health toxicology

1. TOXICOLOGY
For Biomedical and Laboratory Sciences
students
1

2. 2
CHAPTER ONE
INTRODUCTION TO
TOXICOLOGY

3. 3
Objectives
At the end of this chapter, students will be able to:
 Define toxicology and discuss the historical aspects and
classification of toxicology
 Discuss the principles of toxicology
 Discuss the nature of toxic responses, routes of poisoning
 Discuss the Potential causes of toxicity
 Discuss the diagnosis and management of poisoning
 Discuss the analytical and other methods of toxicology

4. 4
Outline
 Definition, classification and principles of toxicology
 Nature of toxic responses, routes of poisoning
 Potential causes of toxicity
 Factors influencing toxicity
 Diagnosis and management of poisoning
 Analytical and other methods of toxicology

5. 5
Definitions
Toxicology
 Is the science dealing with
property,
action,
toxicity,
fatal dose,
detection ,
estimation of poisons &
interpretation of the result of toxicological
analysis

6. 6
Definitions cont’d
• Derived from Greek word, toxikon and logos
• Toxicology is the study of the adverse effects of xenobiotics
 It also deals with foods and cosmetics for public consumption both
in alive or dead victims
 Toxicology is the qualitative and quantitative study of the adverse or
toxic effect of chemicals and other anthropogenic materials or
xenobiotics on organisms
 It has many dimension: the social, the moral & legal aspects of
exposure of populations to chemicals of unknown or uncertain
hazard

7. 7
Historical Aspects of Toxicology
 In the past it was mainly a practical art utilized by murderers &
assassins
 In Ancient time (1500 BC) earliest collection of medicalrecords
contains many references and guidelines about poisons
 Dioscorides (50 AD) a Greek physician, classify poisons as animal,
plant or mineral & recognizing the value of emetics
 Maimmonides (1135-1204 AD), wrote poisons and their antidote
which detailed some of the treatments consideration to be effective

8. 8
Historical aspects of toxicology cont’d
 Paracelsus (1493 AD), summarized his concept in the following
famous phrase ;
 “All substances are poisons; there is none that is not a poison. The
right dose differentiates a poison from a remedy”
 Orifila (1787-1853 AD), Spanish physician who contributed to
forensic toxicology by devising means of detecting poisonous
substances
 From then on toxicology began in a more scientific manner & began
to include the study of the mechanism of action of poisons

9. 9
Historical aspects of toxicology cont’d
 The 20th century- toxicology has now become much more than the
use of poisons
 There are marked improvements in toxicological diagnosis, &
management (production of antidote for them)

10. 10
Toxicological terms and definitions
 Toxin- a poison of natural (biological) origin
 Poison- a chemical that may harm or kill an organism
 Toxic-having the characteristic of producing an undesirable or
adverse health effect
 Toxicity-any toxic (adverse) effect that a chemical or physical agent
might produce within a living organism
 Hazard - is the likelihood that injury will occur in a given situation
or setting: the conditions of use and exposure are primary
considerations

11. 11
Toxicological terms and definitions cont’d
 Risk - is defined as the expected frequency of the occurrence of an
undesirable effect arising from exposure to a chemical or physical
agent RISK= HAZARD + EXPOSURE
Acute poisoning
– is caused by an excessive single dose, or several dose of
a poison taken over a short interval of time.
e.g. Strychnine, potassium cyanide
Chronic Poisoning
– is caused by smaller doses over a period of time, resulting in
gradual worsening
e.g. arsenic, phosphorus, antimony and opium

12. 12
Toxicological terms and definitions cont’d
Sub acute poisoning
– shows features of both acute and chronic poisoning
Fulminant poisoning
– is produced by a massive dose
– in this death occur rapidly, sometimes without preceding
symptoms

13. 13
Classification
Toxicology is broadly divided into different classes
Depending on:
 Research methodology
 Socio-medical
 Organ/specific effects

14. 14
Classification cont’d
I. Based on research methodology
Descriptive toxicology
– Descriptive toxicology deals with toxicity tests on chemicals
exposed to human beings and environment as a whole
Mechanistic toxicology
– Mechanistic toxicology this deals with the mechanism of toxic
effects of chemicals on living organisms
– This is important for rational treatment
– Facilitation of search for safer drugs (e.g. Instead of
organophosphates, drugs which reversibly bind to cholinesterase
would be preferable in therapeutics

15. 15
Classification cont’d
Regulatory toxicology :
 studies whether the chemical substances has low risk to be used in
living systems, Examples:
encompasses the collection, processing and evaluation of
epidemiological and experimental toxicology data to permit
toxicologically based decisions
 Food and drug administration regulates
cosmetics medical devices & supplies in USA
Environmental protection agency regulates
drugs, food,
pesticides, toxic
chemicals, hazardous wastes and toxic pollutants in USA

16. 16
Classification cont’d
 Occupational safety and health administration regulates the safe
conditions for employees in USA authority
 DACA (now EFDA)- regulates drugs, food, cosmetics and
medical devices & supplies in Ethiopia
Predictive toxicology
 Predictive toxicology studies about the potential and actual risksof
chemicals /drugs
 This is important for licensing a new drug/chemical for use

17. 17
Classification cont’d
II. Based on specific socio-medical issues
Occupational toxicology
– It deals with chemical found in the workplace
– E.g. – Industrial workers may be exposed to these agents during
the synthesis, manufacturing or packaging of substances
– Agricultural workers may be exposed to harmful amounts of
pesticides during the application in the field

18. 18
Classification cont’d
Environmental toxicology
– This deals with the potentially deleterious impact of chemicals,
present as pollutants of the environment, to living organisms
Ecotoxicology
– Ecotoxicology has evolved as an extension of environmental
toxicology
– It is concerned with the toxic effects of chemical and physical
agents on living organisms, especially in populations and
communities with defined ecosystems

