Nothing but the BEST

“If you want to succeed, you should strike out on new paths rather than travel the worn paths of accepted business.” J. D.  Rockerfeller   

This happened on 17 July 2000 when the National Poison Centre (PRN) said goodbye to its Founding Director, Professor Dzulkifli Abdul Razak. 

Professor Dzulkifli is Universiti Sains Malaysia’s new Deputy Vice-Chancellor for student affairs. From a position where his presence was felt both from the standpoint of leadership and research capabilities, he is now geared towards the issues of governance, student guidance and administration. 

Dzul, as he often asked to be addressed, headed the National Poison Centre from its inception in March 1994 to July 2000.  In that space of 69 months, he converted his energy into sheer hard work and was able to put the Centre firmly on the map of both the local and international arenas on issues relating to health, drug and poison information and initiatives on tobacco control. This was evident when the Centre, just barely four years in existence, was adopted by the World Health Organization (WHO) as its Collaborating Centre for Drug Information. The designation gave the PRN the honour of being the only centre in the region to be of this service. Dzul also pioneered the Centre into undertaking studies on lead poisoning in children, a project now expanded nationwide with direct participation of the Health Ministry. 

Dzul was born and bred with the kind of character we all so often wish in every man. He is charming and witty, friendly and, most of all, humble. If ever anyone saw the occasional ‘hard’ side of him, it would have to do with his firm stand on a particular issue which he was prepared to lay down his soul for. His strong commitment on issues pertaining to drug abuse, tobacco and health were often voiced fearlessly. Some of these issues turned controversial and put him at odds with various parties as the ‘hot’ issues were debated on the printed media. The reading Malaysians will no doubt remember him for advocating the safe use and labeling of flouridated toothpaste, the safety of Viagra, and his tireless campaigns against tobacco and dangerous or irrational drug use. His courage to highlight and expound aspects on health issues stems from a personal conviction that all humans and earthly living things have the basic right to enjoy good health and he worked unceasingly to achieve the desired results. Dzul never sought or hoped to gain any publicity for the things he did but whenever an achievement was accomplished he unhesitatingly shared with all who worked with him. 

In April 1999, Dzul must have been completely overwhelmed when – unknowing to him – he was nominated and selected as the recipient of the prestigious Olle Hansson Award for that year. The award is given each year in memory of the late Dr. Olle Hansson, a leading Swedish paediatric neurologist, to an individual for promoting the safe use of medicine. Dzul is the first Malaysian to receive this award, and truly worthy of the honour. 

Dzul will always be admired for the leadership qualities he displayed during his tenure as Director of PRN. Always kind and understanding, he dealt with each situation in an unbias and professional manner.  His affable nature and humility attracted people easily. He was a favourite with representatives of the press and television stations whom he never failed to charm with his wit, knowledge and frankness during the interviews he had with them.  Dzul also possessed a special gift recognising potential in people and he brought out the very best in his staff member regardless of rank and file.  His strong and quality leadership earned the Centre the University’s inaugural Anugerah Kualiti for examplary service in 1998. In the following year, the Centre was also one of the two University’s short-listed candidates for the Prime Minister’s Award. Undisputedly, his best attribute must be his foresight and vision in steering PRN to its present day success. 

In the professional circle, Dzul is well respected by his peers for the work he has done and the issues he continues to advocate. A well-read person, coupled with an impressive network of contacts, locally and abroad, he inspired his staff continuously with up-to-date knowledge and information. 

Dzul’s appointment to his current position is a recognition of his various and varied personal and academic capabilities. He is now in a higher place of authority, a recognition accorded by the University and the country and one he richly deserves.  As it stands, it appears that his future may take a slightly different path – in leadership in administration and student guidance, leading ultimately to national educational policy issues. But what he leaves behind in PRN will always be long enduring and a testimony of his strength of leadership. 

Without exception, the staff of PRN truly feel themselves proud to have worked with Dzul, to have reaped the harvest and legacy of his consistent and high calibre stewardship. The highest honour they can bestow upon him – their former beloved head – is to perpetuate and continue his modus operandi, collaborate and cooperate with individuals and agencies at every level of operation so that PRN can move from strength to strength and always remain poised and challenged. This is the best bouquet they can present to Dzul for his 49^th birthday celebrated recently in September. 

