CLINICAL TOXICOLOGY-PharmD Notes

1.     General principles involved in the management of poisoning

2.    Antidotes and the clinical applications.

3.    Supportive care in clinical Toxicology.

4.    Gut Decontamination.

5.    Elimination Enhancement.

6.    Toxicokinetics.

7.    Clinical symptoms and management of acute poisoning with the following agents –

a) Pesticide poisoning: organophosphorouscompounds, carbamates, organochlorines, pyrethroids.

b)    Opiates overdose.

c)    Antidepressants

d)    Barbiturates and benzodiazepines.

e)    Alcohol: ethanol, methanol.

f)     Paracetamol and salicylates.

g)    Non-steroidal anti-inflammatory drugs.

h)    Hydrocarbons: Petroleum products and PEG.

i)     Caustics: inorganic acids and alkali.

j)     Radiation poisoning

8.    Clinical symptoms and management of chronic poisoning with the following agents –

         Heavy metals: Arsenic, lead, mercury, iron, copper

9.    Venomous snake bites: Families of venomoussnakes, clinical effects of venoms, general management as first aid, early manifestations, complications and snake bite injuries.

10.  Plants poisoning. Mushrooms, Mycotoxins.

11.   Food poisonings

12.  Envenomations – Arthropod bites and stings.

Substance abuse: 

Signs and symptoms of substance abuse and treatment of dependence

a)    CNS stimulants :amphetamine

b)    Opioids

c)    CNS depressants

d)    Hallucinogens: LSD

e)    Cannabis group

f)     Tobacco
    Drug abuse PPT#2

References:

a.    Matthew J Ellenhorn. ELLENHORNS MEDICAL TOXICOLOGY – DIAGNOSIS AND TREATMENT OF POISONING.  Second edition.  Williams and Willkins publication, London

b.    V V Pillay.  HANDBOOK OF FORENSIC MEDICINE AND TOXICOLOGY.  Thirteenth edition 2003 Paras Publication, Hyderabad

Substance abuse & Substance Dependence

Substance abuse can be generally thought of as a misuse of a substance but with no prominent physiological or psychological tolerance (needing more for the same effect) orwithdrawal (negative symptoms when without the substance).

Antidote / Reversal Agents

• Acetaminophen: acetylcysteine [Mucomyst] 
• Benzodiazepine: flumazenil [Ramazicon] 
• Curare: edrophonium [Tensilon] 
• Cyanide poisoning: methylene blue 
• Digitalis: digoxin immune FAB [Digibind] 
• Ethylene poisoning: fomepizole [Antizol] 
• Heparin and enoxaprin [Lovenox]: protamine sulfate 
• Iron: deferoxamine [Desferal] 
• Lead: succimer [Chemet] 
• Magnesium Sulfate: calcium gluconate 10% [Kalcinate] 
• Narcotics: naloxone [Narcan] 
• Warfarin: phytonadione [vitamin K]

Classification Of Food Poisoning

I. Based on symptoms and duration of onset:
a. Nausea and vomiting within six hours (Staphylococcus aureus, Bacillus cereus)
b. Abdominal cramps and diarrhoea within 8-16 hours (Clostridium perfringens, Bacillus cereus)
c. Fever, abdominal cramps and diarrhoea within 16-48 hours (Salmonella, Shigella, Vibrio
parahemolyticus, Enteroinvasive E.coli, Campylobacter jejuni)
d. Abdominal cramps and watery diarrhoea within 16-72 hours (Enterotoxigenic E.coli, Vibrio cholerae
O1, O139, Vibrio parahemolyticus, NAG vibrios, Norwalk virus)
e. Fever and abdominal cramps within 16-48 hours (Yersinia enterocolitica)
f. Bloody diarrhoea without fever within 72-120 hours (Enterohemorrhagic E.coli O157:H7)
g. Nausea, vomiting, diarrhoea and paralysis within 18-36 hours (Clostridium botulinum)

Toxicology-Introduction

Definition

Poisoning occurs when any substance interferes with normal body functions after it is swallowed, inhaled, injected, or absorbed. The branch of medicine that deals with the detection and treatment of poisons is known as toxicology.

Supportive care in clinical Toxicology

Resuscitation in Toxicology

Supportive care

Initial resuscitation should be based on the assessment of the patient and not the particular toxin involved and standard advanced life support (ALS) guidelines should be followed.Specific instances where treatment may differ are indicated below.

The majority of patients taking overdoses or with drug toxicity are young and healthy, so cardiac and respiratory support should be continued for much longer periods of time in patients with a toxicity-related cardiorespiratory arrest.

If there is any doubt, cardiac compression and ventilatory support should be continued until the situation has been discussed with a clinical toxicologist. There has been survival with normal neurological function in patients receiving cardiopulmonary resuscitation (CPR) for hours.

Airway

There are no specific differences from Resuscitation except for caustic and corrosive ingestions . CNS depression is a common effect of drugs, so regular and careful assessment of airway protection and patency is important. 

Breathing

Toxicology patients rarely have hypoxia unless they develop aspiration pneumonitis. The commonest problem is hypoventilation secondary to respiratory depression.

