Clinical Toxicology Past Paper 2024-2025 - Uruk University

Uruk University 5th Stage College of Pharmacy First Course Clinical Toxicology Dr. Reem Ghanim Hussein Lecturer at college of Pharmacy Uruk...

Uruk University 5th Stage College of Pharmacy First Course Clinical Toxicology Dr. Reem Ghanim Hussein Lecturer at college of Pharmacy Uruk University 2024 - 2025 Drug toxicity Over the counter drugs Non-steroidal anti-inflammatory drugs Salicylates Aspirin poisoning may affect people of all ages. Children are most susceptible and are usually the victims of accidental ingestions. Adult salicylate toxicity is normally due to chronic misuse or intentional ingestions of large quantities. Children present the greatest risk of developing serious toxic complications after salicylate poisoning.  Mechanism of toxicity 1. C.N.S. will stimulated by salicylate intoxication. 2. The respiratory center is stimulated either: A. Indirectly by an increase in PCO2 production: salicylates enhance oxygen consumption by increasing the cellular metabolic rate, this results in hyperthermia with accumulation of CO2 which then causes hyperpnea. B. Directly acting on respiratory center : producing both hyperpnea (increase depth of respiration) and tachypnea (increase rate of respiration) this will increased respiration rate causes a greater than normal amount of CO2 to be expired by the lungs. As a result, there is less plasma CO2 (alkalosis). ‫اﻵﺛﺎر اﻷﯾﻀﯿﺔ ﻟﺘﺴﻤﻢ اﻟﺴﺎﻟﯿﺴﯿﻼت‬: 3. Metabolic effects of salicylate intoxication: The kidney attempts to compensate for the acid-base imbalance by excreting more HCO3, and retaining H+ and non-bicarbonate anions and this lead to metabolic acidosis. Usually this mechanism operates to correct the acid-base imbalance. The second action of salicylate toxicity results from uncoupling of oxidative phosphorylation ((Uncoupling of oxidative phosphorylation result in a decrease in ATP production.)) which eventually produces metabolic acidosis so the cells attempt to compensate by increasing glycolysis.  The body uses its glycogen stores to obtain energy and eventually, these are depleted and the body switches to lipid metabolism to meet energy demands. Although this is an efficient mechanism, it leads to excessive free fatty acid in the liver, producing increased ketone bodies, which can cause ketoacidosis. Inhibition of amino acid metabolism, resulting in accumulation of amino acids. ‫ ﻣﻤﺎ ﯾﺆدي إﻟﻰ ﺗﺮاﻛﻢ اﻷﺣﻤﺎض اﻷﻣﯿﻨﯿﺔ‬، ‫ﺗﺜﺒﯿﻂ اﺳﺘﻘﻼب اﻷﺣﻤﺎض اﻷﻣﯿﻨﯿﺔ‬. Salicylates also interfere with normal blood glucose concentration. Eventually, however, there is depletion of glucose stores with resultant hypoglycemia. Hypoglycemia may be of greater significance in chronic salicylism, or during the latter stages of acute salicylate toxicity. Ingestion high doses of salicylate result in switching salicylate metabolism from first to zero-order kinetic. That is, the rate of degradation is independent of dose and an increase in dose results in a greater increase in serum and tissue salicylate concentrations especially, the CNS. ‫ أي أن ﻣﻌﺪل اﻟﺘﺤﻠﻞ ﻣﺴﺘﻘﻞ‬.