19. 19
Classification cont’d
Clinical toxicology
– Clinical toxicology deals with diagnosis and treatment of the
normal diseases or effects caused by toxic substances of
exogenous origin.
Forensic toxicology
– Forensic toxicology closely related to clinical toxicology
– It deals with the medical and legal aspects of the harmful effects
of chemicals on man, often in post mortem material, for instance,
where there is a suspicion of murder, attempted murder or suicide
by poisoning
Animal and plant toxicology
– deals with the diagnosis and treatment of harmful effects of
animals and plants

20. 20
Classification cont’d
III.Based on the organ/system effect
– Cardiovascular toxicology
– Renal toxicology
– Central nervous system toxicology
– Gastrointestinal toxicology
– Respiratory toxicology, etc

21. 21
Principles of toxicology
Paracelsus (1493-1541) once said
– "All substances are poisons; there is none which is not a poison
The right dose differentiates a poison from a treatment’’
– It is not easy to distinguish toxic from non toxic substances
– A key principle in toxicology is the
 The chemical form
 routes and sites of exposure
 duration and frequency of exposure(acute, sub-acute, sub-
chronic,chronic)
 Dose-response effects
 There is a graded dose-response relationship in individuals, and
 organophosphate Vs esterase enzyme inhibition in the brain
 A quantal dose-response relationship in the population

22. Diagram of a quantal dose–response relationship
22

23. “All things are poison and nothing is without poison, onlythe
dose permits something not to be poisonous
The dose makes the poison”
therapeutic
effect
toxic
effect
increasing dose
23

24. • There are a number of assumptions that should be
considered before D- R r/n ships are used
appropriately
o The response is due the chemical administered
o The magnitude of the response is related to dose
-There is a molecular target site(s) with which the
chemical interacts to initiate the response
-The production of a response and the degree of response
are related to the concentration of the chemical at the
target site
-The concentration at the target site is related to the dose
administered
o There exists both a quantifiable method of
measuring and a precise means of expressing th2
4
e
Principles of toxicology cont’d

25. Principles of toxicology cont’d
 Dose is the amount, usually per unit body mass, of a toxicant to
which an organism is exposed
 Response is the effect on an organism resulting from exposure to
a toxicant
 In order to define a dose–response relationship, it is necessary to
specify a particular response, such as:
• Death of the organism, as well as
• The conditions under which the response is obtained, such as
the length of time from administration of the dose
• Consider a specific response for a population of the same kinds
of organisms
25

26. Principles of toxicology cont’d
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27. 2
Principles of toxicology cont’d
Thresholds
 An important concept pertinent to the dose–response relationship is
that of threshold dose, below which there is no response
 Threshold doses apply especially to acute effects and are very hard
to determine, despite their crucial importance in determining safe
levels of exposures to chemicals
7

28. 28
Nature of toxic responses
The resulting biologic effect of combined exposure to several agents
can be characterized as:
 Synergism
when the effect of two chemicals is greater than the effect of
individual chemicals 1) Example: 2 + 2 = 20
e .g carbontetrachloride + alcohol= more toxic to the liver than the
sum of the individual drugs.
 Additive effect-
when the total pharmacological action of two or more chemicals
taken together is equivalent to the summation of their individual
pharmacological action
Example: 2 + 3 = 5
Organophosphorus pesticides ⇒ Cholinesterase inhibiters

29. 29
Nature of toxic responses cont’d
 Potentiation effect
when the net effect of two chemicals used together is greater than the
sum of individual effects (the capacity of a chemical to increase the
effect of another chemical without having the effect alone) Example:
0 + 2 = 10
Isopropanol is not hepatoxic, but enhance carbontetrachloride
induced hepatoxicity
 Antagonism - is the phenomenon of
opposing actions of two chemicals on the same
system
Example: 4 + 0 = 1
Dimercaprol (BAL) chalets with metal ions, As, Pb….

30. 30
Nature of toxic responses cont’d
RELATIVE TOXICITIES
 Standard toxicity ratings that are used to describe estimated
toxicities of various substances to humans
 Their values range from one (practically nontoxic) to six
(supertoxic)
 In terms of fatal doses to an adult human of average size, a “taste” of
a supertoxic substances (just a few drops or less) is fatal

31. 31
Parameters
 Median lethal dose (LD50) – is the dose which is expected
to kill 50% of the population in the particular group.
Median effective dose (ED50) –is the dose that produces a
desired response in 50% of the test population when
pharmacological effects are plotted against dosage.

32.  Median toxic dose (TD50) – is the dose which is expected to
bring toxic effect in 50% of the population in the particular group
• TI = LD50 (or TD50)/ED50
32

33. 33
Nature of toxic responses cont’d
REVERSIBILITY AND SENSITIVITY
a) Reversibility Vs. Irreversible
 Sub lethal doses of most toxic substances are eventually eliminated
from an organ system. If there is no lasting effect from the exposure,
it is said to be reversible
 However, if the effect is permanent, it is termed irreversible
 Irreversible effects of exposure remain after the toxic substance is
eliminated from the organism
 For various chemicals and different subjects, toxic effects may range
from the totally reversible to the totally irreversible

34. 34
Nature of toxic responses cont’d
b)Hypersensitivity vs. Hyposensitivity
 In some cases hypersensitivity is induced
 After one or more doses of a chemical, a subject may develop an
extreme reaction to it
 This occurs with penicillin, for example, in cases where people
develop such a severe allergic response to the antibiotic that
exposure results in death if countermeasures are not taken

35. 35
Nature of toxic responses cont’d
 hyposensitivity is induced by repeated exposures to a toxic
substance leading to tolerance and reduced toxicities from
later exposures
 Tolerance can be due to a less toxic substance reaching a receptoror
to tissue building up a resistance to the effects of the toxic substance
example, with repeated doses of toxic heavy metal cadmium