Circulation

Inotropic support

The use of intravenous fluid therapy and inotropic support should be based on patient haemodynamics and the specific toxins ingested.

Although specific inotropes or or other drugs are suggested in toxicology patients, the initial management of cardiogenic shock should be the same as for any other cause  unless there are specific contraindications to particular inotropes. The initial inotrope of choice is adrenaline unless its vasopressor actions are contraindicated, such as in beta blocker overdose. Administration of an inotrope should only be undertaken in consultation with a toxicologist or cardiologist.

Other inotropes are used in toxicology, but should usually be used in consultation with a clinical toxicologist. Usual doses of these are given in Box below

Prolonged cardiopulmonary resuscitation is essential because unlike in arrests due to cardiovascular disease, the majority of patients are healthy prior to the overdose, and survival with normal neurological function after long periods (hours) of cardiopulmonary resuscitation is well documented.

Adult doses of other inotropes used in toxicology.

Milrinone (phosphodiesterase inhibitor) milrinone 50 micrograms/kg IV, slowly over 10 minutes, followed by 0.375 to 0.75 micrograms/kg/minute IV, adjusting according to clinical and haemodynamic response, up to a maximum of 1.13 mg/kg daily. Insulin euglycaemia 1 short-acting insulin 1 unit/kg  IV bolus, followed by 1 unit/kg/hour. The dose can be increased to 2 units/kg/hour or further but this should be discussed with a clinical toxicologist PLUS glucose 10% or 50% IV infusion OR 2 glucagon 5 to 10 mg (= 5 to 10 units) IV bolus, then continue at 5 to 10 mg/hour. Dobutamine dobutamine 2.5 to 10 micrograms/kg/minute IV.

Drug-induced arrhythmias

QT prolongation and torsades de pointes: QT prolongation should be monitored and any other precipitating factors should be determined and treated if possible. Electrolytes, including magnesium and calcium, should be checked and deficiencies corrected.

Patients with hypomagnesaemia should have magnesium replacement. [Note 1]

In adults, use:

magnesium sulfate 50% 5 to 10 mL (= 2.5 to 5 g or 10 to 20 mmol) IV over 30 to 60 minutes.

In children, use:

magnesium sulfate 50% 0.1 mL/kg (= 50 mg/kg or 0.2 mmol/kg) IV over 20 minutes [Note 2], followed by 0.06 mL/kg/hour (= 30 mg/kg/hour or 0.12 mmol/kg/hour) IV infusion.

Patients with hypocalcaemia should have calcium replaced. Use:

In adults, use:

calcium gluconate 10% 10 to 20 mL (= 1 to 2 g or 2.2 to 4.4 mmol) IV, over 10 to 30 minutes.

In children, use:

calcium gluconate 10% 2 to 5 mL/kg/day (= 200 to 500 mg/kg/day) IV infusion.

Patients with hypokalaemia should have potassium replaced. If the patient is able to take and absorb oral potassium, use:

potassium chloride 14 to 16 mmol orally, 3 times daily (child: 1 mmol/kg/day in 2 to 4 doses) [Note 3].

If the serum potassium is less than 3 mmol/L or the patient is unable to take or absorb oral potassium, use:

potassium chloride 10 to 20 mmol (= 0.75 to 1.5 g) IV, over 1 to 2 hours (child: 0.6 mmol/kg IV over 3 hours) preferably as a pre-mixed solution of the appropriate intravenous fluid. [Note 4].

Isoprenaline or transvenous pacing should be considered in patients with a prolonged QT interval and bradycardia. In adults, use:

isoprenaline 20 micrograms IV, repeat according to clinical response, and commence an infusion at 1 to 4 micrograms/minute, but the rate may need to be rapidly increased to give double, quadruple or higher doses as required to overcome the beta blockade.

Torsades de pointes may resolve spontaneously within a minute but if not, first-line treatment is a 200 J DC shock or equivalent. If there is no response to an initial DC shock this can be repeated with increasing voltage shocks. Magnesium should also be given (except in torsades de pointes resulting from beta blocker overdose, see Toxicology: beta blockers).

In adults, use:

magnesium sulfate 50% 2 to 4 mL (= 1 to 2 g or 4 to 8 mmol) IV as a slow injection over 2 to 5 minutes.

In children, use:

magnesium sulfate 50% 0.05 to 0.1 mL/kg to a maximum of 4 mL (= 0.025 to 0.05 g/kg or 0.1 to 0.2 mmol/kg to a maximum of 8 mmol/dose) IV as a slow injection over 10 to 15 minutes.

If there is deterioration to ventricular fibrillation or asystole, standard advanced life support protocols should be followed, see Figure 14.4 and Figure 14.5.

