Review article: drug hepatotoxicity

Background Drug toxicity is the leading cause of acute liver failure in the United States. Further understanding of hepatotoxicity is becoming increasingly important as more drugs come to market. Aims (i) To provide an update on recent advances in our understanding of hepatotoxicity of select commonly used drug classes. (ii) To assess the safety of these medications in patients with pre‐existing liver disease and in the post‐liver transplant setting. (iii) To review relevant advances in toxicogenomics which contribute to the current understanding of hepatotoxic drugs. Methods A Medline search was performed to identify relevant literature using search terms including ‘drug toxicity, hepatotoxicity, statins, thiazolidinediones, antibiotics, antiretroviral drugs and toxicogenomics’. Results Amoxicillin‐clavulanic acid is one of the most frequently implicated causes of drug‐induced liver injury worldwide. Statins rarely cause clinically significant liver injury, even in patients with underlying liver disease. Newer thiazolidinediones are not associated with the degree of liver toxicity observed with troglitazone. Careful monitoring for liver toxicity is warranted in patients who are taking antiretrovirals, especially patients who are co‐infected with hepatitis B and C. Genetic polymorphisms among enzymes involved in drug metabolism and HLA types may account for some of the differences in individual susceptibility to drug hepatotoxicity. Conclusions Drug‐induced hepatotoxicity will remain a problem that carries both clinical and regulatory significance as long as new drugs continue to enter the market. Future results from ongoing multicentre collaborative efforts may help contribute to our current understanding of hepatotoxicity associated with drugs.     

Important drug interactions in patients with rheumatic disorders: interactions of glucocorticoids, immunosuppressants and antimalarial drugs

Despite the fact that biological treatments are very promising, classical immunosuppressants, antimalarial drugs and glucocorticosteroids are still very important and widely used in practice. Although drug interactions can have fatal consequences, few studies have reviewed drug interactions of these classical drugs used in rheumatology, and very few guidelines are available on this subject. Therefore, this report summarizes important interactions of immunosuppressants, antimalarial drugs and glucocorticosteroids with drugs commonly used in internal medicine. In the present study, more than 300 interactions were retrieved from the Micromedex ? database. The selection was reduced to the interactions rated as moderate, major or contraindicated. The selected interactions were further checked against PubMed ?, MEDLINE ?, InfoPharm Compendium of Drug Interactions and Summaries of Product Characteristics. For each interaction, its nature, mechanism, onset and clinical severity were indicated, documentation quality was rated and recommendations for clinical practice were formulated. Twenty significant interactions that we rated as moderate, severe and very severe were identified. Interacting drugs were warfarin, fluoroquinolones, azole antifungals, co-trimoxazole, proton pump inhibitors, amiodarone, cholestyramine, activated carbon, allopurinol, angiotensin-converting enzyme inhibitors, statins, digoxin, iron, aluminium and magnesium salts, and hepatotoxic and nephrotoxic agents.     

Self-Medication: A survey of nonprescription drug use

A sample of adults (n = 148) which reflected age, gender, and race characteristics of the 1980 U.S. Census was surveyed on the incidence of obtaining over the counter (OTC) drugs during the previous year and the nature of the drugs used. Most (78%) reported obtaining OTC drugs, and of 15 categories, headache or pain remedies, cold or flu remedies, and vitamins were most frequently (>50%) reported as used. No gender or race effects were found for obtaining OTC drugs or for the nature of OTC drugs used. Identified patterns of OTC drug use were related to previous research and have implications for drug development, health care, and marketing concerns. © 1993 Wiley-Liss, Inc.     

药物性慢性肝损害40例分析

目的提高临床对引起慢性肝病药物的认识。方法回顾性分析确诊的40例慢性药物性肝病的临床资料。结果药物诱发慢性肝炎18例，慢性肝内胆汁淤积7例，肝硬化3例，脂肪肝6例，肝脏腺瘤3例，肝静脉血栓形成2例，肝肉芽肿1例；40例中治愈35例(87．5％)，好转4例(10．0％)，死亡1例(2．5％)。常见诱导慢性肝病的药物有抗结核药、化疗药、镇静安眠抗惊厥药、非甾体类抗炎药、抗雌激素、降脂药等。结论诱导慢性肝病的药物应引起临床上的重视。     

Use of over-the-counter analgesics in patients with chronic liver disease: physicians' recommendations.

