prn8099 - Number 16, February 1998

PRN Welcomes Move to Label Fluoridated Toothpastes

The National Poison Centre (PRN) welcomes the statement by the Malaysian Dental Association (MDA) and also the Ministry of Health about the labeling of flouridated toothpastes in this country. This issue was first raised during the Seminar on Product Safety, December 6, 1997, focusing on the safe use of fluoride in toothpaste, with particular reference to children.

PRN believes that the move to label will go a long way in creating awareness among the public about the safe use of fluoridated toothpastes. It is rather timely that such proactive action be taken since it is becoming clear from various studies over the years suggesting that excessive use of flouride can be harmful. A recent study published in the Journal of Public Health Dentistry (1995) concluded among others: (a) heavy use of fluoridated toothpaste up to the age of 8 may be a risk factor for dental fluorosis, (b) supplemental, mouthrinse [sic], and professional fluoride sources were not associated with fluorosis in the study, and (c) strict adherence to current protocols for use of fluoride products in both professional and home. The study was carried out at the Pediatric Dentistry clinic at the University of Iowa College of Dentistry involving 157 patients. It looked at fluoride exposure from sources like fluoridated toothpaste, dietary fluoride supplements, fluoridated mouthrinse [sic] use, professional fluoride applications, and drinking water.

Another landmark study in the authoritative Journal of the American Dental Association, as recent as December 1995, reported that 71 percent of the cases result from improper use of fluoridated toothpaste during the first eight years of life. This is compared to 25 percent from fluoride vitamin and mineral supplements during that time.

Not only can toothpaste be found in almost every household and freely sold in the market place, it is also well-advertised. Yet it suffers from one gross discrepancy relative to similar products available in some developed countries - namely inadequate labeling. The need for such labeling has also been acknowledged in an article by John Murray published in the Malaysian Dental Journal (1994).The objective is to keep the users and consumers informed so as to enable them to exercise sufficient precautions when using commercial fluoridated products.

In a survey carried out by PRN on major brands of toothpastes available at various outlets between April - November 1997 noted that there are more than seven of brand types of toothpastes with fluoride sold in Malaysia. Some are produced locally while others imported from overseas. Despite their similarities in brand names and packaging, all of the toothpastes produced locally carry no information about the safe use of toothpaste especially for children - be it in terms of warnings or directions for use as the case may be, either on the outer or inner packaging.

For example, one imported version from UK provided a stark contrast to the equivalent local brand. The former are quite precise on at least six points, including (a) how much fluoride it contains as an active ingredient, and in what form (b) the standard it adopted for the active ingredient, (c) other ingredients in it, (d) how the toothpaste should be used for children under 6 or even 2 years of age, (e) in what amount or quantity (some illustrated this graphically), (f) cautionary statements that the use by children needs parental supervision, and even (d) the expiry date is stated. The US version too carries similar information. Such outright discrepancies in the labeling raised a very perinent question in terms of consumer safety.

This is all the more relevant to the Malaysian public since in the case of locally produced toothpaste no more than three brands names (or more specifically manufacturers), have received the professional endorsement with the logo clearly printed on the packaging.

And in this respect the move to inform the public through adequate labeling must be lauded. It cannot be over- emphasised that the safe use of flouride must follow a proper disclosure of criteria. The International Programme for Chemical Safety (IPCS) has been quoted in a 1997 WHO document that that "the margin between beneficial and toxic levels of fluoride is rather narrow." IPCS further remarked that "higher levels of fluoride have led to adverse health effects, ranging from unsightly dental fluorosis to crippling skeletal fluorosis." In other words, the progression from dental fluorosis to skeletal fluorosis is very much time-dependent and relates to the question of use and exposure. For the toxicological viewpoint, dental fluorosis can be considered as symptomatic of chronic fluoride poisoning, albeit a mild form.

The crux of the matter no doubt is that flouride is a drug (that is, a medicine used for the purposes of treatment) in this case for dental care. The US Food and Drug Administration (FDA) regarded it as an OTC (over-the-counter) item. It is necessary therefore is to mandate that toothpaste containing flouride, like all drugs, be amply labeled about its content, directions of use and precautions for the various age groups so as to avoid such ill-effects, no matter how slight. Moreover, children are encouraged to use the product, at least twice daily for almost throughout their lifetime. This is not too demanding since a medicine would require very stringent labeling because of safety issue, even if it is to be used over a short period of time and for external application only. Without doubt this is precisely one important rationale why toothpastes in US and UK carry the appropriate labels.

