Nephrotoxic drug reactions

Introduction

Many drugs are renally excreted, thus the kidneys are exposed to high concentrations of these drugs and / or their metabolites. Drug-induced nephrotoxicity can be defined as any renal injury resulting directly or indirectly from the administration of medication(s). Evidence suggests that 20% of cases of acute kidney injury are attributable to drug-related nephrotoxicity. 

Factors predisposing to nephrotoxicity: 

• Older age (>70 years)
• Infants and young children 
• Pre-existing renal disease 
• Reduced intravascular volume or reduced effective intravascular volume
• Diabetes mellitus
• Cardiovascular disease
• Sepsis
• Polypharmacy
• Prior administration of intravenous contrast agents

Mechanisms of drug-induced kidney injury

There are various methods of drug toxicity which are influenced by the pharmacological agent’s mechanism of action, metabolism, and excretion. Drug-induced nephrotoxicity can be classified into 3 broad categories as follows: 

• Pre-renal
• Intrinsic 
  • Intrinsic acute renal failure can be further classified as:
  • acute tubular necrosis
  • acute interstitial nephritis
  • thrombotic microangiopathy
  • glomerular disease.
• Post-renal

Pre-renal	Afferent arteriolar vasoconstriction	Non-steroidal anti-inflammatory drugs (NSAIDs), selective COX-2 inhibitors e.g. celecoxib, calcineurin inhibitors, vasopressors
	Efferent arteriolar vasodilation	Angiotensin-converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs)
Intrinsic	Acute tubular necrosis	Aminoglycosides, contrast agents, amphotericin B, cisplatin, cephalosporins, nucleotide analogues e.g. tenofovir, zoledronate, pentamidine, cisplatin, calcineurin inhibitors, intravenous immunoglobulins, statins
	Acute interstitial nephritis	Beta-lactam antibiotics, quinolones, NSAIDs,  proton pump inhibitors e.g. omeprazole, lithium, H2-receptor antagonists e.g. cimetidine, cephalosporins,  sulphonamides, phenytoin, amphotericin B, allopurinol, rifampicin, 5-aminosalicylates e.g. mesalamine
	Thrombotic microangiopathy	Calcineurin inhibitors, gemcitabine, mitomycin C, bleomycin, cisplatin, clopidogrel, oestrogen-containing oral contraceptive pill, quinine
	Glomerular disease	NSAIDs, selective COX-2 inhibitors, lithium, penicillins, quinolone, penicillamine, gold, infliximab, pamidronate
Post-renal	Crystal formation in tubules / ureters	Aciclovir, sulphonamides, methotrexate, triamterene
	Renal calculus formation	Guaifenesin, acetazolamide
	Retroperitoneal fibrosis	Methysergide

Table 1: Mechanisms of drug-induced kidney injury

Pre-renal nephrotoxicity

Pre-renal drug-induced acute kidney injury is a result of reduction in renal perfusion and thus glomerular filtration rate (GFR). Factors putting patients at particular risk of drug-induced pre-renal AKI are: 

• Reduced intravascular volume (e.g. inadequate fluid intake, vomiting, diarrhoea) 
• Reduced effective intravascular volume (e.g. congestive cardiac failure, liver cirrhosis)
• Older age 
• Bilateral renal artery stenosis

Offending drugs may either reduce renal perfusion through inducing afferent arteriolar vasoconstriction, or efferent arteriolar vasodilation. Drugs which reduce prostaglandin synthesis via inhibition of cyclo-oxygenase (COX) enzymes, such as NSAIDs, reduce the vasodilatation effect of prostaglandins on the afferent arteriole hence causing vasoconstriction and reducing renal perfusion. Calcineurin inhibitors such as ciclosporin and tacrolimus promote afferent arteriolar constriction by stimulating the production of angiotensin II, thromboxane A2, leukotrienes and endothelin, and inhibiting the release of endothelial-derived nitric oxide. 

In contrast, angiotensin-converting enzyme inhibitors (ramipril, lisinopril, perindopril) and angiotensin receptor blockers (candesartan, losartan) promote vasodilatation of the efferent arteriole by limiting the action of angiotensin II, which ordinarily acts to promote vasoconstriction and ultimately increases efferent arteriolar resistance. In patients with underlying volume depletion this causes a reduction in trans-glomerular capillary pressure and a resultant drop in glomerular filtration rate.  

In pre-renal AKI, urine volume is low with low sodium concentration and high osmolality. Urinalysis is expected to be negative for red blood cells, leukocytes or protein. The approach to management should include stopping or lowering the dose of the offending drug and any other nephrotoxic medications, administration of intravenous fluids to restore circulating volume, and treating contributing comorbidities.

Intrinsic nephrotoxicity

The aetiology of intrinsic drug-induced AKI may be further split into acute tubular necrosis (ATN), acute interstitial nephritis (AIN), thrombotic microangiopathy (TMA), and glomerular disease. The table below discusses the clinical findings and approach to management of each of these four mechanisms. Further detail on the underlying pathophysiology of each is provided in the text below.