36.  Oral route – the GIT is the most important route of absorption, as
most acute poisonings involve ingestions
 Dermal route – lipid solubility of a substance is an important factor
affecting the degree of absorption through the skin
 Inhalational route – toxic fumes, particulate and noxious gases may
be absorbed through the lungs
 Intramuscular route – unreliable and varied from patient to patient
 Intravenous route – is the most reliable and provides the most rapid
clinical response
 Rectal route – is generally considered to produce erraticabsorpti3o6n
Routes of poisoning

37. 37
Route of Administration/absorption cont’d
 Oral (commonest)
 Inhalation: gas poison
 Parenteral (IM, IV, Sub-Cutaneous, Intra-Dermal)
 Natural Orifices other than mouth (Nasal, Rectal, Vaginal, Urethral),
 Ulcers, wounds and intact skin
The decreasing order of effectiveness in different routes is:
Intravenous, inhalation, intra-peritoneal, subcutaneous, intramuscular,
intra-dermal, oral, and dermal

38. 38
Potential causes of toxicity
The potential causes of toxicities include:
 Therapeutic agents
 Industrial & house hold chemicals
 Environmental contaminants
 Animal & plant toxins
 Drugs of abuse
 Food preservatives
 Traditional drugs
 Fumes …..

39. 39
Sources of Poison
 Domestic or household sources
 Agricultural and horticultural sources
 Industrial sources
 Commercial sources
 From uses as drugs and medicines
 Food and drink
 Miscellaneous sources - snakes bite poisoning, city smoke, sewer
gas poisoning etc.

40. 40
Sources of Poison cont’d
 Domestic or household sources - detergents, disinfectants, cleaning
agents, antiseptics, insecticides, rodenticides etc.
 Agricultural and horticultural sources- different insecticides,
pesticides, fungicides and weedicide
 Industrial sources- In factories, where poisons are manufactured or
poisons are produced as by products
 Commercial sources- From store-houses, distribution centres and
selling shops

41. 41
Sources of Poison cont’d
 From uses as drugs and medicines – Due to wrong medication,
overmedication and abuse of drugs
 Food and drink – contamination in way of use of preservatives of
food grains or other food material, additives like colouring and
odouring agents or other ways of accidental contamination of food
and drink
 Miscellaneous sources- snakes bite poisoning, city smoke, sewer
gas poisoning etc.

42. 42
Common poisons and drugs
 Corrosive poisons
 Irritant poisons
 Analgesic, Hypnotic, Tranquilizer, and Narcotic poisons
 Stimulants, Excitants, and Convulsants poisons
 Paralytic, Anticholinesterase and Antihistamine poisons
 Gaseous and Volatile poisons
 Industrial gaseous and Volatile poisons
 Poisons by Plants, flora, and fungi

43. 43
Factors influencing toxicity
• Discus 4 five minute to what condition
may influence toxicity
????

44. 44
Factors influencing toxicity
1. Quantity:
 A high dose of poison acts quickly and often resulting in  fatal
consequences.
 A moderate dose causes  acute poisoning
 A low dose may have sub-clinical effects and causes  chronic
poisoning on repeated exposure
 Very large dose of Arsenic may produce  death by shock without
dose irritant symptoms,
 While smaller dose than lethal dose produces its  therapeutic
effects

45. 45
Factors influencing toxicity cont’d
2. Physical form:
 Gaseous or volatile poisons are very quickly absorbed and are thus
most rapidly effective
 Liquid poisons are more rapid than solid poisons
 Some poisonous vegetable seeds may pass through the intestinal
canal ineffective when taken intact due to their impermeable pericarp

46. 46
Factors influencing toxicity cont’d
3. Chemical form:
 Chemically pure arsenic and mercury are not poisonous because
these are insoluble and are not absorbed
 But white arsenic (arsenic oxide) and mercuric chloride are deadly
poisonous
 Barium sulphide is deadly toxic but barium sulphate is non-toxic

47. 47
Factors influencing toxicity cont’d
4. Concentration (or dilution):
 Concentrated form of poison are absorbed more rapidly and are also
more fatal but there are some exceptions too

48. 48
Factors influencing toxicity cont’d
5. Condition of the stomach:
 Food content presence of food-stuff acts as diluent of the poison and
hence protects the stomach wall
 Dilution also delays absorption of poison.
 Empty stomach absorbs poison most rapidly
 In cases of achlorohydria, KCN and NaCN is ineffective due to lack
of hydrochloric acid, which is required for the conversion of KCN
and NaCN to HCN before absorption

49. 49
Factors influencing toxicity cont’d
6. Route of administration:
 absorption rate is different for different routes. Decreasing order
IV, inhalation, intra-peritoneal, subcutaneous, intramuscular,
intra-dermal, oral, and dermal
7. Age:
 some poisons are better tolerated in some age groups
 Opium and its alkaloids are tolerated better by elderly subjects but
badly by children and infants.
 Belladonna group of drugs are better tolerated by children than by
adults

50. 50
Factors influencing toxicity cont’d
8. State of body health:
 A well built person with good health can tolerate the action of poison
better than a weak person.
9. Presence of disease:
 In certain diseased conditions some drugs are tolerated exceptionally
well
 e.g.: sedatives and tranquilizers are tolerated in very high dose by
manic and deliriant patients

51. 51
Factors influencing toxicity cont’d
10. Intoxication arid poisoning states
 In certain poisoning cases some drugs are well tolerated, like, in case
of strychnine poisoning, barbiturates and sedatives are better
tolerated.
 Whereas in case of barbiturate poisoning any sedative or tranquilizer
will accentuate the process of death

