1. Management of Poisoning and Overdose of Medications
Dr. A. Shyam Sundar. M.Pharm., Ph.D,
Assistant Dean( Academic Affairs),
Associate Professor in Pharmacology And Toxicology,
University Of Nizwa
Sultanate of Oman

2. Presentation Outline Pretest Introduction Management of Toxic Exposure
Principles of Managing poisoned patient/ Overdose of Medications
Post-test

3. Introduction
There are different severities of poisoning (from mild, moderate to severe).
Severity depends on,
the poison involved,
the duration and the route of exposure (on the skin or by the mouth), and
the age and weight of the patient.
The severity determines the extent of medical treatment needed.
For Example:
Diabetes medicine prescribed by a doctor is beneficial to an elderly grandfather. However, the same dose taken by his 1 year-old grandchild could result in serious toxicity

4. Management of toxic exposure
The holistic management of toxic exposures should include the following considerations:
Stabilization
Toxic Diagnosis
Therapeutic interventions
Decontamination
Enhanced elimination of absorbed toxins
Antidotes
Supportive care
Psychosocial interventions

5. PRINCIPLE-1
Poisoning is a common event that spares no patient population.
Every xenobiotic is a potential poison.
The duration of the exposure and the median lethal dose (LD50) of the drug are the most important determinants of toxicity.

6. PRINCIPLE- 2
Understanding the commonly observed signs and symptoms (Toxidromes), and the underlying pathophysiologic alterations produced by specific toxins, permits the rapid identification of possible poison and risk stratification of poisoned patients.

7. Vital Signs
Vigilant monitoring of BP, Heart rate and Body temperature provide clinically significant leads. Subtle changes are often the only clues that a well-appearing patient is potentially ill.

8. Blood pressure
Normal blood pressure is a reassuring finding but this vital sign may be the last to deteriorate in patients with clinical shock (Cummins et al. 1994).
Individual attention must be given to both the systolic and diastolic blood pressure.
Poisoned patients may demonstrate a widened pulse pressure, in which the difference between the systolic and diastolic pressures is greater than 50 mm Hg.
This effect may occur in patients poisoned by β-adrenergic agonists, such as epinephrine, or by theophylline.

9. Management of hypotension in poisoned patients
Treatment begins with volume expansion.
Patients who fail to respond to adequate volumes of isotonic saline, (due to altered mental status or metabolic acidosis) may require vasoconstrictive or cardiostimulating drugs.
Agents with predominantly alpha-adrenergic effects are considered vasopressor agents, and those primarily stimulating the β1-adrenergic receptor are termed inotropes and chronotropes.

10. Management of hypertension in poisoned patients
It is rarely a medical emergency but acute severe hypertension in younger patients can be associated with substantial morbidity.
Often noted in cocaine-intoxicated patients or in patients exposed to pure a-adrenergic agonists or other sympathomimetic drugs.
If treatment is required, an a-adrenergic antagonist (Lange et al ) or vasodilator such as nitroprusside should be considered.
In reality most of the cocaine-poisoned patients respond to sedation,(Catravas and Waters 1981).

11. Temperature
Thermoregulatory abnormalities are common in poisoned patients.
Precise rectal temperature should be recorded asap.
Patients with hypoglycemia or sedative-hypnotic intoxication, are frequently hypothermic.
Patients with cocaine intoxication frequently manifest life-threatening hyperthermia. Death from cocaine poisoning may be directly related to the severe temperature dysregulation.
Treatment is directed primarily at sedation and cooling.

12. Toxidromes
The recognition of toxicologic syndromes, or “toxidromes,” may be most informative.
A toxidrome is a constellation of individual clinical findings that, when taken together, implicate a specific class of poisons.
Although standard texts in medical toxicology recognize over 25 toxidromes, only a limited number of toxidromes are clinically significant.

13. Anticholinergic Toxidrome:
Agents that interfere with the binding of acetylcholine to muscarinic receptors produce tachycardia, mydriasis, dry mouth and skin, and depressed bowel and bladder motility.
Examples of potential offending agents:
Atropine, Diphenhydramine, Tricyclic antidepressants, Thioridazine, and Botulinum toxin.
The anticholinergic toxidrome refers specifically to antimuscarinic findings.