Disease process	Clinical findings	Management
Acute tubular necrosis (ATN)	May be oliguric or nonoliguric Increased fractional excretion of sodium >2-3% (normal range <1%) Increased urine osmolality  Urinalysis: protein Urine sediment: renal tubular epithelial (RTE) cells, RTE cell casts and dark granular casts	Stop offending drug Intravenous fluid therapy Haemodialysis in severe cases
Acute interstitial nephritis (AIN)	Systemic evidence of hypersensitivity: fever, rash, joint pain  Interstitial immune infiltrate seen on biopsy Urinalysis: leukocytes, red blood cells, white cell casts, protein Proteinuria may be in nephrotic range in severe cases Eosinophilia & eosinophiluria Increased fractional excretion of sodium >1% Note: eosinophilia, rash, fever, absent in NSAID-induced AIN	Stop offending drug (renal function typically improves within 7 days) If no improvement despite cessation of drug 🡪 oral prednisolone  Consider trial of immunosuppressive agents e.g. cyclophosphamide (although limited evidence base) May require sodium and fluid restriction
Thrombotic microangiopathy	Fever Central nervous system symptoms may be present in cases of thrombotic thrombocytopenic purpura (TTP) Blood tests show AKI, new or worsening anaemia and thrombocytopenia, raised lactate dehydrogenase (LDH) and reticulocytes, and reduced haptoglobin New hypertension  Blood film: schistocytes and large platelets (in keeping with microangiopathic haemolytic anaemia) Urinalysis: red blood cells, protein, hyaline, red blood cell casts and granular casts Renal biopsy may show involvement of glomeruli and blood vessels – thickening of glomerular capillary wall, afferent arteriolar and glomerular thrombi	Stop offending drug Late recognition may result in end-stage renal disease requiring dialysis
Glomerular disease	Variable dependent on pathogenetic mechanism	Rapid cessation of offending drug In immune mediated glomerular injury, immunosuppressive therapy may be required

Table 2: Mechanisms, clinical findings and management of intrinsic drug-induced kidney injury

Acute tubular necrosis

In acute tubular necrosis (ATN), the culprit drug or its metabolite has a directly toxic effect on the renal tubules; the proximal tubule is particularly vulnerable due to its role in increasing the concentration of the glomerular filtrate. This is typically a dose-dependent effect, and arises due to apical contact of the tubular epithelium with drugs and / or their metabolites. There are various pathophysiological mechanisms implicated in causing ATN, dependent on the causative drug; among these are deranged metabolism of phospholipids, alterations in cell membrane permeability and transmembrane ionic gradients (particularly calcium ions), mitochondrial disruption, and generation of oxygen free radicals. Of note, aminoglycosides may cause ATN as a small proportion of the drug is retained in the epithelial cells of the proximal tubules, which can result in disruption of the structure and permeability of the cell membranes, inhibition of lysosomal phospholipase function, and reduction in the release of liposomal hydrolases. Ultimately, aminoglycoside-induced ATN leads to inhibition of mitochondrial function, generation of oxygen free radicals and consequently cell death. Once-daily dosing, dose adjustment according to serum levels, and limiting the duration of use, can reduce the likelihood of aminoglycoside-induced ATN. 

Statins may cause ATN by triggering rhabdomyolysis and consequent myoglobinuria; the myoglobin released from myocytes forms casts in the distal convoluted tubule, resulting in occlusion of the tubule, increase in intratubular pressure and ultimately reduction in glomerular filtration rate.

Renal histology in ATN will show degenerative changes in the tubules such as loss of the brush border, nuclear enlargement and pleomorphism, and apoptotic changes. Patients with infection, malignancy, or cardiovascular disease are at higher risk of developing ATN when causative drugs are administered. 

Acute interstitial nephritis

Acute interstitial nephritis (AIN) results from an inflammatory infiltrate in the renal tubule interstitium. The most common causative drugs are beta-lactam antibiotics, fluoroquinolones, proton pump inhibitors and NSAIDs. Patients over the age of 65 years and those with underlying inflammatory disease (e.g. inflammatory bowel disease) are at higher risk. Drug-induced AIN is the result of a hypersensitivity reaction, and the resulting inflammatory infiltrate consists of eosinophils, lymphocytes, mast cells and plasma cells, which can be demonstrated by renal biopsy. Patients present clinically with evidence of a hypersensitivity reaction with fevers, rash, joint pain, and occasionally uveitis. However, they may also be asymptomatic. Blood tests will show AKI and an eosinophilia and there may be elevated circulating IgE levels.

Thrombotic microangiopathy

Thrombotic microangiopathy (TMA) refers to abnormalities within arteriolar and capillary walls which predispose to the formation of microvascular hyaline thrombi, and represents a spectrum of disease that encompasses thrombotic thrombocytopenic purpura (TTP) and haemolytic uraemic syndrome (HUS). In the non-immune-mediated form of the disease, the triggering drug causes endothelial damage within the renal microvasculature leading to platelet activation and aggregation. In the immune form, the offending drug (e.g. clopidogrel) leads to the production of autoantibodies against a metalloproteinase responsible for processing von Willebrand Factor, causing the accumulation of multimers that activate platelets and trigger their aggregation. Both pathogenetic mechanisms of small-vessel platelet thrombi formation result in a microangiopathic haemolytic anaemia and thrombocytopenia. AKI is often severe and mortality from thrombotic microangiopathy is high. In addition to withdrawing the triggering drug, approach to management may warrant renal dialysis, which may be required lifelong. Chemotherapeutic agents such as gemcitabine are classically implicated.