Similarly, if fluoride is a drug then a toothpaste is just another drug-delivery device meant to convey the correct (if not precise) amount of drug for use. What can the ‘correct’ amount be when, unlike other drug-delivery devices, the amount of drug (that is, fluoride in the toothpaste) to be delivered is not indicated; nor the device appropriately designed to make this possible. Most would simply ‘squeezed’ it out of the tube over the entire length of the toothbrush. What is more with the prevailing belief that more is better, this seems to be norm for most people. For children especially 6 years and under such an amount can be excessive and can pose a problem since they are more prone to swallowing toothpaste even while brushing due to the lack of control.

In actual fact, children of 6 years and below are recommended to use only a "pea-sized" (some indicated just a ‘smear’) of toothpaste containing fluoride. Otherwise, it is only a matter of time when the limits of safe use of fluoride in toothpaste is unknowingly exceeded and chronic fluoride poisoning begins to set in insidiously. More so, in reality many of our children share adult fluoridated toothpaste. Frankly, how many parents know this and took the trouble to observe that their children do not swallow the toothpaste used.

Although to those with vested interest the immediate reaction is to cite the "excellent" safety record of toothpaste use in this country, this cannot be the long-term answer. In other countries where there too have been claims of "excellent" safety record, yet the products are consistently labeled.

As we accept the availability of flouride in variety of sources, the contention is surrounding its use. Where possible they must be safeguarded and use with caution. Especially in readily available commercial products like toothpaste, there must be safety features to protect the consumer (including children). The least that could be done in this regard is to ensure that those products carry adequate labelling as soon as possible just like those in the countries cited above.

Safety Tips for Toddlers and Preschoolers 

• Use a very small amount of fluoride toothpaste (pea-size or a smear).
• Ensure toothpaste is put on the toothbrush by an adult. The adult can control the amount of toothpaste used.
• Stand behind the child and have the child face the mirror.
• After brushing, encourage the child to spit out the remaining toothpaste.
• Have the child rinse his or her mouth thoroughly with water.
• Rinse the brush well before storing.

  Source: Adapted from Canadian Paediatric Society, 1996.

 PRN 8099 joins ISDB

The International Society of Drug Bulletins (ISDB) is a global network of independent bulletins and journals on drugs and therapeutics. These bulletins are produced in different countries, often by small groups of professionals. prn8099, the professional bulletin of PRN, has been accorded full membership ISDB in December 1997. PRN is proud to join this select international group of independent bulletins.

ISDB was founded in 1986, with the support of the WHO Regional Office for Europe. It aims to promote the international exchange information of good quality on drugs and therapeutics, to encourage and to assist the development of professionally independent drug bulletins in all countries.

Bulletins which are published at least four times a year and meet certain criteria of independent can be members of ISDB. This is based on the main criteria that the bulletins provide of good quality information, and must have editorial as well as financial independence.

ISDB members which spans over 45 countries are involved in activities and campaigns related to drug information issues. These include the access and exchange of information on drugs, adverse drug reactions, and drug promotion and regulation.

ISDB also organise regional summer schools and training seminars where people can share experiences. Such meetings have so far been held in Algeria, Hungary, Italy, Japan, Philippines, Spain and recently in Malaysia.

PRN is also proud to host ISDB Asia-Pacific Editors Network which was launched this month. PRN is currently assisting in setting up ISDB homepage at its website <http://prn.usm.my>

Review on
Poisoning Involving Antipsychotics
by Associate Professor Rahmat Awang, Pharm.D

Antipsychotics (also known as antipsychophrenic, neuroleptics or "major" tranquillizers) are group of drugs used in the treatment of severe psychiatric disorders. Their high degree of utilization has led to many reported cases of poisoning particularly among psychotic patients. Fortunately, serious morbidity and mortality are rare if taken in as a single entity. However, in cases of suicidal attempt where relatively large amount have been ingested, poisoning can lead to complications involving particularly the cardiovascular and central nervous systems (CNS). The risk of potential danger is even greater if the drug is ingested with other CNS-acting agents such as the tricyclic antidepressants and ethanol. This issue of PRN Consult will highlight important aspects of antipsychotics poisoning.

