prn8099 - Number 35, August 2002

Dangers of Slimming Pills 

Obesity is already a costly problem in developed countries and is significantly becoming one in developing countries, in terms of costs, morbidity and mortality. It is a multifactorial disease affecting both sexes in all age groups, and is linked to many comorbidities  including coronary heart disease, stroke, hypertension, diabetes mellitus, and others. Obese patients having body mass index (BMI) of greater than or equal to 30 kg/m² and at risk of obesity related comorbidities can be managed using anorectic drugs, prescribed as an adjunct in a comprehensive weight-reducing plan which includes dieting, behaviour modification and physical activity.

Among the first anorectic or appetite suppressant drugs available for the treatment of obesity are amphetamine and methamphetamine. However, they are no longer used due to their high abusive potential. Other drugs related chemically and pharmacologically to the amphetamines are benzphetamine, phentermine, mazindol, diethylpropion, and phendimetrazine. In Malaysia, the only approved prescription drug indicated for the management of obesity is phentermine which is controlled as a psychotropic substance under the Poison Act 1952.

Phentermine is a sympathomimetic amine with significant anorectic activity in animal models. Its appetite suppressant effect is generally considered to be exerted through the hypothalamus, but it is not certain that this is the only effect related to weight loss. Phentermine has major effects on the dopaminergic and noradrenergic nervous systems. The cardiovascular effects include a pressor response and increase in heart rate and force of contraction.

Other appetite suppressants that have been used are fenfluramine and dexfenfluramine. Both are serotonergic drugs popularly used as diet pills until September 1997 when they were withdrawn from the markets. The call for withdrawal was made by the  U.S. Food Drug Association (FDA) and later followed by the Ministry of Health, Malaysia,  (MOHM) when evidence surfaced that they were associated with valvular heart disease. Another prescription anorectic, Sibutramine, which acts by inhibiting the re-uptake of norepinephrine, serotonin and possibly dopamine is still under monitoring by the FDA and is not currently available in Malaysia.

Another drug that has been commonly used as an ingredient in many over-the-counter (OTC) cough and cold products and also weight-reducing preparations  is phenylpropanolamine (PPA). It has been withdrawn from the Malaysian market since November 2000 following a study report from the Yale University School of Medicine that taking PPA increases the risk of hemorrhagic stroke in both women and men.

Apart from the centrally acting drugs, FDA has, since 3 years ago approved orlistat (Xenicalâ), a lipase inhibitor which decreases dietary fat absorption and fecal incontinence. However, there are also concerns about a possible association with breast cancer.

Herbal alternatives for weight reduction containing ephedra (Ma Huang) and St John’s wort ( Hypericum perforatum), even though ‘natural’, could not be clearly claimed as ‘safe’. Ephedra is associated with a risk of myocardial infarction and stroke by causing tachycardia and hypertension. Long-term use may decrease endogenous catecholamine levels, possibly resulting in intraoperative haemodynamic instability. Ephedra may also interact with monoamine oxidase inhibitors with life-threatening consequences. Products containing ephedra are not registered in Malaysia.

St. John’s Wort interacts with many drugs by inducing cytochrome P450 isoenzymes, and should not be taken during the 5-day period prior to surgery. In Malaysia, all products containing hypericum carry the following warning statement: "The product may interact with other medicines. Please consult a doctor/pharmacist before using it."

Besides products containing ephedra and St John’s wort which were already known to cause adverse effects, there is also concern on other commercially available herbal alternatives which may be adulterated with banned substances such as fenfluramine as highlighted in media reports recently.

Many weight-reducing products are being promoted to the general public through the electronic medias, print advertisements and health food stores for which there is no evidence of efficacy. It is high time the MOHM develop a better system of screening all weight reducing products especially the herbal alternatives for the presence of banned substances. Health professionals too should query their patients about products purchased over-the-counter and be more vigilant in detecting previously unobserved and/or unreported adverse effects.  