Glomerular disease

Drug-induced glomerular disease is a relatively rare form of drug-induced renal disease. It has been broadly split into two categories in the literature: direct cellular injury and immune-mediated injury. The three targets of drug-induced cellular injury within the glomerulus are the podocytes, endothelial cells and mesangial cells (Figure 1). Podocyte injury can lead to minimal change disease or focal segmental glomerulosclerosis. Endothelial cell damage manifests as thrombotic microangiopathy (see above). Mesangial cell damage causes nodular glomerulosclerosis. Immune-mediated drug injury to the glomerulus can take the form of immune complex disease (which includes membranous nephropathy and drug-induced lupus glomerulonephritis) or small vessel glomerulonephritis (segmental necrotising and crescenteric glomerulonephritis). Examples of drugs causing each of these forms of glomerular damage are provided in the table below.

Figure 1: Diagram illustrating cells within the glomerulus which may be affected by glomerular drug injury. Image reproduced with thanks to original artwork creator Holly Fischer, available at: http://open.umich.edu/educational/med/resources/second-look-series/materials – Urinary Tract Slide 10. License for image use available at: https://creativecommons.org/licenses/by/3.0/legalcode. Figure annotations added after acquiring image for use in the current publication. – Can’t find this reference Drug-induced glomerular disease type			Examples of causative agents
Direct cellular toxicity:
	Podocytes:	Minimal change disease	NSAIDs, selective COX inhibitors, lithium, penicillins, quinolone
		Focal segmental glomerulosclerosis	Pamidronate, morphine, lithium, interferon therapy
	Endothelial cells:	Thrombotic microangiopathy	Gemcitabine, clopidogrel, quinine
	Mesangial cells:	Nodular glomerulosclerosis	Smoking
Immune-mediated toxicity:
	Immune-complex disease:	Membranous nephropathy	Gold, penicillamine, NSAIDs
		Drug-induced lupus glomerulonephritis	Hydralazine, sulfasalazine, procainamide, infliximab, propylthiouracil
	Small vessel glomerulonephritis:	Segmental necrotising glomerulonephritis & crescenteric glomerulonephritis	Propylthiouracil, minocycline, ciprofloxacin, hydrazlazine

Table 3: Toxicity and Causative Agents

Post-renal nephrotoxicity

Three major mechanisms of drug-induced post-renal nephrotoxicity are outlined below:

1. Tubule / ureter crystal formation – drugs and / or their metabolites which are insoluble in urine may directly result in crystal formation, most commonly within the distal renal tubules, e.g. methotrexate, ciprofloxacin, aciclovir. This causes damage through local inflammation and necrosis via oxygen free radical formation.
2. Renal calculus formation – drugs and / or their metabolites may themselves form components of renal tract calculi (ciprofloxacin, sulfonamides, triamterene), or they may influence purine or calcium oxalate metabolism, the accumulation of which leads to calculus formation (carbonic anhydrase inhibitors e.g. acetazolamide, topiramate, loop diuretics). 
3. Retroperitoneal fibrosis – this is a rare inflammatory process resulting in the deposition of fibrotic material around the infrarenal abdominal aorta and iliac vessels, resulting in an obstructive nephropathy. Drugs which are believed to possibly demonstrate this effect include bromocriptine, L-dopa, hydralazine, and methysergide (a specific serotonin 5HT2A receptor antagonist historically used to treat migraine and cluster headaches).

Prevention of nephrotoxicity

General steps to minimise the likelihood of nephrotoxicity include:

• Check baseline renal function & monitor as appropriate during therapy with potentially nephrotoxic medications 
• If appropriate, adjust dosages to account for renal function 
• Ensure patients are sufficiently hydrated and any depletion of circulating volume is restored with intravenous fluids as necessary
• Correct risk factors for nephrotoxicity where possible (e.g. treatment of sepsis, congestive cardiac failure)
• Avoid concomitant use of nephrotoxic drugs 
• Use non-nephrotoxic alternatives when possible.

Drug-induced interstitial lung disease 

Introduction

The lungs have a large contact surface area and act as a site of metabolism for certain drugs; drug-induced lung injury is therefore not uncommon. Of this large collection of diseases, drug-induced interstitial lung disease (DILD) is the most common manifestation of drug-induced lung injury. DILD is caused by a wide range of drugs. Its incidence, severity and underlying mechanisms are variable dependent on the causative drug. Often, the precise mechanism of DILD for a particular drug is unclear. DILD severity can range from relatively innocuous benign infiltrates to respiratory failure and acute respiratory distress syndrome. The pathologic, radiologic and physiologic changes seen in DILD are highly variable and non-specific, which can make it difficult to recognise. The most common causative drugs are anti-neoplastic agents, disease-modifying anti-rheumatic drugs, antibiotics, and anti-arrhythmic agents. The diagnosis of DILD should be made by exclusion. Re-challenge of the suspected causative agent is generally not advised due to the risk of harm. Treatment is cessation of the drug, avoidance of further exposure and in severe cases systemic glucocorticoid therapy should be considered.