What are the types of antipsychotics

Antipsychotics consist of a number of chemical classes classified into the well-known phenothiazines, thioxanthenes and butyrophenones as well as the newly developed classes, i.e. the indole compound (e.g. molindone) and the dibenzoxapine (eg. loxapine).

The phenothiazine is the prototype for the antipsychotics. It is made up of 3 sub-classes i.e. the aliphatics, the piperidines and the piperazines derivatives. Among these, the aliphatic compounds are the least potent while the piperazines are the most potent and has been responsible for most of the poisoning fatalities.

The thioxanthenes are similar to the phenothiazines in terms of structure-activity relationship while the butyrophenones (eg. haloperidol) possesses a heterocyclic structure and are also considered potent antipsychotics. The indole compound (eg. molindone) has a unique structure of its own while loxapine, a dibenzoxapine, has a tricyclic structure similar to that of the imipramine-like antidepressant drugs. These newer classes of drugs have not been shown to be more efficacious or to have significantly fewer side effects than the original prototype drugs. Experience with respect to poisoning for the newer agents are very limited.

Table 1 Types of Antipsychotics

What are the pharmacologic properties of antipsychotics?

Antipsychotics block a number of receptors in the CNS and the periphery. The dopamine receptors, alpha-1 receptors, cholinergic receptors and the histamine receptors are all affected by the antipsychotics at varying degrees. This in turn will determine the nature of the pharmacological effects seen.

• It is believed that blocking the dopamine receptors in specific areas of the CNS (i.e. limbic system, basal ganglia, hypothalamus) will determine the relative potency of the antipsychotics as well as the incidence of extrapyrimidal side-effects, and various neuroendocrine effects.
• Blocking the alpha-1 receptors in the periphery will result in postural hypotensionand reflex tachycardia, as commonly encountered with low-potency drugs. In overdose situation, miosis is also seen from the blockade.
• Blocking the cholinergic (muscarinic) receptor will cause various anticholinergic effects such as sinus tachycardia, blurred vision, dry mouth, decreased intestinal motility, and less frequently, urinary retention. These are seen especially with the use of low-potency drugs. The anticholinergic potency of the antipsychotics has also been found to be inversely related to the frequency of acute dystonic reactions.
• Blocking the histamine (H1) receptor will result in sedation seen commonly with low-potency drugs.

What effects do they have in overdose situation?

Overdoses of antipsychotic drugs may result in a wide variety of symptoms. However, the primary organ systems affected are the central and autonomic nervous systems as well as the cardiovascular systems.

Central nervous system involvement from antipsychotic overdose can present in the form of CNS depression, extrapyrimidal syndromes, seizures and disorders of thermoregulation.

CNS depression is manifested in the form of lethargy and ataxia which may progresses to stupor and coma if significant amount has been ingested. Respiratory depression though not very common can happen especially in mixed ingestions involving drugs that can also depress the respiratory centre. Seizures can occur but is not common; and prolonged or recurrent seizure activity has been reported with loxapine. Patients at risk are those who have a history of a seizure disorder or an abnormal electroencephalogram (EEG). Disorders of thermoregulation have also been documented, especially hypothermia. Hypothermia may be due to peripheral vasodilatation or the drug's effect on the hypothalamus. Hyperthermia, on the other hand, occur occasionally, and in warm environments, as a result of peripheral vasoconstriction and sweat inhibition.

Various extrapyrimidal effects including stiff neck, oculogyric eye movements, torticollis, protruding tongue and trismus have been also observed with antipsychotic poisoning. They are more common with some of the antipsychotics such as the piperazine derivatives, the butyrophenones and the thioxanthines. Acute dystonic reactions which is presented as involuntary spasm of the muscles of the face, tongue, neck and trunk is seen in up to 10% of the antipsychotic drug ingestions. This is usually due to antipsychotic drugs that are potent and have low antimuscarinic activity such as prochlorperazine, trifluoperazine, fluphenazine and haloperidol. This reaction occurs more commonly in children even with one dose.

