Drugs With Cardiotoxic Effects PDF

DRUGS WITH CARDIOTOXIC EFFECTS S. K. AMPONSAH 1/24/2022 1 INTRODUCTION Cardiotoxicity, which may be caused by drugs, includes a range of cardiac effects from changes in blood pressure, arrhythmias and cardiomyopathy. In literature, mechanisms of drug-inducedcardiotoxicity include cellular dam...

DRUGS WITH CARDIOTOXIC EFFECTS S. K. AMPONSAH 1/24/2022 1 INTRODUCTION Cardiotoxicity, which may be caused by drugs, includes a range of cardiac effects from changes in blood pressure, arrhythmias and cardiomyopathy. In literature, mechanisms of drug-inducedcardiotoxicity include cellular damage due to the formation of free oxygen radicals. Often, agents that cause cardiotoxicity are cytotoxic drugs. 1/24/2022 2 Introduction Cytotoxic drugs such as anthracyclines, are known to have cardiotoxic side effects. Their clinical use is often limited by this cardiotoxicity. Other cytotoxic drugs with cardiotoxic effects include the taxoids, 5-fluorouracil, cisplatin, and trastuzumab (monoclonal antibody). 1/24/2022 3 1. ANTHRACYCLINES Cardiotoxicity has been extensively reviewed with the use of anthracyclines. Anthracyclines have been reported to cause cardiomyopathy, congestive heart failure and ECG alterations. Both early and late onset cardiotoxic effects are reported. 1/24/2022 4 Anthracyclines Early onset effects occur within one year after start of the anthracycline therapy. In children, early onset cardiotoxicity seems to occur less frequently than late onset clinical cardiotoxicity. Late onset effects can occur up to 20 years after completion of anthracycline therapy. 1/24/2022 5 Risk factors ü ü ü ü ü The risk factors for anthracycline induced cardiotoxicity include; cumulative dose age concomitant administration with other chemotherapeutics underlying heart disease previous radiotherapy 1/24/2022 6 Risk factors Of the risk factors, cumulative dose seems to be the most important. The usual dosage of doxorubicin is 60 – 75 mg/m2 , every 3 weeks. Above a cumulative dose of 450 – 550 mg/ m2 , cardiomyopathy and congestive heart failure are likely to occur. 1/24/2022 7 Risk factors The maximum cumulative dose needed to obtain minimal cardiotoxicity varies among the different anthracyclines. With epirubicin, a lower frequency of cardiotoxicity occurs at therapeutic doses compared with doxorubicin. 1/24/2022 8 Mechanism of toxicity The most common hypothesis by which anthracyclines cause cardiotoxicity includes formation of free radicals and superoxides. This hypothesis is based on in vitro experiments and a few human ones. With the free radical theory, the reaction starts with one-electron reduction of doxorubicin that forms a doxorubicin-semiquinone radical. 1/24/2022 9 Mechanism of toxicity This semiquinone radical forms a complex with iron, leading to an anthracycline-iron (Fe2+) free radical complex. This complex reduces oxygen to yield superoxide. With the production of superoxide, lipid peroxidation may be initiated. 1/24/2022 10 Mechanism of toxicity Some studies also indicate that the myocardial damage caused by doxorubicin involves apoptosis. Another possible mechanism involves the influence of anthracyclines on the calcium homeostasis. Changes in calcium transport can lead to tissue injury, cell killing and impaired cardiac contraction. 1/24/2022 11 Mechanism of toxicity Involvement of an immunogenic reaction after oxidative stress is also an alternative mechanism. 1/24/2022 12 Monitoring and markers of cardiotoxicity Echocardiogram can be used to identify (sub)clinical myocardial dysfunction. Also, endomyocardial biopsy directly measures the presence and extent of fibrosis due to anthracycline cardiotoxicity. However, this biopsy is limited by its invasiveness, need for histologic expertise and costs. 1/24/2022 13 Monitoring and markers of cardiotoxicity Troponin T is indicative of myocardial cell damage and is currently used in the diagnosis and prognosis of myocardial ischemia. Elevated levels of Troponin T have been found in children treated with anthracyclines. Studies in adults have given conflicting results regarding Troponin T elevations. 