Clinical features

Signs and symptoms

Symptoms are typically non-specific e.g. dyspnoea, cough, and pleuritic chest pain. Rash, wheeze and haemoptysis may be seen. Signs may include hypoxaemia, crackles on auscultation, clubbing of the fingers, and signs of pulmonary hypertension causing right ventricular dysfunction such as peripheral oedema and jugular venous distention. 

Pulmonary function tests 

Changes are nonspecific. Most drugs causing DILD cause a restrictive lung disease pattern with decreased total lung capacity. Reduction in diffusing capacity for carbon monoxide (DLCO) is typically seen. Drugs causing bronchiolitis obliterans may cause an obstructive pattern.

Histology

In general, if there is exposure to a drug resulting in damage to the pulmonary interstitium, particularly in the case of persistent exposure or dysregulated repair processes, interstitial tissue replaces the capillaries and alveoli. Often nonspecific histopathological changes are seen, and almost all patterns of interstitial lung disease caused by therapeutic agents have been demonstrated, including: diffuse alveolar damage (DAD), hypersensitivity pneumonia (HP), granulomatous pneumonitis (GP), bronchiolitis obliterans organising pneumonia (BOOP), non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), organising pneumonia (OP), eosinophilic pneumonia (EP), and granulomatous lung disease (GLD). Some drugs may be responsible for more than one pattern of DILD. Several drugs demonstrate characteristic histopathologic changes; amiodarone may cause NSIP, and methotrexate causes an acute granulomatous ILD which closely resembles opportunistic infective histological changes.

Radiographic findings

Plain film radiographs commonly show bilateral pulmonary infiltrates but may also be normal. 

Computed tomography (CT) may demonstrate numerous patterns of interstitial change; most commonly ground glass opacification, with or without consolidation which can follow a basal, peripheral and bilateral distribution. Changes in keeping with OP, NSIP and HP are most commonly seen. 

High-resolution CT (HRCT) has been reported to be the best modality to demonstrate changes in DILD, which can correspond to the histological subtype. It can also be useful in identifying findings suggestive of an alternate pathology. As a general rule, pneumonitis induced by anti-neoplastic agents shows a pattern of scattered or diffuse ground glass opacities with intralobular interstitial thickening. Those agents causing hypersensitivity pneumonia, including cyclophosphamide, sulfonamides or sulfasalazine may show bilateral patchy ground-glass opacities and/or centrilobular upper lobe nodules. Antibiotic-induced pneumonitis has been reported as showing scattered ground-glass and centrilobular opacification and interlobular septal lines.

Serological tests

A sensitive marker for interstitial lung disease in general is Krebs von den Lungen-6 (KL-6), however its specificity in DILD is not yet established. SP-A and SP-D are serum biomarkers specific for pulmonary fibrosis; again, at present the diagnostic value in DILD is unclear. 

Bronchoscopy + bronchoalveolar lavage 

When performing bronchoalveolar lavage in DILD the most common finding is a lymphocytic alveolitis. Raised lymphocyte, neutrophil and eosinophil counts are typically seen. The presence of reactive type II pneumocytes has been reported in severe DILD cases. Bronchoscopy is also useful for detecting key differentials such as vasculitis, alveolar haemorrhage, pneumonia, and lymphangitic carcinomatosis. 

Biopsy

Lung biopsy is not typically recommended as part of the diagnostic workup as it is unlikely to aid in providing a definitive diagnosis of DILD, however it can be useful for excluding key differential diagnoses.

Pathophysiological mechanisms

The underlying pathophysiology driving DILD in general is split into two categories: direct cytotoxic effects, and immune-mediated effects. Different drugs follow different aetiological mechanisms within these two classes, and some drugs may produce both patterns of disease.  

Direct cytotoxic effects

Some of the key directly cytotoxic mechanisms via which causative mechanisms may result in DILD are listed below: 

• Formation of reactive oxygen species
• Decreased deactivation of metabolites within lungs
• Cytokine release
• Impaired repair mechanisms within alveoli

The above mechanisms result in direct injury to pneumocytes or the alveolar capillary endothelium. This leads to alveolitis and pulmonary oedema. Acute damage to the lung parenchyma may progress to chronic inflammation and eventually fibrosis. Some examples of drugs with direct cytotoxic effects causing DILD and further details on the underlying mechanisms are given below.

Amitriptyline – endothelial damage secondary to disruption of tight junctions as a result of dysregulated intracellular calcium levels.

Methotrexate – stimulates release of free oxygen radicals (e.g. nitric oxide) and cytokines. The effect is not dose-dependent, has variable time and rate of onset; time of onset reportedly ranges from 23 days to 4 years, including after treatment cessation. 

