Toxicology 3 PDF

3…Therapy Dr. Suhair Hikmat Faculty of Pharmacy Al-Zaytoonah University of Jordan Therapy Stages in Work-Up of Suspected Poisoning I.Evaluation: Stabilization History and physical Exam Toxidrome Laboratory testing II.Management: Decontamination & Enhanced elimination Symptomatic Treatment Administ...

3…Therapy Dr. Suhair Hikmat Faculty of Pharmacy Al-Zaytoonah University of Jordan Therapy Stages in Work-Up of Suspected Poisoning I.Evaluation: Stabilization History and physical Exam Toxidrome Laboratory testing II.Management: Decontamination & Enhanced elimination Symptomatic Treatment Administration of antidote Stabilization of the patient • The first priority in the treatment of the poisoned patient is clinical stabilization. This is the so-called ABCs (Airway, Breathing, Circulation) of initial emergency treatment. Assessment of the vital signs and the effectiveness of respiration and circulation are the primary objectivesSecuring the airway • ensuring cardiopulmonary function • Vital signs must be recorded frequently. • Oxygen should be administered to any patient with respiratory distress or altered mental status. • Continuous ECG, pulse oximetry (measures pulse rate and the degree of oxygen saturation of hemoglobin), and establishment of IV access are necessary early steps for the patient who is delirious, stuporous, or comatose • Patients with altered mental status must be considered for possible administration • of oxygen, glucose, thiamine, naloxone( and/or flumazenil). • DONT therapy? • Glucose should be provided for any patient with altered mental status if the serum glucose is less than 80 mg/dL or if the glucose level is unknown due to delayed testing. • Oxygen should be given when there is evidence of inadequate oxygenation. • Naloxone is recommended for any patient for whom clinical evaluation suggests a history of opiate use. • Thiamine should be provided when a patient is malnourished and is receiving glucose Treating seizures • Many overdoses cause seizures as one of their most problematic features. Benzodiazepines are often effective in treating seizures. • Two unique situations are seizures induced by theophylline or isoniazid. • The former may not respond to benzodiazepines and phenobarbital or dialysis may be necessary. For isoniazid overdose, pyridoxine is usually effective. HISTORY AND PHYSICAL EXAMINATION • The primary goal of taking a medical history in poisoned patients is to determine, whenever possible, what substance the poisoned patient has been exposed to and to determine the extent and time of exposure. • Determine the mode of exposure(inhalation, ingestion, etc.). • state of the toxin (solid, liquid, gas). • Quantity. • time of exposure. (All of this information may help to estimate the patient’s risk for mortality). Physical exam should be focus on : • respiratory abnormalities • abnormal pulse rate • abnormal blood pressure • CNS aberrations • GI disturbances • Cardiac irregularities • skin disorders • One very helpful tool for the clinical toxicologist is to categorize the patient’s physical examination parameters into broad classes referred to as toxic syndromes. These toxic syndromes have been called toxidromes toxidromes • A toxidrome is a constellation of clinical signs and symptoms,are likely associated with exposure from certain toxicologic classes of chemicals. • Advantages include: • 1. Recognition of a toxidrome can help with the selection of therapeutic steps, especially administration of an antidote if one is available. • 2. Recognition of a toxidrome also will allow for faster initiation of therapy than waiting for laboratory results. • Disadvantages include problems associated with the concept of diagnosis based on categorizing into toxidromes. • 1. if a patient has been using multiple drugs • 2. if a patient presents at a significant time lapse since ingestion • So in these two problems it may not be possible to accurately determine the class of agents which caused the overdose • Following is a description of the major toxidromes: Anticholinergic Toxidrome • • • • • • • • • Tachycardia Delirium Dry skin Urinary retention Seizures Dilated pupils Decreased bowel sounds Coma Raised body temperature Agitation Toxins that Cause Anticholinergic Syndrome • • • • • • • • Antihistamines Antipsychotic drugs Antiparkinson drugs Antidepressants Atropine Antispasmodics Muscle relaxants Plants:Jimsonweed Sympathomimetic Toxidrome • • • • • • • • Delusions Hyperpyrexia Diaphoresis Hypertension Tachycardia Mydriasis Seizures Note: Distinction from anticholinergic: diaphoresis and no urinary retention are characteristic of sympathomimetic; dry skin and absent bowel soundsmore likely in anticholinergic. Toxins that Cause Sympathomimetic Toxidrome • Cocaine • Amphetamine & Methamphetamine • Decongestants such as: Phenylpropanolamine, Ephedrine, & Pseudoephedrine Opiate