1/24/2022 14 Prevention/management of anthracycline-induced cardiotoxicity Apart from cumulative dose limitations, a number of methods can prevent anthracycline-induced cardiotoxicity. Antioxidants used as free radical scavengers have been tested in clinical trials but without significant success. Considering the role of iron and the doxorubicin-iron complex, iron chelators have been developed to circumvent cardiotoxicity. 1/24/2022 15 Prevention/management of anthracycline-induced cardiotoxicity Dexrazoxane (an iron chelator) has been found to be a promising agent. Dexrazoxane can be administered intravenously either as a slow injection or fast infusion before doxorubicin is initiated. The dosage to be given is usually a 10-fold of the doxorubicin dose. 1/24/2022 16 Prevention/management of anthracycline-induced cardiotoxicity Lipid lowering agents also seem to be able to lower the cardiotoxic effects of anthracyclines. Another strategy used is the development of liposomal drug formulations of the anthracyclines. Preclinical studies have shown a decreased uptake of doxorubicin in cardiac muscle cells when a liposomal formulation are used. 1/24/2022 17 2. TAXOIDS The taxoids, paclitaxel and docetaxel, are important agents in the treatment of a variety of tumors. They have been found to have cardiotoxic adverse effects. During therapy with paclitaxel, various cardiac disturbances like brady- and tachyarrhythmias, AV block and cardiac ischemia can occur. 1/24/2022 18 Taxoids Hypotension is also reported, probably as a result of a hypersensitivity reaction. Another concern with the use of taxoids is development of congestive heart failure. The heart failure usually occurs in patients treated with a combination of doxorubicin and taxoids. 1/24/2022 19 Taxoids Risk factors of taxoid-induced cardiotoxicity include unstable angina, severe coronary artery disease, congestive heart failure and atrial fibrillation. However, a study in patients with cardiac risk factors revealed that paclitaxel could be safe if administered as single therapy. 1/24/2022 20 Mechanism of toxicity Paclitaxel is formulated in a cremophor EL vehicle to enhance drug solubility. It is suggested that the vehicle and not the drug itself is responsible for the cardiac disturbances. However, the cardiac rhythm disturbances are not reported with use of other drugs containing cremophor EL such as cyclosporin. 1/24/2022 21 Mechanism A possible mechanism is that the cremophor EL may cause massive histamine release. Indeed, stimulation of histamine receptors in cardiac tissue in animal studies has resulted in conduction disturbances and arrhythmias. An alternative explanation for paclitaxel cardiotoxicity could be damage via effects on subcellular organelles. 1/24/2022 22 Mechanism Enhanced cardiac toxicity has been found in combined therapy with doxorubicin. Generally, at doses of doxorubicin exceeding 380 mg/m2 , toxicity increases. A pharmacokinetic interaction appears to be responsible for this effect. 1/24/2022 23 Mechanism Paclitaxel has been found to decrease doxorubicin hepatic elimination. This, results in an increased plasma concentration of doxorubicin. 1/24/2022 24 Prevention/management of taxoidinduced cardiotoxicity When taxoids are combined with anthracyclines, the cumulative dose of the anthracycline should be lowered. Cumulative doses of doxorubicin up to 340 – 380 mg/m2 have been reported to be safe. 1/24/2022 25 3. 5-FLUOROURACIL The use of 5-fluorouracil (5-FU) is associated with myelosuppression, diarrhea, mucositis and dermatitis. Cardiotoxicity may also occur, and estimates of the incidence vary from 1% to 5%. Cardiotoxicity with 5-FU is usually described with continuous infusion and less with bolus injection. 1/24/2022 26 5-Fluorouracil Symptoms of 5-FU cardiotoxicity include cardiac arrhythmias, silent myocardial ischemia, angina and congestive heart failure. Risk factors include preexisting coronary artery disease and concurrent radiotherapy. 1/24/2022 27 Mechanism of toxicity The pathophysiological mechanism of 5-FU related cardiotoxicity is still unclear. Some of the hypotheses postulated include: vasospasms leading to ischemia, direct toxicity on the myocardium and activation of coagulation system. Others are: coronary artery thrombosis, immunoallergic phenomena and cardiotoxic impurities in the 5-FU formulation. 