Amiodarone – activates pathways that trigger pulmonary epithelial cell apoptosis. Amiodarone is one of the commonest causes of DILD. Presentation is most commonly subacute, but an acutely fatal form has been reported. High mortality rates (37%) are reported in patients who are admitted to hospital with DILD caused by amiodarone. Cumulative dose is a key risk factor.

Mitomycin C, nitrofurantoin, bleomycin – trigger release of reactive oxygen species which generate hydrogen peroxide, and oxide ions.

Nitrofurantoin – can cause an acute pulmonary reaction within days of initiation, and in some cases within hours if there has been previous exposure. Most cases demonstrate rapid resolution on cessation of the drug. It is seen more commonly in patients taking long-term nitrofurantoin for urinary tract infection prophylaxis.

Immune-mediated effects

In general, immune reactions leading to DILD are influenced and ultimately triggered by multiple key factors: 

• antigenic features of drug’s molecular structure  
• genetic factors of individuals including gene polymorphisms encoding metabolic enzymes
• environmental factors including concurrent infection, pollution
• drug factors including dose, frequency of administration, duration of therapy

Immune-mediated DILD reactions are largely T-cell mediated. Specific examples are given below:

• Minocycline – minocycline-induced pneumonia is an example of an immune-mediated DILD– it manifests as an EP. Cytotoxicity develops as a result of lymphocyte-mediated processes. 
• Amiodarone – in addition to having directly cytotoxic effects, amiodarone can also trigger an immune-mediated reaction; this is reported to be influenced by an individual’s balance of Th1/Th2. 
• Bleomycin – demonstrates both direct cytotoxicity and immune-mediate effects. Bleomycin produces variable clinical presentations of DILD including asymptomatic cases. Changes may occur any time during treatment.

Pulmonary fibrosis causative agents 

Anti-TNF-alpha – these drugs cause systemic / pulmonary shifts towards a pro-fibrotic state, eventually causing pulmonary fibrosis. It also potentiates the pulmonary toxicity of methotrexate.

Rituximab – rituximab is an anti-CD20 antibody which causes DILD via release of cytokines. It may also activate complement or cytotoxic T cell lymphocytes. Activated cytotoxic lymphocytes can damage alveoli and pulmonary vasculature causing pulmonary inflammation and eventually fibrosis.

Causative drugs
Chemotherapeutic agents bleomycin gemcitabine carmustine cyclophosphamide mitomycin C busulfan chlorambucil vinblastine methotrexate penicillamine azathioprine gold rituximab anti-TNFα
Cardiovascular agents amiodarone tocainide
Antimicrobials nitrofurantoin sulfasalazine minocycline amphotericin B
Anti-inflammatory agents aspirin NSAIDs
Recreational drugs Heroin Methadone Talc
Miscellaneous Oxygen Radiation Amitriptyline Bromocriptine Cabergoline

Table 4: list of the most commonly implicated drugs in DILD

Diagnosis

Diagnosis of DILD should be one of exclusion, and is based on: 

• a confirmed history of exposure to a suspected offending medication
• clinical features, imaging and histopathology in keeping with recognised patterns of DILD associated with this medication
• meticulous exclusion of other lung disease
• improvement in symptoms and signs following cessation of the drug
• Re-challenge of offending drug not advised due to the risk of harmful sequelae – lung damage is generally considered irreversible.

Risk factors for DILD

• Increased age (>60 years) – may be in part due to reduced renal excretory function 
• Pre-existing lung disease e.g. pre-existing ILD, COPD, bronchiectasis and asbestosis
• Smoking
• Drug dose – clear dose-dependency exists for DILD caused by amiodarone and bleomycin 
• Poor performance status 
• Pre-existing advanced lung cancer
• Drug interaction – concomitant use of certain drugs can increase an agent’s potential to cause DILD e.g. higher rates of bleomycin-induced interstitial lung disease when given concomitantly with cisplatin or gemcitabine
• Prior or concomitant thoracic radiotherapy – higher rates of pulmonary toxicity with concomitant radiotherapy e.g. for bleomycin
• Pattern of HLA class II allele presentation may be responsible either for resistance or preponderance to DILD e.g. increased risk of gold-induced pneumonitis with HLA-B40 in patients with rheumatoid arthritis
• Cytochrome P450 single nucleotide polymorphisms are believed to be a key genetic factor influencing individual differences in drug absorption, distribution, metabolism and excretion

Management

Withdrawal of the offending drug once DILD is suspected is key. 

The role of glucocorticoid therapy is controversial; evidence with regards to its benefit is limited as many studies employed steroid administration at same time as the suspected offending drug was stopped. Reports on efficacy are highly variable between studies. Current recommendations are to use glucocorticoid therapy in severely affected patients, and in those in whom DILD appears to progress despite cessation of the suspected offending drug. Some sources advise pneumococcal vaccination and annual influenza vaccination in patients with DILD.  

Prognosis 

Prognosis varies between causative agents. In some cases, complete recovery is seen following dose reduction or cessation of the causative agent, with or without glucocorticoid use. Mortality of DILD in patients with underlying malignancy is reported as between 14 and 52.3%, while in the non-cancer population it is from 0 to 41%. Cases of rapid onset, high disease severity and hypoxia on initial diagnosis demonstrate higher mortality.  Possible complications include pulmonary fibrosis and respiratory failure necessitating mechanical ventilation.