BACKGROUND: Over-the-counter analgesics (OTCAs), principally paracetamol (acetaminophen)-containing compounds and NSAIDs, are commonly used medications. Guidelines for the use of these agents in patients with chronic liver disease (CLD) are not available, despite the possibility that such patients may be more susceptible to the effects of an adverse reaction. Notwithstanding the lack of guidelines for healthcare providers, patients are often counselled to modify their use of these drugs. Therefore, the primary aim of this study was to assess healthcare providers' recommendations on how OTCAs should be used by patients with CLD. METHODS: An 11-question web-based survey was distributed via email to healthcare providers participating in four healthcare networks in the US, to determine what recommendations they make to patients with cirrhosis (compensated and decompensated) and chronic hepatitis regarding the use of paracetamol and NSAIDs. Healthcare providers were also queried about the recommendations they make to patients with cirrhosis regarding pain control, and on the use of paracetamol for patients who consume alcohol daily. RESULTS: Overall, a 12% response rate was obtained. Internal medicine, family practice, paediatrics, and gastroenterology were the most represented practice types. Recommendations against the use of NSAIDs were significantly less common than recommendations against paracetamol use, in cases of both compensated and decompensated cirrhosis (p = 0.001). Non-gastroenterologists and non-primary care physicians were the least likely to recommend against NSAID use (p = 0.001), while gastroenterologists were the least likely to recommend against paracetamol in these patients (p = 0.001). It was the recommendation of most respondents that OTCAs should be avoided in patients with cirrhosis, and that paracetamol should be avoided or its dose reduced in the setting of daily alcohol use. CONCLUSIONS: Significant variability exists among healthcare providers on their recommendations for OTCA use in the setting of chronic liver disease. Non-gastroenterologists are more likely to recommend against the use of paracetamol than NSAIDs, and patients with chronic liver disease may be under-treated for pain.     

216例药物性肝炎的临床分析

目的：提高对药物性肝炎的认识。方法：对216例药物性肝炎的发病规律及临床特征进行分析。结果：药物性肝炎多发生于长期、联合使用有肝毒性的药物而又无肝功监测的患者，多见于农民及工人。多发生于服药后十天至一个月。有HBsAg阳性者更易发生药物性肝炎及重症肝炎，且病死亡率高。结论：影响药物性肝炎的因素有患者的文化程度、药物的种类、用药时间、联合用药、HBsAg阳性、肝功能的监测等。     

A Review of Epidemiologic Research on Drug-Induced Acute Liver Injury Using the General Practice Research Data Base in the United Kingdom

Drug hepatotoxicities have been evaluated in case histories, surveys based on retrospective record reviews, and spontaneous adverse drug reactions reported to national pharmacovigilance systems, but in relatively few epidemiologic studies. To identify and quantify the risk of acute liver injury associated with individual drugs, we reviewed and integrated all the published epidemiologic research on the subject. The source population for the eight studies was general population registered on a single large general practice-based computerized data base. All were retrospective cohort studies, but some had a case-control design nested within the source cohort. Participants were selected according to their use of selected agents (nonsteroidal antiinflammatory drugs [NSAIDs], antibiotics, acid-suppressing drugs, other drugs suspected of being hepatotoxic) during the study period. Among the agents, we found a group of important hepatotoxic drugs with an associated incidence rate of acute liver injury greater than 100/100,000 users, including chlorpromazine and isoniazid. Agents with less risk but greater than 10/100,000 users were amoxicillin-clavulanic acid and cimetidine. A third group of drugs had an associated incidence rate of acute liver injury of less than 10/100,000 users. Our results provide evidence of relative safety for commonly administered agents such as NSAIDs, amoxicillin, omeprazole, and ranitidine. We also quantified important suspected liver toxicity, providing a reasonable precise risk estimate of clinical liver injury associated with chlorpromazine, isoniazid, and amoxicillin-clavulanic acid.     

Using suitability profiles to better inform consumers' choice of commonly used over‐the‐counter analgesics

Objective To quantify the impact of labelled contraindications, precautions and warnings for use on the population that may take commonly used over‐the‐counter (OTC) analgesics. Setting Primary care: data were collected from a general practitioner database in Australia. Methods Patient data were audited retrospectively (n = 107553) to determine the number of patients with contraindications, warnings or precautions to the use of OTC paracetamol and the non‐steroidal anti‐inflammatory drugs aspirin and ibuprofen. The primary outcome measure was the suitability rate (i.e. the proportion of patients with no contraindications, warnings or precautions) of these commonly used analgesics. Key findings In this Australian dataset, the proportions of patients who had no contraindications, warnings or precautions to the use of paracetamol or ibuprofen were 98.1 and 76.9%, respectively (P = 0.0001); 83.4% of patients had no contraindications, warnings or precautions to the use of aspirin (P = 0.005 compared with paracetamol). Conclusion Of the three OTC analgesics examined, paracetamol is suitable for use by a larger proportion of the general population without the need to seek medical advice.     

Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

The advances in the drug development that allowed the replacement of many potentially hepatotoxic agents by safer alternatives have been out-weighed by the vast expansion of the total number of agents now available for use. Now, rare adverse reactions to several commonly prescribed medications contribute to the total burden of drug-induced liver injury. Studies involving well-characterised patients with diclofenac-induced hepatotoxicity indicate that multiple steps are involved in the development of liver injury. Individual susceptibility to idiosyncratic hepatotoxicity is determined by the interaction of metabolic and immunological factors. Immunomodulatory and anti-inflammatory cytokines, such as IL-10, may have a protective role in reducing drug-induced liver injury. Understanding the mechanisms of idiosyncratic hepatotoxicity may increase our ability to identify susceptible individuals and hence, prevent serious adverse reactions.     

Diclofenac-induced liver injury: a paradigm of idiosyncratic drug toxicity

The advances in the drug development that allowed the replacement of many potentially hepatotoxic agents by safer alternatives have been out-weighed by the vast expansion of the total number of agents now available for use. Now, rare adverse reactions to several commonly prescribed medications contribute to the total burden of drug-induced liver injury. Studies involving well-characterised patients with diclofenac-induced hepatotoxicity indicate that multiple steps are involved in the development of liver injury. Individual susceptibility to idiosyncratic hepatotoxicity is determined by the interaction of metabolic and immunological factors. Immunomodulatory and anti-inflammatory cytokines, such as IL-10, may have a protective role in reducing drug-induced liver injury. Understanding the mechanisms of idiosyncratic hepatotoxicity may increase our ability to identify susceptible individuals and hence, prevent serious adverse reactions.     

Antacids revisited: a review of their clinical pharmacology and recommended therapeutic use.

Antacids are commonly used self-prescribed medications. They consist of calcium carbonate and magnesium and aluminum salts in various compounds or combinations. The effect of antacids on the stomach is due to partial neutralisation of gastric hydrochloric acid and inhibition of the proteolytic enzyme, pepsin. Each cation salt has its own pharmacological characteristics that are important for determination of which product can be used for certain indications. Antacids have been used for duodenal and gastric ulcers, stress gastritis, gastro-oesophageal reflux disease, pancreatic insufficiency, non-ulcer dyspepsia, bile acid mediated diarrhoea, biliary reflux, constipation, osteoporosis, urinary alkalinisation and chronic renal failure as a dietary phosphate binder. The development of histamine H2-receptor antagonists and proton pump inhibitors has significantly reduced usage for duodenal and gastric ulcers and gastro-oesophageal reflux disease. However, antacids can still be useful for stress gastritis and non-ulcer dyspepsia. The recent release of proprietary H2 antagonists has likely further reduced antacid use for non-ulcer dyspepsia. Other indications are still valid but represent minor uses. Antacid drug interactions are well noted, but can be avoided by rescheduling medication administration times. This can be inconvenient and discourage compliance with other medications. All antacids can produce drug interactions by changing gastric pH, thus altering drug dissolution of dosage forms, reduction of gastric acid hydrolysis of drugs, or alter drug elimination by changing urinary pH. Most antacids, except sodium bicarbonate, may decrease drug absorption by adsorption or chelation of other drugs. Most adverse effects from antacids are minor with periodic use of small amounts. However, when large doses are taken for long periods of time, significant adverse effects may occur especially patients with underlying diseases such as chronic renal failure. These adverse effects can be reduced by monitoring of electrolyte status and avoiding aluminum-containing antacids to bind dietary phosphate in chronic renal failure. Antacids, although effective for discussed indications of duodenal and gastric ulcer and gastro-oesophageal reflux disease, have been replaced by newer, more effective agents that are more palatable to patients. Antacids are likely to continue to be used for non-ulcer dyspepsia, minor episodes of heartburn (gastro-oesophageal reflux disease) and other clear indications. Although their wide-spread use may decline, these drugs will still be used, and clinicians should be aware of their potential drug interactions and adverse effects.     

COVID-19 treatment by repurposing drugs until the vaccine is in sight

Corona virus disease (COVID-19) has created pandemic in the world as declared by WHO on March 12, 2020. It is a viral disease caused by SARS-CoV 2 virus and has affected large populations in over 120 countries. There is no specific treatment available and management is empirical. Until such time that an effective vaccine is available for COVID-19 viral infection, one can repurpose known therapeutic drug molecules such as angiotensin receptor 2 blocker, a commonly used antihypertensive drug, to control COVID-19 virus from gaining entry into the host cell by blocking the angiotensin receptor. Clinical trials should also be undertaken to use statins, which are lipid-lowering drugs but have anti-inflammatory and immunomodulatory properties to prevent acute lung injury in COVID-19 infection.     