1/24/2022 28 4. CYCLOPHOSPHAMIDE AND IFOSFAMIDE Cyclophosphamide and ifosfamide are alkylating agents that need to be metabolized in vivo to form the active cytotoxic metabolites. High dose cyclophosphamide used in organ transplant regimen is often associated with acute cardiotoxicity. The incidence is estimated to range from 2% to 10%. 1/24/2022 29 Mechanism The exact mechanism is not fully understood but an increase in free oxygen radicals seems to play a role in this cardiotoxicity. 1/24/2022 30 5. CISPLATIN Cisplatin is a platinum substance used in the treatment of many tumors (e.g. testicular cancer). A number of cases of acute myocardial infarction after cisplatin therapy are reported. 1/24/2022 31 Mechanism Several factors suggested to be involved include vascular damage, alterations in platelet aggregation and hypomagnesemia. Activation of an arachidonic pathway in platelets by cisplatin seemed to be involved. 1/24/2022 32 DRUGS WITH TOXIC RENAL EFFECTS S. K. AMPONSAH 10/11/2017 1 INTRODUCTION The complex nature of critical illness often necessitates the use of multiple therapeutic agents. Many of these drugs may individually or in combination have the potential to cause renal injury. The incidence of drug-induced nephrotoxicity is well documented with a number of drugs. Drugs with direct nephrotoxic effects may induce renal injury by several mechanisms. 10/11/2017 2 Introduction Drug-induced renal impairment involves many classes of drugs: prescription agents and overthe-counter drugs. Some of these drugs include antimicrobials, NSAIDs, chemotherapeutic agents, etc. There are also drug-, kidney- and patient-specific risk factors that influence the development of drug-related nephropathy. 10/11/2017 3 1. Drug-specific risk factors Toxicity of therapeutic agents may be inherent in the pharmacological compound itself. This toxicity may be heightened in the kidney microenvironment. For example, the aim of chemotherapy is to kill malignant cells, however, healthy tissues, including renal parenchyma can be affected. 10/11/2017 4 2. Kidney-specific risk factors The kidney is a target for toxicity because it receives a significant percentage of cardiac output, exposing it to drugs and drug metabolites. The kidney also oxidizes drugs via CYP 450, and yield metabolites which could have direct effects on renal cells. 10/11/2017 5 Kidney-specific risk factors In addition, certain therapeutic agents may gain toxic potential within the kidney microenvironment. For example, methotrexate nephrotoxicity depends upon crystallization of the parent compound and its metabolites in renal tubules. This crystallization is highly favored with an acidic urine pH, which exists in the normal host. 10/11/2017 6 3. Patient-specific risk factors Certain patient characteristics can predispose one to drug-induced nephrotoxicity. Among these are; old age and being female. These individual have reduced muscle mass and low total body water. 10/11/2017 7 Patient-specific risk factors This reduced muscle mass would translate to a low serum creatinine. Depending on the type of estimation used, the GFR calculated may be false (high GFR), leading to inappropriately high drug dosing. Decreased total body water also increases the concentration of drug in serum. Both factors work in concert to raise serum drug concentration to potentially toxic levels. 10/11/2017 8 Patient-specific risk factors In addition, the risk of drug-induced nephrotoxicity is increased in the patient with acute or chronic kidney disease. Similarly, the patient with hepatic failure is susceptible to nephrotoxic effects of certain drugs. Hyperbilirubinemia is also a predictive factor for nephrotoxicity because of renal tubular damage from bile salts. 10/11/2017 9 Patient-specific risk factors Also populations at risk for drug-induced renal injury are neonates. Critically ill neonates using multiple nephrotoxic agents may be at a higher risk. 10/11/2017 10 NEPHROTOXIC DRUGS Drugs can impair renal function by interfering with renal blood flow, GFR, tubular fluid formation, and exit of urine. While many drugs have a single mechanism of injury, some classes of drugs possess multiple ways of inducing renal dysfunction. 