14. Cholinergic Toxidrome
Enhanced muscarinic receptor stimulation augments the physiology of rest.
Patients manifest bradycardia, miosis, salivation, diarrhea, vomiting, urination, and bronchorrhea.
Nicotinic receptor stimulation at the autonomic ganglia (as produced by cholinesterase inhibitors) may produce various combinations of increased sympathetic or parasympathetic findings.
Patients may manifest isolated nicotinic or muscarinic findings, but in most instances they coexist.

15. Opioid Toxidrome
Opioid receptors are associated with those areas of the brain involved in regulation of pain and mood.
These receptors bind endogenous opioids (e.g., endorphins) and likely provide an autologous mechanism for pain reduction or mood enhancement.
Exogenous opioids, such as morphine, stimulate these receptors and produce analgesia (µ1) or euphoria (µ1).
However, opioid receptors also modulate ventilation (µ2) and adrenergic outflow (µ1).
Excessive stimulation of these opioid receptor subtypes produces significant obtundation, hypoventilation, and miosis, as well as modest decline in the heart rate and blood pressure.

16. Sympathomimetic Toxidrome
Patients with cocaine, amphetamine, or theophylline poisoning manifest features of Sympathetic overactivity, manifested as the sympathomimetic toxidrome.
Patients typically demonstrate hypertension, tachycardia, diaphoresis, mydriasis, hyperthermia, and a heightened state of alertness ranging from euphoria to agitation.
The mechanisms by which agents induce this toxidrome vary.

17. Sedative-hypnotic Toxidrome
Augmentation of GABA activity produces enhanced neuronal inhibition, which manifests as sedation and hypnosis, or sleep.
With increasing dose, profound mental status depression and coma occur.
Since benzodiazepines have little pharmacologic effect other than GABA agonism, coma with normal blood pressure, pulse, and respiratory rate are the expected finding after benzodiazepine overdose.
Other sedative-hypnotic agents may produce differing effects, such as tachycardia because of the anticholinergic effects of glutethimide or hypoventilation because of the respiratory depressant effects of barbiturates.

18. TOXIN
VITAL SIGNS
MENTAL STATUS
SIGNS AND SYMPTOMS
CLINICAL FINDINGS
Acetaminophen
Normal (early)
Normal
Anorexia, nausea, vomiting
Right upper quadrant tenderness, jaundice (late)
Amphetamines
Hypertension, tachycardia, tachypnea, hyperthermia
Hyperactive, agitated, toxic psychosis
Hyperalertness, panic, anxiety diaphoresis
Mydriasis, hyperactive peristaltism, diaphoresis
Antihistamines
Hypotension, hypertension, tachycardia, hyperthermia
Altered (agitation, lethargy to coma), hallucinations
Blurred vision, dry mouth, inability to urinate
Dry mucous membranes, mydriasis, flush, diminished peristaltism, urinary retention

19. TOXIN
VITAL SIGNS
MENTAL STATUS
SIGNS AND SYMPTOMS
CLINICAL FINDINGS
Barbiturates
Hypotension, bradypnea, hypothermia
Altered (lethargy to coma)
Slurred speech, ataxia
Dysconjugate gaze, bulae, hyporeflexia
Beta-adrenergic antagonists
Hypotension, bradycardia
Dizziness
Cyanosis, seizures
Carbamazepine
Hypotension, tachycardia, bradypnea, hypothermia
Hallucinations, extrapyramidal movements, seizures
Mydriasis, nystagmus( rapid involuntary movement of eyes)
Clonidine
Hypotension, hypertension, bradycardia, bradypnea
Dizziness, confusion
Miosis

20. TOXIN
VITAL SIGNS
MENTAL STATUS
SIGNS AND SYMPTOMS
CLINICAL FINDINGS
Cyclic antidepressants
Hypotension, tachycardia
Altered (lethargy to coma)
Confusion, dizziness, dry mouth, inability to urinate
Mydriasis, dry mucous membranes, distended bladder, flush, seizures
Digitalis
Hypotension, bradycardia
Normal to altered, visual distortion
Nausea, vomiting, anorexia, visual disturbances
None
Disulfiram/ethanol
Normal
Nausea, vomiting, headache, vertigo
Flush, diaphoresis, tender abdomen

21. Isoniazid
Often normal
Normal or altered (lethargy to coma)
Nausea, vomiting
Seizures
Isopropanol
Hypotension, tachycardia, bradypnea
Altered (lethargy to coma)
Hyporeflexia, ataxia, acetone odor on breath
Lithium
Hypotension (late)
Diarrhea, tremor, nausea
Weakness, tremor, ataxia, myoclonus, seizures

