Chapter -4- toxicology and the multifactorial ppt
- 1. Monas K. (MSc) Clinical Toxicology of Some Chemicals, Drugs and Household Agents
- 2. Chapter outline A. Pesticide poisoning B. CNS drugs poisoning B. CV drugs poisoning C. Antidiabetic drugs
- 3. Pesticide poisoning: insecticides 1.Organophosphates •Ester/amides/thioderivatives of phosphoric/phosphonic acids •Arylphosphates are activated by liver •Act by binding ChE •Routes of exposure: Oral/inhalation/dermal
- 4. Mechanism of poisoning –Inhibit ChE leading to accumulation ofAch •S/S –M-effects •DUMBELS (Defecation/Urination/Miosis/Brady arrhythmias/Excitation/Lacrimation/Salivation –N-effects •MATCH(Muscle fasciculation/Adrenal medulla activity/Tachycardia/Cramping/Hypertension
- 5. •Rx -MaintainABC (supportive therapy)-clear Airway for vomiting, Artificial Rp for Rp failure, and maintain circ. for excess vomiting, NVD by giving fluid electrolyte. if person comes unconcious give glucose or dextrose =TAKE SPECIMEN FOR LAB dX-i.e,analysis –continue with symptomatic therapy »Re »IV diazepam for seizures »antiarrhythmic drug for arrythmia –if confirmed- –Atropine to counteract M-effects –Pralidoxime to reactivate ChE
- 6. Carbamates •Carbamylase ChE •Little CNS toxicity •Routes of exposure •oral only,(no dermal or inhalational b/c not used as insecticides) •Mechanism of poisoning •Inhibit ChE (reversible) •S/S •Similar to those of organophosphates (but very milder)
- 7. Rx --MaintainABC (supportive therapy)-clear Airway for vomiting, Artificial Rp for Rp failure, and maintain circ. for excess vomiting, NVD by giving fluid n electrolyte. if person comes unconcious give glucose or dextrose =TAKE SPECIMEN FOR LAB dX-i.e,analysis •continue with symptomatic therapy •If confirmed-No specific antidote •Atropine •Artificial Rp •GI technique
- 8. 2. Organochlorins: dichlorodiphenyltrichloro-ethane (DDT) •Get accumulated for longer period in tissues (adipose tissue) NB: doesn't affect the adipose tissue. •Highly absorbed-b/c its highly lipid soluble Affect nerve transmission Sensitize myocardium to catecholamines (NA andA)-increase Heart activity in its presence Routes of exposure •Oral/dermal/inhalation Mechanism of poisoning •Alter membrane Na/K-ATPase Affect nerve impulse → transmission
- 9. S/S •Cough, sneezing{irritation to bronchi},NVD{irritation to GI} •Tremors, agitation, headache, seizure{due to its effect on CNS} Rx •MaintainABC (supportive therapy)-clearAirway for vomiting, Artificial Rp for Rp failure, and maintain circ. for excess vomiting, NVD by giving IV fluid n electrolyte. if person comes unconcious give glucose or dextrose) =TAKE SPECIMEN FOR LAB dX-i.e,analysis •continue with symptomatic therapy, ex: IV diazepam for seizures
- 10. If confirmed-No specific antidote, -Removal of cloths (and change) and washing body/hand thoroughly-for Skin -If in GI-use the all technique -If in circulation-Use any of technique -Lidocaine for arrhthmias
- 11. Pesticide poisoning: rodenticides In form of bait packs, powders, pellets or cream Routes of exposure-oral,(i.e. accidental, suicide or homicide.) 1.Anticoagulants Mechanism of poisoning: •Inhibit Vit K utilization by liver to produce clotting factors S/S •Spontaneous bleeding
- 12. Rx •MaintainABC (supportive therapy)-clearAirway for vomiting, Artificial Rp for Rp failure, and maintain circ. for excess vomiting, NVD by giving IV fluid electrolyte. if person comes unconcious give glucose or dextrose) =TAKE SPECIMEN FOR LAB dX-i.e,analysis •continue with symptomatic therapy •If confirmed: specific antidote is there: •Vit K •GI decontamination (activated charcoal)
- 13. 2. Sodium monofluoroacetate Mechanism of poisoning •Inhibit citric acid cycle S/S •arrhythmias, cyanosis, convulsion, vomiting, nausea Rx •MaintainABC(supportive therapy)-clear Airway for vomiting,Arteficial Rpfor Rp failure,and maintain circ. for excess vomiting,NVD by givingIV fluid n electrolyte. if person comes unconcious give glucose or dextrose) =TAKE SPECIMEN FOR LAB dX-i.e,analysis •continue with symptomatic therapy, ex: diazepam for seizures