Drug-induced Liver Injury

Introduction

The term drug-induced liver injury (DILI) refers to all forms of hepatotoxicity that result from the administration of a medicinal agent. It encompasses a broad range of presentations of hepatic disease and may manifest as either acute or chronic disease. DILI is the commonest cause of acute liver failure (ALF) in the UK. 

A diagnosis of DILI is one of exclusion, once liver injury has been identified clinically and/or biochemically. Nearly all cases of DILI are idiosyncratic, with the notable exception of paracetamol overdose. Idiosyncratic drug reactions affecting the liver are generally understood to arise from immune-mediated processes. 

The treatment of DILI involves cessation of the causative therapeutic agent. ALF may benefit from treatment with N-acetylcysteine early within the disease course and liver transplantation should be considered early.

DILI classification

DILI can be classified into one of several groups, on the basis of either its clinical manifestations, or the underlying pathophysiological mechanism of hepatotoxicity.

When the classification of DILI is made on the basis of its clinical presentation, three distinct classes emerge: hepatocellular injury, cholestatic injury, or mixed disease. The features of each of these are outlined in the table below. When classifying DILI based on the clinical manifestations, the ‘R’ value is used; this is calculated by the following equation: R = (ALT/ULN)/(ALP/ULN) where ALT = alanine transferase, ALP = alkaline phosphatase, and ULN = upper limit of normal.

Hepatocellular	Cholestatic	Mixed
ALT ≥3 x ULN AND R ≥5 Serum bilirubin may be raised Synthetic liver function tests may be abnormal	ALP ≥2 x ULN AND R <2 Serum bilirubin may be raised (can be extremely high in certain cases) Synthetic liver function tests may be abnormal	ALT ≥3 x ULN AND ALP ≥2 x ULN AND 2 < R > 5

Table 5: The Features of DILI

Examples of causes of hepatocellular DILI: diclofenac, fenofibrate, isoniazid, rifampicin, pyrazinamide, disulfiram, minocycline, nitrofurantoin

Examples of causes of cholestatic DILI: co-amoxiclav, cephalosporins, flucloxacillin, terbinafine, erythromycin, chlorpromazine

Examples of causes of mixed DILI: carbamazepine, sulphonamides, lamotrigine, phenytoin

When the pathophysiological mechanism is used to distinguish DILI types, it may be separated into either predictable or unpredictable (i.e. idiosyncratic) types. The majority of cases of DILI are idiosyncratic, with the exception of paracetamol overdose. The differences between predictable and idiosyncratic DILI are summarised in the table.

Predictable DILI	Idiosyncratic DILI
Dose-related	Unexpected based on known pharmacological effects
Short latency (days)	Not seen in animal studies
Result of direct toxicity of drug or its metabolite
Demonstrable within animal studies

Table 6: Predictable and Idiosyncratic DILI

Idiosyncratic DILI can be further subdivided on the basis of the underlying pathophysiology, i.e. immune-mediated vs non-immune mediated. The features of each are outlined in the table below. The lion’s share of instances of idiosyncratic DILI are immune-mediated.

Immune-mediated idiosyncratic DILI	Non-immune mediated idiosyncratic DILI
Latency period is a matter of days to weeks	Latency period is months to years
Associated fevers, rash, eosinophilia, autoantibodies	Lack of associated clinical symptoms and serological markers found in immune-mediated

Table 7: Features of Idiosyncratic DILI

Some drugs which result in DILI that does not fit into the above classifications include:

• Amiodarone, methotrexate, valproate, tamoxifen – can induce hepatic steatosis
• Androgens, contraceptive steroids, anti-neoplastic agents – peliosis hepatis (multiple foci of blood-filled cavitations within the hepatic parenchyma). 
• Anabolic steroids – hepatocellular adenomas
• Thiopurine therapy (including azathioprine, mercaptopurine) – nodular regenerating hyperplasia 

Epidemiology

It is likely that the incidence of DILI is underestimated due to underreporting and variable diagnostic criteria, however it is thought to be in the region of 14-19 cases per 100 000 people per annum. DILI is the most common reason for withdrawal of medications from the marketplace.

Aetiology

Risk factors

Factors which increase the risk of developing idiosyncratic DILI include: 

• Female gender – in addition, women are more likely to be of younger age and have hepatocellular DILI, whereas affected males are more likely to be older and demonstrate cholestatic DILI. Women are also more likely to demonstrate severe hepatotoxicity.
• Increased age
• Drug factors – increased duration of use, higher dose
• Genetic factors – certain HLA genotypes appear to confer greater risk of DILI caused by certain drugs such as flucloxacillin
• Race and ethnicity – the commonest agent causing DILI in African Caribbean population groups is co-trimoxazole, while for Caucasian population groups it is co-amoxiclav
• Pre-existing liver disease – however the evidence is as yet unclear as to whether this is a true risk factor
• Methotrexate induced liver injury is 3-4x more likely in patients with a history of alcohol excess, chronic viral hepatitis or those with risk factors predisposing to non-alcoholic fatty liver disease (diabetes, obesity).