Review on

Management of Mercury Toxicity (Part II)

By Dr Syed Azhar Syed Sulaiman, PharmD, Clinical Pharmacy Discipline, School of Pharmaceutical Sciences, Universiti Sains Malaysia.

How do we treat mercury toxicity?

Prehospital Care: Prehospital management includes gathering information on the time, type, and mode of mercury exposure.

• Initial assessment (ABCs)

• Oxygen

• IV access

Emergency Department Care: Supportive care begins with the ABCs, especially when managing the inhalation of elemental mercury and the ingestion of caustic inorganic mercury, both of which may cause the onset of airway obstruction and failure. The next step in supportive care is the removal of contaminated clothing and copious irrigation of exposed skin. Aggressive hydration may be required for acute inorganic mercury poisoning because of its caustic properties.

• Do not induce emesis if the compound ingested is of the caustic inorganic form.

• Gastric lavage is recommended for organic ingestion, especially if the compound is observed on the abdominal x-ray series. Gastric lavage with protein-containing solutions (eg, milk, egg whites, salt-poor albumin) or 5% sodium formaldehyde sulfoxylate solution may bind gastric mercury and limit its absorption.

• Activated charcoal is indicated for GI decontamination because it binds inorganic and organic mercury compounds to some extent.

• Whole bowel irrigation may be used until rectal effluent is clear and void of any radiopaque material. However, effectiveness in decreasing the GI transit time of elemental mercury is doubtful because of the high density of elemental mercury and the low density of the whole bowel irrigant solutions. Likewise, whole bowel irrigation has no adsorptive effect on any type of mercury within the GI tract.

• Use chelating agents if the patient is symptomatic, if systemic absorption is anticipated, or if increased blood or urine levels are present. Chelating agents contain thiol groups, which compete with endogenous sulfhydryl groups.

• Hemodialysis is used in severe cases of toxicity when renal function has declined. The ability of regular hemodialysis to filter out mercury is limited because of mercury's mode of distribution among erythrocytes and plasma. However, hemodialysis, with L-cysteine compound as a chelator, has been successful.

• Neostigmine may help motor function in methylmercury toxicity. This toxicity often leads to acetylcholine deficiency.

• Polythiol is a nonabsorbable resin that can help in facilitating the removal of methylmercury (short chain alkyl organic mercury), which is then excreted in the bile after enterohepatic circulation.

Use chelating agents if the patient is symptomatic, systemic absorption is anticipated, or increased blood or urine levels are present. The drug therapy for mercury toxicity management is summarized in table I below.

Table I: Drugs usually used to manage mercury toxicity

Some researchers suggested other agents to be used in management of mercury toxicity. Those suggestions are listed in table II.

Table II: Other alternative agents for treating mercury toxicity

Conclusions

The clinical outcome of the toxicity depends on the form of the mercury compound and severity of exposure. Mild exposure to inorganic (ie, elemental, mercuric salt) and organic compounds can result in a complete recovery. Fatality is usually the result of severe exposure to mercuric salt. Most organic mercury exposures leave a neurological sequela. Very minimal dermal exposure to dimethyl mercury has resulted in progressive neurologic deterioration and death, with initial symptoms delayed for several months.

Individuals who need to be admitted to the hospital include the following:

• Individuals who ingested (or are thought to have ingested) mercury salts

• Individuals thought to have elemental mercury inhalation and have pulmonary injury

• Individuals who require intensive chelating therapy.

POSITION STATEMENTS : CATHARTICS

American Academy of Clinical Toxicology ; European Association of Poison Centres and Clinical Toxicologists

Introduction

Overall, the mortality from acute poisoning is less than one percent. The challenge for clinicians managing poisoned patients is to identify promptly those who are most at risk of developing serious complications and who might potentially benefit, therefore, from gastrointestinal decontamination.

The two general types of osmotic cathartics used in poisoned patients are saccharide cathartics (sorbitol) and saline cathartics (magnesium citrate, magnesium sulfate, sodium sulfate).