22. TOXIN
VITAL SIGNS
MENTAL STATUS
SIGNS AND SYMPTOMS
CLINICAL FINDINGS
Methanol
Hypotension, tachypnea
Altered (lethargy to coma)
Blurred vision, blindness, abdominal pain
Hyperemic disks, mydriasis
Opioids
hypotension, bradycardia, bradypnea, hypothermia
Slurred speech, ataxia
Miosis, decreased peristaltism
Phencyclidine
Hypertension, tachycardia, hyperthermia
Altered (agitation, lethargy to coma)
Hallucinations
Miosis, diaphoresis, myoclonus, blank stare, nystagmus, seizures

23. TOXIN
VITAL SIGNS
MENTAL STATUS
SIGNS AND SYMPTOMS
CLINICAL FINDINGS
Phenothiazines
Hypotension, tachycardia, hypothermia
Altered (lethargy to coma)
Dizziness, dry mouth, inability to urinate
Miosis or mydriasis, decreased bowel sounds, dystonia
Salicylates
Hypotension, tachycardia, hyperthermia
Altered (agitation, lethargy to coma)
Tinnitus, nausea, vomiting
Diaphoresis, tender abdomen, pulmonary edema
Sedative-hypnotics
Hypotension, bradypnea, hypothermia
Slurred speech, ataxia
Hyporeflexia, bullae
Theophylline
Altered (agitation)
Nausea, vomiting, diaphoresis, anxiety
Diaphoresis, tremor, seizures dysrhythmias

24. Non Drugs but clinically significant poisons

25. TOXIN
VITAL SIGNS
MENTAL STATUS
SIGNS AND SYMPTOMS
CLINICAL FINDINGS
Carbon monoxide
Often normal
Altered (lethargy to coma)
Headache, dizziness, nausea, vomiting
Seizures
Ethylene glycol
Tachypnea
Altered (lethargy to coma)
Abdominal pain
Slurred speech, ataxia
Iron
Hypotension, tachycardia
Normal or lethargy
Nausea, vomiting, diarrhea, abdominal pain, hematemesis
Tender abdomen
Lead
Hypertension
Altered (lethargy to coma)
Irritability, abdominal pain (colic), nausea, vomiting, constipation
Peripheral neuropathy, seizures, gingival pigmentation
Mercury
Hypotension (late)
Altered (psychiatric disturbances)
Salivation, diarrhea, abdominal pain
Stomatitis, ataxia, tremor

26. TOXIN
VITAL SIGNS
MENTAL STATUS
SIGNS AND SYMPTOMS
CLINICAL FINDINGS
Organophosphates/ carbamates
Hypotension/ hypertension, bradycardia/ tachycardia, bradypnea/ tachypnea
Altered (lethargy to coma)
Diarrhea, abdominal pain, blurred vision, vomiting
Salivation, diaphoresis, lacrimation, urination, bronchorrhea defecation, miosis, fasciculations, seizures
Cocaine
Hypertension, tachycardia, tachypnea, hyperthermia
Altered (anxiety, agitation, delirium)
Hallucinations, paranoia, panic anxiety, restlessness
Mydriasis, nystagmus

27. Principle 3
Prevention of absorption of toxin remaining in the GI tract is important in managing the poisoned patient.
The clinical condition of the patient,
The nature and quantity of the toxin
GI Decontamination:
Emesis
Orogastric Lavage
Activated Charcoal
Whole Bowel Irrigation
Cathartics?

28. What’s the need for Gastrointestinal Decontamination?
Not all xenobiotics have antidotes.
Those patients who are exposed to a potentially toxic substance subsequently require decontamination as a method of secondary prevention.
As most exposures occur through the gastrointestinal tract, the major focus must be on gastrointestinal decontamination.
It includes small but genuine risks such as gastrointestinal perforation or pulmonary aspiration. However, gastrointestinal decontamination is the cornerstone in the early management of acutely poisoned patients.
Primary prevention of toxicity, such as parental education, drug storage in child-resistant containers, or the use of computerized adverse drug effects programs by medical professionals, are the optimal means of reducing the incidence of poisoning. Although typically helpful from an epidemiologic perspective, such measures cannot eliminate poisoning.