- 14. •If confirmed: specific antidote •Glycerol monoacetate •Gastric decontamination
- 15. Pesticide poisoning: rodenticides (cont.) 3. Strychnine Mechanism of poisoning •Inhibits glycine/inh.NT/=excitation S/S •Convulsion, Muscle spasm Rx •Supportive therapy: maintain ABCD •Symptomatic Rx: Iv diazepam for siezure, competitive NMBs- galamine, tubocuraraine •GI decontamination (b/c no specific antidote) •if in circulation removal by any of techniques
- 16. CNS drugs poisoning Toxicity of Therapeutic Agents
- 17. 1. Anticonvulsants 17 Anticonvulsants: carbamazepine, phenytoin, valproic acid, & many newer agents They are widely used in the mgt of seizure disorders & some are also used forTx of mood disorders or pain
- 18. Anticonvulsants… 18 i. Phenytoin Can be given orally or IV Rapid IV inj of phenytoin can cause acute myocardial depression & cardiac arrest secondary to the propylene glycol diluent & is probably related to rate & conc of infusion & possibly to total dose as well Fosphenytoin does not contain this diluent Chronic phenytoin intoxication can occur following only slightly ed doses ↑ B/c of zero order kinetics & a small toxic-therapeutic window
- 19. Phenytoin poisoning… 19 Phenytoin intoxication can also occur following acute intentional or accidental overdose The most common manifestations are ataxia, nystagmus, & drowsiness
- 20. Phenytoin toxicity: approx correlation of serum drug level & clinical findings Level, mg/L Clinical findings <10 None 10-20 (therapeutic) Mild nystagmus 20-30 Nystagmus 30-40 Ataxia, slurred speech, N, V 40-50 Lethargy & confusion >50 Coma
- 21. Phenytoin poisoning: Lab evaluation 1. Specific testing: Most emergency depts in developed nations can perform total serum phenytoin levels, which often correlate with pt examination findings Discordant exam findings & serum conc should prompt consideration of alternative dx E.g. the presence of coma is generally not consistent with a serum phenytoin level < 30 mg/L
- 22. Phenytoin poisoning: Laboratory evaluation… A serum albumin level may help explain any discordance b/n serum phenytoin level & clinical symptoms Hypoalbuminemia results in a higher free phenytoin conc at any given total phenytoin level B/c it is the free phenytoin level that determines toxicity but the total phenytoin level that is reported, hypoalbuminemic pts with a therapeutic or mildly elevated phenytoin level may exhibit significant toxicity The free phenytoin conc is generally not measured, unless the dx remains in doubt following a careful clinical & lab evaluation An ECG can identify the dysrhythmias
- 23. Phenytoin poisoning: Laboratory evaluation 2) General testing: Routine lab evaluation in the potentially poisoned pt should include the following: Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status Acetaminophen & salicylate levels, to rule out these common co-ingestion ECG: to rule out conduction system poisoning by drugs that effect the QRS or QTc intervals
- 24. Anticonvulsants… 24 ii. Carbamazepine Used forTx of trigeminal neuralgia & seizure disorders Intoxication causes drowsiness, stupor &, with high levels,AV block, coma, & seizures Dilated pupils & tachycardia are common Toxicity may be seen with serum levels > 20 mg/L , though severe poisoning is usually associated with conc > 30–40 mg/L B/c of erratic & slow absorption, intoxication may progress over several hrs to days
- 25. Anticonvulsants… 25 iii. Valproic acid Intoxication produces a unique syndrome consisting of: Hypernatremia, anion gap metabolic acidosis, hypocalcemia, elevated serum ammonia, & mild liver aminotransferase elevation Hypoglycemia may occur as a result of hepatic metabolic dysfunction Coma with small pupils may be seen & can mimic opioid poisoning Encephalopathy & cerebral edema can occur