52. 52
Factors influencing toxicity cont’d
11. Sleep
 Due to slow metabolic process and depression of other body
functions during sleep, usually the absorption and action of the
poison is also slow
 But depressant drugs may cause, more harm during the state of sleep.
12. Exercise
 Action of alcohol on C.N.S. is slowed during exercise because more
blood is drawn to the muscles during exercise

53. 53
Factors influencing toxicity cont’d
13. Cumulative action of poisons:
 Preparations of cumulative poisons (poisons which are not readily
excreted from the body and are retained in different organs of the
body for a long time) like lead may not cause any toxic effect when
enters the body in low dose
 But when such poisons enter over a long period of time, may cause
harm when their concentration in different tissue reaches high level
due to their cumulative property

54. 54
GENERAL MANAGEMENT PRINCIPLES
Initial Approach to the Poisoned Patient
 Focus on six major areas:
o Resuscitation and stabilization
o History and physical examination, including evaluation
for a specific toxidrome
o Appropriate decontamination of the gastrointestinal
tract, skin, and eyes
o Judicious use of laboratory tests, electrocardiograms,
and radiographic studies
o Administration of specific antidotes, if indicated
o Utilization of enhanced elimination techniques for
selected toxins

55. 55

56. I. How does the poisoned pt die?
a) CNS depression:
Comatose pts frequently lose their airway protective reflexes & their
respiratory drive
Thus, they may die as a result of:
Airway obstruction by the flaccid tongue,
Aspiration of gastric contents into the
tracheobronchial tree, or
Respiratory arrest
Most common causes of death due to overdoses of narcotics & sedative
hypnotic drugs (eg, barbiturates & alcohol)
56

57. How does the poisoned pt die?
b) Cardiovascular toxicity:
i. Hypotension:
May be due to:
Depression of cardiac contractility
Hypovolemia resulting from V, D, or fluid
sequestration
Peripheral vascular collapse due to blockade of α-
adrenoceptor mediated vascular tone; or
Cardiac arrhythmias
57

58. How does the poisoned pt die?..
CV toxicity…
ii. Lethal arrhythmias:
Can occur with overdoses of:
Many cardioactive drugs such as ephedrine,
amphetamines, cocaine, digitalis, & theophylline
Drugs not usually considered cardioactive, such as
TCAs, antihistamines
58

59. How does the poisoned pt die?..
c) Cellular hypoxia:
May occur in spite of adequate ventilation & oxygen administration when
poisoning is due to cyanide, hydrogen sulfide, CO, & other poisons that
interfere with transport or utilization of oxygen
Such pts may not be cyanotic, but cellular hypoxia is
evident by the development of:
Tachycardia, hypotension, severe lactic acidosis,
& signs of ischemia on the ECG
59

60. How does the poisoned pt die?..
d) Seizures, muscular hyperactivity, & rigidity:
Seizures: may cause pulmonary aspiration, hypoxia, & brain damage
Hyperthermia: may result from sustained muscular hyperactivity & can lead
to muscle breakdown & myoglobinuria, renal failure, lactic acidosis, &
hyperkalemia
Drugs & poisons that often cause seizures include:
Antidepressants, isoniazid, diphenhydramine, cocaine,
& amphetamines
60

61. How does the poisoned pt die?..
e) Other organ system damage:
May occur after poisoning & is sometimes delayed in onset
Example:
Paraquat attacks lung tissue, resulting in pulmonary
fibrosis, beginning several days after ingestion
Massive hepatic necrosis due to poisoning by
acetaminophen results in hepatic failure & death 48–
72 hrs or longer after ingestion
61

62. How does the poisoned pt die?..
f) Some pts may die before hospitalization:
B/c the behavioral effects of the ingested drug may result in traumatic injury
Intoxication with alcohol & other sedative-hypnotic
drugs is a common contributing factor to motor
vehicle accidents
Pts under the influence of hallucinogens such as
PCP(phencyclidine) or LSD (lysergic acid diethylamide)
may suffer trauma when they become combative or
fall from a height
62

63. II. Initial management of the poisoned patient
Initial evaluation: poisoning or overdose
Pts with drug overdoses or poisoning may initially have no symptoms or
they may have varying degrees of overt intoxication
a) Asymptomatic patient:
May have been exposed to or may have ingested a
lethal dose but not yet exhibit any manifestations
of toxicity
63

64. Initial management of the poisoned patient…
 Asymptomatic pt….
It is important to:
Quickly assess the potential danger
Consider gut decontamination to prevent absorption
Treat complications if they occur, &
Observe the asymptomatic pt for an appropriate
interval
64

65. Initial management of the poisoned patient…
b) The symptomatic patient:
Tx of life-threatening complications takes precedence over in-depth
diagnostic evaluation
Pts with mild Sxs 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, hypothermia, hypotension, HTN, arrhythmias,
seizures, hyperthermia
65

66. Initial management of the poisoned patient…
a) Coma:
Commonly associated with ingestion of large doses of:
Antihistamines (eg, diphenhydramine)
Bzs & other sedative-hypnotic drugs
Ethanol
Opioids
Antipsychotic drugs
Antidepressants
66

67. Initial management of the poisoned patient…
Coma..
The initial emergency management of coma can be remembered by the
mnemonic ABCD,
Airway, Breathing, Circulation, & Drugs (dextrose,
thiamine, & naloxone or flumazenil), respectively
67

68. Initial management of the poisoned patient…
Coma..
Airway: should be cleared of vomitus or any other obstruction & an oral
airway or endotracheal tube inserted if needed
Breathing: should be assessed by observation & pulse oximetry &, if in
doubt, by measuring arterial blood gases
Pts with respiratory insufficiency should be intubated
& mechanically ventilated
68

69. Initial management of the poisoned patient…
Coma…
Circulation: should be assessed by continuous monitoring of pulse rate,
BP, urinary output, & evaluation of peripheral perfusion
At this point an IV line should be placed & blood drawn for serum glucose
& other routine determinations
69