29. Emesis
If emesis is induced shortly after a drug is ingested, a substantial portion of the ingested agent may be removed.
Syrup of ipecac, the most commonly used emetic, contains two alkaloids, cephaline and emetine. These alkaloids, which primarily induce emesis centrally through stimulation of the medullary chemoreceptor trigger zone.
Syrup of ipecac has a requisite lag time of at least 20 minutes before it produces emesis. The greatest risk of ipecac is related to this lag time.
Also, since ipecac-induced emesis persists for about an hour, the administration of activated charcoal (a valuable adsorbing agent) must be delayed.

30. Orogastric Lavage
Orogastric lavage involves the insertion of a large-bore tube via the esophagus into the stomach to evacuate the gastric contents with subsequent large volume serial irrigations.
Practical limitations of orogastric lavage include the time delay after ingestion until the procedure is performed and the ingestion of pills that are larger than the holes in even the largest (40 French) orogastric lavage tubes.
Hemodynamic changes related to enhanced vagal tone, and structural damage such as esophageal perforation, may occur.
Most patients who have ingested a potentially life-threatening amount of drug should probably have orogastric lavage performed.

31. Activated Charcoal
Activated charcoal able to physically (adsorb) a wide range of substances through electrostatic interactions.
Once bound to the activated charcoal within the lumen of the gastrointestinal tract, toxins are no longer available for systemic absorption.
It is effective immediately after administration, and its utility is not so compromised by pyloric outflow, since toxins may bind within the duodenum.
It may be administered as a drink to conscious patients and through a conventional nasogastric tube in patients with altered consciousness.
Experimental and clinical models have demonstrated that activated charcoal is at least as effective as ipecac or orogastric lavage in preventing the absorption of various toxins (Pond et al. 1995).
is produced by the treatment of burned wood pulp with acid and steam. This renders the surface of the individual particles porous.
The use of activated charcoal eliminates many of the problems associated with emesis and orogastric lavage.

32. Activated Charcoal
Activated charcoal in the gastrointestinal tract may actually enhance the elimination of certain systemically absorbed toxins, such as phenobarbital (Berg et al. 1982) and theophylline (Berlinger et al. 1983).
This effect, termed gastrointestinal dialysis, uses the gastrointestinal capillary bed as a dialysis membrane.
MDAC involves the repeated administration (more than 2 doses) of oral activated charcoal to enhance the elimination of drugs already absorbed into the body

33. Whole-Bowel Irrigation
Whole-bowel irrigation has been used extensively to prepare the colon for surgery or endoscopy.
The administration of a nonabsorbable, isotonic polyethylene glycol solution results in the evacuation of all intestinal contents over several hours.
Whole-bowel irrigation is ideal for the gastrointestinal decontamination of patients who have ingested sustained-release tablets or capsules (Tenenbein et al. 1987b).

34. Whole-Bowel Irrigation
The critical determinants for the success of whole-bowel irrigation are speed and volume of administration.
Delivery of 2 L/h to most adult patients results in gastrointestinal clearance of drug within 3 hours.
Used to clear drug leak from Cocaine- or heroin-filled condoms or balloons from the gastrointestinal tracts of “body packers” (Hoffman et al ).

35. J Indian Acad Forensic Med. Jan-Mar 2011, Vol. 33, No. 1

36. J Indian Acad Forensic Med. Jan-Mar 2011, Vol. 33, No. 1

37. PRINCIPLE- 4
Providing an “antidote” to a potential toxin may not be optimal therapy.

38. ANTIDOTE
INDICATION (TOXIN)
MECHANISM OF ACTION
Antivenin
Pit viper bite Coral snake bite Black Widow spider bite
Binding of toxin by antibody
Botulinal trivalent antitoxin
Botulism
Cyanide kit (amyl nitrite inhalation, sodium nitrite parenteral, sodium thiosulfate parenteral
Cyanide poisoning
Bind cyanide to methemoglobin, then enhance conversion to thiocyanate for excretion
Deferoxamine mesylate (Desferal™)
Iron poisoning
Chelate iron, enhance renal excretion

39. ANTIDOTE
INDICATION (TOXIN)
MECHANISM OF ACTION
Digoxin-specific antibody fragments (Digibind™)
Digoxin poisoning (and other cardiac glycosides)
Binding of digoxin to antibody
Dimercaptosuccinic acid (DMSA, Succimer™, Chemet™)
Lead, mercury, arsenic poisoning
Chelate heavy metal, enhance renal excretion
Ethanol
Methanol, ethylene glycol poisoning
Inhibit alcohol dehydrogenase, slow conversion to toxic aldehydes and acids
Ethylenediaminetetraacetic acid (calcium disodium EDTA)
Lead poisoning