- 26. Anticonvulsants… 26 iv. The newer anticonvulsants: gabapentin, levetiracetam, vigabatrin, & zonisamide Generally, cause somnolence, confusion & dizziness Felbamate can cause crystalluria & kidney dysfunction after overdose, & may cause idiosyncratic aplastic anemia with therapeutic use Lamotrigine, topiramate, & tiagabine have been reported to cause seizures after overdose
- 27. Anticonvulsants… 27 Treatment A. Emergency & supportive measures For recent ingestions, give activated charcoal orally or by gastric tube For large ingestions of carbamazepine or valproic acid —esp of SR formulations—consider whole bowel irrigation Multiple-dose activated charcoal & whole-bowel irrigation may be beneficial in ensuring gut decontamination for selected large ingestions
- 28. Anticonvulsants… 28 B. SpecificTreatment There are no specific antidotes Naloxone was reported to have reversed valproic acid overdose in one anecdotal case Consider hemodialysis for massive intoxication with valproic acid or carbamazepine (e.g., carbamazepine levels > 60 mg/L or valproic acid levels > 800 mg/L
- 29. 2. Antipsychotic drugs 29 Promethazine, chlorpromazine, haloperidol, droperidol, risperidone, olanzapine, quetiapine, & aripiprazole They are used as antipsychotic agents, & sometimes as antiemetics
- 30. Antipsychotic drugs… 30 Phenothiazines (particularly CPZ) Induce drowsiness & mild orthostatic hypotension in as many as 50% of pts Larger doses can cause obtundation, miosis, severe hypotension, tachycardia, convulsions, & coma Abnormal cardiac conduction may occur, resulting in prolongation of QT intervals (or both) & ventricular arrhythmias Among the newer agents, quetiapine is more likely to cause coma & hypotension
- 31. Antipsychotic drugs… 31 With therapeutic or toxic doses: An acute extrapyramidal dystonic reaction may develop in some pts Spasmodic contractions of the face & neck muscles, extensor rigidity of the back muscles & motor restlessness More common with haloperidol & other butyrophenones & less common with newer atypical antipsychotics such as olanzapine, aripiprazole, & quetiapine Severe rigidity accompanied by hyperthermia & metabolic acidosis may occasionally occur & is life threatening
- 32. Antipsychotic drugs… Typical antipsychotics ATypical antipsychotics Chlorpromazine Fluphenazine Loxapine Perphenazine Thioridazine Thiothixene Trifluoperazine Haloperidol Molindone Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Common antipsychotics
- 33. Antipsychotic drugs… 33 NB: No specific lab tests are needed to diagnose or treat antipsychotic medication overdose Treatment A. Emergency & supportive measures Administration of activated charcoal for large or recent ingestions For severe hypotension,Tx with IV fluids & vasopressor agents may be necessary Treat hyperthermia & Maintain cardiac monitoring
- 34. Antipsychotic drugs… 34 B. SpecificTreatment Hypotension & cardiac arrhythmias associated with widened QRS intervals on the ECG in a pt with thioridazine poisoning may respond to IV Na bicarbonate Prolongation of the QT interval & torsades de pointes is usually treated with IV Mg or overdrive pacing For extrapyramidal signs, could be alleviated by diphenhydramine, IV, or benztropine mesylate, IM
- 35. Barbiturates & Benzodiazepine poisoning CNS drugs poisoning …
- 36. Introductory case study A 36-year old male, weighing 89kg was brought to ED via ambulance with decreased conscious state, approx 1 hr after intentionally ingesting 100 x 1mg of alprazolam tablets with one alcoholic drink (approx 30mls of scotch with coke) following a disagreement with his partner. He had no prior history of suicidality or drug misuse & had been prescribed alprazolam for management of anxiety attacks in the setting of PTSD following a motor vehicle crash the previous yr.