Responsible self-medication: perceived risks and benefits of over-the-counter analgesic use

Objectives This study examines awareness of the potential risks associated with over‐the‐counter (OTC) use of paracetamol and non‐steroidal anti‐inflammatory drugs (NSAIDs) among Australian consumers to better understand patterns of usage of these products. Methods We employed two self‐reported cross‐sectional surveys (conducted in 2001 and 2009) using computer‐aided telephone interviewing. Both survey samples were weighted to match national population proportions; data were collected for 3702 respondents (study 1, 2001, n = 1901; study 2, 2009, n = 1801). The inclusion criteria were age over 18 years and willingness to participate in the survey. Key findings Self‐reported regular use (once or more per month) of OTC analgesics declined between 2001 (67.5%) and 2009 (55.0%; P < 0.05). In 2009 42.0% of regular OTC analgesic users were purchasing NSAIDs outside the pharmacy setting (compared with none in 2001). Stated awareness of potential risks has increased slightly among regular paracetamol users (from 49.0% in 2001 to 52.0% in 2009) and regular NSAID users (from 25.0% in 2001 to 41.0% in 2009). Regular OTC analgesic users were considered to be using the product appropriately if there were no contraindications, warnings, precautions or potential drug interactions to the analgesic that they had used. In 2001, significantly more people were using paracetamol appropriately than were using NSAIDs appropriately (98.3 compared with 79.3%; P < 0.05). Corresponding figures for 2009 were 96.4 and 69.1% (P < 0.5). Conclusions Increasing consumer awareness of the need to consider potential risks prior to taking OTC analgesics is a positive sign. However, this has not translated to an increase in appropriate use of OTC NSAIDs; since ibuprofen has become available outside the pharmacy setting in Australia fewer people are using NSAIDs appropriately according to the label. The quality use of medicines, in particular OTC NSAIDs, is becoming increasingly reliant on product labelling and the ability of consumers to understand and self‐assess risk.     

The new Swedish Prescribed Drug Register--opportunities for pharmacoepidemiological research and experience from the first six months

PURPOSE: To describe the content and potentials of the new Swedish national register on prescribed and dispensed medicines. METHODS: The Swedish Prescribed Drug Register contains information about age, sex and unique identifier of the patient as well as the prescriber's profession and practice. Information regarding drug utilization and expenditures for prescribed drugs in the entire Swedish population was extracted from the first six months July-December 2005 and compared with total drug sales in the country including OTC and hospital use. RESULTS: The total quantity of drugs sold in Sweden was 2666 million DDDs, corresponding to 1608 DDD/1000 inhabitants daily. The total expenditures were 1.6 billion Euro. The prescribed drugs, included in the register, accounted for 84% of the total utilization and 77% of the total expenditures. About half of all men and two-thirds of all women in the country purchased drugs. The proportion increased by age. The most common drugs for chronic treatment were diuretics among women (8.8% of the population) and antithrombotic agents among men (7.6%). Psychotropic drugs, corticosteroids and analgesics were more common among women, while men used antithrombotic agents, antidiabetic drugs, lipid lowering agents and ACE inhibitors to a greater extent. CONCLUSIONS: The new register provides valuable data on exposure to drugs and is useful to study patterns of drug utilization. The possibilities for record linkage to other health registers gives from an international perspective good opportunities to explore drug and disease associations and the risks, benefits, effectiveness and health economical effects of drug use.     

Hepatotoxicity of chemotherapy

The selection of a chemotherapeutic regimen for the oncology patient is based on a thorough assessment of potential hazards relating to the patient’s clinical condition and the toxicities of chemotherapy. Liver function abnormalities are commonly seen in this patient population and deducing their aetiology may be difficult. Immunosuppression, paraneoplastic phenomena, infectious disease, metastases and polypharmacy may all confound the clinical picture. While criteria for standardising liver injury have been established, dose modifications often rely on empirical clinical judgement. Therefore, a comprehensive understanding of hepatotoxic manifestations for the most common chemotherapeutic agents is essential. This article reviews the hepatotoxicity of commonly utilised antineoplastic agents.     

Hepatotoxicity of chemotherapy

The selection of a chemotherapeutic regimen for the oncology patient is based on a thorough assessment of potential hazards relating to the patient's clinical condition and the toxicities of chemotherapy. Liver function abnormalities are commonly seen in this patient population and deducing their aetiology may be difficult. Immunosuppression, paraneoplastic phenomena, infectious disease, metastases and polypharmacy may all confound the clinical picture. While criteria for standardising liver injury have been established, dose modifications often rely on empirical clinical judgement. Therefore, a comprehensive understanding of hepatotoxic manifestations for the most common chemotherapeutic agents is essential. This article reviews the hepatotoxicity of commonly utilised antineoplastic agents.