Note 1: In toxicology patients, the correction of magnesium deficiency, if required, needs to be done rapidly while the patient has a prolonged QT interval and is at risk of torsades de pointes. Note 2: Magnesium can be given intramuscularly in infants or children if urgent IV access not possible. Note 3: Effervescent immediate-release tablets of potassium contain 14 mmol potassium per tablet, and slow-release tablets contain 8 mmol potassium. The slow-release formulations of potassium are almost completely absorbed within one hour. Note 4: If pre-mixed IV solution is unavailable, potassium chloride concentrate injection must be added to a large volume of parenteral fluid and mixed thoroughly before infusion. The usual maximum concentration is 40 mmol/L.

Gut Decontamination

 The choice of gut decontamination procedure depends on the toxin and the circumstances

  Observation of the Patient

Asymptomatic or mildly symptomatic patients should be observed for at least 4–6 hours. Longer observation is indicated if the ingested substance is a sustained-release preparation or is known to slow gastrointestinal motility or if there may have been exposure to a poison with delayed onset of symptoms (such as acetaminophen, colchicine, or hepatotoxic mushrooms). After that time, the patient may be discharged if no symptoms have developed and adequate gastric decontamination has been provided. Before discharge, psychiatric evaluation should be performed to assess suicidal risk. Intentional ingestions in adolescents should raise the possibility of unwanted pregnancy or sexual abuse.

The Symptomatic Patient
In symptomatic patients, treatment of life-threatening complications takes precedence over in-depth diagnostic evaluation. Patients with mild symptoms may deteriorate rapidly, which is why all potentially significant exposures should be observed in an acute care facility. The following complications may occur, depending on the type of poisoning.

Coma and gut decontamination
Coma is commonly associated with ingestion of large doses of antihistamines, benzodiazepines and other sedative-hypnotic drugs, -hydroxybutyrate (GHB), ethanol, opioids, antipsychotic drugs, or antidepressants. The most common cause of death in comatose patients is respiratory failure, which may occur abruptly. Pulmonary aspiration of gastric contents may also occur, especially in victims who are deeply obtunded or convulsing. Hypoxia and hypoventilation may cause or aggravate hypotension, arrhythmias, and seizures. Thus, protection of the airway and assisted ventilation are the most important treatment measures for any poisoned patient.

Treatment of Gut Contamination

The initial emergency management of coma can be remembered by the mnemonic ABCD, for Airway, Breathing, Circulation, and Drugs (dextrose, thiamine, and naloxone or flumazenil), respectively.

Airway
Establish a patent airway by positioning, suction, or insertion of an artificial nasal or oropharyngeal airway. If the patient is deeply comatose or if there is no gag or cough reflex, perform endotracheal intubation. These airway interventions may not be necessary if the patient is intoxicated by an opioid or a benzodiazepine and responds rapidly to intravenous naloxone or flumazenil (see below).

Breathing
Clinically assess the quality and depth of respiration, and provide assistance if necessary with a bag-valve-mask device or mechanical ventilator. Provide supplemental oxygen. The arterial blood CO2 tension is useful in determining the adequacy of ventilation. The arterial blood PO2 determination may reveal hypoxemia, which may be caused by respiratory arrest, bronchospasm, pulmonary aspiration, or noncardiogenic pulmonary edema. Pulse oximetry provides an assessment of oxygenation but is not reliable in patients with methemoglobinemia or carbon monoxide poisoning.

Circulation
Measure the pulse and blood pressure and estimate tissue perfusion (eg, by measurement of urinary output, skin signs, arterial blood pH). Place the patient on continuous ECG monitoring. Insert an intravenous line, and draw blood for glucose, electrolytes, serum creatinine and liver tests, and possible quantitative toxicologic testing.

Drugs in Gut Decontamination

Dextrose and thiamine
Unless promptly treated, severe hypoglycemia can cause irreversible brain damage. Therefore, in all comatose or convulsing patients, give 50%dextrose, 50–100 mL by intravenous bolus, unless a rapid bedside blood sugar test is available and rules out hypoglycemia. In alcoholic or very malnourished patients who may have marginal thiamine stores, give thiamine, 100 mg intramuscularly or over 2–3 minutes intravenously.

Narcotic antagonists
Naloxone, 0.4–2 mg intravenously, may reverse opioid-induced respiratory depression and coma. It is often given empirically to any comatose patient with depressed respirations. If opioid overdose is strongly suspected, give additional doses of naloxone (up to 5–10 mg may be required to reverse the effects of potent opioids or propoxyphene). Note: Naloxone has a much shorter duration of action (2–3 hours) than most common opioids; repeated doses may be required, and continuous observation for at least 3–4 hours after the last dose is mandatory. Nalmefene, a newer opioid antagonist, has a duration of effect longer than that of naloxone but still shorter than that of the opioid methadone.

Gut Decontamination and Flumazenil
Flumazenil, 0.2–0.5 mg intravenously, repeated every 30 seconds as needed up to a maximum of 3 mg, may reverse benzodiazepine-induced coma. Caution: Flumazenil should not be given if the patient has coingested a tricyclic antidepressant, is a user of high-dose benzodiazepines, or has a seizure disorder because its use in these circumstances may precipitate seizures. In most circumstances, use of flumazenil is not advised as the potential risks outweigh its benefits. Note: Flumazenil has a short duration of effect (2–3 hours), and resedation requiring additional doses is common.