- 37. Introductory case study… Following the ingestion, he notified his partner almost immediately & she contacted emergency services. He denied ingestion of any other substances & no other medication was found at the scene by paramedics.At the ED, he became drowsier & at the time of assessment, was opening eyes only to painful stimuli, localizing to pain & groaning (GCS 9) with a heart rate of 70/min & BP 110/65 mmHg. ECG was normal. Other blood investigations were unremarkable. The GCS measures the following functions Eye Opening (E) 4 = spontaneous 3 = to voice 2 = to pain 1 = none Verbal Response (V) 5 = normal conversation 4 = disoriented conversation 3 = words, but not coherent 2 = no words, only sounds 1 = none Motor Response (M) 6 = normal 5 = localized to pain 4 = withdraws to pain 3 = decorticate posture (an abnormal posture that can include rigidity, clenched fists, legs held straight out, & arms bent inward toward the body with the wrists & fingers bend & held on the chest) 2 = decerebrate (an abnormal posture that can include rigidity, arms & legs held straight out, toes pointed downward, head & neck arched backwards) 1 = none
- 38. Introductory case study… Questions: Describe the toxicokinetics of alprazolam? What are the clinical features of alprazolam overdose? What is the risk assessment for this patient? How is alprazolam overdose managed? What are the possible issues with the administration of flumazenil? Do you agree with the decision to give this patient flumazenil?
- 39. a. Barbiturates Barbiturates can be classified as long-, intermediate & short acting They bind to GABA receptors & prolong the opening of Cl- channels, thus inhibiting excitable cells of the CNS They are frequently involved in over dosage, & are generally taken with suicidal intent Short acting barbiturates are more dangerous than long acting Shock & anoxia appear much more quickly & coma is more severe with short acting barbiturates
- 40. Barbiturates… The poisonous effect of barbiturates is potentiated by alcohol, narcotics, tranquilizers & antidepressants Death occurs from respiratory failure, severe hypotension, vasomotor failure, non cardiogenic pulmonary edema, hypothermia (which aggravates shock) or oliguria with renal failure
- 41. Barbiturates… Symptoms: Neurologic: Lethargy & impairment in thinking Coma Hypothermia Decreased pupillary light reflex Nystagmus Respiratory depression Cardiovascular: Tachycardia or bradycardia, a hypotension
- 42. Barbiturates… Management of barbiturate poisoning: Emergency & supportive measures: ABCs Check for hypothermia & if present, warm the pt to avoid precipitating a fall in BP Measures to prevent absorption: Gastric lavage: If no more than 2-4 hrs have passed since ingestion of the barbiturate, gastric lavage is done Activated charcoal administration
- 43. Barbiturates… Emergency & supportive measures… Measures for removal of barbiturates Multiple doses of activated charcoal Forced diuresis with alkalinisation of urine Haemodialysis & haemoperfusion
- 44. b. Benzodiazepines Mechanism of Action: Potentiates the activity of GABA Symptoms: Drowsiness, nystagmus, confusion, slurred speech, ataxia, coma, weakness, amnesia, hypotension & respiratory depression
- 45. Benzodiazepines… Toxic dose: TI for benzodiazepines is very high Oral doses of diazepam that are 15-20 times the normal therapeutic dose have been reported without serious depression Death from overdose with benzodiazepines alone is rare, however, respiratory arrest has been reported after rapid iv injection of benzodiazepines Ingestion of other CNS-depressant drugs will produce additive effects