 PRN ties up with Planet Connections 

PRN and Planet Connections (M) Sdn Bhd has recently signed a memorandum of understanding to initiate a joint collaborative work to develop and package a poison database that is accessible through the internet. The system is expected to help provide the informational needs of health care providers in managing poisoning cases.

This database will contain description of individual poison entity, manifestation from the poisoning/overdose, laboratory investigation and diagnosis, treatment guidelines and other relevant information and cover various types of poison including:  

• pharmaceuticals
• agrochemicals
• natural toxins
• industrial chemicals 
• household products 

In the first phase of the project, PRN will focus on chemical substances that are more commonly involved in poisoning incidences in the country - the agrochemical groups, followed by pharmaceuticals, household products, industrial chemicals and natural toxins. The company on the other hand will package the database into various multimedia forms before marketing the product. 

Planet Connections (M) Sdn Bhd, a company that is in the business of providing information technology consultancy services, application and content development, maintenance and management, leverages quite heavily on the latest internet and multimedia technologies. The company has signed a contract with Medical Online Sdn Bhd, a Consortium that has been awarded a  Concession Agreement from the Ministry of Health to provide  services pertaining to the computerised health applications and content(s) in respect to the Multimedia Super Corridor’s Telemedicine Flagship Application.  

2-Phenylphenol

General

CAS registry number: 90-43-7

Molecular formula: C₁₂H₁₀O

Formula weight: 170.20

CAS chemical name: o-Hydroxybiphenyl

Chemical structure:

Physical and chemical properties

2-Phenylphenol is a light purple colored crystals. 

Melting point: 55.5 - 57.5^oC

Boiling point: 280^oC - 284^oC

Specific gravity: 1.213 at 25^oC

Solubility in water: <0.1 mg/mL at 20.5^oC

Uses

Intermediate for dyes and resins, rubber chemicals, fungicide, germicide,  preservative, food packaging. Dis-infectant and fungicide for impregnation of  fruit wrappers and disinfection of seed boxes.  Applied during dormant period to control apple canker. Reagent for the determination of trioses. Household disinfectant; dishwashing formulations.

Clinical effects

Phenol compounds are very toxic poisons, corrosive and irritating. Symptoms of exposure to this compound include eye irritation with possible corneal injury (necrosis); paleness, cyanosis, weakness, sweating, headache, diarrhea, nausea, vomiting, dizziness, fainting, dark urine, central  nervous system depression, and deoxyribonuclease inhibition. Chronic exposure  may include irritation to mucous membranes and lesions of the respiratory system.N

Analytical method

Sample:  Apple, pear, carrot, citrus fruit, tomato, cherry and sweet potato.

Specimen requirement: 0.5 – 1.0 Kg

Scope of analysis: 2-Penylphenol 

Method of analysis:  HPLC

Reporting limit: 0.03 ppm.

Cost per sample: RM 150.00

*For  advice on sample collection and delivery, please contact  04 – 6570099 

  Attention: En. Noor Hasani Hashim or En. Razak Hj.Lajis

 Review on

Introduction 

Digoxin is one of the cardiac glycosides which has been used for centuries in the treatment of congestive heart failure (CHF) and other ailments. Digoxin was initially extracted from the leaves of Digitalis lanata. Other cardiac glycosides include those obtained from the leaves of the common foxglove plant, Digitalis purpurea and seeds of Strophanthus gratus. 

Digoxin is a water-soluble drug and is not well absorbed after oral administration. Its bioavailability is about 50-80%. Digoxin has a large volume of distribution (6-7L/kg) with a distinct distribution phase that lasts about 8 hours. It has a high level of tissue binding particularly in cardiac tissue. The heart to serum digoxin concentration ratio is 70:1. Digoxin is metabolized in the stomach and intestines. The metabolites (e.g., digoxi-genin and monodigitoxoside) may contribute to its therapeutic and toxic effects. Both the parent drug and metabolites are predominantly excreted via the kidneys, with 50-70% of the dose is excreted unchanged. In the presence of normal renal function the half-life of digoxin is 24-48 hours, however, this is likely to increase in overdose as the active secretion of digoxin in the kidney becomes saturated. There is also some enterohepatic circulation. 