10/11/2017 11 Nephrotoxic drugs Nephrotoxic drug classes include; ü antibacterials ü NSAIDs ü ACE inhibitors and angiotensin II receptor blockers ü antivirals ü antifungals ü chemotherapeutics agents 10/11/2017 12 1. ANTIBACTERIAL AGENTS Some antibacterial agents that posses nephrotoxic effects include: ü aminoglycosides ü sulfamethoxazole-trimethoprim and sulfa-based antibiotics ü vancomycin ü ciprofloxacin 10/11/2017 13 I. Aminoglycosides Aminoglycosides (AGs) are well known nephrotoxic and ototoxic agents. In spite of these risks, they are still widely used in the treatment of Gram-negative bacterial infections. Even at therapeutic doses, the incidence of nephrotoxicity is reported to be as high as 10% – 25%. 10/11/2017 14 Aminoglycosides Risk for nephrotoxicity is higher with prolonged duration of therapy. Neomycin is the most toxic drug in this group, followed by gentamicin, tobramycin, amikacin, and streptomycin. AGs actively concentrate in the renal cortex and proximal tubular cells. 10/11/2017 15 Aminoglycosides After entering the cortical cells AMGs bind to lysosomes with formation of myeloid bodies/secondary lysosomes. Thereafter, mechanisms are unclear. To prevent nephrotoxicity, drug doses should be calculated based on estimated creatinine clearance. Monitoring peak and trough serum AG levels would also minimize risk. 10/11/2017 16 II. Sulfamethoxazole–trimethoprim and sulfa-based antibiotics Sulfamethoxazole (SMX) is probably the most widely used sulfa-based antibiotic. It is generally prescribed along with synergistically acting trimethoprim (TMP) as a combination antimicrobial agent. SMX–TMP is known to possess renal adverse effects. 10/11/2017 17 SMX–TMP TMP inhibits proximal tubular secretion of creatinine and can result in elevation of measured serum creatinine. Also, the use of high-dose sulfadiazine can, on rare occasions, also cause crystal nephropathy. The overall incidence of SMX–TMP-associated renal disease is generally low. 10/11/2017 18 III. Vancomycin Vancomycin (VCM), a glycopeptide antibiotic, is commonly used in the critical care setting. VCM-related nephrotoxicity is generally due to acute tubular necrosis or acute interstitial nephritis. High trough levels (> 15 mg/L), long duration of therapy, and concomitant administration of other nephrotoxins (eg, AGs) are significant risk factors. 10/11/2017 19 Vancomycin Given its widespread use, clinicians should be aware of this risk and should monitor patients for development of nephrotoxicity. In patients with chronic kidney disease, the dosing should be strictly based on estimated creatinine clearance. 10/11/2017 20 IV. Ciprofloxacin Ciprofloxacin, a commonly prescribed fluoroquinolone has been reported to cause acute interstitial nephritis and crystalluria. Ciprofloxacin crystallizes in alkaline urine. Crystallization could be avoided by making sure patients are volume replete. 10/11/2017 21 2. NSAIDs NSAIDs are widely used to relieve pain and signs of inflammation. Prostaglandin (PG) inhibition mediated by NSAIDs explains many of its renal complications. Endogenous PGs play a significant role in maintaining normal renal physiology. 10/11/2017 22 NSAIDs PG-induced renal vasodilation is critical for maintaining adequate renal perfusion. NSAIDs impair this renal vasodilation and alter renal hemodynamics. Acute kidney injury can occur with either nonselective NSAIDs or selective (COX-2-specific) NSAIDs. 10/11/2017 23 NSAIDs PGs have also been shown to play a role in stimulating renin and angiotensin-mediated aldosterone release. Thus, NSAID-mediated PG inhibition can result in hyperkalemia and metabolic acidosis. 10/11/2017 24 3. ACE inhibitors and angiotensin II receptor blockers (ARB) These groups of drugs are widely used in the treatment of hypertension and CHF. Angiotensin II constricts both the afferent and efferent arterioles, but the effect is more pronounced on the efferent arteriole. The net effect of angiotensin II is an increased intra-glomerular pressure. 