70. Initial management of the poisoned patient…
Coma…
Drugs: Dextrose & thiamine:
Unless a rapid bedside blood glucose test
demonstrates that the pt is not hypoglycemic: adults;
25 g (50 mL of 50% dextrose solution) IV & children 0.5
g/kg (2 mL/kg of 25% dextrose)
Alcoholic or malnourished pts should also receive 100 mg of
thiamine IM or in the IV infusion solution at this time to
prevent Wernicke’s syndrome
70

71. Initial management of the poisoned patient…
Coma…
Opioid antagonist:
Naloxone may be given in a dose of 0.4–2 mg IV
Reverses respiratory & CNS depression due to all
varieties of opioid drugs
Benzodiazepine (BZ) antagonist:
Flumazenil may be of value in pts with suspected BZ
overdose
71

72. Initial management of the poisoned patient…
b) Hypothermia:
It commonly accompanies coma due to:
Opioids, ethanol, hypoglycemic agents,
phenothiazines, barbiturates, benzodiazepines, &
other sedative-hypnotics & CNS depressants
It may cause or aggravate hypotension, which will not reverse until the
temp is normalized
Gradual rewarming is preferred unless the pt is in cardiac arrest
72

73. Initial management of the poisoned patient…
c) Hypotension:
It may be due to poisoning by many different drugs & poisons, including:
Antihypertensive drugs, disulfiram, Fe, trazodone,
quetiapine, & other antipsychotic & antidepressants
agents
Cyanide, CO, hydrogen sulfide, Al phosphide, arsenic,
& certain mushrooms
73

74. Initial management of the poisoned patient…
• Hypotension…
It may be caused by:
Venous or arteriolar vasodilation
Hypovolemia
Depressed cardiac contractility, or
Combination of these effects
74

75. Initial management of the poisoned patient…
d) Hypertension (HTN):
It may be due to poisoning with:
Amphetamines, anticholinergics, cocaine,
performance-enhancing products (containing
caffeine, ephedrine, or yohimbine), MAOIs, & other
drugs
Severe HTN (eg, DBP > 105–110 mm Hg in a person who does not have
chronic HTN) can result in acute intracranial hemorrhage or MI
75

76. Initial management of the poisoned patient…
e) Arrhythmias:
May occur with a variety of drugs or toxins
They may also occur as a result of:
Hypoxia, metabolic acidosis, or electrolyte
imbalance, or following exposure to chlorinated
solvents or chloral hydrate overdose
Atypical ventricular tachycardia (torsades de pointes) is often associated
with drugs that prolong the QT interval
76

77. Initial management of the poisoned patient…
f) Seizures:
May be due to poisoning with many poisons & drugs, including:
Amphetamines, antidepressants (esp TCAs, bupropion, &
venlafaxine), antihistamines (esp diphenhydramine),
antipsychotics, camphor, cocaine, isoniazid, chlorinated
insecticides, & theophylline
It may also be caused by hypoxia, hypoglycemia, hypocalcemia, hyponatremia,
withdrawal from alcohol/sedative-hypnotics, head trauma, CNS infection
77

78. Initial management of the poisoned patient…
• Seizures…
Administer lorazepam, 2–3 mg, or diazepam, 5–10 mg, IV over 1–2 minutes,
or
If IV access is not immediately available midazolam,
5–10 mg IM
If convulsions continue, administer phenobarbital, 15–20 mg/kg slowly IV
over no less than 30 minutes
78

79. Initial management of the poisoned patient…
g) Hyperthermia:
May be associated with poisoning by amphetamines (esp methylene dioxy
methamphetamine [MDMA; “Ecstasy”]), atropine & other anti-cholinergic
drugs, cocaine, salicylates, strychnine, TCAs, & various other medications
Overdoses of SSRIs or antipsychotic agents can cause rigidity &
hyperthermia
79

80. Initial management of the poisoned patient…
•Hyperthermia…
Treat hyperthermia aggressively by removing the pt’s clothing, spraying the
skin with tepid water, & fanning
If this is not rapidly effective, as shown by a normal rectal temp within 30–
60 min, or if there is significant muscle rigidity or hyperactivity, induce NM
paralysis with a non-depolarizing NM blocker
Once paralyzed, the pt must be intubated &
mechanically ventilated & sedated
80

81. III. Antidotes & other treatment
A. Antidotes:
They are agents with a specific action against the activity or effect a poison
Give an antidote (if available) when there is reasonable certainty of a specific dx
Be aware that some antidotes themselves may have serious side effects
81

82. Antidotes ..
Antidote administration is appropriate when:
There is a poisoning for which an antidote exists
The actual or predicted severity of poisoning warrants its use
Expected benefits of therapy outweigh its associated risk, & there are no
C/Is
82

83. Common Antidotes
Poison/syndrome Antidote(s)
Acetaminophen N-acetylcysteine
Anticholinergic agents Physostigmine
Beta-blockers 1) Glucagon
2) Calcium
3) Insulin + dextrose
Calcium-channel blockers 1) Calcium
2) Glucagon
3) Insulin + dextrose
Crotalid snakebite Wyeth polyvalent crotalidae antivenin (equine)
Cyanide 1) Amyl nitrate pearls
2) Sodium nitrite (3% solution)
3) Sodium thiosulfate (25%)
83

84. Common antidotes…
Poison/syndrome Antidote(s)
Digitalis Digoxin immune Fab (Digibind)
Ethylene glycol
Methanol
1) Ethanol 10% in D5W ± hemodialysis
2) Fomepizole [4-MP] (Antizol) ± hemodialysis
Heparin Protamine sulfate
Hydrofluoric Acid Calcium gluconate
Iron Deferoxamine
Isoniazid Pyridoxine (Vitamin B6)
Lead 2,3-dimercaptosuccinic acid [DMSA] (Succimer)
Mercury
Arsenic
Gold
British antilewisite, dimercaprol (BAL); in peanut oil
84