Toxidrome • • • • • • • • Hypotension Respiratory depression Bradycardia Hypothermia Altered mental status Meiosis Decreased bowel sounds Note: Seizures secondary to hypoxia, trauma, multiple drugs, or hypoglycemia. Toxins that Cause Opiate Toxidrome • • • • • • Morphine Heroin Codeine Synthetic opiates Semi-synthetic opiates Note: Check for needle tracks. Reversal of symptoms with naloxone is essentially diagnostic. Cholinergic Toxidrome • Confusion , Agitation, Tremors, CNS depression , Delirium , Coma, Seizures Meiosis , Tachycardia, & Hypertension. • SLUDGE (Salivation, Lacrimation, Urination,Defecation, Gastrointestinal sounds, Emesis) Toxins that Cause Cholinergic Toxidrome • Organophosphate insecticides • Carbamate insecticides • Pilocarpine Sedative-Hypnotic Toxidrome • • • • • • Sedation Delirium Loss of CNS function Confusion Coma Apnea Drugs that Cause Sedative-Hypnotic Toxidrome • • • • • • • Anticonvulsants Ethanol Methadone Fentanyl Barbiturates Benzodiazepines Tricyclic antidepressants MANAGEMENT I.DECONTAMINATION • This term refers to removal of the toxin from the patient, either from clothing or the physical environment of the patient, or from inside the body of the person affected. • Decontamination more commonly refers to efforts made to reduce the load of toxin in the stomach or intestine prior to its absorption into the blood. Methods of GI Decontamination • • • • Induction of emesis Lavage Activated charcoal Whole bowel irrigation EMESIS (VOMITING) • • • This is typically induced with syrup of ipecac. Syrup of ipecac induces vomiting both by local activation of peripheral emetic sensory receptors in the proximal small intestine, and by central stimulation of the chemoreceptor trigger zone. Serotonin3 (5HT3) receptors mediate the nausea and vomiting produced by syrup of ipecac by both mechanisms. Ipecac is a plant extract and contains two alkaloids emetine and cephaline. Cephaline is considered cardio toxic. The amounts used in poisoning therapy are too low to constitute a cardiac threat; however, there are cases of persons who abused ipecac by using it in a bulimic manner and such persons exhibited cardiac arrhythmias. • On average, 30% of a toxic substance load will be removed by emesis with ipecac if the emetic is given within 1 hour of ingestion. • Dose: adult 30 ml • children 6 – 12 months 10 ml • 1 -5 years 15 ml • over 5 years 30 ml • One additional dose ( a 2nd dose ) may be given if the patient has not vomited within 30 minutes. • Ipecac should not be given in the following cases: • 1. hydrocarbons which can be aspirated into the lung that leads to pneumonitis. • 2. corrosives ( acids & basis) because of possible perforation of stomach or esophagus • 3.with charcoal therapy,( ipecac induces emesis and, therefore, interferes with the mixing of charcoal and toxic substance). • 4. patient with cardiac disease. • 5. patients who either vomited copiously or who are vomiting. • 6. child less than 6 months of age. • 7. comatose patient (risk of aspiration) • 8. patient experiencing seizure( risk of aspiration) • 9. patient who ingests foreign material • 10. advanced pregnancy( increase contraction) GASTRIC LAVAGE • This method consists of rinsing the patient’s stomach with water or saline lavage solution by means of a tube inserted through the patient’s mouth or nose. • Placement of the tube is difficult and any indication of problems such as cyanosis suggests that the tube has entered the larynx rather than the esophagus. • Once the tube is in place and solution delivered, a syringe is attached to the tube and the stomach contents are suctioned. • The lavage process is continued until the return solution is clear and free of any evidence of the presence of further toxin. • It is of some value when initiated within1 hour of ingestion of the poison. • Dose: • Adult 200 – 300 ml • Children 50 – 100 ml Gastric lavage contraindications • • • • • • 1. corrosives ingestion( risk of perforation) 2. hydrocarbones ( risk of aspiration) 3.comatose patient 4. patient experiencing seizure 5. patient who ingests foreign material 6. patient with hemorrhage in esophagus or stomach • 7. when airway cannot be protected( incorrect insertion of the tube…. Cyanosis) • Specific lavage fluids: • 1.Thiosulfate solution for CN • 2. Calcium gluconate solution for oxalic acid • 3. deferioxamine solution for iron • 4. potassium permenganate for alkaloids • 5. castor oil:water ( 1 : 2) for carbolic acid ACTIVATED CHARCOAL (AC) • AC is a fine, black, odorless powder. • The theory behind the use of charcoal is that it is an extremely efficacious adsorbent material with large surface area & it binds many chemicals and prevents their absorption into the bloodstream. Instead, the toxin– charcoal complex ideally passes through the GI tract and is excreted together with the feces. • Dose: 10:1 charcoal to-toxin ratio or 1 gm/kg b.wt. is