Digoxin is indicated in the treatment of CHF and to slow the ventricular rate in tachyarrhythmias such as atrial fibrillation and supraventricular tachycardia. The narrow therapeutic window of digoxin (0.8-2.5 ng/ml) mandates serum concentration monitoring in all patients.  It has been reported that up to 15% of all medical patients admitted to hospital are on digitalis therapy, and 30% of these patients will have signs of toxicity. The mortality rate due to intoxication ranges from 3 to 25%. Others have shown that digitalis preparations are also the most common cause of unintentional poisoning in the elderly. 

Acute digoxin poisoning in massive doses may be lethal and occurs fairly common, being intentional or attributed to inadvertent overdosing, alterations in the drug pharmacokinetic parameters due to concomitant diseases or drug interactions that cause elevated digoxin serum concentration. 

In Malaysia, digoxin is marketed both in generic form and under the proprietary name LanoxinÒ. Digoxin comes in various dosage strengths and forms, including 0.25mg and 0.0625mg tablets, 0.05mg/ml elixir and 0.5mg/2ml ampoules.  

What is the mechanism of digoxin toxicity? 

Digoxin inhibits the sodium/potassium ATPase transport mechanism in myocardial and cardiac conducting tissue. Digoxin binds to the potassium-binding site and prevents potassium being transported into the cell which leads to intracellular increases in sodium and calcium ions. These effects result in increased automaticity and excitability with both early and after delayed depolarisations. Digoxin also causes AV nodal block and decreased conduction velocity throughout the His-purkinje system. The binding of digoxin to the sodium/potassium ATPase transport system is inhibited by high levels of potassium and the level of activity of this enzyme is increased by the presence of magnesium. Thus both hypo-kalaemia and hypomagnesaemia increase digoxin toxicity and hyper-kalaemia and hypermagnesaemia are protective. 

What are the signs and symptoms of digoxin poisoning? 

The manifestations of digoxin poisoning are difficult to distinguish from the effects associated with cardiac disease. The most common early symptoms of toxicity are nausea and vomiting, which may precede or follow evidence of cardiotoxicity. Other signs and symptoms include anorexia, diarrhea, abdominal discomfort, headache, weakness, drowsiness, visual disturbances, mental depression, confusion, restlessness, disorientation, unifocal or multifocal premature ventricular contractions (PVCs), paroxysmal nodal rhythms, atrial-ventricular (A-V) dissociation, excessive slowing of the pulse, A-V block, P-R prolongation, S-T depression and fibrillation of the atrial and ventricular. Digoxin serum concentration >2.5ng/ml usually confirms the diagnosis of poisoning. 

Digoxin naive patients with no preexisting cardiac abnormalities are relatively resistant to developing ventricular arrhythmias after acute poisoning. Heart blocks with or without supraventricular arrhythmias are most oftenly observed. Other effects include vomiting, bradycardia, and hyperkalemia. 

Chronic poisoning usually occurs in elderly patients with preexisting renal and cardiac disease mostly as a result of too large a dose of digoxin, changing renal function, concurrent diuretic administration that may produce hypokalemia and hypomagnesemia, and other digoxin drug interactions (e.g., verapamil, quinidine, erythromycin and amiodarone). Patients may present with a variety of types of arrhythmias, most being ventricular in nature. It has been reported that ventricular fibrillation following digoxin poisoning is the most common cause of death. Other effects seen include nausea, vomiting, visual disturbances and altered mental status. Prior to the use of digoxin antidote, digoxin-specific-antibody Fab fragments, mortality from chronic digoxin intoxication was reported to be up to 20%. 

How should digoxin poisoning be managed? 

Supportive care is the general management for digoxin overdose. This includes the provision of respiratory and cardiovascular support as necessary. Patients who are hypotensive may require placement of a CVP line. Digoxin levels taken 6 or more hours after ingestion correlate well with clinical signs and symptoms of digoxin poisoning. Earlier levels may be difficult to interpret as digoxin may still be in a distribution phase and therefore plasma levels do not correlate with tissue levels. Thus digoxin levels may serve to confirm an overdose but do not serve as a good guide to the need for specific treatment. Digoxin levels rise rapidly with the administration of digoxin Fab fragments and then only free digoxin levels will indicate the level of digoxin still unbound. 