Causative Agents 

Paracetamol is the leading cause of drug-induced acute liver failure (ALF) in Western civilisation. Antibiotics are the commonest cause of idiosyncratic DILI, with co-amoxiclav as the most commonly implicated individual drug. Complementary and herbal medicines and dietary supplements, antiepileptics, cardiovascular drugs, anti-neoplastic agents and analgesics are among the other most commonly involved drug classes. On a global scale, over half of the total cases of DILI are attributable to antibiotics and antiepileptics alone. 

Drugs which are associated with relatively high incidences of severe liver injury include isoniazid and methotrexate. 

Drugs which have been seen to cause idiosyncratic DILI include isoniazid, methyldopa, phenytoin, and diclofenac.

Drugs which have been seen to cause asymptomatic progression to cirrhosis include methotrexate, methyldopa and amiodarone.

Pathophysiological mechanisms

The pathogenesis of idiosyncratic DILI is unclear. Current schools of thought are that drug-related factors (dosage, metabolic pathways, duration of treatment) and patient factors (age, gender, genetic factors) and their interactions are together responsible for the development of hepatotoxicity. 

Clinical features

There are no diagnostic tests or biomarkers for DILI. It therefore relies upon the identification of exposure to a drug which precedes the onset of liver injury, exclusion of alternative causes of liver pathology, and an improvement in markers of liver injury on cessation of the drug. Drug rechallenge is generally not advised due to the risk of associated morbidity and mortality. Recreational drugs and herbal and complementary medicines must be considered.

Clinical manifestations

Nearly three quarters of cases of DILI present with jaundice. The clinical spectrum of DILI includes:

• Asymptomatic, mild liver test abnormalities
• Significant elevation in liver enzymes with clinical features of acute hepatitis (malaise, abdominal pain, nausea and vomiting, jaundice, dark urine, pale stools)
• Cholestasis, with clinical features seen in acute hepatitis plus pruritus
• ALF; evidence of coagulopathy and hepatic encephalopathy may be present.
• Chronic liver disease with progression to cirrhosis 
• Chronic liver injury resembling autoimmune hepatobiliary disease; elevated serum markers of autoimmunity are seen e.g. raised anti-nuclear antibody.

A significant proportion of patients with DILI are asymptomatic. Some groups of patients develop signs of a hypersensitivity reaction, with fever and rash, and in some cases Stevens-Johnson syndrome, the mortality of which is higher than in patients without these features.

Histopathological findings

Liver biopsy may be useful to exclude alternative aetiologies for abnormal liver function. In the case of DILI, non-specific findings such as portal neutrophils and intra-hepatocellular cholestasis are seen. 

If other tests for alternative causes of liver injury are negative and the patient has been exposed to a drug known to be associated with liver injury in other patients, liver biopsy may not be necessary.

Serological testing

As mentioned, there are no serological tests or biomarkers specific to DILI. 

Patients with DILI who meet at least one of the following criteria are deemed to have ‘clinically significant’ liver injury: 

• AST or ALT >5x ULN or ALP >2x ULN, on at least two occasions
• Bilirubin > 2.g mg/dL in association with raised AST, ALT or ALP 
• INR > 1.5 with raised AST, ALT or ALP

Modified Hy’s law states that patients with DILI with serum bilirubin 2 or more times greater than the ULN is associated with increased mortality, and drugs demonstrating this phenomenon within clinical trials are at high risk of causing DILI when introduced to a wider population. 

In cases of idiosyncratic DILI, AST in the realm of 18 times ULN and AST to ALT ratio greater than 1.5 indicates significant risk of progression to ALF.

Radiographic findings

Imaging studies are useful in DILI to exclude venous outflow obstruction as an alternative cause of liver injury.  If there is evidence of cholestasis, imaging can also help to exclude obstruction within the biliary tree.

Management

Immediate cessation of the offending therapeutic agent once DILI is suspected is vital. 

In some instances, there is a case for the use of corticosteroid therapy, particularly when an immune-mediated aetiology is suspected or in cases of DILI which demonstrate biopsy features of autoimmune hepatitis. 

Some specific treatment agents for DILI exist depending on the offending drug; among these are N-acetylcysteine for paracetamol overdose and L-carnitine for valproic acid overdose. N-acetylcysteine occasionally also has a role in the treatment of non-paracetamol induced ALF, particularly when identified early in the disease course. 

There is no evidence at present in support of the use of ursodeoxycholic acid in cholestatic DILI with pruritus but its use is common in practice.

Acute Liver Failure

Approximately 4% of case idiosyncratic DILI progress to acute liver failure (ALF). Factors increasing the likelihood of developing ALF include hepatocellular DILI and female gender. 

The most common drugs responsible for DILI which progresses to ALF include anti-tuberculosis medications, herbal/complementary medicines and dietary supplements, co-amoxiclav, nitrofurantoin, sulfa-based drugs, phenytoin and valproate. 