The cardiovascular effects of antipsychotic poisoning is often manifested in the form of hypotension and/or conduction abnormalities and arrhythmias. Of these, hypotension is most commonly seen in its mild form. It is usually due to peripheral vasodilatation or from a direct myocardial depressant effect of the drug at toxic levels. Conduction abnormalities and life-threatening ventricular arrhythmias have also been reported with thioridazine and mesoridazine and occasionally with chlorpromazine overdose.

At therapeutic doses, antipsychotics have a "quinidine-like" effect. This is the result of decreased conduction velocity and delayed repolarization. On the ECG, the PR and QT intervals appeared prolonged, the T wave widened and blunt with a prominent U waves.

At toxic levels, the intracardiac conduction can be further depressed to cause atrioventricular (AV) block, an indication of serious toxicity. Life-threatening reentrant arrhythmias such as ventricular tachycardia and fibrillation may also occur. Torsade de pointes has also been described. Sinus tachycardia is common in antipsychotic poisoning. It is secondary to hypotension and anticholinergic effects. Sinus bradycardia occurs rarely and is seen with serious ingestions.

In addition to these, patients may also developed anticholinergic symptoms including decreased bowel sounds and ileus, urinary retention, and dry mucous membranes. Miosis is also frequently seen with severe ingestions while mydriasis has been described with thioridazine and other drugs that have potent anticholinergic effects.

Table 2 Relative Adverse Effects of Representative Antipsychotic Drugs

What approach should be taken in managing antipsychotic poisoning?

The fatality rate in antipsychotic poisoning is low. Death is usually due to cardiac complications and most patients require only supportive care. When confronted with cases of antipsychotic poisoning, all of them should be assessed quickly. The patient should be intubated if he shows any signs of respiratory depression. If the patient’s mental status is altered, consider administering 2mg naloxone, 100ml of dextrose 50%, and 100mg thiamine. Venous access using a large-bore intravenous line should be put in place and the patients' ECG arterial blood gases and serum electrolytes monitored for at least 6 hours if the patient is asymptomatic and up to 24 hours if signs of signifcant ingestion are present.

Once the patient is stabilised, decontamination procedures can be initiated. Gastric lavage using a large-bore orogastric tube (28-40 French in adults) should be performed within 30-60 minutes post-ingestion. Activated charcoal should be administered initially at a dose of 1gm/kg together with a cathartic. The charcoal may be repeated at a dose of 0.5gm/kg every 4 to 6 hours to facilitate elimination. Syrup of ipecac is not recommended since seizure and/or CNS depression is likely to occur.

Coma, seizures, hypotension and hyperthermia have to be treated accordingly once they occur. Severe hypotension should be treated by giving IV fluids. The use of sympathomimetic amines is contraindicated under this circumstances.

There is no specific antidote for antipsychotic poisoning. Physostigmine, a short-acting cholinesterase inhibitor have been used to reverse sinus tachycardia and coma. Its effect is only temporary and may actually cause seizures, bradycardia and asystole. Its use is no longer recommended.

Diphenhydramine 0.5-1mg/kg IM or IV, or benztropine 1-2mg/kg IM or IV have been used quite specifically for antipsychotic poisoning to treat the dystonic reactions. The therapy is usually continued for about 48-72 hours even after the patients condition is under control so as to prevent recurrences.

Sodium bicarbonate has also been advised to overcome the cardiac conduction problems when standard therapy fails. Its efficacy in antipsychotic poisoning is still uncertain but the mechanism of cardiotoxicity is said to be similar to the tricyclic antidepressants. When indicated, 1-2mEq/kg IV of sodium bicarbonate may be administered over several minutes followed by an intravenous drip to maintain the serum pH at 7.45-7.55.N

ANTIPSYCHOTIC TOXICITY

Toxic Doses

As a group, antipsychotics have high therapeutic index. The toxic dose are highly variable. In general, the acute fatal dose for the phenothazines is believed to be between 15 and 150mg/kg depending on the agent. Specifically, acute ingestion of between 2.5 to 8 grams of mesoridazine or 3 to 5 grams of thioridazine have resulted death in adults. Besides this, co-ingestion with other CNS depressants and benzodiazepines have been reported to lower the dose required to cause this toxicity.

