Disposition of Toxic Compounds PDF

TOXICOLOGY DISPOSITION OF TOXIC COMPOUNDS: It is a process by which toxicants cross body membrane and enter bloodstream by absorption. There is no specific system or pathways for the absorption of toxicants. Xenobiotics penetrate membrane during absorption via same process as the biologically essen...

TOXICOLOGY DISPOSITION OF TOXIC COMPOUNDS: It is a process by which toxicants cross body membrane and enter bloodstream by absorption. There is no specific system or pathways for the absorption of toxicants. Xenobiotics penetrate membrane during absorption via same process as the biologically essential substances such as oxygen, food stuff and other nutrients are absorbed. The main sites of absorption are GI, lungs and skin. The structure of biological membrane determines the function and characteristic. The most important feature from a toxicological point of view is that they are selectively permeable. Only certain substances are able to pass through them depending on particular physic-chemical characteristics including size, lipid solubility, similarity to endogenous molecule, polarity or charge. Foreign substances pass through biological membrane by: FILTRATION THROUGH PORES: Small molecules may pass through pores or membranes formed by protein. This movement occurs down the concentration gradient. Examples are urea and ethanol. PASSIVE DIFFUSION: It is the most important mechanism for absorption of foreign and toxic compounds. For passive diffusion certain condition are required. There must be concentration gradient across the membrane Foreign molecule must be lipid soluble Compound must be unionized ACTIVE TRANSPORTATION: Active transportation of compound across membrane have several important features. The specific membrane carrier is required The process may be inhibited by metabolic poison The process may be saturated at high substrate concentration. Hence, it is zero order rather than first order. This type of membrane transport is specific for endogenous and nutrient substances but analogue and similar molecules or ions may be transported by this system. Example is fluorouracil and other analogues of uracil and lead ions are absorbed from the gut by specific transport system. FACILITATED DIFFUSION: Specific membrane carrier is required for it. Specific concentration gradient across the membrane is necessary. The process may be saturated by high substrate concentration. PHAGOCYTOSIS AND PINOCYTOSIS: Phagocytosis and pinocytosis is Invagination of the membrane to enclose particle or droplet, respectively. This is a mechanism by which particle of insoluble substance such as uranium dioxide or asbestos are absorbed in lungs. August 7, 2013 ABSORPTION OF TOXICANTS VIA GIT: Many environmental toxicants enter the food chain and are absorbed together with food from GIT. If the toxicant is an organic acid or base, then it is absorbed by simple diffusion through specific part of GIT. Some absorbed from stomach rest from intestine depending on pH. Molecules are absorbed when they are in lipid soluble unionized form. Lipid solubility of weak acid and weak base is different in stomach. In stomach, gastric juice is acidic and absorption can be determined by Henderson Hassel Balch equation. As weak organic acid is present in stomach in unionized form, so it is more lipid soluble and rate of absorption increases. [𝐴− ] 𝑝𝐻 = 𝑝𝐾𝑎 + log [𝐻𝐴] In the intestine, intestinal content are neutral. If benzoic acid is present in intestine in lipid soluble form, so the rate of absorption is considered slow and less. Henderson equation is interpreted on the basis of some factors: Mass action law- According to it equilibrium will always be maintained 1% on unionized form, provided that there is constant availability of benzoic acid Surface area- simple diffusion is directly proportional to the surface area. More surface area, more is the absorption. Small intestine contains villi and microvilli and consists of approximately 600 folds. Blood flow rate ABSORPTION OF TOXICANTS VIA LUNGS: It is well known that toxic responses of chemical results from absorption after inhalation. Frequent death due are reported due to CO and occupational diseases, cyanosis and both due to absorption and distribution of air borne toxicants via lung. Toxicants absorbed via lungs are usually gases like CO, vapors of volatile or volatilized liquids (methylene chloride), aerosol and particulate matter (asbestos). In Urban or home environment gases such as sulfur dioxide, nitrogen dioxide fiber glass, colon, solvent vapor and aerosol are present. Lungs have large surface area i.e. around 50-100 m3. They have excellent blood supply. The barrier between air in the alveolus and blood stream may be as little as two cell membranes thick. Rapid rate of blood flow