- 46. Benzodiazepines… Antidote/Treatment: Flumazenil is the drug of choice to reverse effects of benzodiazepines Flumazenil is an antagonist for the benzodiazepine binding site Naloxone can also be administered at a very low dose if the dx is unclear & an opiate co-ingestion is suspected (eg, evidence of severe respiratory depression) ABCs
- 47. Benzodiazepines… Antidote/Treatment… Single-dose activated charcoal is recommended for GI decontamination in pts who present within 4 hrs of ingestion or in symptomatic pts when the time of ingestion is unknown Ipecac syrup is C/I for prehospital or hospital use b/c of the risk for CNS depression & subsequent aspiration with emesis Respiratory depression may be treated with assisted ventilation
- 48. Theophylline poisoning 48 Theophylline exerts most of its effects by antagonizing adenosine receptors similar to caffiene It can also inhibit phosphodiesterase It affects the CV, neurological, GI, & metabolic systems Hypokalemia, hyperglycemia, hypercalcemia, hypophosphatemia, & acidosis commonly occur after an acute overdose Medication, diet, and underlying diseases can alter its narrow therapeutic window
- 49. Theophylline poisoning… 49 Adverse effects can be evident at therapeutic serum levels Symptoms: Nausea, vomiting, abdominal pain Mild metabolic acidosis Hypokalemia, hypophosphatemia, hypomagnesemia Hyperglycemia Sinus tachycardia Seizures (& tremors) Hypotension Arrhythmias
- 50. Theophylline poisoning… 50 Treatment: ABCs Aggressive gut decontamination with repeated doses of activated charcoal & whole bowel irrigation Propranolol or other beta blockers can block a beta-mediated sinus tachycardia & hypotension Phenobarbital is preferred over phenytoin for treatment of convulsions Hemodialysis is indicated for serum levels >100mg/L and for intractable seizures
- 51. CVS drugs poisoning CV drugs poisoning
- 52. 1. Digitalis & other cardiac glycosides 52 Cardiac glycosides are derived from a variety of plants & are widely used to treat HF & arrhythmias These drugs paralyze the Na+-K+-ATPase pump & have potent vagotonic effects Intracellular effects include enhancement of Ca-dependent contractility & shortening of the APD
- 53. Digitalis & other cardiac glycosides… 53 A number of plants (e.g., oleander, foxglove, lily-of-the-valley) contain cardiac glycosides Bufotenine, a cardiotoxic steroid found in certain toad secretions & used as herbal medicine & a purported aphrodisiac, has pharmacologic properties similar to cardiac glycosides
- 54. Digitalis & other cardiac glycosides… 54 Clinical Findings Intoxication may result from acute single exposure or chronic accidental overmedication After acute over-dosage, N &V, bradycardia, hyperkalemia, & AV block frequently occur Pts in whom toxicity develops gradually during long-term therapy may be hypokalemic & hypomagnesemic owing to concurrent diuretic treatment & more commonly present with ventricular arrhythmias
- 55. Digitalis & other cardiac glycosides… 55 Treatment A. Emergency & supportive measures After acute ingestion, administer activated charcoal Monitor K+ levels & cardiac rhythm closely Atropine is used for treating the bradycardia B. Specific treatment For pts with significant intoxication, administer digoxin- specific antibodies (digoxin immune Fab
- 56. Antidiabetic drugs 56 Medications used for DM include: Insulin, sulfonylureas & other insulin secretagogues, - α glucosidase inhibitors (acarbose, miglitol), biguanides (metformin), thiazolidinediones (pioglitazone, rosiglitazone) etc Of these, insulin & the insulin secretagogues are the most likely to cause hypoglycemia Metformin can cause lactic acidosis, esp in pts with renal insufficiency or after intentional drug overdose
