Antibiotics - Mechanism of Action

 

Chlamydia Trachomatis

•  Pelvic inflammatory is most commonly caused by Chlamydia trachomatis and Neisseria gonorrhoeae.
• C. trachomatis is an obligate intracellular organism.
• It can cause cervicitis, urethritis, and proctitis
• In women, these infections can lead to 
• Pelvic inflammatory disease PID
• tubal factor infertility
• ectopic pregnancy 
• chronic pelvic pain
• Lymphogranuloma venereum (LGV) is another type of STD caused by C. trachomatis. LGV is the cause of recent proctitis outbreaks among gay, bisexual, and other men who have sex with men (MSM) worldwide.

Octreotide

• Octreotide is a synthetic somatostatin analog that inhibits multiple hormones including vasoactive intestinal polypeptide (VIP), luteinizing hormone, growth hormone, glucagon & insulin.

Granulosa Cell Tumors

•  Granulosa cell tumors develop from granulosa cells & may actively secrete estrogens.

Tularemia

• Tularemia is caused by Francisella Tularensis.
• Fifty percent of cases have been reported in Missouri, Arkansas & Oklahoma.

Dyspareuria

 Dyspareunia can affect all genders, but it is most commonly reported in women. Therefore, this article focuses on dyspareunia in women.

Red flag symptoms

• Dysmenorrhoea
• Intermenstrual bleeding
• Menorrhagia
• Pelvic discharge
• Pelvic pain
• Postcoital bleeding
• Unintentional weight loss
• Fever

Classification

Dyspareunia can be classified as primary or secondary, and as superficial or deep.

• Primary: pain on intercourse since the onset of sexual activity.
• Secondary: development of pain during a patient's sexual lifetime.
• Superficial: symptoms are localised to the introitus, vulva, and vestibule.
• Deep: symptoms relate to the pelvis.

History

There are many causes of dyspareunia. A complete gynaecological history, including sexual history and any history of abuse, is imperative. Although a pelvic examination can be a key element of the work-up, it may not always be necessary.

The consultation may be difficult and clinicians need to be sensitive to the patient in broaching this subject. Creating a rapport with the patient by using open-ended questions may help communication.

Of note, dyspareunia may not be a presenting symptom and may be revealed in response to a screen in a person presenting with other gynaecological symptoms (for example, inter-menstrual bleeding or post-coital bleeding).

The main things to establish in the history are the onset and location of symptoms and any associated complaints.

• Associated pruritus may indicate eczema, candidiasis, or vulvar dystrophy.
• Dysmenorrhoea and sharp pains may indicate endometriosis.
• Pelvic aching may suggest fibroids, and tearing pains may allude to vaginal atrophy.
• A past medical history of cancer that required chemotherapy or radiotherapy may have resulted in vaginal atrophy, fibrosis or adhesions.
• Drugs, such as the contraceptive pill, some antidepressants and antihypertensives, can reduce vaginal lubrication.
• A past obstetric history of traumatic childbirth, or episiotomies, may result in dyspareunia.
• A detailed sexual history may be relevant.
• Any psychological trauma may be very relevant. For example, experiencing sexual assault or abuse. 

Examination

Examination should begin with inspection of the external genitalia. Look out for any dermatological abnormalities or infective lesions, such as herpes simplex virus sores. Pale vaginal mucosa may suggest vaginal atrophy, and candidiasis may also be very obvious on examination.

Depending on the history, an internal exam should also be considered. Mucopurulent discharge may suggest cervicitis or pelvic inflammatory disease. Bimanual examination may show fibroids. Other important features on examination may be a degree of prolapse.

Pale vaginal mucosa may suggest vaginal atrophy.

Investigations

In many cases of dyspareunia, investigations are not necessary. However,  you may wish to consider vaginal swabs for chlamydia and gonorrhoea if pelvic inflammatory disease is suspected. Herpes simplex virus polymerase chain reaction (PCR) swabs may also be pertinent. Other potential investigations are listed below.