usually used as single dose. • Repetitive doses (MDAC): charcoal administration may be repeated several times at 3- to 4-hour intervals especially drugs with long half lives, or those with enterohepatic cycles, or those with low Vd, or those with prolonged elimination half life. • Charcoal is used by mixing with water( and/or a cathartic) 1 : 4 to form a slurry which should be passed through orogastric tube. • Drugs & chemicals bound poorly to charcoal such as iron, alcohols, lithium, magnesium, and potassium heavy metals, corrosives, hydrocarbons. • Multiple dose activated charcoal (MDAC)is useful in overdose of theophylline, phenobarbital, quinine, dapsone & carbamazepine. Other binding resins • cholestyramine can enhance the fecal elimination of chlordecone (kepone) organochlorine insecticide. • Cholestyramine also enhances the elimination of digoxin & digitoxin. • Sodium polystyrene enhances the elimination of lithium & potassium • Sodium bicarbonate for iron • Cellulose sodium phosphate for calcium WHOLE BOWEL IRRIGATION WBI • • • • • • • This process consists of flushing the entire GI tract with the intention of reducing transit time and, therefore, limiting the opportunity for toxins to be absorbed into the bloodstream. Whole-bowel irrigation (WBI) is the most effective process for evacuating the intestinal tract in poisoned patients. This technique is typically accomplished utilizing polyethylene glycol (PEG) and an added electrolyte lavage solution (ELS). MECHANISM OF ACTION Polyethylene glycol is a nonabsorbable, isoosmotic indigestible xenobiotic. It remains in the colon, and together with the water diluent, is evacuated, resulting in WBI without producing flatus and cramps. Electrolytes are added to limit electrolyte and fluid shifts. Whole bowel irrigation is continued for approximately 5 to 6 hours or until the effluent from the rectum has the same characteristics as the fluid being instilled. This procedure is especially valuable for toxins such as lithium or iron which are not removed by charcoal, for sustained – release drugs, or for foreign bodies. it must be employed soon after the toxin exposure has occurred. II.ENHANCED ELIMINATION • An acid or base load may be provided to a patient and will result in change in the urinary pH. If a substance is present in the blood and it has a pK near the pH of the blood, then this manipulation may change the charge status of the substance. This is shown by the following equations: • Acidify Blood → Increased H+ concentration • Drug(–) + H(+) → DrugH(0) (uncharged drug) • DrugH(0) + OH(–) → Drug(–) (negatively charged drug) • This technique is also called ion trapping and depends on the fact that charged species are less likely to cross biological membranes. • Thus, if the urine is rendered alkaline, an acidic drug such as salicylic acid is converted to a salt within the kidney. The salicylate anion which carries a negative charge is now more prone to remain in the renal filtrate than to be reabsorbed back into the blood. In other words, it is more rapidly excreted from the body. • Converting urine to an alkaline pH is, therefore, an effective means for enhancing the elimination of acids. such as salicylates, phenobarbital, chlorpropamide, formate, diflunisal, fluoride, methotrexate, and the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D). • Conversely, it is possible to increase the acidity of the urine and thereby increase the charged character of drugs which are basic. Basic drugs such as tricyclic antidepressants or phencyclidine can be excreted more rapidly by acidifying the urine. This is not recommended,however, because the benefits of improved elimination usually are more than offset by the deleterious effects of the blood acidosis on cardiac and CNS function. cathartics • These are drugs that promote intestinal evacuation (laxatives) • Laxatives promote a soft or semi fluid stool within 6-8hrs or1-3 days depending on the type and dose. While cathartics promote a rapid watery evacuation in 1 – 3 hrs. • Saline cathartics such as magnesium citrate and magnesium sulfate and sorbitol are usually used which can draw water into the gut by establishing an osmotic gradient. Increased water retention leads to increase intestinal pressure and this leads increase in intestinal motility. • Adverse effects of cathartics are related to dehydration and electrolytes disturbances. In addition to that abdominal cramps is considered another effect. • Contraindication include intestinal obstruction, also pt with renal insufficiency should not be given Mg cathartics. DIALYSIS AND HEMOPERFUSION • Dialysis is the process in which the blood is circulated through a bath in which a semi permeable membrane separates the components of the blood from the constituents of the dialysis fluid . hemodialysis • In dialysis the various substances in blood will diffuse across into the dialysis