases only by 5% with forced diuresis. On the other hand, long acting barbiturates such as phenobarbitone has pKa of 7.24. The percentage of ionized phenobarbitone increases with the alkalization of urine. The ionized phenobarbitone is not reabsorbed by the renal tubules and the renal clearance increases up to 17ml/min was reported with forced alkaline diuresis.

Dialysis either peritoneal dialysis or hemodialysis have been used for the management of barbiturate poisoning. Again, the low lipid soluble barbiturates are more dialysable than high lipid soluble barbiturates. Hemodialysis is more effective than peritoneal dialysis and forced diuresis in increasing the clearance of barbiturates. In practice, almost all barbiturates are dialysable by hemodialysis. Addition of fats or activated charcoal into the dialysate has no additional benefit to hemodialysis.

Hemoperfusion is another method of increasing barbiturates clearance. Hemoperfusion, either using activated charcoal or resin have been found effective in increasing the clearance of both high and low lipid soluble barbiturates. The resin hemoperfusion is more efficient than activated charcoal hemoperfusion in removing the lipid soluble barbiturates. Hemodialysis and hemoperfusion however, are not be available in every hospitals. Therefore hemodialysis and hemoperfusion are only considered in severely intoxicated patients in Stage IV coma who do not respond to intensive supportive care and alkaline forced diuresis.

Conclusion

Barbiturates poisoning, although is no longer as common, should be managed aggressively. Maintenance of respiratory and cardiovascular functions are vital to avoid complications. Induction of emesis and gastric lavage should be carried out within 8 hours of barbiturates ingestion. Repeated activated charcoal administration should be started immediately after gastric lavage and should be continued until patient recovers. Forced alkaline diuresis should be utilised in patient who ingesting long-acting barbiturates. Hemodialysis and hemoperfusion should be tried in all barbiturate poisoning patients whom do not respond to other intensive supportive care.N

   Pharmacotherapeutic of Barbiturates

Barbiturates act as nonselective de pressants of the central nervous system (CNS). Barbiturates are capable of producing CNS mood alteration ranging from excitation, to mild sedation, hypnosis and deep coma. The high lipid soluble barbiturates (i.e. thiopentane) rapidly penetrate CNS to produce anaesthetic action. The peak CNS concentration could be achieved within a few minutes after an IV administration and the drug will be redistributed back to the peripheral within 30 minutes. For barbiturates with low lipid solubility (i.e. phenobarbitone), the cerebral uptake is slower and sedative effect may not be attained until as long as 20 minutes after an IV administration. The distribution of barbiturates to the other parts of the body is influenced by the blood supply to that particular tissues. Distribution is slowest in a poorly vascularised organ such as fat and adipose tissues.

Oral absorption of barbiturates are complete and take place in the small intestine. The absorption of sodium salt is better than the free acid. The absorption is more rapid when it is taken during empty stomach or diluted with water. Barbiturates with high lipid solubility will be taken up and metabolized in the liver before entering the general circulation. The protein binding of the barbiturates ranges from 5% to 80% and is determined by their lipid solubility. A low lipid soluble derivatives such as phenobarbital has lower protein binding affinity. The unbound barbiturate concentration in plasma and in CNS is equal at equilibrium. The ability to penetrate CNS is poorer with the less lipid soluble barbiturates and this explains the slower onset of action among low lipid soluble barbiturates.

Barbiturates are eliminated from the body through the renal route. The fraction of unbound drug also influences the rate of filtration by the renal. A less lipid soluble barbiturates are readily filtered by the kidney and are largely excreted unchanged in the urine. A highly lipid soluble barbiturates are poorly filtered but it is easily taken up by the liver cells. Therefore the bulk of the highly lipid soluble barbiturate is metabolised by the liver. Some barbiturates especially those with sulphur group are metabolised not only by the liver but also by the kidney, brain and other tissues. Although majority of the barbiturates are metabolised into inactive metabolites, some barbiturates (i.e. methabarbitone) is metabolised to an active metabolite (barbitone in case of methabarbitone).

The main indication of barbiturates is for sedation and hypnosis. Barbiturates exert the sedative and hypnotic effects by depressing the sensory cortex, decrease motor activity, alter cerebral function and produce drowsiness, sedation and hypnosis. Barbiturate is also capable of inhibiting transmission of impulses from the thalamus to the cortex in order to induce sedative and hypnotic effects. Excessive dose of barbiturates will result in oversuppression of the CNS and producing hypotension, respiratory depression and deep coma. Other indications are:

• for the management of seizures disorder and epilepsy. Barbiturates suppress the monosynaptic and polysynaptic neurotransmission in the CNS thus limiting the transmission of impulses that produce seizures. The barbiturates also increase the threshold for the electrical stimulation in the cortex.
• in refractory status epilepticus, the use of either short- or long-acting barbiturates is indicated (pentobarbitone coma). This is to depress the electrical discharge and to depress the cerebral metabolism.
• in the management of hyperbilirubinemia in neonates is not uncommon. It is useful in a patient with elevated unconjugated hyperbilirubinemia. Barbiturates reduce the serum bilirubin by inducing glucoronyl transferase, the enzyme responsible for the conjugation of bilirubin.
• for the management of hypertension and increase intracranial pressure especially phetobarbitone to protect the brain from ischemia in hypertensive crisis. Pentobarbitone is also used for induction of coma and to suppress metabolism of the brain.