85. Common Antidotes…
Poison/syndrome Antidote(s)
Carbon monoxide Oxygen ± hyperbaric chamber
Methemoglobinemia Methylene blue (1 percent solution)
Opiates Naloxone
Nalmefene, naltrexone
Organophosphates
Carbamates
Nerve agents
1) Atropine
2) Pralidoxime [2-PAM]
Sulfonylurea Octreotide (Sandostatin) + dextrose
Benzodiazepines Flumazenil
Tricyclic
antidepressants
Sodium bicarbonate (NaHCO3)
85

86. B. Decontamination
i. Decontamination of the skin
Corrosive agents rapidly injure the skin & eyes & must be removed
immediately
In addition, many toxins are readily absorbed through
the skin, & systemic absorption can be prevented
only by rapid action
Wash the affected areas with copious quantities of
lukewarm water or saline
Wash carefully behind the ears, under the nails, & in
skin folds
86

87. Decontamination…
•Decontamination of the skin…
For oily substances (eg, pesticides):
Wash the skin at least twice with plain soap &
shampoo the hair
For exposure to chemical warfare poisons such as nerve agents or
vesicants, some authorities recommend use of a dilute hypochlorite
solution (household bleach diluted 1:10 with water), but not in the eyes
87

88. Decontamination…
ii. Decontamination of Eyes:
Ocular exposure’s should be treated immediately by copious irrigation
Usually 2 L NS
Use of tetracaine may be needed
Alkalies require specific considerations
Lengthy continuous irrigation until pH < 8.0
Need ophthalmologic consult
88

89. Decontamination…
iii. GI Decontamination:
It involve 3 general methods
Removing toxin from stomach via the mouth
Binding it inside gut lumen, or
Mechanically flushing it through GIT
Each method has benefits & risks
89

90. Decontamination…
a) Emesis:
Achieved by using syrup of ipecac
Dosing: 15 ml for 1-12 yo & 30 ml for adults; may repeat once if no emesis in
12 hr
90% vomit within 20 min of 1st dose & 97% vomit with 2nd dose
Usually 3-5 episodes of emesis & resolve in 2 hrs
NB: if protracted emesis occurs consider toxin as etiology
90

91. Decontamination…
Emesis …
The accepted C/Is of induction of emesis:
In children < 6 months of age
In the ingestion of a caustic agent (acid or alkali),
In a pt with a depressed level of consciousness or gag reflex or when the
toxin ingested is expected to cause either condition within a short period
of time
Active or prior V
Toxin with more pulmonary than GI toxicity (HCs)
Ingestion of toxins with potential for seizures
Complications: aspiration, intractable vomiting
91

92. Decontamination…
b) Gastric lavage:
It is a procedure that is intended to remove material from the stomach
Should be reserved for:
Those pts who have ingested a significant dose of
a medication or chemical that is likely to result in
morbidity, &
Only if the procedure can be done very soon after
ingestion
92

93. Decontamination…
Gastric lavage…
C/I: large pills, nontoxic ingestion, non-life threatening, caustic ingestion,
airway integrity not secured, more toxic to lung than GI
Complications: insertion into trachea, aspiration, esophageal or gastric
perforation, ↓ed O2, inability to withdrawal tube
Drug removal range from 35-56%
Indicated if w/in 1 hr of ingestion
93

94. Decontamination…
c) Activated charcoal:
Most appropriate agent to decontaminate GIT
Adsorbs toxin in gut lumen
Benefits include capability to decontaminate w/out requiring invasive
procedures
Safety proven in adults & children
Dose 1g/kg
94

95. Decontamination…
Activated Charcoal…
C/Is: Should not be given if esophageal or gastric perforation suspected or
emergent endoscopy possibly needed
Complications rare; aspiration or impaction possible
Indications: any drug known to absorb it or after unknown ingestions by
pt’s with protected airways
95

96. Decontamination…
d) Cathartics:
Osmotic cathartic usually given with activated charcoal
70% sorbitol (1 g/kg) or 10% Mg citrate
Shown to ↓ transit time of activated charcoal
No definitive clinical human data suggest that a cathartic limits toxins
bioavailability or changes pt’s outcome
96

97. Decontamination…
e) Whole-Bowel Irrigation:
Entails flushing the entire GIT with a non-absorbable isotonic electrolyte
solution containing PEG
Common indications:
Heavy metals, Iron, Lithium
Sustained or delayed release formulations
Potential for bezoar formation
97

98. C. Enhanced Elimination
Enhanced elimination techniques involves
Manipulations of urine pH, with subsequent ↑ed urinary excretion
of certain toxins
Extracorporeal removal via hemodialysis
98

99. Enhanced Elimination…
General indications:
Ingestion of a poison whose elimination can be enhanced
Failure of a pt to respond to max supportive care
The clinical course is predicted to be complicated based on:
Nature &/or conc of the toxin
Impaired clearance of the toxin
Comorbid illness, or some combination of these 3
elements
99

100. Enhanced Elimination...
a) Urinary manipulation:
The urinary excretion of some drugs can be enhanced by altering the urine pH
Altering the pH converts a lipid-soluble intact acid (HA) or base (BOH) in the
tubular lumen into the charged salt (A- or B+):
HA <— > H+ + A-
BOH <— > B+ + OH-
The charged particle is lipid-insoluble & cannot easily move back across the renal
epithelium
→ a marked ↑ in drug excretion
10
0

101. Enhanced Elimination...
Urinary manipulation…
Drugs that are likely to respond to urinary alkalinization usually meet 4
criteria:
Predominantly eliminated unchanged by the kidney
Distributed primarily in the ECF
Minimally protein-bound
Weak acids with pKa ranging from 3.0 - 7.5
10
1

