• call pusat racun websiteToxicology Laboratory Services
    Office hours

    Tel: +604 653 2171 / +604 653 2191
    Monday - Friday: 8:10am - 5:10pm
    E-mail: This email address is being protected from spambots. You need JavaScript enabled to view it. 

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 Both are serotonergic drugs popularly used as diet pills until September 1997 when they were withdrawn from the markets.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. Johns 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

Drug Name

Dimercaprol : The drug of choice for treatment of acute mercury toxicity.
Administered IM q 4h, mixed in a peanut oil base. Excreted in urine and bile. May be given to patients with renal failure. Used only in acute ingestion.

Adult Dose

3-5 mg/kg IM q4h for 2 d, followed by 2.5-3 mg/kg IM q6h for 2 days, followed by 2.5-3 mg/kg IM q12h for 7 days.

Pediatric Dose

Administer as in adults

Contraindications

Documented hypersensitivity; concurrent iron supplementation therapy; methylmercury toxicity

Interactions

Toxicity may increase when co-administered with selenium, uranium, iron, or cadmium

Pregnancy

Safety for use during pregnancy has not been established.

Precautions

May be nephrotoxic and may cause hypertension; caution in oliguria or G-6-PD deficiency; may induce hemolysis in G-6-PD deficiency; adverse effects include abdominal pain, nausea, vomiting, headache, elevated blood pressure, tachycardia, burning sensation to the lips and throat, constricting feeling of the throat, conjunctivitis, blepharospasm, lacrimation, rhinorrhea, salivation, burning sensation to the penis, and urticaria (some adverse effects are responsive to diphenhydramine co-therapy)

Drug Name

Penicillamine : Forms a complex with mercury and is excreted in urine; therefore, do not use in renal failure. Cannot be considered as first-line agent because of the safer and more efficacious agent, dimercaptosuccinic acid.

Adult Dose

15-40 mg/kg/d; not to exceed 250-500 mg PO q6h ac (continue 1 wk until decline in urine mercury levels)

Pediatric Dose

20-30 mg/kg/d PO qd or bid ac

Contraindications

Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia

Interactions

Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; effects may decrease with coadministration of zinc salts, antacids, and iron

Pregnancy

 Unsafe in pregnancy

Precautions

Thrombocytopenia, agranulocytosis, and aplastic anemia may occur; adverse effects include GI disturbances, rash, leukopenia, thrombocytopenia, and proteinuria; caution in renal insufficiency

Drug Name

DMSA (2,3-dimercaptosuccinic acid) is used in inorganic and organic mercurials. Considered superior to penicillamine because can be given as PO and with fewer adverse effects. Because of ease of use, good efficacy, and safety, initiate treatment if good evidence indicates that significant absorption can occur (mercury levels may not be readily available).

Adult Dose

10 mg/kg PO tid for 5 days, followed by 10 mg/kg PO bid for 14 days

Pediatric Dose

10 mg/kg or 350 mg/m2 PO q8h for 5 days, followed by 10 mg/kg PO bid for 14 days

Contraindications

Documented hypersensitivity

Interactions

Do not administer concomitantly with edetate calcium disodium, or penicillamine

Pregnancy

Safety for use during pregnancy has not been established.

Precautions

Caution in renal or hepatic impairment; patient should be well hydrated to prevent toxicity; adverse effects include mild GI disturbances and a transient rise in liver enzymes; product has a strong sulfur smell; thrombocytosis, eosinophilia, and neutropenia reported with use and are reported to resolve when therapy ends

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

Drugs Comments
DMPS (Sodium 2,3-dimercaptopropane-1-sulfonate) It is an acid-molecule with two free sulfhydryl groups that forms complexes with heavy metals such as zinc, copper, arsenic, mercury, cadmium, lead, silver, and tin.  It is a water-soluble complexing agent. It has an abundance of international research data and an excellent safety record in removing mercury from the body and has been used safely in Europe as Dimaval for many years.