  R.D.U - The ‘Magic Bullet’ for Economic Impotence

Meeting on Impotence held in Kuala Lumpur, October last year, ‘impotence’ was dubbed as one of the most misunderstood medical disorders in the world today. Medically, impotence is defined as the consistent inability to get or keep an erection suitable for sexual intercourse. The cause to this problem is varied, and drugs are not excluded. Over 200 prescription drugs are known to cause impotence, apart from illicit drugs and cigarettes (see Table 1).

While the disorder has its own stigma, today that seems to be vanishing with the introduction of the drug, Viagra. This new anti-impotent drug received FDA approval earlier this year is making headlines all over the world. Within a short span of time, Viagra becomes almost a household name. Hailed as a ‘magic bullet’, Viagra is predicted to be an instant best-seller. It is poised to replace the various devices, implants, equipment, and other drugs like including hormone placement therapy. Practically everyday one reads about the much hyped drug in the local daily and how it is transforming the male sexuality - now that the men too can be on the ‘pill.’ It looks like the economic downturn is not the only thing that is preoccupying the minds of many Malaysians.

The Economic of Viagra

But one thing is for sure - Viagra is not going to cure the impotent state of our economy. On the contrary, it is likely to add to whatever little resources left due to the economic constraints in the health care sector including drug expenditures. One insurance company in Germany recently reported that Viagra is likely to place a serious strain on health insurance costing up to 15 billion marks (RM 33.8 billion) a year. This estimate is based on some 7.5 millions Germans suffering from impotence having sex twice a week. They are potential users of the pills. This not taking into consideration ‘drug misadventures’ that are likely to take place, for example the ‘Viagra sex tours’ that are purported to have been conducted in a neighbouring country. The ‘indirect’ and ‘hidden’ cost can be enormous.

Although the drug is still to be formally registered in Malaysia, the possible socio-economic impact cannot be much different. The situation could be even worse given the fact that most of pharmaceutical expenditures in this country are out-of-pocket payments and there is no system that could moderate the payment of such drugs. In fact it is indeed very frightening to note that even before the drug is registered in this country, it is already very well-promoted through the media. The apprehension is further compounded by reports of recent deaths involving users of Viagra which are yet to be fully investigated. Countries like Egypt has slapped a ban on it until the cause of death are thoroughly investigated. We therefore will have to tread very carefully, not least also because the recommended price, based on the US price, will be exorbitant given today’s exchange rate.

According to one medical estimate, the number of Malaysian men that have some degree of erectile dysfunction and hence may benefit from drugs like Viagra is close to one million. Assuming that Viagra will cost about RM 30 a piece, this would translate to at least RM30 million if all of them use it just once in a year. In other words without proper awareness and control, the risk of use can be high - medically, socially and economically speaking.

Rational Drug Use

This message has to be properly communicated and understood by everyone. More so because Viagra is not as safe and as exciting as it is made out to be. Viagra has a number of downsides if the drug is improperly used or indeed use by the ‘wrong’ person (for example, women) for the ‘wrong’ reasons (off-label use). Some could result in deaths. All new drugs including Viagra has yet to be fully understood as to their adverse effects which normally do not appear despite the stringent clinical trials that they are subjected to. There is no denying that Viagra could be a medical breakthrough, but this at best is a qualified one at least for the time being. We must continue to be cautious.

The underlying message in understanding the use of Viagra, is that all drugs must be used judiciously in order to realise the full clinical potentials. This is normally terms as ‘Rational Drug Use (RDU),’ that is, the rule of ‘rights’ which emphasises the use of the ‘right’ drug for the ‘right’ patient, in the ‘right’ dose, at the ‘right’ time, in the ‘right’ way (i.e., how the drug should be used), for the ‘right’ duration, based on the ‘right’ information, and of course at the ‘right’ price (cost). It is such a fundamental rule of thumb in the use of medicines that it is often taken for granted. Consequently, one can be exposed to a number of potential side-effects, some can be life-threatening, as a result of drugs being ‘irrationally’ used. Hence, irrational drug use is not only a loss in clinical and medical value for the drug concern, but also the quality of life of the patient, and a drain in the health expenditures of the country. The case in point is of course the use (or rather the misuse) of antibiotics - a phenomenon recognised globally. The likelihood that drugs like Viagra being irrationally used (more aptly, misused or abused) seems to be great given the anecdotal reports frequently encountered even in the lay press.

Given the present economic status, the principle of RDU can be regarded as the all-important ‘magic bullet.’ It must be made an integral part of our drug policy so that drug-related resources are used optimally both in the public as well as the private sectors, and the patients are accorded more protection. Irrational drugs use is in fact a global concern that it can jeopardise the quality of health care due to drug misadventures and by draining the limited financial resources allocated for health. This point was highlighted more than a decade ago by World Health Organization (WHO) in a conference of experts in Nairobi in 1985 where Malaysia actively participated.

In order to ensure the success of RDU, WHO recommends a comprehensive National Drug Policy, so that strategies for improving Rational Drug Use (Table 2) could be further explored and optimised.