• A urinalysis may reveal a urinary tract infection.
• A pelvic ultrasound can be useful to show fibroids or a hydrosalpinx.
• A cystoscopy may be necessary to identify interstitial cystitis.
• A diagnostic laparoscopy may be relevant for suspected endometriosis.

Possible causes of dyspareunia

• Bartholin's cyst
• Cervicitis
• Endometriosis
• Herpes simplex virus
• Iatrogenic causes
• Irritable bowel syndrome
• Inflammatory bowel disease (occasionally)
• Ovarian cysts
• Pelvic inflammatory disease
• Psychosexual syndrome
• Vaginal atrophy (secondary to menopause)
• Vaginismus
• Vaginitis and vulvovaginitis
• Vulvodynia

This article was updated by Dr Pipin Singh, a GP in Northumberland in February 2024. It was written originally by Dr Mehul Mathukia and updated in June 2020 by Dr Anish Kotecha a GP in Gwent.

Gastric Mucosa Barrier

Tardive Dyskinesia

•  Tardive dyskinesias (TDs) are involuntary movements of the tongue, lips, face, trunk, and extremities that occur in patients treated with long-term dopaminergic antagonist medications.
• Although they are associated with the use of neuroleptics, TDs apparently existed before the development of these agents.
• People with schizophrenia and other neuropsychiatric disorders are especially vulnerable to te development of TDs after exposure to conventional neuroleptics, anticholinergics, toxins, substances of abuse, and other agents.
• TDs are most common in patients with schizophrenia, schizoaffective disorder, or bipolar disorder who have been treated with antipsychotic medication for long periods, but they occasionally occur in other patients as well. For example, people with fetal syndrome, other developmental disabilities, and other brain disorders are vulnerable to the development of TDs,  even after receiving only 1 dose of the causative agent.
• TD has been associated with polymorphisms of  both the dopamine receptor D2 (DRD2) gene, 

TD has been associated with polymorphisms of both the dopamine receptor D2 (DRD2) gene, ^[1]  TaqI A and TaqI B and associated haplotypes, ^[2]  and of the dopamine receptor D3 (DRD3) gene, ^[1, 3]  the dopamine transporter (DAT) gene, and the manganese superoxide dismutase (MnSOD) gene.

Dysfunction of the dopamine transporter has been hypothesized to play a role in the development of TD. However, Lafuente et al did not find evidence of involvement of a polymorphism with a variable number of tandem repeats (VNTD) in the DAT gene (SLC6A3) in dyskinesias induced by antipsychotics. ^[4] Thus, further research is needed to investigate the role of the dopamine transporter in the development and maintenance of TD.