10/11/2017 25 ACE inhibitors and ARBs ACE inhibitors and ARBs antagonize the activity of angiotensin II, thereby interfering with the renal autoregulation of GFR. In certain situations the loss of autoregulation could precipitate acute kidney injury. 10/11/2017 26 4. ANTIVIRAL AGENTS Some antivirals that posses nephrotoxic effects include: ü acyclovir ü foscanet ü antiretroviral drugs 10/11/2017 27 I. Acyclovir High-dose IV acyclovir can induce acute kidney injury secondary to crystal precipitation in the renal tubules. Nephrotoxicity can be prevented by low-dose infusion, and slower rate of infusion. 10/11/2017 28 II. Foscanet Foscarnet is nephrotoxic by inciting acute kidney injury. Foscarnet can also cause significant electrolyte abnormalities. Foscarnet can result in symptomatic hypocalcemia by chelating free (ionized) calcium. 10/11/2017 29 III. Antiretroviral drugs The most prominent of the nephrotoxic antiretroviral agents is tenofovir, a nucleoside reverse transcriptase inhibitor. This agent can cause acute kidney injury with or without proximal tubulopathy. Acute kidney injury results from direct toxicity to tubular cells. 10/11/2017 30 Antiretroviral drugs Protease inhibitors, another class of antiretroviral drugs, can also be nephrotoxic. Indinavir, a once-prominent protease inhibitor, can crystallize in renal tubules, resulting in crystal-related kidney injury. 10/11/2017 31 5. ANTIFUNGAL AGENTS Amphotericin B (AmB) is an agent used in the treatment of life-threatening fungal infections. AmB is available for use in two forms: a conventional form and the more recent liposomal form. Liposomal AmB has an improved renal safety profile compared to conventional AmB. 10/11/2017 32 Antifungal agents The antifungal effect of AmB is related to its ability to alter membrane permeability of fungal cells, which leads to death. This effect can be toxic to renal tubular cells and result in tubular dysfunction. 10/11/2017 33 6. CHEMOTHERAPEUTIC AGENTS Chemotherapeutic drugs play a central role in the treatment of various neoplasms. Unfortunately, they can result in serious multisystem complications. Nephrotoxicity is common with many chemotherapeutic agents. 10/11/2017 34 Chemotherapeutic agents Some of the commonly used chemotherapeutic agents with nephrotoxic side effect include: ü cisplatin ü ifosfamide ü methotrexate 10/11/2017 35 I. Cisplatin Cisplatin is a standard component in the treatment regimens for various solid organ tumors. Cisplatin use can result in a variety of clinical renal syndromes: acute kidney injury, hypocalcemia, and hyponatremia. The main mechanism for causing acute kidney injury is a direct cellular toxic effect at the proximal tubule. 10/11/2017 36 Cisplatin Various strategies, such as co-administration of hypertonic saline and sodium thiosulfate, have been tried to prevent cisplatin nephrotoxicity. Kidney function and serum electrolytes should be monitored during cisplatin therapy to detect metabolic abnormalities. 10/11/2017 37 II. Ifosfamide Ifosfamide is an alkylating agent used in the treatment of solid organ tumors. Like cisplatin, ifosfamide also undergoes cellular uptake at the proximal tubule. Once inside the cell, the drug is then metabolized into chloroacetaldehyde, which is chiefly responsible for cellular toxicity. 10/11/2017 38 III. Methotrexate (MTX) MTX is an antifolate agent widely used as chemotherapy against several malignancies. MTX-induced kidney injury occurs after an IV administration of a high-dose (1,000 – 33,000 mg/m2 ). This results from crystallization in the renal tubules, as well as direct tubular toxicity. 10/11/2017 39 Methotrexate (MTX) The crystallization is enhanced by high urinary MTX concentration and low urine volume. Preventive strategies include maintaining high urine output and urinary alkalinization. 10/11/2017 40 DRUGS WITH HEPATOTOXIC EFFECTS S. K. AMPONSAH 1/25/2022 1 INTRODUCTION Drug-induced liver toxicity is a common cause of liver injury. It accounts for approximately one-half of the cases of acute liver failure and mimics all forms of acute and chronic liver disease. More than 900 drugs have been implicated in causing liver injury. 