Patient exposed to antipsychotics may present with findings of sedation, miosis, hypotension, hypothermia and prolongation of QT interval. Anyone with a history of ingesting antipsychotic medications accompanied with these presentations should be suspected for antipsychotic poisoning.

Some of these features can also be seen in CNS depressants overdose such as sedatives-hypnotics, tricyclic antidepressants, narcotics, alcohols and carbon monoxide, however they in general do not cause hypotension, hypothermia, and miosis. Besides this, children who develop acute dystonic reactions should also be suspected of being exposed to antipsychotics.

Confirmatory Investigations

Exposure can be confirmed by determining the presence of the drug in the blood. Quantification of the level is not so useful since it does not reliably predict severity and are not used to guide therapy. In addition, there can be numerous active metabolites produced and this may complicate further the interpretaion of the blood level data.

Toxicology screening are usually recommended. This method can also screen for possibilities of mixed ingestions. Abdominal roentgenograms are also useful since antipsychotics are radiopaque and should be quite visible. A negative film, however does not rule out significant ingestion.

The Proper Use of Skin Bleaching Products

Associate Professor Mohd Isa Abdul Majid Ph.D

The recent statement made by the Minister of Health against beauticians prescribing skin bleaching products containing more than 2% hydroquinone follows the world-wide concern on the use of these products. The move to create awareness among the potential users on the adverse effects caused by these products should be promoted considering that these products have now been illegally manufactured locally to meet the high demand for lighter skin complexion. Although they serve as cosmetic function, it is important to emphasise that these products are drugs and have potential toxicity if used without adequate advice from the professionals. This review serves to provide a background on the safe use of skin bleaching products containing hydroquinone.

Risks of Skin Bleaching Products

Historically, a number of topical agents have been used in skin-bleaching preparations. These included hydroquinone, the monobenzyl and monomethyl ethers of hydroquinone, ammoniated mercury, ascorbic acid, and peroxides. Unfortunately, most of these agents have limited clinical use because of their adverse effects and resultant complications. For example mercury compounds have been used with varying success to lighten skin pigment. The mercury ions are thought to inhibit tyrosinase activity and thus inhibit the synthesis of melanin. However, the use of mercury has been banned in many countries because of percutaneous absorption and potential nephrotoxicity. On the other hand, the monobenzyl and monomethyl ehters of hydroquinone was used initially in the late 1930s to bleach skin. Due to its unpredictable actions and cosmetic disasters, it is now being used exclusively in people with extensive vitiligo.

In Malaysia, the Drug Control Authority has approved the use of seven skin bleaching products containing hydroquinone in concentrations of 2.0% for OTC use while 4% concentrations are allowed for professional use only. These approved products of hydroquinone are Eldopague Forte (4%), Eldopague (2%), Eldoquine Forte (4%), Solaquine (2%), Solaquine Forte (4%) and Esoterica F (2%). As a comparison with other countries like Nigeria and several other African nations, products containing more than 2% hydroquinone are banned as they are found to cause irreversible hyperpigmentation.

From animal experiment, hydroquinone produces reversible depigmentation of the skin and hair of mice, guinea pigs and humans by a complex mechanism of action. At the cellular level, hydroquinone and its derivatives are oxidized by tyrosinase to form highly toxic, free radicals that cause selective damage to the lipoprotein membranes of the melanocyte, thereby reducing conversion of tyrosine to dopa and subsequently to melanin. It disrupts membranous cytoplasmic organelles, affecting formation, melanization, and degradation of melanosomes. Several studies demonstrate that topical preparations of 2 - 5% hydroquinone are effective in producing cutaneous depigmentation. The 2% concentration is safer and has produced results equal to higher concentrations.

Effectiveness of Hydroquinone

The effectiveness of hydroquinone varies among patients. In a prospective controlled study carried in the US (Arndt and Fitzpatrick, 1965), hydroquinone 2% and 5% creams were applied on the hyperpigmented skin of 56 patients with 12% of the patients were black. Hydroquinone creams were applied twice daily and the treatment was continued for three months. Hydroquinone was effective as a depigmenting agent in 44 of the cases. The use of hydroquinone 5% cream was accompanied by adverse effects (primarily irritation). However, at the lower concentration (2% cream), the drug appeared to be equally effective therapeutically with fewer irritant reactions. From the result, it seems that hydroquinone is best on lighter skin and on lighter lesions. In blacks the response to hydroquinone depends on the amount of pigment present. The earlier it is used to treat minor skin blemishes, the more likely the results will be satisfactory. When depigmentation does occur, melanin production is reduced by about one-half. When beginning treatment, melanin excretion may transiently increase. A decrease in skin color usually becomes noticeable in about 4 weeks; however, the time of onset varies from 3 weeks to 3 months. Depigmentation lasts for 2 - 6 months but is reversible. Darker lesions repigment faster than lighter lesions. Because the ability of the sun to darken lesions is much greater than that of hydroquionone to lighten them, strict avoidance of sunlight is important.