means that foreign substances are continuously removed from absorption site and there is always concentration gradient. HEMATOTOXICITY: Hematotoxicity is the study of adverse effects of drugs and non-therapeutic chemicals and another agent in environment on blood and blood forming tissues. Various blood cells are produced at the rate of approximately 1-3 million in healthy adults and up to several times of this rate in conditions where demand for the these cells is high as in case of hemolytic anemia or in inflammation. Direct or indirect damage to the blood cells and their precursor are predictable and potentially life threatening. They include hypoxia, hemorrhage and infection. Erythrocyte production is a continuous process that is dependent on frequent cell division and high rate of hemoglobin synthesis. Adult hemoglobin HbA is composed of two alpha and two beta chains. Synthesis of hemoglobin is dependent on production of globin chain and heme moiety. Abnormalities that lead to decrease in hemoglobin synthesis and imbalance between alpha and beta chain production are the basis for congenital thalassemia. It results in decrease hemoglobin production and microcytosis. Xenobiotics can affect globin synthesis and alter the composition of hemoglobin within erythrocyte. Synthesis of heme molecule requires incorporation of iron into a Porphyrin ring. Iron deficiency is usually the result of dietary deficiency or increased blood loss. Any drug that contributes to blood loss such as NSAIDs, with their increased risk of gastro-intestinal ulceration and bleeding may potentiate risk of developing iron deficiency anemia. Defects in the synthesis of Porphyrin ring of heme can lead to sideroblastic anemia, a nucleated molecule containing iron in it. Cytoplasmic mitochondria can lead to cytoplasmic anemia and accumulation of iron in bone marrow to form erythroblast. Accumulated iron precipitates within mitochondria and cause intracellular injury. Xenobiotics associated with cytoplasmic anemia are ethanol, isoniazid (INH), cycloserine, hydrazine amide and chloramphenicol. Folate and vitamin B12 are necessary to main synthesis of thymidine in DNA. Deficiency of folate and vitamin B12 results in megaloblastic anemia. Para-aminosalicylic acid, neomycin, ethanol, omeprazole and zidovudinecontribute in a deficiency of vitamin B12. Phenytoin, carbamazepine, phenobarbital and sulfasalazine contribute in deficiency of folate. Pure red cell aplasia is a syndrome of bone marrow. A number of drugs have been indicated in the development of red cell aplasia like isoniazid, phenytoin, azathioprine, cimetidine and sulfonamide. Hemoglobin is necessary for effective transport of oxygen and carbondioxide between lungs and tissues. Some xenobiotics hence decrease binding affinity with hemoglobin and oxidation of heme iron to ferric state to form methemoglobin. It is not capable of binding and transporting oxygen. Most common cause of methemoglobinemia is exposure to oxidizing xenobiotics and therapeutic agents like benzocaine, lidocaine, dapsone, nitroglycerin and sulfonamide. Environmental agents including nitrate, nitrite, nitrobenzene and gasoline. TOXICOLOGY OF LEUKOCYTES: Ethanol and glucocorticoids can impair phagocytosis and microbe ingestion. Components of radiographic contrast media have also been reported to inhibit phagocytosis including iohexol. Hemotaxis is also impaired with the treatment of zinc salt in anti-acne preparation. Most alkylating agents used in cancer chemotherapy can cause acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) including cyclophosphamide, melphalan, busulfan, chlorambucil, and nitrous urea compound. The incidence of MDS and AML in patients treated with alkylating agents has been reported to be 0.6-17 %. Exposure to high dose ɣ or x-ray radiation is associated with acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML) was reported in survivors of atomic bombing. Other agents include non-ionizing radiation such as electromagnetic, microwave, infrared and high end of UV spectrum may cause leukemia, but it is difficult to interpret dose response. TOXICOLOGY OF PLATELETS: Platelets are essential for the formation of stable hemostatic plaque in response to vascular injury. Platelets initially adhere to the damaged wall through binding of VWF with the platelet glycoprotein. Xenobiotics may interfere with the platelet response by causing thrombocytopenia or interfering with platelet function. Some agents are capable of affecting both platelet number and function. Thrombocytopenia is may be due to decrease production or increase destruction of platelet. Thrombocytopenia is common side-effect of chemotherapy. Few agents including thiazide diuretics, diethylstilbestrol and procarbazine have been associated with isolated suppression of