Morphine

•  FDA-approved usage of morphine sulfate includes moderate to severe pain that may be acute or chronic.
• Most commonly used in pain management, morphine provides major relief to patients afflicted with pain.
• Clinical situations that benefit greatly from medicating with morphine include management of palliative/end-of-life care, active cancer treatment, and vase-occlusive pain during a sickle cell crisis.
• Morphine is widely used off-label for almost any condition that causes pain.
• In the emergency department, morphine is given for musculoskeletal pain, chest pain, arthritis, and even headaches when patients fail to respond to first and second-line agents. 
• Morphine is rarely used for procedural sedation. However, for small procedures, physicians will sometimes combine a low dose of morphine with a low dose of benzodiazepine-like lorazepam.
• Patients who are actively having acute coronary syndrome are often given morphine in the emergency setting before going to the cath lab.
• Morphine to relieve pain during a myocardial infarction (MI) has been in use since the early 1900s. 
• In 2005, an observational study raised some concerns, but there are very few effective alternatives.
• Morphine is a potent opioid; it decreases pain, which in turn leads to a decrease in the activation of the autonomic nervous system.
• These are desirable effects when a patient is having an Ml. 
• Morphine has hemodynamic side effects that can be beneficial during an MI.   
• In theory, the combination of these can reduce myocardial oxygen demand.     
• Mechanism of Action: 
• Morphine is considered the classic opioid analgesic with which other painkillers are compared.
• Like other medications in this class, morphine has an affinity for delta, Kappa and mu-opioid receptors. 
• This drug produces most of its analgesic effects by binding to the mu-opioid receptor within the central nervous system (CNS) and the peripheral nervous system (PNS). 
• The net effect of morphine is the activation of descending inhibitory pathways of the CNS as well as inhibition of the nociceptive afferent neurons of the PNS, which leads to an overall reduction of nociceptive transmission.
• Administration:         
• Morphine administration can occur through various vehicles. Its administration is most often via the following routes: orally (PO), intravenously (IV), epidural, and intrathecal. 
• Oral formulations are available in both immediate and extended-release for the treatment of acute and chronic pain.
• Pain that is more severe and not well controlled may be manageable with single or continuous doses of IV, epidural, and intrathecal formulations. 
• Infusion dosing can vary significantly between patients and largely depends on how naive or tolerant they are to opiates. 
• It is interesting to point out that IV morphine formulation is also commonly given intramuscularly (IM). 
• Morphine is also available as a suppository. 
• Morphine is widely used and abused. As a result of this, people have found ways to insufflate (snort) the medication.
• Morphine is also available as an oral solution and can be administered sublingually.
• Sublingual morphine is very popular in palliative care.
• Adverse Effects
• Among the more common unwanted effects of morphine use is constipation. This effect occurs via stimulation of mu-opioid receptors on the myenteric plexus, which in turn inhibits gastric emptying and reduces peristalsis.
• Other common side effects include central nervous system depression, nausea, vomiting and urinary retention. 
• Respiratory depression is among the more serious adverse reactions with opiate use that is especially important to monitor in the postoperative patient population.
• Other reported side effects include lightheadedness, sedation, and dizziness.
• Patients often report nausea and vomiting, which is why in many emergency departments, morphine administration is with an antiemetic such as ondansetron.
• Other effects include euphoria, dysphoria, agitation, dry mouth, anorexia, and biliary tract spasm. which is why some physicians will avoid morphine when patients present with right upper quadrant pain and they suspect possible biliary tract pathology.
• Morphine can also affect the cardiovascular system and reportedly can cause flushing, bradycardia, hypotension, and syncope.
• It is also important to note that patients can experience pruritus, urticaria, edema and other skin rashes.
• Contraindications
• Morphine is an extremely beneficial medication when used appropriately. However, in certain situations, this medication may be strongly contraindicated. Extreme caution is necessary with severe respiratory depression and asthma exacerbation cases since morphine can further decrease the respiratory drive. Additionally, morphine should be avoided in cases of previous hypersensitivity reaction and immediately discontinued in the presence of an active reaction.[11] Caution is also necessary with the concurrent use of monoamine oxidase inhibitors (MAOIs) as these medications have an additive effect with morphine. This combination can then trigger severe hypotension, serotonin syndrome, or increase respiratory depression in patients. GI obstruction is another important contraindication.[1] It is also considered by many as a contraindication to provide opioids to individuals that have a history of substance misuse, especially if a patient has had a history of abusing opioids. Although this is a very controversial topic, most clinicians would agree that pain requires management.[12] However, most will agree and acknowledge that there are alternatives to opioid analgesics.
• Monitoring
• The efficacy and therapeutic index of morphine are assessable with a combination of subjective and objective findings. Controlling pain, which is usually the first symptom evaluated in patients, is the ultimate goal of morphine use. Other essential parameters requiring monitoring include mental status, blood pressure, respiratory drive, and misuse/overuse.[2] Although it may seem intuitive, it is also important to monitor what other medications a patient is taking. This list includes but is not limited to prescription medications. All patients taking morphine should understand the need to avoid any other substances that could lead to respiratory depression.[13] These medications include but are not limited to alcohol, additional opioids, benzodiazepines, and barbiturates. Patients can become apneic at lower doses if combining morphine with any of these substances.
• Toxicity
• Morphine can potentially be a lethal medication when not used properly.[14] It causes a host of symptoms related to depression of the CNS. Severe respiratory depression is the most feared complication of morphine in cases of overdose. Immediate injection of naloxone is required to reverse the effects of morphine.
• Enhancing healthcare Team outcomes