- 57. Antidiabetic drugs… 57 Clinical findings Hypoglycemia may occur quickly after injection of short acting insulins or may be delayed & prolonged, esp if a large amt has been injected into a single area, creating a “depot” effect Hypoglycemia after sulfonylurea ingestion is usually apparent within a few hrs but may be delayed several hrs, esp if food or glucose containing fluids have been given
- 58. Antidiabetic drugs… 58 Lab evaluation When hypoglycemia is absent following an unintentional exposure, additional testing is generally unnecessary Pts with known or suspected sulfonylurea poisoning should have a serum creatinine measured, as a in renal ↓ clearance may contribute to toxicity Serial measurements of serum glucose & baseline measurements of serum electrolytes are appropriate
- 59. Antidiabetic drugs… 59 Lab evaluation… Routine lab evaluation of any poisoned pt, particularly those with a suspected intentional overdose, includes the following: Fingerstick glucose, to rule out hypoglycemia as the cause of any alteration in mental status Acetaminophen & salicylate levels ECG Pregnancy test, when appropriate
- 60. Antidiabetic drugs… 60 Treatment Administration of sugar & CHO-containing food or liquids by mouth, or IV dextrose if the pt is unable to swallow safely For severe hypoglycemia, administration of with D50W, 50 mL IV (25 g dextrose); repeat, if needed Follow up with dextrose-containing IV fluids (D5W or D10W) to maintain a blood glucose > 70–80 mg/dL
- 61. Poisoning with household products •Most common household products include –Bleaches •Include oxalic acid, hypochlorate •Commercial liquid bleaches cause esophageal damage •Granular bleaches-more toxic –Cosmetics •perfumes/colognes/,aftershave lotions, oral hygiene products ,shampoo–mainly dependent on their concentration of alcohol •deoderants composed of Al and Zn -low toxicity •for accidental, homicide or sucicide
- 62. –Hair products •Dyes/bleaches (hydrogen peroxide-low toxicity) •Hair straightening/hair waving (contains NaOH, ammonium hydroxide, potassium carbonate, potassium bicarbonate-corrosive) –Detergent and soaps •Soaps-salts of fatty acid –low toxicity (nausea, vomiting, diarrhea) •Detergents –non-soap (granular, liquid or spray) –Contain surfactants »Nonionic »Ionic -cationic (ammonium quaternary compounds) -amphoteric
- 63. Prevention of household products poisoning –Advocating child resistant containers –Keeping products in their original containers –Storing food and chemicals separately –Purchasing least toxic chemicals/check exp.date and small chem ingredient/ –Purchasing smallest possible amount –Not giving medicines in presence of children –Keeping chemicals out of sight or reach of children –Keeping a bottle of emetic
- 64. ThankYou!
Editor's Notes
- #18: Phenytoin sodium injection solutions contain propylene glycol 40 per cent and ethanol 10 per cent for stability
- #25: Hyperammonemia is believed due to propionic acid, a metabolite of VPA, which inhibits mitochondrial carbamoyl phosphate synthetase, an enzyme necessary for ammonia elimination via the urea cycle
- #28: This hyperammonemia results from valproate-induced increases in propionic acid that inhibit carbamyl phosphate synthetase I, the enzyme that catalyzes the initial reaction in the urea cycle
- #34: Treatment with oral doses of these agents should be continued for 24–48 hours.
- #48: EDTA is poorly absorbed from the gastrointestinal tract so it must be given parenterally, which distributes it rapidly throughout the body.
- #49: EDTA is poorly absorbed from the gastrointestinal tract so it must be given parenterally, which distributes it rapidly throughout the body.
- #50: EDTA is poorly absorbed from the gastrointestinal tract so it must be given parenterally, which distributes it rapidly throughout the body.