1. CLINICAL TOXICOLOGY Lecture 1 & 2
Dr. Tavga A. Baban
Assistant Professor

2. Introduction
Clinical toxicology:- is concerned with diseases and illnesses associated with short term or long term exposure to toxic chemicals.

3. Introduction
The development of clinical toxicology as a medical subspecialty and the important role of poison control centers began shortly after World War II.
Serious attention to the problem of household poisonings, contaminated food and unsafe drugs in the United States encourage establishment of few regulatory and legislative antipoisoning activities.

5. Sources of Intoxication
1. Gas Disasters
2. Food Disasters
3. Pharmaceutical Agents Disasters
4. Occupation-Related Chemical Diseases
5. Radiation Disasters
6. Alcohol and Drug Abuse Disasters

6. Gas Disasters • Toxic gas exposures may be the result of:
Natural disaster (volcanic eruption)
industrial accidents (fire, chemical release)
chemical warfare, or an intentional homicidal or genocidal attempt (concentration camp gas chamber).
• Depending on the toxin, the clinical presentation may be:
Acute: (cyanide)
Subacute or chronic: (air pollution).

7. Food Disasters
Unintentional contamination of food and drink has led to numerous toxic disasters.
Ergot, produced by the fungus Claviceps purpurea, caused epidemic ergotism as the result of eating breads and cereals made from rye contaminated by C. purpurea. Ergot-induced severe vasospasm producing convulsive manifestations or gangrenous manifestations .

8. Mass epidemic of methyl mercury poisoning occurred in Iraq in 1971, when the local population consumed homemade bread prepared from wheat seed treated with a methyl mercury fungicide hospital admissions and more than 400 deaths were associated with this mass poisoning.

9. More than 50,000 infants were hospitalized in China in 2008 from the toxic effects of melamine-contaminated powdered infant formulas, which has been associated with the development of nephrolithiasis; obstructive uropathy; and in some cases, acute kidney failure.

10. Pharmaceutical Agents Disasters
• Illness and death as a consequence of therapeutic drug use occur as sporadic events, usually affecting:
individual patients: Sporadic single-patient medication-induced tragedies usually result from errors or non-identified idiosyncratic reactions.
mass poisoning: affecting multiple (sometimes hundreds or thousands) patients.

11. Mass therapeutic drug disasters have generally occurred:
Secondary to poor safety testing
A lack of understanding of diluents and excipients.
Drug contamination
Problems with unanticipated drug-drug interactions or drug toxicity.

12. In the early 1960s, one of the worst drug-related modern-day events occurred with the release of thalidomide as an antiemetic and sedative-hypnotic. Its use as a sedative–hypnotic by pregnant women caused about 5000 babies to be born with severe congenital limb anomalies.

13. A number of pharmaceuticals previously approved by the FDA have been withdrawn from the market because of concerns about health risks.
Many more drugs have been given “black box warnings” by the FDA because of their propensity to cause serious or life-threatening adverse effects.

14. Some of the withdrawn drugs had been responsible for causing:
A. Serious drug–drug interactions (astemizole, cisapride, mibefradil, terfenadine).
B. Serious hepatotoxicity (troglitazone)
C. Anaphylaxis (bromfenac sodium)
D. Valvular heart disease (fenfluramine, dexfenfluramine)
E. Rhabdomyolysis (cerivastatin)
F. Hemorrhagic stroke (phenylpropanolamine)

15. Mibefradil with beta blockers resulted in cardiogenic shock

16. Weight-loss drug combination fenfluramine and phentermine or dexfenfluramine resulted in cardiac valvulopathy and pulmonary hypertension

17. Occupation-Related Chemical Diseases
Unfortunately, occupation-related toxic epidemics have become increasingly common.
A specific xenobiotic may cause unlimited numbers of problems, among the most worrisome being the carcinogenic and mutagenic potentials.

18. In the early 20th-century occupational tragedies included an increased incidence of mandibular necrosis (phossy jaw) among workers in the matchmaking industry who were exposed to white phosphorus

19. An increased incidence of aplastic anemia among artificial leather manufacturers who used benzene.
Increased incidence of angiosarcoma of the liver was first noticed among polyvinyl chloride polymerization workers who were exposed to vinyl chloride monomer.

20. An increased incidence of bladder tumors among synthetic dye makers who used β-naphthylamine

21. Radiation Disasters
Radiation Disasters
The first significant mass exposure to radiation occurred among several thousand teenage girls and young women employed in the dial-painting industry. These workers painted luminous numbers on watch and instrument dials with paint that contained radium.
Exposure occurred by licking the paint brushes and inhaling radium-laden dust. Studies showed an increase in bone-related cancers, as well as aplastic anemia and leukemia, in exposed workers.