• Ordering and administering morphine requires an interprofessional team of healthcare professionals, including clinicians, mid-level practitioners, nurses, and pharmacists.[15] However, patients may be transferred throughout the hospital while under the effects of these medications. Morphine use, monitoring, and administration can utilize many resources, including laboratory technologists, pharmacists, and nurses/nursing assistants. Without proper training and careful monitoring, often starting in the emergency department, patients can develop serious side effects and have adverse reactions to morphine. The clinician is responsible for coordinating the care, which includes the following:

  • Ordering the drug
  • Monitoring the patient for signs and symptoms of respiratory depression[16]
  • Administering the drug
  • Consulting with the pharmacist about the use of morphine with other medications that can cause respiratory depression.
  • Consulting with a specialist if an overdose or allergic reaction occurs.
  • Consulting with the radiology if a patient has received morphine prior to imaging
  • consulting with the cardiologist if using morphine in a STEMI                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 

Antipsychotic Drugs and Liver Injury

•  Drug-induced liver injury (DILI) refers to liver injury caused by various prescription or non-prescription chemical drugs, biological agents, traditional Chinese medicine (TCM), natural medicine (NM), health care products (HP), dietary supplements (DS), and their metabolites and even excipients.
• It was reported that DILI accounted for 10-15% of adverse drug effects.
• Among the main drugs causing DILI in our country, sedatives, and neuropsychiatric drugs accounted for 2.6%.
• Systematic reviews have found that all patients treated with conventional antipsychotic therapy have an increased risk of hepatic dysfunction.
• The risk factors for DILI were host factors (including genetic factors, age, gender, pregnancy, and underlying disease), drug factors (including chemical properties of drugs, interactions, and pollution in the course of planting and processing the traditional Chinese medicinal materials) and environmental factors (excessive drinking and smoking, etc.)
• The pathogenesis of DILI is complicated, and it is often the result of successive or combined effects of various mechanisms that still need to be fully clarified.
• The clinical manifestations were mostly asymptomatic transaminase elevation and it happened in the initial 6 weeks of using antipsychotic drugs.
• Abnormal liver function can be stabilized or improved via treatments and fatal hepatitis rarely happens. 
• It is necessary to point out that chlorpromazine often triggers cholestatic liver injury. This injury is generally regarded as a relatively severe liver injury.
• DILI has a complex pathogenesis that can be summarized into direct hepatotoxicity and idiosyncratic hepatotoxicity reactions to drugs.
• The process involves the upstream events caused by drugs and their metabolites, and the downstream events constituted by the imbalances in hepatic target cell damage pathways and protective pathways. 
• Direct hepatotoxicity of drugs refers to the drugs ingested into the body and/or the direct damage of its metabolites to the liver and was often dose-dependent, usually predictable, and also called intrinsic DILI.
• Direct hepatotoxicity of drugs can further induce other liver injury mechanisms such as immunity and inflammatory response.
• The pathogenesis of idiosyncratic hepatotoxicity has been a hot topic in research in recent years. 