102. Enhanced Elimination...
Urinary manipulation…
The goal of urinary alkalinization is to achieve a urine pH of 7.5 or higher
while maintaining a serum pH no higher than 7.55 to 7.60
This is generally done by administering an IV bolus of
1-2 mEq/kg of 8.4 % NaHCO3, followed by continuous
infusion of NaHCO3
10
2

103. Enhanced Elimination...
b) Hemodialysis (HD)
It is most useful in removing toxins with the following characteristics:
Low mol wt (<500 daltons)
Small Vd (<1 L/kg)
Low degree of protein-binding
High water solubility
Low endogenous Cl (<4 mL/min per kg)
High dialysis Cl relative to total body Cl
10
3

104. Enhanced Elimination...
Hemodialysis…
Benefits: removal of toxins already absorbed by gut, ability to remove
parent compound & active metabolite
Dialysis reserved for specific toxins:
Salicylates, methanol, ethylene glycol, lithium,
theophylline, amanita (mushrooms)
10
4

105. IV. Diagnosis of poisoning
Once the pt has been stabilized, the potential poison has to
be identified
The dx of poisoning involves the following;
History given by the pt himself or relatives
Physical examination of the pt
Lab investigations
10
5

106. Diagnosis of poisoning...
A. History:
Need to obtain as much info as possible about exposure
Number of exposed persons, type of exposure, amount
or dose, route
Pt’s intent must be determined
Info from pt’s PCP, witness or EMT helpful
Check for empty bottles or containers, smells or unusual
containers, or suicide note
10
6

107. Diagnosis of poisoning...
B. Physical Exam:
Gives important clues to both the severity & the cause of poisoning
Vital sign & mental status abnormalities are important signs of the severity
of toxicity & may also suggest the class of toxin involved
Examples:
Respiratory depression of barbiturate or opioid
poisoning &
Tachycardia & HTN of poisoning with
sympathomimetic agents
10
7

108. Diagnosis of poisoning...
Physical Exam…
Characteristic “toxidromes” indicate the presence of agents with
cholinergic, anticholinergic, sympathomimetic, & opioid effects, etc
Less specific findings, such as nystagmus, myoclonus, asterixis, & tremor,
also suggest various toxins
Characteristic odors suggest the presence of toxins, such as cyanide
(almond odor)
10
8

109. TOXIDROMES
• Are groups of signs and symptoms that consistently
result from particular toxins
• These syndromes are usually best described by a
– combination of the vital signs and clinically obvious
end-organ manifestations
• The signs that prove most clinically useful are:
– Those involving the central nervous system (mental
status); ophthalmic system (pupil size)
– Gastrointestinal system (peristalsis)
– dermatologic system: skin (dryness vs. diaphoresis)
and
– mucous membranes (moistness vs. dryness) and
– Genitourinary system (urinary retention vs.
incontinence) 61

110. 11
0
• Anticholinergic Syndrome
– “hot as a hare, blind as a bat, dry as a bone, red as a
beet, mad as a hatter, bloated as a bladder,”
• Sympathomimetic Syndrome
– hypertension, diaphoresis, tachycardia, tachypnea,
hyperthermia, and mydriasis
– Restlessness, agitation, excessive speech, tremors,
and insomnia also occur
• Opioid Syndrome
– mental status depression, respiratory depression, and
pinpoint pupils, Bradycardia, hypotension (rare),
hypothermia, hyporeflexia, and needle marks

111. 11
1
• Anticholinesterase Syndrome
– Organophosphates are commonly available as
insecticides
– DUMBELS is a mnemonic used: defecation,
urination, miosis, bronchorrhea, bronchospasm,
bradycardia, emesis, lacrimation, and salivation.
– Clinical findings suggestive of acute
anticholinesterase intoxication.
• Sedative-Hypnotic Syndrome
– Hypotension, bradypnea, hypothermia, mental status
depression, slurred speech, ataxia, and hyporeflexia

112. 11
2

113. Diagnosis of poisoning...
C. Laboratory & Imaging Procedures
a. Arterial blood gases
Hypoventilation results in an elevated PCO2
(hypercapnia) & a low PO2 (hypoxia)
The PO2 may also be low in a pt with aspiration
pneumonia or drug-induced pulmonary edema
Poor tissue oxygenation due to hypoxia,
hypotension, or cyanide poisoning will result in
metabolic acidosis
11
3

114. Diagnosis of poisoning...
b. Electrolytes
Na, K, Cl, & bicarbonate should be measured
The anion gap is then calculated by subtracting the measured anions from
cations:
Anion gap = (Na+ + K+) – (HCO3– + Cl–)
Normally, the sum of the cations exceeds the sum of the anions by no more
than 12–16 mEq/L (or 8–12 mEq/L if the formula used for estimating the
anion gap omits the K level)
11
4

115. Diagnosis of poisoning...
Electrolytes…
Larger than expected anion gap is caused by the presence of unmeasured
anions (lactate, etc) accompanying metabolic acidosis
This may occur with numerous conditions, such as DKA, renal failure, or
shock-induced lactic acidosis
Drugs that may induce an elevated anion gap metabolic acidosis include
aspirin, metformin, methanol, ethylene glycol, isoniazid, & iron
11
5

116. Diagnosis of poisoning...
Electrolytes…
Alterations in the serum K level are hazardous b/c they can result in
cardiac arrhythmias
Drugs that may cause hyperkalemia despite
normal renal function include K itself, β-blockers,
digitalis glycosides, K-sparing diuretics, & fluoride
Drugs associated with hypokalemia include
barium, β- agonists, caffeine, theophylline, &
thiazide & loop diuretics
11
6