1/25/2022 2 Introduction It is the most common reason for a drug to be withdrawn from the market. Most often, these drugs tend to cause acute hepatitis, cholestasis, or a combination of conditions. The clinical picture often resembles acute viral hepatitis with jaundice, malaise, anorexia, nausea, and abdominal pain. 1/25/2022 3 PATHOGENESIS The pathogenesis of drug-induced liver injury usually involves the participation of a toxic drug or its metabolite. This either elicits an immune response or directly affects the biochemistry of the cell. In each case, the resultant cell death leads to the clinical manifestation of hepatitis. 1/25/2022 4 Pathogenesis Drug metabolites can be free radicals that promote a variety of chemical reactions. This could result in depletion of reduced glutathione or induce lipid peroxidation. All of these have consequent direct effects on organelles such as mitochondria, endoplasmic reticulum or the nucleus. 1/25/2022 5 Pathogenesis In addition, sensitization to liver-specific cytokines can also occur, thereby causing cytokine-induced hepatotoxicity. Alternatively, the parent drug or reactive metabolite may alter liver proteins, such as CYP450 enzymes, leading to an immune-mediated injury. 1/25/2022 6 RISK FACTORS The risk of drug-induced hepatotoxicity involves a complex interplay of factors. These include: chemical properties of the drug, concomitant use of drugs or alcohol, age, genetic factors and underlying diseases. The most documented risk factors are concomitant drug use and underlying diseases. 1/25/2022 7 Risk factors There is evidence for an increase in druginduced liver disease among patients with HIV and hepatitis C. Genetic factors often include genes that control drug metabolism, and transport. 1/25/2022 8 MECHANISMS OF DRUG-INDUCED LIVER DAMAGE Certain drugs will produce predictable liver damage in a majority of cases. Others however will cause liver injury only rarely and unpredictably. There is thus a whole spectrum varying between these extremes. 1/25/2022 9 Mechanisms of drug-induced liver damage In some cases the mechanism may involve parent compound, and in others a metabolite. Direct cytotoxicity is known to be a most common cause of liver damage. 1/25/2022 10 Mechanisms of drug-induced liver damage ü ü ü ü Other mechanisms may include: Interference with bilirubin uptake, excretion and conjugation Cholestatic injury Fatty liver (steatosis) Chronic hepatitis 1/25/2022 11 1. Direct cytotoxic injury Direct damage to hepatic parenchyma may be caused by a number of drugs. Acetaminophen causes predictable centrilobular hepatic necrosis. Doses of 10 g may lead to liver damage, and doses greater than 15 g may be sufficient for fatal hepatic damage. 1/25/2022 12 Cytotoxic injury Liver damage may be detected by raised serum transaminases, AST and ALT. Bilirubin levels may be only moderately elevated. This liver damage is due to direct cytotoxic effects of a metabolite of acetaminophen. 1/25/2022 13 Cytotoxic injury Acetaminophen is metabolized via three pathways, two of which are conjugation reactions. A minor pathway catalyzed by the microsomal enzymes yields a reactive metabolite, N-acetyl-p-benzoquinoneimine. Following normal doses, this metabolite is conjugated to glutathione, and excreted as the N-acetylcysteine derivative in the urine. 1/25/2022 14 Cytotoxic injury During high doses of acetaminophen, glutathione levels get depleted. The reactive metabolite then reacts covalently with cellular macromolecules, causing damage. The mechanism by which this binding causes cellular damage remains unknown. 1/25/2022 15 Cytotoxic injury Halothane, a general anesthetic, is also known to cause direct hepatic injury. The majority of cases of halothane-induced hepatic injury (more than 80%) occur in patients after more than one exposure. This halothane-induced liver injury often presents as a syndrome. 1/25/2022 16 Cytotoxic injury The syndrome may include fever and myalgia, but arthralgia and rash are rare. It has been suggested that there are two forms of hepatic injury from halothane. There is a mild form with slightly raised serum transaminases and perhaps mild necrosis. 1/25/2022 17 Cytotoxic injury Then there is a more serious form which leads to massive hepatic necrosis and death in some cases. It is suggested that this latter severe form has an immunological basis, whereas the more mild form is due to the direct cytotoxicity. 