thrombopoiesis. Thrombotic thrombocytopenic purpura (TTP) is a syndrome characterized by the onset of sudden thrombocytopenia involving small blood vessels likemicroangiopathic hemolytic anemia and multi- system organ failure which often include neurological dysfunction. Syndrome tends to occur due to some pharmacological agents. Development of TTP or TTP like syndrome has been associated with drugs such as ticlopidine, cocaine, mitomycin and cyclosporine. The hemolytic uremic syndrome (HUS) is a disorder characterized by clinical features with microangiopathic hemolytic anemia, thrombocytopenia and renal failure. Neurological complications tend to be less severe while renal failure often dominates the clinical features. HUS has been linked to infection with E.Coli but it may also occur during therapy with some drugs including mitomycin and desmopressin. These increase platelet destruction which induces 2-5 folds increase in the plasma concentration of VWF and factor VIII. It is commonly used in the treatment of patient with VWF disease and mild bleeding syndrome. September 4, 2013 Desmopressin has been associated with the thrombocytopenia. In some patients with type 2B VWB disease, thrombocytopenia in such cases is related to the release of an abnormal VWF from endothelial cells. A variety of drugs and foods have been found to inhibit platelet function. Major drug groups that affect platelet function include NSAIDs, β-lactam containing antibiotics, β-blockers, anesthetics, antihistamines and chemotherapeutic agents. Xenobiotics may interfere with platelet function through variety of functions. Some inhibit phospholipase A2 or cyclooxygenase pathway and synthesis of thromboxane A2 such as NSAIDs. Other agents appear to interfere in the interaction between platelet agonist and their receptor. For example, antibiotic as platelet response depend on rapid increase in cytoplasmic calcium. Any agents can interfere with translocation of calcium may inhibit platelet function such as CCBs. Drugs which induce antibodies (like penicillin, heparin) and bind with platelet receptor and inhibit the function. The functional effect induce such antibodies may initiate the bleeding risk associated with xenobiotics induced thrombocytopenia. TOXIC EFFECTS OF FIBRIN CLOT FORMATION: It is result of sequential activation of series of serine protease. Thrombocytopenia is multifunctional enzyme convert fibrinogen to fibrin. Activated factor VI, VIII, XI, XIII, XIV and platelet and interact with variety of cells, leukocytes and endothelial cell. Most common effect of xenobiotics on fibrin clot formation is related to decrease level of one or more protein necessary for this process. Reduction in clotting factor activity may be due to reduced synthesis of the protein or increased clearance from the circulation. The majority of proteins involved in the coagulation are synthesized in the liver. Any agent that impairs liver function may cause decrease in production of coagulation factor like factor II, VII, IX and X are dependent on vitamin K for their complete synthesis. Anything that interfere with vitamin K metabolism may lead to deficiency of factors and bleeding tendency may occur with agents that interfere with absorption of vitamin K from intestine or an agent that interferes with reduction of vitamin K epoxide. The combination of antibiotic therapy and limited oral intake is the common cause of required deficiency of vitamin K dependent proteins. Warfarin, cephalosporin, dietary deficiency and super rodenticide are another cause of vitamin K deficiency. These agents have very prolonged half-life. Effect may persist for weeks or months following exposure. Rodenticide exposure may occur accidentally. September 18, 2013 Anything that interferes with vitamin K metabolism may lead to deficiency of factor II, VII, IX and X. This may occur with agents that interfere with the absorption of vitamin K from intestine or with agents that interfere with the reduction of vitamin K epoxide. Toxicological agents used to modulate hemostasis. Patients with bleeding and thrombotic problems are commonly encountered with variety of agents available to treat such patients. Oral anticoagulants like warfarin interfere with vitamin K metabolism by preventing the reduction of vitamin K epoxide, resulting in functional deficiency of reduced vitamin K. These agents are widely used for prophylaxis and therapy of venous and arterial thrombosis. Various xenobiotics including food have been found to affect the response of oral anticoagulants. The most common mechanism of interference of oral anticoagulant is mediated by cytochrome 2C9. Heparin is widely used anticoagulant for both prophylaxis and therapy of acute venous thromboembolism. Long term administration of heparin is associated with an increased risk