• Gene polymorphisms of the drug-metabolizing enzymes, transmembrane transporters and solute transport proteins, and human leukocyte antigen systems (HLA) result in adaptive immune responses to some drugs relatively easily, increasing the host's susceptibility to DILI.
• Hepatic mitochondrial damage and oxidative stress induced by drugs and active metabolites can cause hepatocyte damage and death through various molecular mechanisms. 
• Persistent and excessive endoplasmic reticulum stress response (ERSR) broke the alleviating effect of the unfolded protein response (UPR) on stress, facilitating the progress of DILI. 
• Drugs and their metabolites are capable of activating a variety of death signaling pathways, promoting the occurrence of cell necrosis and autophagic cell death.
• The adaptive immune attack may be the last common event of DILI.
• Most antipsychotic drugs (except sulpiride, amisulpride, risperidone, and paliperidone) are metabolized through the cytochrome P450 (CYP) system. 
• The majority of antipsychotic drugs mainly metabolize through CYP2D6 and CYP3A4 and some antipsychotic drugs are through CYP1A2 (such as clozapine and olanzapine).
• There may be three main mechanisms underlying the hepatic injury induced by antipsychotic drugs: 
• firstly, phenothiazines (especially chlorpromazine) or their metabolites can affect bile secretion, and excretion, resulting in cholestasis which may be related to immune-mediated hypersensitivity.
• Secondly, the direct toxic effects of the drugs or their metabolites attack hepatocytes; the delayed toxic effect is caused by a gradual accumulation of small toxic metabolites. Although the drug continues to damage the hepatocytes, the hepatocyte can adapt to this change by up-regulation of antioxidant genes or chaperone proteins. 
• Thirdly, antipsychotic drugs indirectly affect the liver by increasing the risk of metabolic syndrome, leading to an increased risk of non-alcoholic fatty liver disease. Some studies have found that clozapine and olanzapine increase the risk of non-alcoholic fatty liver disease compared with other novel antipsychotic drugs and there were 2 case reports regarding acute liver damage after using clozapine.
• Clozapine, olanzapine, quetiapine and risperidone resulted in 40%, 30%, 27% and 31% of asymptomatic elevation of aminotransferase respectively.
• Generally, it takes place in the first few days to weeks of taking the mediction. The target cells of DILI are mainly the hepatic cells, bile duct epithelial cells, and vascular endothelial cells in the hepatic sinusoid and hepatic vein system. The injury modes are complex and diverse; the pathological changes cover almost all the areas of liver pathological changes. Most of the pathological changes caused by antipsychotics are mainly in the form of acute cellular lysis.[14] The hepatotoxicity induced by conventional antipsychotic drugs is represented by phenothiazine. Especially liver injury caused by chlorpromazine is manifested as acute cholestasis. The hepatic injury modes of the novel antipsychotics are diverse. Studies[14] have shown that clozapine can cause acute necrotic hepatitis, cholestatic hepatitis with necrosis of a single hepatocyte, and eosinophil infiltration; risperidone usually results in cholestatic hepatitis and rare allergic symptoms; olanzapine induces hepatocyte damage, accompanied monocytes, centrolobular necrosis of lymphocytes, and eosinophils infiltration in the portal area; quetiapine is the leading cause of hepatocyte damage, extensive necrosis of hepatocytes, and nonspecific inflammatory infiltration; ziprasidone usually causes hepatocyte damage, hypersensitivity, eosinophilic and systemic symptoms drug-induced reaction syndrome; aripiprazole, paliperidone, aripiprazole, amisulpride have no relevant reports.