40. ANTIDOTE
INDICATION (TOXIN)
MECHANISM OF ACTION
Methylene blue
Methemoglobinemia
Help reduce Fe+++ to Fe++, thereby improving oxygen delivery to tissues
N-Acetylcysteine (Mucomyst™)
Acetaminophen poisoning
Bind to toxic reactive metabolite, protect liver cells from damage
Octreotide
Poisoning with oral hypoglycemic agents
Block release of insulin from pancreas
Oxygen
Carbon monoxide poisoning
Displace CO from hemoglobin

41. ANTIDOTE
INDICATION (TOXIN)
MECHANISM OF ACTION
Physostigmine salicylate (Antilirium™)
Some cases of poisoning with anticholinergic drugs
Enhance duration of action of acetylcholine at cholinergic receptors by inhibiting acetylcholinesterase
Pralidoxime chloride (Protopam™)
Organophosphate or carbamate poisoning
Reactivate cholinesterase inactivated by organophosphate
Starch
Iodine poisoning
Convert iodine to iodide (nontoxic)
Vitamin K1 (Aquamephyton™ Konakion™)
Warfarin poisoning
Enhance vitamin K1-dependent synthesis of clotting factors II, VII, IX, and I

42. Limitations of Antidotes- Multiple xenobiotic intake
For example, a patient awakening promptly after a dextrose bolus suggests the presence of severe hypoglycemia.
A patient who fails to return to a normal mental status even after receiving dextrose, despite documented hypoglycemia, may have also ingested ethanol.

43. Tolerant Patients
Naloxone, an opioid receptor competitive antagonist, is a generally safe agent in opioid-naive patients and is extremely effective in reversing opioid-induced respiratory depression.
However, Naloxone may precipitate an acute withdrawal syndrome in an opioid-tolerant patient

44. When the xenobiotic is a poor suicidal agent
Flumazenil, a benzodiazepine receptor antagonist, may produce seizures in benzodiazepine-tolerant patients.
Flumazenil may precipitate seizures in patients who coingested tricyclic antidepressants.
Flumazenil may precipitate cardiac dysrhythmias in patients who coingested chloral hydrate.

45. PRINCIPLE- 5
There are many techniques for treating symptomatic poisoned patients. These additional techniques may be beneficial if used rationally.

46. Forced Diuresis
Increasing the flow of urine by volume loading (not by administering diuretics) is the basis of forced diuresis.
This method of enhancing renal elimination has never been conclusively shown to increase the amount of drug removed from the body, even for drugs that are entirely eliminated by the kidney, such as lithium (Hansen and Amdisen 1978).
In addition, forced diuresis may be complicated by iatrogenic volume overload or hyponatremia.

47. Manipulation of the Urine pH
pH of the urine is most commonly raised to allow toxins with low pKa values (i.e., weak acids or onions such as salicylate) to become ionized and excreted without being reabsorbed.
A pH change can only be of benefit if a drug or toxin is ionizable within the pH range of urine, such as salicylic acid, phenobarbital, or formic acid.
Alkalinization of the urine is most commonly achieved by the administration of sodium bicarbonate intravenously.

48. Manipulation of the Urine pH
Acidification of the urine, which would conceivably enhance the elimination of weak bases with high pKa values, is considered dangerous, due to rhabdomyolysis.
Further myoglobin may precipitate within and to obstruct the renal tubule.

49. Hemodialysis
In general, small, water-soluble molecules having masses less than 500 daltons and a Vd less than 1 L/kg and exhibiting low protein binding are removed by hemodialysis.
Toxins commonly removed by dialysis that meet these requirements include salicylate, lithium, methanol, and ethylene glycol.
However, hemodialysis is invasive, expensive, and involves the risk of systemic anticoagulation in most cases.
However, in patients with severe poisoning from salicylates, lithium, methanol or ethylene glycol, the benefits of dialysis often outweigh these rules.

50. Hemoperfusion
The blood from the poisoned patient is percolated through the activated charcoal, which removes a certain percentage of those substances capable of binding to activated charcoal.
However, hypocalcemia and thrombocytopenia occur commonly and limit the appeal of hemoperfusion.
Severe toxicity from theophylline and phenobarbital is the most frequent indication for the use of hemoperfusion.

51. PRINCIPLE- 6
Timely consultation the regional poison center may be life saving… Any Idea? Poison Information/control Center, Sultanate of Oman

52. http://www.deohoman.org/poison.html Support patient management
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Coordination with other agencies
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