‫ﯾﺆدي ﺗﻨﺎول ﺟﺮﻋﺎت ﻋﺎﻟﯿﺔ ﻣﻦ اﻟﺴﺎﻟﯿﺴﯿﻼت إﻟﻰ ﺗﺒﺪﯾﻞ اﺳﺘﻘﻼب اﻟﺴﺎﻟﯿﺴﯿﻼت ﻣﻦ اﻟﺤﺮﻛﯿﺔ اﻷوﻟﻰ إﻟﻰ اﻟﺤﺮﻛﯿﺔ اﻟﺼﻔﺮﯾﺔ‬ ‫ﻋﻦ اﻟﺠﺮﻋﺔ وﺗﺆدي اﻟﺰﯾﺎدة ﻓﻲ اﻟﺠﺮﻋﺔ إﻟﻰ زﯾﺎدة أﻛﺒﺮ ﻓﻲ ﺗﺮﻛﯿﺰات ﺳﺎﻟﯿﺴﯿﻼت اﻟﻤﺼﻞ واﻷﻧﺴﺠﺔ ﺧﺎﺻﺔ اﻟﺠﮭﺎز اﻟﻌﺼﺒﻲ اﻟﻤﺮﻛﺰي‬. This result of decreased plasma protein binding of salicylate at high doses. ‫ھﺬه اﻟﻨﺘﯿﺠﺔ ﻻﻧﺨﻔﺎض ارﺗﺒﺎط ﺑﺮوﺗﯿﻦ اﻟﺒﻼزﻣﺎ ﻣﻦ اﻟﺴﺎﻟﯿﺴﯿﻼت ﺑﺠﺮﻋﺎت ﻋﺎﻟﯿﺔ‬.  Characteristics of poisoning The major toxic manifestations of salicylate poisoning result from ‫اﻟﻤﻈﺎھﺮ اﻟﺴﺎﻣﺔ اﻟﺮﺋﯿﺴﯿﺔ ﻟﻠﺘﺴﻤﻢ ﺑﺎﻟﺴﺎﻟﯿﺴﯿﻼت ﻧﺎﺗﺠﺔ ﻋﻦ ﺗﺤﻔﯿﺰ اﻟﺠﮭﺎز اﻟﻌﺼﺒﻲ اﻟﻤﺮﻛﺰي‬. stimulation of CNS. These may include nausea, vomiting, tinnitus, headache, hyperpnea, and ‫ﺗﺪاﺧﻞ اﻟﻜﻼم‬ neurologic abnormalities, such as confusion, hyperactivity, slurred speech, and generalized convulsions. Salicylate results in hyperventilation, decreased PCO2, and respiratory alkalosis. Management of poisoning Management strategies involve : 1. Removal of aspirin from the GI tract 2. Correction of metabolic acidosis, dehydration, hyperthermia, hypoglycemia, and hypokalemia. The general sequence for managing salicylate toxicity should begin with gastric decontamination in children, emesis is easier to accomplish and probably more effective.  Dehydration is common in salicylate poisoning and appropriate fluid replacement is critical. This may be managed by administration oral fluids. When toxicity is within the moderate to severe range, dehydration is usually treated with parenteral fluids. Sodium bicarbonate is given to help correct metabolic acidosis associated with moderate to severe toxicity, and to produce an alkaline urine that will promote movement of salicylate from intracellular site to plasma to enhance excretion by the kidney. ‫ﯾﺘﻢ إﻋﻄﺎء ﺑﯿﻜﺮﺑﻮﻧﺎت اﻟﺼﻮدﯾﻮم ﻟﻠﻤﺴﺎﻋﺪة ﻓﻲ ﺗﺼﺤﯿﺢ اﻟﺤﻤﺎض اﻷﯾﻀﻲ اﻟﻤﺮﺗﺒﻂ‬ ‫ وﻹﻧﺘﺎج ﺑﻮل ﻗﻠﻮي ﯾﻌﺰز ﺣﺮﻛﺔ اﻟﺴﺎﻟﯿﺴﯿﻼت ﻣﻦ‬، ‫ﺑﺎﻟﺴﻤﯿﺔ اﻟﻤﺘﻮﺳﻄﺔ إﻟﻰ اﻟﺸﺪﯾﺪة‬ ‫اﻟﻤﻮﻗﻊ داﺧﻞ اﻟﺨﻼﯾﺎ إﻟﻰ اﻟﺒﻼزﻣﺎ ﻟﺘﻌﺰﯾﺰ إﻓﺮاز اﻟﻜﻠﻰ‬ Potassium chloride is added to correct hypokalemia and help prevent alkalosis from sodium bicarbonate administration. Alkaline diuresis is only effective in removing salicylate from the body when potassium depletion is corrected. Fever can be reduced by cold or tepid water. Other symptomatic treatment include diazepam for seizures, calcium supplements for hypocalcemic tetany, and vitamin k for coagulation defects.  