Rationale

Cathartics are intended to decrease the absorption of substances by accelerating the expulsion of the poison from the gastrointestinal tract.

Sorbitol improves the palatability of activated charcoal by imparting a sweet taste and by masking the grittiness of the charcoal.

In vitro Studies

• Seven studies have investigated the effect of cathartics on the adsorption of drugs by activated charcoal.
• One study evaluated the effect of magnesium citrate on the binding of salicylates to charcoal and found apparent pH-dependent changes in adsorption.
• Four other studies have evaluated the impact of magnesium citrate at controlled pH on the adsorptive capacity of activated charcoal.
• In another study where the pH was unknown, but controlled, the presence of magnesium citrate apparently increased the adsorption of C14-labeled paraquat at charcoal to paraquat ratios of 10:1 and 20:1.
•  A study using simulated gastric fluid with an unstated pH showed an apparent decrease in the adsorption of aspirin to charcoal when magnesium citrate was added and an apparent increase in adsorption to charcoal when simulated intestinal fluid was used.

Volunteer Studies

Cathartics Alone – 5 studies demonstrated the following results :

• Magnesium sulfate did not alter significantly the serum concentrations of lithium and salicylate when administered 30 minutes after dosing.
• Sodium sulfate did not change significantly the urinary recovery of acetaminophen (paracetamol) and its metabolites when compared with control.
• After the administration of sorbitol, urine salicylate recovery was not reduced significantly when compared to control.
• The mean peak plasma theophylline concentration was significantly greater in volunteers given sorbitol than in the control group.The mean time to peak concentration was significantly shorter in the sorbitol group than in the control group.
• Sorbitol did not alter significantly the area under the curve (AUC) of theophylline whether administered at 1 hour or 6 hours after dosing when compared with control.

Sorbitol Plus Activated Charcoal – Several studies showed that :

• Sorbitol and activated charcoal reduced significantly the AUC of theophylline when compared with charcoal and with no treatment groups.
• Sorbitol and activated charcoal reduced significantly salicylate elimination in the urine when compared with charcoal alone.
• Sorbitol and activated charcoal did not reduce significantly the AUC of theophylline when compared with charcoal alone.
• Urinary salicylate excretion was not reduced significantly by the administration of sorbitol and activated charcoal  when compared to activated charcoal alone.

Clinical Studies

Dosage Regimens

Sorbitol. The recommended dose is 70% sorbitol 1-2 mL/kg in adults and 35% sorbitol 4.3 mL/kg in children. These recommendations apply only to single doses of cathartics.

Magnesium Citrate. A commonly recommended dose is 10% magnesium citrate solution 250 mL in an adult and 4 mL/kg body weight in a child.

Indications

Based on available data, there are no definite indications for the use of cathartics in the management of the poisoned patient.

Contraindications

• Absent bowel sounds, recent abdominal trauma, recent bowel surgery, intestinal obstruction, or intestinal perforation.
• Ingestion of a corrosive substance.
• Volume depletion, hypotension, or significant electrolyte imbalance.
• Magnesium cathartics should not be given to patients with renal failure, renal insufficiency, or heart block.

• Cathartics should be administered cautiously to the very young (<1 year of age) and to the very old patients. 

Complications 

Single Dose

• Nausea, abdominal cramps, vomiting.
• Transient hypotension.
• Multiple or Excessive Doses
• Dehydration.
• Hypernatremia in patients receiving sodium-containing cathartics.
• Hypermagnesemia in patients receiving a magnesium-containing cathartic.

Multiple or Excessive Doses

Serious adverse reactions including dehydration and electrolyte imbalance (hypermagnesemia, hypernatremia) may occur in patients receiving multiple doses of sodium or magnesium-containing cathartics. Patients with renal dysfunction are at increased risk.

(Full text of this article can be obtained from the National Poison Centre, USM, Penang, or from http://www.clintox.org/Pos_Statements/Intro.html)