Immediate measurement of potassium, sodium, magnesium, calcium and bicarbonate is warranted. Any hypokalemia, hypomagnesemia or an imbalance of the other electrolytes should be corrected. Magnesium enhances the activity of the Na+-K+-ATPase without altering digoxin levels or digoxin binding. It may be useful in situations where digoxin Fab fragments are indicated but are not immediately available. The calcium channel blocking properties of magnesium mean that it is useful in tachy-arrhythmias but may paradoxically initially worsen AV block in bradyarrhythmias. 

However, no attempt should be made to correct hyperkalemia since the high potassium level is an indicator of the antagonism of the potassium binding site. Thus potassium levels over 6 mEq/L are usually present in severe acute toxicity. However, in chronic toxicity occurring in patients with heart disease, normokalemia or hypokalemia is more common. This is due to the use of diuretics and the renal excretion of potassium over preceding days. Vomiting should be controlled reasonably aggressively with medium to high doses of metoclopramide (10-50 mg IV) as the increased vagal tone associated with vomiting may increase the cardiac toxicity and may disturb electrolytes.

Decontamination using activated charcoal at a dose of 1 gram/kg patient body weight is warranted. Lavage or ipecac syrup may be used but there is no evidence that either provides additional benefit over charcoal alone in digoxin overdoses. In addition, it should be noted that additional vagal stimulation might worsen bradycardia. Activated charcoal will also bind digoxin undergoing enterohepatic recirculation. Repeated doses of activated charcoal (1/2 gram per kg q 4 hours without cathartic) decreases digoxin half life by at least 40% in patients with decreased renal function. The effects of multiple doses of activated charcoal in patients with normal renal function are extremely limited.

A more definitive care for the more serious complications such as atrial arrhythmias includes atropine for sinus and A-V block at a dose of 1 mg IV repeated as necessary and cardiac pacing for bradycardia unresponsive to atropine. Atropine should be given to all patients with bradyarrhythmia. If other antiarrhythmic drugs are required, Class 1B drugs (e.g., lidocaine, mexiletine, tocainide) should be used, as they do not impair AV nodal conduction. For patients presenting with ventricular arrhythmias, lidocaine or phenytoin is recommended. It is imperative to avoid antiarrhythmic drugs that delay A-V node conduction, namely class 1A agents (quinidine, disopyramide, procainamide). Since digoxin has large volume of distribution (6-7L/kg) secondary to high tissue binding, hemodialysis and hemoperfusion do not significantly increase drug clearance. Attempts to alkalinize urine do not enhance elimination and may lead to fluid imbalances, exacerbate CHF, and worsen pulmonary edema. Digoxin Immune Fab should then be administered for arrhythmias unresponsive to conventional treatment.

When should digoxin immune Fab be used in the management of digoxin poisoning?

Digoxin Immune Fab (DigibindÒ), derived from specific antidigoxin antibodies produced in sheep, acts as digoxin antidote by directly binding to molecules of digoxin and thus removing it from the Na+-K+-ATPase pump. These complexes are then excreted by the kidneys and removed from the body. The Fab digoxin complex is excreted with a half life of 12 to 24 hours but may be greatly prolonged in the presence of renal failure.

DigibindÒ is indicated for the treatment of potentially life threatening digoxin intoxication, including ventricular arrhythmias (V-tachycardia, V-fibrillation), progressive bradyarrhythmias (severe sinus bradycardia or second or third degree A-V block not responsive to atropine), acute digoxin ingestions of >10mg in adults or >4mg in children, hyperkalemia (serum potassium concentrations >5mEq/L) and/or post distribution (6-8 hours after dosing) serum digoxin concentrations >10ng/ml.

The use of Digibind is recommended for the treatment of digitalis poisoning in infants and young children who have ingested up to 0.3 mg of digoxin per kilogram, who have underlying heart disease and who have other certain physical conditions.

Fab fragments bind to digoxin in a one to one ratio. Thus the dose of digoxin Fab fragments depends on the dose of digoxin that is to be neutralised. To determine the dose of DigibindÒ, first determine the total body load of digoxin. If no information regarding amount or post distribution serum digoxin concentrations is available, the usual adult dosage is 20 vials (800mg) IV infusion. Three different methods have been suggested in calculating the dose of DigibindÒ, i.e., using the digoxin dose ingested, serum digoxin level and dosing by titration.