The DMPS dose is 3-5 mg /kg of body weight once a month which is injected slowly intravenously over five minutes. DMPS-stimulated excretion of all heavy metals reaches a maximum 2-3 hours after infusion and decreases thereafter to return to baseline levels after 8 hours

One should use DMPS with great caution and NEVER use it in patients with amalgam fillings. Ideally DMPS should be administered after 25 grams of ascorbic acid administered intravenously. This will minimize any potential toxicity from the DMPS

DMPS is administered over a five-minute period since hypotensive effects are possible when given intravenously as a bolus. Other possible side effects include allergic reactions and skin rashes.

Chlorella It is an algae that take up toxic trace metals from their environment, resulting in an internal concentration greater than those of the surrounding waters

Chlorella also enhances mobilization of mercury compartmentalized in non-neurologic structures such as the gut wall,muscles, ligaments, connective tissue, and bone.

The mucopolysaccharides in chlorella's cell wall absorb rather large amounts of toxic metals similar to an ion exchange resin.

Chlorella is an important part of the systemic mercury elimination program, as approximately 90% of the mercury is eliminated through the stool. Using large doses of chlorella facilitates fecal mercury excretion. After the intestinal mercury burden is lowered, mercury will more readily migrate into the intestine from other body tissues from where chlorella will effectively remove it.

Chlorella is not tolerated by about one-third of people due to gastrointestinal distress. Chitosan can be effectively used as an alternative in these individuals. Chitosan makes up most of the hull of insects shellfish and also bind metals like mercury from the lumen of the intestines.

Antioxidants Vitamin E doses of 400 I.U per day have been shown to have a protective effect when the brain is exposed to methyl-mercury. Selenium, 200-400 mcg daily, is a particularly important trace mineral in mercury elimination and should be used for most patients.

Selenium facilitates the function of glutathione, which is also important in mercury detoxification. Some clinicians find repetitive high dose intravenous glutathione useful, especially in neurologically compromised patients.

Vitamin C is also a helpful supplement for mercury elimination as it will tend to mobilize mercury from intracellular stores

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

No clinical studies have been published to investigate the ability of cathartics, with or without activated charcoal, to reduce the bioavailability of drugs or to improve the outcome of poisoned patients.

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.
Precaution
  • 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)


Clinical Updates
 

Quinine Overdose : Hypoglycemia Potentiated by Age  and Alcohol

Author (s): Cox C D; Anderson A C; Chittivelu S

Source: J Pharm Technology, Vol 17, Issue 6, Pg 270-272, Yr 2001

Abstract     :  A case of a 55 year old white woman with a history of ethanol abuse developed quinine toxicity after accidentally consuming approximately 4 grams of quinine. During her hospital stay, the patient developed life-threatening hypoglycemia, signs of cinchonism, hypotension and hypokalemia. She was treated successfully with intravenous fluids, dextrose and potassium.

Pharmacologic Interventions in Suicide Prevention

Author (s):  Tondo L ; Ghiani C; Albert M

Source: J Clin Psychiatry, Vol 62, Issue S25, Pg 51-55, yr 2001

Abstract     :  Suicide rates vary by country and by mental disorder but the number of suicides per year is not declining and that a person with a mental disorder is more likely to commit suicide than one without such an illness. Although many pharmacologic interventions have been reported to reduce the risk of suicide among mentally ill patients, especially those with bipolar disorder, the effects of such interventions are inconsistent at best. Lithium is the only medication for which the evidence consistently shows an antisuicidal effect.

Toxic Effects Toxic Effects Associated with Consumption of Zinc

Author(s): Igic P G; Lee E; Harper W; Roach K W

Source: Mayo Clin Proc, Vol 77, Iss 7, Pg 713-716, Yr 2002

Abstract: A case of a 27-year-old man who had been taking several vitamins and zinc gluconate, 850-1000 mg/day for a year as a therapy for acne. He presented to his  primary care physician because of fatigue and dyspnea on exertion of 4 weeks' duration. He was remarkably pale, orthostatic pulse changes were noted, and a systolic ejection murmur was heard. He was admitted for further evaluation. A zinc toxic and copper-deficient state was confirmed by laboratory studies. The patient was treated with intravenous copper sulfate, followed by 3 months of oral therapy. The complete blood cell count, serum copper level, and serum zinc level returned to normal.

 

 

 

 


s utube s fb