The clinical manifestations of acute DILI are usually non-specific. The incubation period varies considerably in that it can last as short as one to several days and up to several months. Most patients had no obvious symptoms with only an increase of varying degrees on hepatic biochemical indicators such as serum ALT, AST and ALP, GGT, and so forth. Some patients may have digestive symptoms such as fatigue, loss of appetite, distending pain in the liver area, and epigastric discomfort. People with cholestasis can have yellow skin over the entire body, pale stool color, itching, and so forth. A small number of patients may have allergic reactions such as fever, rash, eosinophilia, and even arthralgia, and possibly be accompanied with manifestations of other extrahepatic organ injuries. Acute liver failure (ALF) or subacute liver failure (SALF) may be present in severe cases. Studies have found that new antipsychotic drugs rarely showed hepatic injury that was accompanied with jaundice in clinical practice, and the cause was unknown.[1] Chronic DILI in clinical practice can be manifested as chronic hepatitis, hepatic fibrosis, compensated and decompensated cirrhosis, autoimmune-like hepatitis (AIH) DILI, chronic cholestasis, vanishing bile duct syndrome (VBDS), and so forth. It is relatively easy for cholestatic DILI to develop into a chronic condition.[15]

The clinical manifestations of acute DILI are usually non-specific. The incubation period varies considerably in that it can last as short as one to several days and up to several months. Most patients had no obvious symptoms with only an increase of varying degrees on hepatic biochemical indicators such as serum ALT, AST and ALP, GGT, and so forth. Some patients may have digestive symptoms such as fatigue, loss of appetite, distending pain in the liver area, and epigastric discomfort. People with cholestasis can have yellow skin over the entire body, pale stool color, itching, and so forth. A small number of patients may have allergic reactions such as fever, rash, eosinophilia, and even arthralgia, and possibly be accompanied with manifestations of other extrahepatic organ injuries. Acute liver failure (ALF) or subacute liver failure (SALF) may be present in severe cases. Studies have found that new antipsychotic drugs rarely showed hepatic injury that was accompanied with jaundice in clinical practice, and the cause was unknown.[1] Chronic DILI in clinical practice can be manifested as chronic hepatitis, hepatic fibrosis, compensated and decompensated cirrhosis, autoimmune-like hepatitis (AIH) DILI, chronic cholestasis, vanishing bile duct syndrome (VBDS), and so forth. It is relatively easy for cholestatic DILI to develop into a chronic condition.[15]

The severity of DILI was graded according to clinical features and laboratory indexes ALT, ALP, TBil, and INR (international normalized ratio). It is divided into 5 grades, including no liver injury, mild, moderate and severe liver injuries, ALF, and faAt present, the diagnostic criteria commonly used for drug-induced liver injury (DILI) in the world are: the Japanese Diagnostic Criteria for Drug-induced Liver Injury developed by the Japanese Liver and Drug Research Society in 1978; the European Consensus Meeting Criteria for Acute Drug-induced Liver Injury developed by Danan and colleagues in 1988; the ICM standard developed by the Council for International Organization of Medical Sciences (CIOMS) in 1993 (this had improvements to the Danan standards); the Maria Diagnositc Criteria developed by Maria in 1997; the DDW Japan criteria developed by the Japanese Society of Hepatology in 2004. In our country, the most commonly used set of criteria was the one that used medical history, symptoms, and signs combined with laboratory markers as the diagnostic criteria for DILI.[16]

The clinical manifestations and histological features of drug-induced liver injury were similar to most types of liver diseases, and the same drug can present different characteristics (including clinical features, pathological manifestation, and latency manifestation). Additionally, the diagnosis of DILI is not convincing enough at present due to the lack of specific biological indicators (laboratory, radiological, imaging or histological manifestations).[14] Therefore, some studies[14] have proposed a train of thought for diagnosis: 1) establishing diagnostic procedures: there is a need for understanding comprehensively the relationship between patients’ medication use situation and liver injury in clinical practice, awareness of the risk of liver injury caused by drugs, knowing the liver injury risk caused by drugs, and excluding other factors that could lead to liver injury (for example, viruses, infections, autoimmune diseases, and ischemic and metabolic diseases). 2) Observing the clinical manifestations and evaluating risk factors: acute and chronic liver injuries can have all kinds of clinical manifestations, mainly in the form of acute cytolysis; hepatocellular injury, being female, high total bilirubin, high AST, and AST/ALT > 1.5 are the risk factors for developing acute liver injury. 3) Evaluating the biochemical markers of liver at baseline: weight gain and metabolic syndrome caused by new antipsychotic drugs impair the liver function indirectly. Therefore, it is necessary to define the type of liver injury and, more importantly, to record the patients’ liver and other metabolic markers before taking medication. 4) Age: age can determine the biochemical expression of hepatotoxicity. Elderly patients have a strong relationship with cholestatic or mixed liver injury. It is more common to express as hepatocellular toxicity in young patients. 5) Comorbidity and concomitant medication: psychiatric patients have more comorbidity and concomitant medication situations. The past history, medication history, including the use of traditional Chinese medicine and dietary supplements of this kind of patients should be known. In addition, it should be noted that the recent use of drugs does not necessarily mean it is relevant to liver injury.