Side effects of topical hydroquinone are mild when used in low concentrations. Tingling or burning on application and subsequent erythema and inflammation were observed in 8% of patients using a 2% concentration and 32% of patients using a 5% concentration of hydroquinone. Higher concentrations frequently irritate the skin and if used for prolonged periods cause disfiguring effects including epidermal thickening, ochronosis-like pigmentation and yellowish papules. The mechanism for the formation of the rare ochronosis-like pigments on the skin is thought to occur by the inhibition of hydroquinone on the epidermal homogentisic acid oxidase. This inhibition would lead to the accumulation of homogentisic acid which then polymerises to form the ochronotic pigments.The proposed mechanism for this pigmentation is shown in Figure 1.

In some cases lesions become slightly darker before fading. A transient inflammatory reaction may develop after the first few weeks of treatment. Occurrence of inflammation makes subsequent lightening more likely, although inflammation can occur without the development of depigmentation. Topical hydrocortisone may be used temporarily to alleviate the reaction. Reversible brown discoloration of nails has been reported occasionally following application of 2% hydroquinone to the back of the hand. The discoloration is probably caused by formation of oxidation products of hydroquinone.

Fig. 1 The Oxidation of Phenylalanine to maleylactoacetic acid.

Phenylalanine

ò

Tyrosine

ò

p-hydroxyphenylpyruvic acid

ò

Homogentisic acid

ò Homogentisic acid oxidase

Maleylacetoacetic acid

ò

Further catabolism

If hydroquinone is accidentally ingested, it seldom produces serious systemic toxicity. However, oral ingestion of 5 - 15g doses has produces tremor, convulsions, and hemolytic anemia. Because of lack of safety data, it is not recommended for children under 12, except with the supervision of a physician. If no improvement is seen within 3 months, the use of hydroquinone should be discontinued and further advice of a physician is sought. Once the desired benefit is achieved, hydroquinone can be applied as often as needed to maintain depigmentation of the skin. It should never be applied near the eyes or to cuts, abraded or sunburned skin.

Physiology of Skin Pigmentation

Skin bleaching products are used to treat hyperpigmentation. This condition of the skin may result from a variety of causes. It is usually asymptomatic and of no medical consequence, although it occasionally may signify systemic illness. Hyperpigmentation, particularly on the face, however, can be a source of cosmetic disability and mental distress. Thus, agents that can bleach away excess pigment when applied topically have a large market among all racial and ethnic groups around the world. Most of the skin-bleaching products are available without prescription. Under normal circumstances, these products are intended to lighten only limited areas of the hyperpigmented skin. They are normally recommended in areas of brownish colour of the face. For reddish or bluish areas as well as areas that are changing in size, shape or colour, these products have been found to be not effective in lightening the skin. An effective product would normally produce changes in within 2 to 3 months.

A normal skin color is contributed by melanocytes in the basal layer of the epidermis, which produce pigment granules called melanosomes. These pigment granules contain a complex protein called melanin, a brown-black pigment. Melanocytes can be viewed as tiny one-celled glands with long projections to pass pigment particles into the keratinocytes, which synthesize skin keratin. As keratinocytes migrate upward, they carry the pigment with them and deposit it on the surface of the skin as they die. Melanocytes are also present in the hair bulb cells and pass pigment granules on to the hair. Melanin is the most efficient sunscreen known. It prevents damaging ultraviolet (UV) rays from the sun from entering deeper parts of the skin. Solar radiation also stimulates melanocytes to provide more melanin. This results in gradual skin darkening or a "tan." The various human races have roughly the same number of melanocytes, but dark-skinned peoples have more active cells.