117. Diagnosis of poisoning...
c. Renal function tests:
Some toxins have direct nephrotoxic effects
In other cases, renal failure is due to shock or myoglobinuria
BUN & creatinine levels should be measured & urinalysis performed
Elevated serum CK & myoglobin in the urine suggest muscle necrosis due
to seizures or muscular rigidity
Oxalate crystals in large numbers in the urine suggest ethylene glycol
poisoning
11
7

118. Diagnosis of poisoning...
d. Serum Osmolality:
The calculated serum osmolality is dependent mainly on the serum sodium &
glucose & the BUN & can be estimated from the following formula:
2 × Na+ (mEq/L) + Glucose (mg/dL) + BUN (mg/dL)
18 3
This calculated value is normally 280–290 mOsm/L
11
8

119. Diagnosis of poisoning...
Serum Osmolality…
Ethanol & other alcohols may contribute significantly to the measured serum
osmolality but, since they are not included in the calculation, cause an osmol
gap:
Osmolar gap = Measured osmolality – Calculated osmolality
11
9

120. Diagnosis of poisoning...
e. Electrocardiogram
Widening of the QRS complex duration (to more than 100 milliseconds) is
typical of tricyclic antidepressant & quinidine overdoses
The QT c interval may be prolonged (to more than 440 milliseconds) in many
poisonings, including quinidine, antidepressants & antipsychotics, lithium, &
arsenic
12
0

121. Diagnosis of poisoning...
Electrocardiogram…
Variable AV block & a variety of atrial & ventricular arrhythmias are common
with poisoning by digoxin & other cardiac glycosides
Hypoxemia due to CO poisoning may result in ischemic changes on the ECG
12
1

122. Diagnosis of poisoning...
f. Imaging Findings
A plain film of the abdomen may be useful b/c some tablets, particularly Fe &
K, may be radiopaque
Chest radiographs may reveal aspiration pneumonia, HC pneumonia, or
pulmonary edema
When head trauma is suspected, a CT scan is recommended
12
2

123. Diagnosis of poisoning...
D. Toxicology Screening Tests
It is a common misconception that a broad toxicology “screen” is the best
way to diagnose & manage an acute poisoning
Unfortunately, comprehensive toxicology screening is time consuming &
expensive & results of tests may not be available for days
12
3

124. Diagnosis of poisoning...
The clinical examination of the patient & selected routine
lab tests are usually sufficient to generate a tentative dx &
an appropriate treatment plan
Although screening tests may be helpful in confirming a
suspected intoxication or for ruling out intoxication as a
cause of apparent brain death, they should not delay
needed treatment
12
4

125. Diagnosis of poisoning...
When a specific antidote or other Tx is under consideration,
quantitative lab testing may be indicated
E.g., determination of the acetaminophen level is useful in
assessing the need for antidotal therapy with acetylcysteine
Serum levels of salicylate, ethylene glycol, methanol,
theophylline, carbamazepine, lithium, valproic acid, & other
drugs & poisons may indicate the need for hemodialysis
12
5

126. Clinical toxicology laboratory
• The toxicology laboratory provide appropriate
testing in three general areas:
– Identification of agents responsible for acute
or chronic poisoning
– Detection of drugs of abuse; and
– Therapeutic drug monitoring
• Know that
– The majority of toxicological diagnoses and
therapeutic decisions are made on a clinical
basis 69

127. Situations in which qualitative toxicology
tests or screens have utility
• When the differential diagnosis is sufficiently narrowed to
a drug cause vs. a disease cause (e.g., psychosis—
functional vs. amphetamines)
• Documentation that the working diagnosis was correct
(post facto)
• After admission if the diagnosis is still unclear
70

128. Role: Toxicology Lab
• The most important role for the toxicology laboratory to
be the quantitation of drug concentrations to determine
the need for dangerous or expensive treatment
• Therapeutic Drug monitoring
– For instance,
• Drugs that require:
– hemoperfusion (e.g., theophylline,
phenobarbital)
– hemodialysis (e.g., salicylate, methanol,
lithium) to avoid life-threatening concentrations
• To shorten coma, and to evaluate the efficacy of
extracorporeal elimination
• When deciding to treat a digoxin overdose with
Fab fragments (Digibind) and for the appropriate
use of chelators in metal poisoning 71

129. 12
9
Serum quantitation of overdosed drugs: TDM
• Rationale and Uses
– Quantitative drug levels in overdose can monitor
• the course of the patient, predict whether toxicity is
occurring but not yet clinically apparent, or predict
that toxicity will occur in the future
• Two criteria need to be satisfied for blood levels to be
useful
– should be an absence of reliable clinical indicators
that reveal the status or condition of the patient
– the existence of a concentration-effect relationship

130. 13
0
Assay methods…
• The techniques for detecting the presence
of drugs include
– a variety of chromatographic methods,
immunoassays, and chemical and
spectrometric techniques
• can be adapted to detect a wide number of drugs
and chemicals, or focused to detect and quantitate
certain drugs
– Immunoassays are most widely used for
discrete analysis, and gas chromatographic
techniques are used for broad screens

131. 13
1
Serum conc…..cont’d
• Availability and Reliability
– Measurements should be available on an immediate,
24-hour basis and should be precise (not
semiquantitative)
– Increasing use of quantitative IAs on rapid chemistry
analyzers
– Serum quantitations require adequate precision to
recognize change from time point to time point and
should also be accurate so that management
decisions can be made correctly

132. 13
2
Consideration in serum measurement
• Serum drug quantitation's must be evaluated
with respect to each patient’s clinical condition
• Interpretation of serum concentration should
consider:
– variation in pharmacology from person to
person
– the interactions of diseases and medications
– the altered pharmacodynamics and
pharmacokinetics with overdose
– potential interferences in assays

133. 13
3
Administration of specific antidotes
• Specific antidotes exist for a few toxins
• Are definite treatment available
• There are different types:
• Pharmacodynamic antidotes
• Pharmacokinetic antidotes
• Chemical antidotes
• Physiological antidotes