1/25/2022 18 2. Interference with bilirubin uptake, conjugation and excretion A number of drugs interfere with bilirubin transport. This leads to elevated plasma bilirubin (hyperbilirubinaemia). Rifampicin, used in the treatment of tuberculosis, inhibits both uptake and excretion of bilirubin in a dose related manner. 1/25/2022 19 Interference with bilirubin transport This gives rise to elevated plasma levels of both conjugated and unconjugated bilirubin. Other effects of rifampicin include interference with DNA synthesis and the ability to induce hepatic microsomal enzymes. These two effects, however, are not thought to be responsible for hepatic damage. 1/25/2022 20 3. Cholestatic injury Chlorpromazine, a tranquilizer, is an important cause of drug-induced jaundice. The incidence is estimated at between 0.5 and 1% of recipients of therapeutic doses. Jaundice commonly develops after 3 weeks of therapy, with often the development of fever, itching, abdominal pain, nausea and anorexia. 1/25/2022 21 Cholestatic injury This is often similar to extrahepatic obstructive jaundice, with elevated serum cholesterol and alkaline phosphatase (more than 4 times normal). The lesion is generally one of cholestasis particularly in the centrilobular region. There may also be scattered areas of focal necrosis. 1/25/2022 22 Cholestatic injury Chlorpromazine clearly has a number of effects on membranes and on transport mechanisms. It is probable that its primary site of injury is the bile ductules. The actual mechanism however remains unclear. 1/25/2022 23 Cholestatic injury Steroids with alkyl group at C17, such as methyltestosterone, may also be hepatotoxic. This is normally a cholestatic injury generally without parenchymal damage. The degree of injury and rate of development seem to be dependent on dose. 1/25/2022 24 4. Fatty liver (steatosis) Tetracycline occasionally causes fatty liver after large IV doses. This toxic effect is rare after oral doses, and occurs more commonly in females than males. Biochemically, the changes may only be slight, with moderate elevations of aspartate transaminase (AST). 1/25/2022 25 Fatty liver Bilirubin levels are usually only moderately elevated. This toxic effect of tetracycline is direct, predictable and dose dependent. 1/25/2022 26 5. Chronic active hepatitis and subacute necrosis The anti-tubercular drug isoniazid can cause hepatic dysfunction in a significant proportion of recipients. The syndrome of isoniazid-induced hepatic damage is similar to viral hepatitis. Usually, AST and ALT levels are elevated (up to 10-20 times normal). 1/25/2022 27 Chronic active hepatitis and subacute necrosis Histologically, necrosis ranges from focal to massive, and cholestasis may at times be very significant. There are a number of predisposing factors for isoniazid-induced hepatic damage. Pre-existing liver dysfunction, such as alcoholic cirrhosis, increases susceptibility. 1/25/2022 28 Chronic active hepatitis and subacute necrosis Studies reveal that Asian males are more susceptible to isoniazid induced hepatic disease than white males. Also, black males are markedly less susceptible. An important factor for isoniazid-induced hepatic damage is the acetylator phenotype. 1/25/2022 29 Chronic active hepatitis and subacute necrosis Isoniazid is metabolized by several routes, acetylation being a major one. There are well known genetic and ethnic effects with this reaction. Thus, human subjects may be divided into rapid and slow acetylators. 1/25/2022 30 Chronic active hepatitis and subacute necrosis The mechanism of isoniazid induced hepatic damage involves production of a toxic metabolite. Data suggests that rapid acetylation might be a predisposing factor as this would produce more of the metabolite acetylisoniazid and hence more acetyl-hydrazine. 1/25/2022 31 Chronic active hepatitis and subacute necrosis These metabolites are extremely hepatotoxic causing centrilobular hepatic necrosis. The relatively high incidence of hepatic dysfunction associated with isoniazid has curtailed its prophylactic use. 1/25/2022 32