Ibuprofen Ibuprofen can be predicted to be safe. After absorption it is quickly metabolized with an elimination half-life of approximately 2 hr. A single therapeutic dose is completely eliminated within 24 hr. An acute overdose does not prolong the elimination half-life of ibuprofen. ‫ﺟﺮﻋﺔ زاﺋﺪة ﺣﺎدة ال ﺗﻄﯿﻞ ﻧﺼﻒ ﻋﻤﺮ اﻟﻘﻀﺎء ﻋﻠﻰ اﻹﯾﺒﻮﺑﺮوﻓﯿﻦ‬ Mechanism of toxicity Acute renal failure is believed to result from decreased production of intra-renal prostaglandins. ‫ﯾﻌﺘﻘﺪ أن اﻟﻔﺸﻞ اﻟﻜﻠﻮي اﻟﺤﺎد ﻧﺎﺗﺞ ﻋﻦ اﻧﺨﻔﺎض إﻧﺘﺎج اﻟﺒﺮوﺳﺘﺎﺟﻼﻧﺪﯾﻦ داﺧﻞ اﻟﻜﻠﻰ‬ This in turn decreases the renal blood flow and glomerular filtration rate. ‫وھﺬا ﺑﺪوره ﯾﻘﻠﻞ ﻣﻦ ﺗﺪﻓﻖ اﻟﺪم اﻟﻜﻠﻮي وﻣﻌﺪل اﻟﺘﺮﺷﯿﺢ اﻟﻜﺒﯿﺒﻲ‬ Characteristics of poisoning Patients have either no symptoms, or mild manifestations of gastrointestinal irritation, such as nausea and vomiting. Drowsiness, lethargy, and mild coma have been reported but generally resolve in 24 hr even with large doses. ‫ ﺳﺎﻋﺔ ﺣﺘﻰ ﻣﻊ اﻟﺠﺮﻋﺎت اﻟﻜﺒﯿﺮة‬24 ‫ﺗﻢ اﻹﺑﻼغ ﻋﻦ اﻟﻨﻌﺎس واﻟﺨﻤﻮل واﻟﻐﯿﺒﻮﺑﺔ اﻟﺨﻔﯿﻔﺔ وﻟﻜﻦ ﯾﺘﻢ ﺣﻠﮭﺎ ﺑﺸﻜﻞ ﻋﺎم ﻓﻲ ﻏﻀﻮن‬  Management of poisoning Treatment of acute overdoses of ibuprofen and similar NSAIDs should consist of basic poison management, including symptomatic and supportive care. 73% of the patients received emetic or gastric lavage and another 20% were given oral fluids. The remainder required no treatment. Activated charcoal will adsorb NSAIDs including ibuprofen. Vitamins Accidental poisoning by vitamin products currently rank as a major cause of poisoning in children under the age of five, similar toxicity also occurs in adults, and reports of such poisonings have increased since the advent of the megadose concept of dosing vitamins. Fortunately, few deaths have been reported.  Megadosing Toxic manifestation of vitamin over-ingestion are more commonly seen with fat-soluble vitamin A and D. Fat-soluble vitamin K has been frequently reported to induce toxicity, probably because it is not available for self- administration in OTC products. Vitamin E is practically nontoxic, at least according to current knowledge. For the most part, excessive intake of the water-soluble B complex group and vitamin C is eliminated by the kidney. Although they produce minor adverse reactions and may cause drug interactions or modify laboratory values, these are not generally life-threatening. An exception is vitamin C which can induce renal toxicity in a small number of susceptible individuals. 1. Vitamin A Hypervitaminosis A has occurred in patients receiving large doses of vitamin A or other vitamin A analogs such as isotretinoin and tretinoin to treat skin diseases, such as ichthyosis ‫داء السمكة‬, acne, and Drier's disease (a genetically transmitted disease in which the skin becomes extremely crusty‫)قشري‬. Large doses of vitamin A taken during pregnancy are teratogenic, causing a variety of fetal malformation ‫تشوه‬.  