of clinically significant osteoporosis. Heparin administration may cause a rise in enzyme called serum transaminase. This change may suggest significant liver dysfunction. Fibrinolytic agents are used in treatment of thromboembolic diseases with goal of resolving pathogenic thrombus. Complications associated with fibrinolysis are thrombosis at the site of pathogenic thrombus. Allergic reactions also occur with other fibrinolytic agents containing streptokinase. Acute allergic reactions may occur in 1-5% of patients exposed to streptokinase such as fever and life threatening anaphylactic reactions. Inhibitors of fibrinolysis are commonly used to control bleeding in patients with congenital abnormalities of hemostasis such as Von Willebrand Disease (VWD). Tranexamic acid and amino- caproic acid are small molecules that belong to binding of plasminogen and plasmin to fibrin and another substrate protein through interaction with lysine binding sites on plasminogen. Protamine is naturally occurring polypeptide inhibitor given IV infusion, as it is inactive when given orally. Allergic reactions that are reported, ranges from minor cutaneous manifestation to anaphylactic reactions. TOXICITY OF LIVER: Venous blood from the stomach and intestine flows into the portal vein and then to the liver before entering the systemic circulation. Liver is the first organ to encounter injected nutrients, vitamins, metals, drugs and environmental toxicants as well as waste products of bacteria that enter portal blood. All of the major functions of liver altered by acute or chronic exposure to toxicants. When toxicants inhibit hepatic transport and synthetic precursor, this function occurs without cell damage. Loss of function of liver occur when occur when toxicants kill number of hepatocytes. Alcohol abuse is the major cause of lover damage. Early stage of ethanol abuse or characterize by lipid accumulation or fatty liver due to unavailability to synthesize lipoprotein that transport lipid out of liver. As alcohol induce liver disease, it progresses to most of the hepatocyte cell death occur. The functioning mass of the liver is replaced by scar tissue and hepatic capacity of biotransformation of certain drugs progressively decline. Uncontrollable hemorrhage due to insufficient clotting factor is a common fatal indication of alcoholic cirrhosis. Liver is divided into hexagonal lobules oriented around terminal hepatic venules, also known as central vein. Apicom of lobules is portal tract or triad, containing a branch of portal vein, hepatic arteriole and a bile duct. A unit of hepatic acinus has three zones Zone 1: closest to the entry of blood Zone 2: is intermediate Zone 3: closest to terminal hepatic vein BILE: Bile is a yellow fluid containing bile salt, glutathione, phospholipid, cholesterol, bilirubin and other organic anions, proteins, metals and xenobiotics. Hepatic response by chemical depends on the intensity of population of cells affected whether the exposure is acute or chronic. Acute poisoning with carbon tetrachloride (CCl4)causes rapid lipid accumulation before necrosis, some chemical produce a very specific type of damage especially ethanol produce sequential type of damage or combination of damages. FATTY LIVER: This change is also known as steatosis. Increase in hepatic lipid content which is more than 5% by weight in normal human liver. Hepatocytes containing excess fats appear to the multiple round empty vacuoles that displace the nucleus periphery. Over supply of free fatty acid to the liver interfere with triglyceride cycle and increase the synthesis or esterification of fatty acid. Decrease fatty oxidation, decrease lipoprotein synthesis and decrease synthesis or secretion of very low density lipoprotein. Steatosis is a common response of acute exposure to all hepatotoxins. CCl4, ethanol, valproic acid are the common compounds causing hepatotoxicity. HEPATOTOXIC AGENTS: AFLATOXIN: Naturally, occurring mycotoxins (secondary metabolic product produced by organism of fungi) that are produced by Aspergillusflavus and Aspergillusparasiticus. After entering the body aflatoxin may be metabolized by the liver to a reactive epoxide, intermediate of hydroxylated form to become the less harmful aflatoxin M1. At least 14 different aflatoxins are produced in nature. Aflatoxin b1 is considered the most toxic and is produced by A. flavus and A. parasiticus. Aflatoxin producing members of aspergillus are common and wide-spread in nature. They can colonize and contaminate grain before harvesting or storage. Prolong exposure to high humidity environment or damage from stressful condition. Toxicity can also be found in the milk of animal. Source of commercial products like peanut butter, cooking oil and cosmetics have been identified to be contaminated with