bath provided that they are small enough (low molecular weight) to transit the membrane and their concentration is lower in the bath than in blood. • Many factors relate to the potential effectiveness of dialysis: • Tissue binding of the toxin, high volume of distribution for the toxin, and high molecular weight are three factors which diminish the efficacy of dialysis. • Lithium, methanol, isopropanol, salicylates, theophylline, and ethylene glycol are examples of substances which respond well to this therapy and are quite rapidly removed. • Hemoperfusion is a process in which the blood is pumped through an external cartridge. It has the advantage of rapidly exposing the blood to a filtering device and is theoretically faster for removal of toxins. • The cartridge used may contain charcoal or some other adsorbent. • Hemoperfusion can be effective for toxins that are sluggish in responding to dialysis due, for example, to their protein binding in serum or their relatively high molecular weights. III. Symptomatic treatment • To treat the symptoms accompanied the poisoning cases. • It is usually based on functional antagonism. ANTIDOTES • Once the toxin has reached the biological receptor it is very difficult to provide any further specific treatment other than supportive care. The one exception to this statement is use of antidotes when available. • This term is understood to mean a medicinal intervention that is specific to a toxin and is effective only for that toxin or others closely related to it. • An antidote might appear to be the ideal treatment for poisoning. However, no antidote is completely without side effects. All must be given in a timely manner. • It is useful to subdivide antidotes into four classes: chemical, receptor, dispositional, • and functional. • Chemical antidotes react with the poison, resulting in formation of a compound with lesser toxicity or reduced absorbability. • An example is calcium chloride for oxalic acid poisoning. This antidote forms calcium oxalate when it reacts with oxalic acid and the calcium oxalate has low solubility which effectively limits its toxicity. • Metal chelating agents are also examples of this type of antidote. • Receptor antidotes compete with the poison for receptor sites. • Naloxone,for example, reverses opiate-induced respiratory depression by binding to receptors • and, thus, displaces the opiate from the receptor. • Physostigmine also belongs to this category, It inhibits the activity of cholinesterase. This action limits the poisonous effects of atropine and other anti-cholinergic compounds,which extends the activity of cholinesterase to harmful limits. • Dispositional antidotes reduce the amount of toxin available to tissues. They can do this in various ways including altering absorption, metabolism, distribution, or excretion of toxic agents. • Acetaminophen is potentially extremely toxic and exerts its detrimental action by forming a toxic metabolite. The antidote, N-acetylcysteine, a dispositional antidote, limits the supply of this toxic metabolite by converting it to a nontoxic form. • Functional antidotes are antagonists. They have no direct action on the toxin itself nor on its action. However, they act on one biochemical system to offset the actions of a second biochemical system, the latter being the one affected by the toxin. • As an example, the toxicity of many drugs or insect stings includes an immunological reaction which can reach anaphylactic proportions as the victim experiences severe breathing difficulties from bronchoconstriction. Epinephrine can reverse this by causing bronchial dilation with the restoration of normal breathing. Clinically useful antidotes • N-Acetyl cysteine for acetaminophen • Nitrite & thiosulfate for cyanide • Atropine & pralidoxime for organophosphate insecticides • Atropine for carbamate insecticides • Calcium disodium EDTA for lead • Deferoxamine for iron • Ethanol for methanol • Penicillamine for copper • Digoxin immune Fab for digoxin & digitoxin • Methylene blue for methemoglobin inducers • Antivenin for snake venom • Oxygen for carbon monoxide • Flumazenil for benzodiazepines • Naloxone for opiates • Physostigmine for atropine & anticholinergics • Dimercaprol(BAL) for arsenic , mercury • Pyridoxine for isoniazid • Calcium gluconate for oxalic acid,& for hydrofluoric acid Diagnostic clues (aids) 1. colored emesis Blue with boric acid Blue-green with copper sulfate Red with iron. 2. colored stool Black with iron Rice-water diarrhea with arsenic Phosphorescent stool with phosphorus 3. colored urine Gray with phenol and cresol Orange – red with rifampin Green-blue with methylene blue 4. Colored nails Yellow for lithium Brown for methotrexate 5. Odor Bitter almond for CN Rotten egg for hydrogen sulfide Fish odor for zinc phosphide Acetone for isopropanol Garlic odor for arsenic, selenium, thallium ,yellow phosphorus