Mechanisms of poisoning A retinol-binding protein is involved in transport of the vitamin to peripheral tissues. Clinical manifestation of hypervitaminosis A occur when this protein becomes saturated with the vitamin the cellular membrane are then exposed to unbound vitamin, which leads to degradation of the membrane structure. This mechanism may be responsible for increased cerebral spinal fluid pressure and other CNS manifestations that characterize vitamin A toxicity. Vitamin A is normally stored in hepatocytes. When massive doses are consumed, the Ito cells (lipocytes) take up the vitamin. It is believed that this transforms, the Ito cells into fibroblasts that can produce collagen, which in turn causes subsequent hepatic pathology. ‫ ﻋﻨﺪﻣﺎ ﯾﺘﻢ اﺳﺘﮭﻼك ﺟﺮﻋﺎت‬.‫ﯾﺘﻢ ﺗﺨﺰﯾﻦ ﻓﯿﺘﺎﻣﯿﻦ (أ) ﻋﺎدة ﻓﻲ ﺧﻼﯾﺎ اﻟﻜﺒﺪ‬ ‫ ﯾﻌﺘﻘﺪ أن ھﺬا ﯾﺤﻮل‬.‫ ﺗﻤﺘﺺ ﺧﻼﯾﺎ إﯾﺘﻮ (اﻟﺨﻼﯾﺎ اﻟﺸﺤﻤﯿﺔ) اﻟﻔﯿﺘﺎﻣﯿﻦ‬، ‫ﻛﺒﯿﺮة‬ ‫ واﻟﺬي ﺑﺪوره ﯾﺴﺒﺐ‬، ‫ﺧﻼﯾﺎ إﯾﺘﻮ إﻟﻰ ﺧﻼﯾﺎ ﻟﯿﻔﯿﺔ ﯾﻤﻜﻦ أن ﺗﻨﺘﺞ اﻟﻜﻮﻻﺟﯿﻦ‬ ‫أﻣﺮاض اﻟﻜﺒﺪ اﻟﻼﺣﻘﺔ‬  Characteristics of poisoning Vitamin A-induced symptoms of toxicity are: Gastrointestinal: nausea/vomiting, anorexia, Diarrhea Central nervous system: headache, irritability and restlessness, fatigue Skin: Dry, pruritic skin, rash Muscle and joints: myalgia, muscle fasciculation, tender Bone: hyperostosis Management of poisoning Treatment of vitamin A intoxication includes immediate discontinuation of the substance. Most signs and symptoms will disappear within a week or two. If symptoms are ignored and the vitamin is not withdrawn, irreversible hepatic damage, including cirrhosis, may result. Vitamin E is reported occasionally to protect against hypervitaminosis A. 2. Vitamin D Vitamin D is the most toxic of all vitamins. A large number of toxicity have been reported in people using vitamin D to treat arthritis, muscle cramp, cold hand and feet, and a variety of other real or imagined disorders. The vitamin is used occasionally in excess to treat various nutritional disorder in persons of all ages. Because excessive and repeated doses are frequently taken, reports of toxicity have increased in recent years. Mechanisms of poisoning Vitamin D toxicity are caused by its action to elevate the concentration of plasma calcium. 1,25-dihydroxycholicalciferol exerts activity at several sites, including intestinal epithelium to promote calcium absorption.  Characteristics of poisoning Symptoms of vitamin D toxicity are largely suggestive of hypercalcemia. Deaths occurring after acute toxic doses are usually attributed to this finding. Toxic effects from chronic use are due to deposition of calcium in soft tissues, especially the kidney and heart. Aortic valvular stenosis (narrowing) and nephrocalcinosis with calcification other soft tissues are characteristic finding. ‫ﺗﻀﯿﻖ اﻟﺼﻤﺎﻣﺎت اﻷﺑﮭﺮي (ﺗﻀﯿﯿﻖ) و اﻟﻜﻠﻮي ﻣﻊ ﺗﻜﻠﺲ اﻷﻧﺴﺠﺔ اﻟﺮﺧﻮة اﻷﺧﺮى ھﻲ ﻧﺘﯿﺠﺔ ﻣﻤﯿﺰة‬. Renal function may be severely and irreversibly impaired. Cardiac rhythm may become abnormal after prolonged deposition of calcium salts within the heart's myofibrils. ‫ﻗﺪ ﯾﺼﺒﺢ إﯾﻘﺎع اﻟﻘﻠﺐ ﻏﯿﺮ طﺒﯿﻌﻲ ﺑﻌﺪ ﺗﺮﺳﺐ أﻣﻼح اﻟﻜﺎﻟﺴﯿﻮم ﻟﻔﺘﺮة طﻮﯾﻠﺔ داﺧﻞ اﻟﻠﯿﯿﻔﺎت اﻟﻌﻀﻠﯿﺔ ﻟﻠﻘﻠﺐ‬ Management of poisoning Hypervitaminosis D treatment consist of immediately discontinuing vitamin intake, reducing calcium intake, administering glucocorticoids, and assuring a generous fluid intake.  