22. The unintentional nuclear disaster at Chernobyl, Ukraine, in April 1986 again forced the world to confront the medical consequences of 20th-century scientific advances that created the atomic age.
The release of radioactive material resulted in 31 deaths and the hospitalization of more than 200 people for acute radiation sickness. By 2003, the predominant long-term effects of the event appeared to be childhood thyroid cancer and psychological consequences.

23. Alcohol and Drug Abuse Disasters
Unintended toxic disasters have also involved the use of alcohol (ethanol, methanol and other drugs of abuse (opioids, cannabinoids, cocaine, --- etc.).

24. TREATMENT OF ACUTE POISONING
Treat the patient, not the poison", promptly
Supportive therapy essential
Maintain respiration and circulation – primary
Judge progress of intoxication by:
Measuring and charting vital signs and reflexes

25. TREATMENT OF ACUTE POISONING
- 1st Goal - keep concentration of poison as low as possible by preventing absorption and increasing elimination
- 2nd Goal - counteract toxicological effects at effector site, if possible

26. PREVENTION OF ABSORPTION OF POISON
Induce emesis in the following ways:
mechanically by stroking posterior pharynx;
use of syrup of ipecac, 15ml for children and 30ml for adults followed by one glass of water;
use of apomorphine parenterally

27. PREVENTION OF ABSORPTION OF POISON
Inducing emesis by Syrup of ipecac is used rarely in the prehospital setting, and virtually never in hospitals.
Limited indications for the use of orogastric lavage, nasogastric suction, and whole-bowel irrigation exist.

28. PREVENTION OF ABSORPTION OF POISON
Chemical Adsorption
activated charcoal will adsorb many poisons thus preventing their absorption, it used within 1 hour of ingestion.
adsorbent in intestines may interrupt enterohepatic circulation.

29. PREVENTION OF ABSORPTION OF POISON
Purgation
Used for ingestion of enteric coated tablets when time after ingestion is longer than one hour
Use saline cathartics such as sodium or magnesium sulfate
The use of cathartics has never been shown to alter clinical outcome. However, their inappropriate use has been associated with significant morbidity and mortality, and their routine use is no longer recommended.

30. PREVENTION OF ABSORPTION OF POISON
Chemical Inactivation
Not generally done, particularly for acids or bases or inhalation exposure
For ocular and dermal exposure as well as burns on skin; treat with copious water

31. Dermal decontamination
is best accomplished with large amounts of water. However, the use of water on skin contaminated with metallic sodium, metallic potassium, or phosphorus (white, yellow) may result in further skin injury owing to heat generation and explosive injury.
Irrigation of phenol burns with low molecular weight polyethylene glycol is effective.

32. Other therapies, such as topical calcium salts for hydrofluoric acid burns, may be indicated following initial water decontamination.
Ocular decontamination can be accomplished with water or normal saline irrigation.

33. Increase Elimination Of Toxic Agents
Increasing urinary excretion by acidification or alkalinization
Decreasing passive resorption from nephron lumen
Diuresis
Cathartics
Peritoneal dialysis
Hemodialysis
Hemoperfusion

34. Forced diuresis and pH alteration
It is useful when compounds or active metabolites are eliminated by the kidney and diuresis enhances their excretion.
Mannitol and furosemide are generally used.
This method is no longer indicated because it increase the excretion of chemical only two fold.
Alkaline diuresis is achieved by administration of sodium bicarbonate, 1-2 mEq/kg every 3-4 hr.

35. The potential uses of urine alkalinization have been with weak acid such as salicylates and phenobarbital.
Acid diuresis is possible by using ammonium chloride, 75mg/kg/24hr.
Acid diuresis increase the elimination of weak bases, such as amphetamine, phencyclidine, and quinidine. This procedure is no longer recommended.

36. Dialysis and hemoperfusion
Peritoneal Dialysis
The procedure is undertaken by inserting a tube through a small incision made in the abdominal area into the peritoneum.
The peritoneal membrane serves as the semipermeable (dialyzing) membrane. The dialyzable chemical diffuses from blood across the peritoneal membrane into the dialyzing fluid (from higher concentration to lower concentration).