According to the preliminarily established and posteriorly revised DILI classification criteria by the Council for International Organization of Medical Sciences (CIOMS), DILI was classified into 3 types: liver cell type, intrahepatic cholestasis type and mixed type. Liver cell type: ALT≥ 3 normal upper limit (ULN), and R≥ 5 [R= (ALT measured value/ ALT ULN) / (ALP measured value/ ALP ULN)]; cholestatic type: ALP≥ 2 ULN, and R≤ 2; mixed type: ALT≥ 3 ULN, ALP≥ 2 ULN, and 2< R<5. If ALT and ALP do not meet the above criteria, they are called the abnormal liver biochemical test. The cholestatic type DILI accounts for approximately 30% of DILI.

Go to:

5. Clinical management strategy

The basic treatment principle of DILI is: 1) stop using the suspected liver injury drugs promptly and try to avoid using suspicious or similar drugs again; 2) one should weigh the progression of primary diseases after stopping medication and the risk of aggravating liver injury caused by continuous use of medication; 3) choosing appropriate medication treatment according to the clinical type of DILI; 4) patients with acute liver failure / subacute liver failure can consider emergency liver transplantation when necessary.

Currently, there is no clear guideline for the impairment of liver function caused by antipsychotic drugs in clinical practice and it is still based on clinical recommendations, or guidelines from various centers. A more consistent suggestion is that liver function tests should be performed prior to the use of antipsychotic drugs,[17] to understand the patient’s baseline period status. Once liver function impairment is found in the baseline period, it is recommended to use antipsychotic medication that has low doses or metabolize less through livers (for instance, sulpiride, amisulpride, and paliperidone). Patients with liver injury should avoid using phenothiazines. Some common adverse drug reactions (such as excessive sedation or constipation) can also aggravate the impairment of liver function. For those who had liver injury before the use of antipsychotic drugs, liver function tests should be performed at least once a week in the early stage.[18] If the patient has normal liver function at baseline, regular liver function tests are needed even after using antipsychotic medication.[18] It is recommended to have the exam at least once a year (patients who take clozapine have the test every six months). Some centers believe that liver function should be evaluated frequently (usually every three months) during the first year of using antipsychotic drugs (especially with patients with alcohol or drug use). Patients with clinical symptoms, (such as jaundice, nausea, vomiting, anorexia, weakness, pale urine, or black stool) should increase the number of liver function tests. Once the patient was found to be suffering from liver damage due to the use of antipsychotic drugs (ALT≥ 3 times ULN or ALP≥ 2 times ULN or TB> 2mg/dl), it is suggested to stop the medication treatment as soon as possible[8] receive liver-protecting treatment, or get a referral to a general hospital. If mild and asymptomatic liver injuries occur and they do not meet the above criteria, whether there is alcohol or substance use should be assessed including other possible risk factors. Clinical observation should be strengthened without the discontinuation of antipsychotic drugs.[8] If patients suffer from transient liver damage that mostly had a low correlation with antipsychotic drugs, clinical and laboratory monitoring can be strengthened without discontinuation of antipsychotic drugs.[8]

Go to:

6. Conclusions

The mechanism of liver injury induced by antipsychotic drugs is different. The liver injuries induced by typical antipsychotic drugs that represented by chlorpromazine are mostly presented as cholestasis type. Novel antipsychotics primarily cause liver injury indirectly through adverse events associated with metabolism (weight gain, obesity, metabolic syndrome, etc.). Liver function monitoring is still necessary before and after treatment. It is necessary to continue the promotion of clinical and basic research on DILI induced by antipsychotic medication in the future, including applied genomics, transcriptomics, proteomics, metabonomics and other “omics” techniques assessing the incidence of DILI before and after onset and genetics between individuals, as well as studies of immunology, molecular biology, the change of biochemistry and such events, conducting big data analysis, and promoting the study of pathogenesis. These will all serve to identify patients’ susceptibility, adaptability, and tolerance to specific antipsychotic drugs in the early stage, thereby improving prevention of DILI.tal [4]