3. Vitamin K Vitamin K is not a component of over the counter remedies thus there are few cases of toxicity reported in the literature. Characteristic of poisoning The major toxicity is associated with water soluble synthetic analogs such as menadione. These derivatives are oxidants and may cause erythrocytic membranes to rupture with resultant cell hemolysis, and jaundice ‫ھﺬه اﻟﻤﺸﺘﻘﺎت ھﻲ ﻣﺆﻛﺴﺪات وﻗﺪ ﺗﺘﺴﺒﺐ ﻓﻲ ﺗﻤﺰق أﻏﺸﯿﺔ ﻛﺮات‬ ‫اﻟﺪم اﻟﺤﻤﺮاء ﻣﻊ اﻧﺤﻼل اﻟﺪم اﻟﺨﻠﻮي اﻟﻨﺎﺗﺞ واﻟﯿﺮﻗﺎن‬ 4. Vitamin E At present, vitamin E is believed to have a low toxicity profile. Undesirable side effects of megadoses of vitamin E include headache, nausea, fatigue, dizziness, and blurred vision, gastrointestinal disturbance. 5. Vitamin C Serous toxicity to vitamin C is uncommon. However, numerous untoward effects may occur when it is taken in overdose, or by persons susceptible to larger-than- normal doses. It is often reported that large doses of vitamin C destroy substantial amounts of vitamin B12, and therefore reduce its concentration in the blood. Kidney stone formation Ascorbic acid increases renal excretion of oxalate, uric acid and calcium. These may increase the potential for stone formation in the kidney and bladder. This potential seems to be governed by general factors, and only occurs in a small segment of the population.  6. Vitamin B1 Symptoms from parenterally administered vitamin B1 (thiamine) ranged from nervousness, convulsions, weakness, trembling, headache and neuromuscular paralysis to cardiovascular disorders With the subsequent decline in use of thiamine in its parenteral form, there have been fewer toxicities reported and it is longer considered to possess a major toxicological threat. 7. Niacin In single doses of 50 mg niacin (nicotinic acid), intense flushing and pruritus have been reported. When the practice of giving niacin in doses ranging upward to 30 g or more a day advocated, more serious toxicity was noted. The most common serious toxicities reported for niacin include abnormal liver function and jaundice. 8.Vitamin B6 Vitamin B6 (pyridoxine)-induced reactions are rare. Convulsive disorder have occurred due to both vitamin excess as well as a deficiency state. 9.Vitamin B12 Vitamin B12 (cyanocobalamin) is associated on rare occasion with allergic reactions to the injectable products, Symptoms of edema of the face, urticarial, shivering, bronchospasm, rash, dyspnea, aphonia ‫فقدان الصوت‬, and anaphylaxis has appeared, but only after years of continuous vitamin administration. 10.Folic acid Long-term folic acid therapy increased seizure frequency in some epileptic patients and may precipitate vitamin B12 deficiency neuropathy in some cases of megaloblastic anemia. Thank You