37. Peritoneal Dialysis Advantages:- Easy. Lowest risk for complications.
Disadvantages:-
The least effective method for removing most poisons. It is 5-10 time less efficient than hemodialysis.
Not suitable when rapid removal of a toxic substance is needed.
Complications include:- abdominal pain, intraperitoneal bleeding, intestinal, bladder, liver, or spleen perforation; peritonitis; water and electrolyte imbalance; and protein loss.

38. Procedure for peritoneal dialysis

39. Hemodialysis
Two catheters are inserted into the patient’s femoral vein. Blood is pumped from one catheter through the dialysis unit, across the semipermeable membrane, and back through the other catheter.
The procedure is continued for 6-8 hr. the solubilized chemical diffuses across the semipermeable membrane into the dialysis solution.
Clearance of the toxic agent is based on differences in osmotic and concentration gradients.

40. Procedure for hemodialysis

41. Procedure for hemodialysis

42. Disadvantages
The chemical that removed by this way must have a low molecular size.
Less effective for drug that are highly protein-bound.
Useless for chemicals that are extensively taken by the tissues.
Complications include clotting, and seepage of blood from around connections, hypotension, convulsions, arrhythmias, infection, and hematologic defects.

43. Hemoperfusion
The passage of blood through columns of adsorptive material, such as activated charcoal, to remove toxic substances from the blood.
It is more effective than peritoneal dialysis and hemodialysis for removing compound that are:
Lipid soluble.
Protein bound.
Poorly dialyzable.
Complications include:- trapping of white blood cells and platelets and microembolization. Newer systems solved this problem.

44. Procedure for hemoperfusion

46. Antidotes

47. Antidotes

48. Antidotes Digoxin Digoxin-specific antibody fragments (Fab) Digitalis
Other cardiac glycosides, e.g., bufodienalides (Bufo toads)
Oleander
Dimercaprol
Arsenic
Lead
Mercury
Ethanol
Diethylene glycol
Ethylene glycol
Methanol
Experimental: sodium monofluoroacetate
Flumazenil
Benzodiazepines
Venlafaxine

49. Antidotes Folic acid/tetrahydrofolic acid (leucovorin) Methanol
Methotrexate
Fomepizole
Ethylene glycol
Glucagon
Beta-adrenergic receptor antagonists
Calcium channel antagonists
Hyberbaric oxygen
Carbon monoxide
Experimental: carbon tetrachloride
Cyanide, hydrogen sulfide
Methylene blue
Methemoglobin-producing agents

50. Antidotes N-Acetylcysteine Acetaminophen
Experimental: carbon tetrachloride, chloroform, pennyroyal oil
Naloxone, nalmefene, naltrexone
Opioids
Physostigmine
Anticholinergic agents, e.g., diphenhydramine, Jimsonweed (Datura spp.), scopalamine
Pralidoxime
Organophosphates
Protamine
Heparin
Pyridoxine
Isoniazid
Monomethylhydrazine mushrooms (Gyrometra esculenta)

51. Antidotes
Sodium bicarbonate
Myocardial sodium channel blockers, e.g., cyclic antidepressants, cocaine, norpropoxyphene, class Ia and Ic antidysrhythmics, piperidine phenothiazines (thioridazine, mesoridazine)
Altered tissue distribution/enhanced elimination: chlorophenoxy herbicides, chlorpropamide, formic acid (methanol), methotrexate, phenobarbital, salicylates
Neutralization: inhaled chlorine gas, hydrogen chloride, phosgene
Succimer
Arsenic
Lead
Mercury
Vitamin K
Anticoagulants, e.g., warfarin, long-acting anticoagulant rodenticides

52. Pediatric poisoning
Approximately 54% of childhood exposures are to xenobiotics that are commonly found around the house, such as cleaning products, cosmetics, plants, hydrocarbons, and insecticides; approximately 46% are pharmaceuticals.
In older children and adolescents, approximately 49% of exposures are to non-pharmaceutical xenobiotics, and approximately 51% are to pharmaceuticals.

53. Who is more prone to toxicity? Children less than 5 years old. Why?

54. The environment: includes the area around the home.
Children are curious and investigative.
Many household products are marked in attractive packages.

55. 4. The natural tendency of children to place everything into their mouth.

56. 5. Taking medication in the presence of children “If I see it, I can do it,” 6. Dosing errors 7. Poisons are often left in easy view and accessible. Poisoning also occur because many products are used in unvented areas. Another factor that increase toxicity is the absence of information about the constituents of many products.

57. The leading causes of reported exposures in children and adolescents

58. The leading causes of reported exposures in children and adolescents