One vial of digoxin Fab fragments (40mg) binds to 0.6mg of digoxin. Thus an ingestion of 3mg of digoxin, for example, requires 5 vials. In calculating the dose using serum digoxin level, the average volume of distribution (adults 7-8L/kg, neonates 10 L/kg, infants 16L/kg) is used along with the measured digoxin level. For example, a patient with a level of 13 nmol/L six hours after an overdose can have the amount of digoxin they have absorbed calculated as follows:

Convert the units to mcg/L from SI units by dividing by 1.281, thus the level is approximately 10 mcg/L. If the patient is a 80 kg man then the volume of distribution may be as high as 700L and therefore up to 7000mcg or 7mg of digoxin has been ingested. As a 40mg vial binds about 0.6mg of digoxin, this patient requires 11 or 12 vials of digoxin Fab fragments. Thus, in an adult the number of 40mg vials = concentration in mcg/L (nmol/L/1.28) x weight (kg)/75.

The third method of dosing digoxin Fab fragments is to titrate it against clinical effects, where 4-6 vials of digoxin Fab fragments can be given and repeated depending on the clinical effect. This may be most useful in patients with hyperkalemia or heart block rather than patients with ventricular tachyarrhythmias where the treatment is more urgent.

DigibindÒ is available as a lyophilized powder. It needs to be refrigerated (2-8°C) and reconstituted with 4ml of sterile water, resulting in 10mg/ml for IV infusion. Mix gently to avoid foaming. The reconstituted solution may be further diluted with NS to a convenient volume, e.g. 1mg/ml. Reconstituted solutions should be used within 4 hours if refrigerated. Product should be infused through a 0.22-micron filter over 30 minutes. Drug may be given via bolus injection if cardiac arrest is imminent.

What are the monitoring parameters for DigibindR?

Improvement in signs and symptoms should occur within 2-30 minutes post administration of DigibindÒ .

A few cases of minor allergic reactions in humans have been reported. Although skin testing for allergic reaction is not routinely recommended, it is advisable to make epinephrine immediately available. Low cardiac output states may be induced because of reversal of the inotropic effects of digoxin. Hypokalemia may occur due to reactivation of Na-K-ATPase.

Thus, monitor potassium every hour after DigibindÒ has been given. Digoxin serum levels may increase precipitously after DigibindÒ administration as digoxin is pulled from the cardiac sites and bound to antibody in the blood. But, the bound drugs will not be able to react with the receptors nor exert any pharmacological actions. Monitoring of digoxin levels immediately after DigibindÒ administration is unnecessary as these levels are clinically misleading. Several days to one week (or longer in renal failure patients) are usually required to eliminate DigibindÒ from the body.

Fab fragments may remove the beneficial effects of digoxin in patients with underlying congestive heart failure or atrial fibrillation. However, in clinical practice, this occurs rarely. In patients with severe underlying cardiac disease, digoxin Fab may be given slowly until the desired clinical effect is achieved. This strategy can only be used in patients without immediately life threatening toxicity.  

Essential Oils and its effect in Poisoning 

Essential oils are used widely as an active ingredient in herbal preparations. Since herbal preparations are touted to the public to be ‘natural’,  people believed that they are less toxic and more effective than conventional drugs. 

Essential oils are extracted from plants, packaged and sold unregulated to the public for medicinal purposes. It is is a volatile oil composed of a mixture of complex hydrocarbons (usually terpenes) and other chemicals extracted from a plant by distillation. Naturally it gives the plants its characteristic aroma. 

Like other herbal remedies, they are used in a variety of ways, therapeutically as antimicrobials, antispasmo-dics, carminatives, analgesics, sedatives, antidepressants etc. and  available in formulations like topical applications, baths, inhalants, oral as well as parenteral preparations. 

Although the efficacy of most essential oils are unknown, some have shown to be beneficial in improving certain health conditions. As with other herbal preparations, they also possess inherent toxicities related to product variation, adulteration, adverse reactions, overdose, and the possibility of as yet undetected toxicities such as mutagenesis or carcinogenesis. To ascertain their usefulness in medicine, essential oil must undergo rigorous scientific testing typical of regulated drugs especially in vulnerable populations such as children and pregnant women. 

Table 1 shows examples of therapeutic use of essential oils and Table 2 shows some of its toxic effect and its management. 

Table 2  Examples of Toxic Essential Oils - the Chemical Constituents,  Toxic Effects and Poisoning Management.