aflatoxin. FDA had established action level for aflatoxin present in the food or feed to protect human and animal health which ranges between 20 and 300 parts/billion. High level aflatoxin exposure produces an acute hepatic necrosis resulting in cirrhosis or carcinoma of the liver. Acute hepatic failure is manifested by edema, hemorrhage, alteration in digestion, absorption and metabolism of nutrients and mental changes. Regular diet including apiaceous vegetables (family apiaceae) carrot, parsley may decrease the carcinogenic effects of aflatoxin. Aflatoxin B1 can permeate the skin. Dermal exposure to B1 in particular environmental condition can lead to serious health risk because aflatoxin B1 can lead to serious health risk because aflatoxin b1 can cause immune suppression. Some studies show significant relationship between exposure of aflatoxin B1 (4 mg/kg) can cause teratogenicity. Two principle techniques that have been used most often to detect levels of aflatoxin in human 1st method is to measure aflatoxin B1 in patient’s urine. Presence of breakdown product indicates exposure of aflatoxin B1 product in 24 h urine. Another techniqueused is to determine aflatoxin B1 albumin in blood serum α-AMANITIN: Toxin found in several species of amanita genus of mushroom. LD50 is 0.1 mg/kg. α-amanitin is inhibitor of RNA polymerase can also be used to determine which type of RNA-polymerase is present. This is done by testing the sensitivity of polymerase in the presence of α-amanitin. RNA polymerase I is insensitive, II is highly sensitivity inhibited at 1 mcg/mL, III is moderately sensitive and inhibited at 10 mcg/mL, Iv us slightly sensitive and inhibited at 50 mcg/mL. NEPHROTOXICITY: It is a poisonous effect of some substances like toxic chemicals and medication. There are various forms of toxicity. Nephrotoxic effects of most of drugs are profound in patients already suffering from renal impairment (direct tubular effects including proximal convoluted tubule, distil tubule and tubular obstruction), acute interstitial nephritis, chronic interstitial nephritis, acute glomerular nephritis. In proximal convoluted tubule nephrotoxic agents are aminoglycosides like gentamicin, amphotericin B, cisplatin, radio contrast media, immunoglobulin and NSAIDs. Agents affecting distil tubule are NSAIDs such as aspirin, ibuprofen, diclofenac, ACEIs, cyclosporine, lithium salts, cyclophosphamide and amphotericin B. Tubular obstruction is caused by sulfonamide, methotrexate, polyethylene glycol and triamterene. Acute interstitial nephritis is a form of nephritis affecting the interstitium of the kidneys surrounding the tubules. Agents involved in this type of toxicity are β-lactam antibiotics, vancomycin, rifampicin, sulfonamide, ciprofloxacin, NSAIDs, ranitidine, cimetidine, furosemide, thiazide and phenytoin. Chronic interstitial nephritis occur due to lithium salt, cyclosporine, acute glomerular nephritis, gold salt therapy, heroine and penicillin amide. NEPHROTOXIC AGENTS: NSAIDs: NSAIDs are a class of medication used for analgesic and anti-inflammatory benefits. NSAIDs can induce several different forms of kidney injuries including hemodynamically mediated acute kidney injury (AKI). Electrolyte and acid-base disorder, acute interstitial nephritis (AIN) followed by nephrotic syndrome and papillary necrosis. NSAIDs are also associated with relatively high incidence of renal adverse drug reactions. Most of these ADRs are due to change in renal hemodynamics or kidney blood flow, which is mediated by prostaglandins and are affected by NSAIDs. Prostaglandin normally causes vasodilation of afferent arterioles of the glomeruli. This helps in maintaining normal glomerular perfusion and GFR and indicates renal function. This is particularly important in renal function where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated level angiotensin II also causes the afferent arteriole into the glomeruli in addition to the efferent arteriole it normally constrict. Prostaglandin serve to dilate the afferent arteriole by blocking the prostaglandin mediated effect particularly in renal failure. NSAIDs cause unopposed constriction of the afferent arteriole and decrease renal perfusion pressure. Normal ADR associated with altered renal function include salt especially sodium and fluid retention and hypertension. These agents may also cause renal impairment especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also taking ACEI which remove angiotensin II and vasoconstriction of the efferent arteriole and diuretics. In rare condition NSAIDs may also cause more severe renal conditions including interstitial nephritis, nephrotic syndrome, acute renal failure and acute tubular necrosis. In combination with excessive use of penicillin and paracetamol may lead to analgesic nephropathy.