In cases of drug-induced ALF, early discussion regarding liver transplantation is crucial as survival without transplant is poor (27% at 3 weeks). Evidence suggests steroids confer little survival benefit in ALF.

Prognosis

Prognosis is variable dependent on the classification of DILI. Studies have demonstrated that: 

• The majority of cases of DILI resolve after cessation of the causative agent / reduction in dosage.
• 17% progress to chronic DILI (abnormal liver function tests for greater than 6 months)
• 10% require liver transplantation and/or lead to mortality as a result of liver failure.  
• An underlying mechanism which is hepatocellular rather than cholestatic confers a greater likelihood of requiring liver transplant and shows higher mortality. 
• Conversely, cholestatic DILI is more likely than hepatocellular DILI to progress to chronic liver disease.

Adverse Reactions of Specific Drugs

Angiotensin-Converting Enzyme (ACE)-inhibitors

Indications

Angiotensin-converting enzyme (ACE) inhibitors are used in the treatment of hypertension, heart failure, diabetic nephropathy, and coronary artery disease.

Mechanism of action

ACE-inhibitors block angiotensin-converting enzyme, which acts to convert angiotensin I to angiotensin II. Angiotensin II is responsible for:

• producing vasoconstriction of precapillary arterioles and postcapillary venules
• the production and release of aldosterone
• inhibiting norepinephrine reuptake
• stimulating the adrenal medulla to release catecholamines
• the hypertrophy of smooth muscle cells within blood vessels and cardiac myocytes
• reducing excretion of water and sodium within urine.

The majority of side effects produced by ACE-inhibitors are therefore a result of reduced angiotensin II production, which results in increased urinary excretion of water and sodium, reduced arterial and venous pressure, and reduced hypertrophy of vascular and cardiac musculature.

Examples

Ramipril, lisinopril, enalapril, captopril, fosinopril.

Adverse effects

Adverse drug effect	Mechanism	Comments
Dry cough	Precise mechanism unknown; postulated to be due to increased local concentrations of kinins and substance P. These substances are metabolised by ACE; concentrations are therefore increased with ACE inhibitor use. This may lead to stimulation of sensory (C-) fibres present in the upper airway. ACE inhibition may also lead to increased levels of thromboxane via activation of the arachidonic pathway, which may cause bronchoconstriction.	Usually begins 1-2 weeks of starting therapy and resolves within 1-4 days of discontinuation. Females more commonly affected than males. Patients should be switched to angiotensin II receptor blocker.
Hypotension	Reduced angiotensin II production, which results in increased urinary excretion of water and sodium and reduced arterial and venous pressure.	May manifest as dizziness, weakness or syncope. May be seen in volume-depleted patients or those with heart failure. Commencement at low dose e.g. 2.5mg enalapril BD can reduce effect.
Impaired renal function	Reduced glomerular filtration rate (GFR); more commonly seen in patients with pre-existing chronic kidney disease (CKD), bilateral renal artery stenosis, heart failure, polycystic kidney disease. Believed a result of pre-existing reduction in intrarenal perfusion pressure, with a resulting angiotensin II-induced increase in postglomerular arteriole resistance. Reduced angiotensin II will therefore lower intraglomerular pressure and reduce GFR.	Rise in serum creatinine seen 3-5 days after institution of ACE-inhibitor. Most often GFR reduces by 5-25% but can be >30%. If serum creatinine rises >30% above baseline within 6-8 weeks, ACE-inhibitor should be discontinued.
Hyperkalaemia	Aldosterone is the main hormone that stimulates urinary potassium excretion. Angiotensin II increases aldosterone production, so reduction of angiotensin II with ACE-inhibitor use increases serum potassium concentration.	Usually only mild increase in serum potassium seen in patients with normal renal function; more severe in CKD, diabetes, older patients, and simultaneous use of potassium-sparing diuretics or NSAIDs.
Anaemia	Suppression of erythropoietin production; increased risk in presence of CKD. In this setting, the accumulation of N-acetyl-seryl-aspartyl-lysyl-proline suppresses stem cell division.
Angioedema / anaphylactoid reactions	ACE is involved in the metabolism of bradykinin, its metabolite, des-Arg9-BK, and substance P. The accumulation of these three peptides during ACE-inhibition leads to an increase in secondary metabolic enzymes which predispose patients to developing angioedema.	Risk factors include history of previous angioedema, female gender, age over 65 years, concurrent aspirin/NSAID use, smoking and genetic factors.
Pancreatitis	Precise mechanism unknown; may be a result of angioedema of pancreatic duct resulting in obstruction
Complications in pregnancy	ACE-inhibitors are contraindicated during pregnancy; they cross the placenta and reduce fetal angiotensin II levels, which are normally required to maintain fetal GFR. Exposure in second and third trimesters leads to impaired renal function and can lead to oligohydramnios and renal failure after delivery. Little is known about first-trimester exposure but there is a higher risk of major congenital malformations compared with nonexposed foetuses.

Table 8: Adverse Effects

Amiodarone

Indications

The main indications for amiodarone are: 

• atrial arrhythmias (restoration and maintenance of sinus rhythm in patients with atrial fibrillation, ventricular rate control in atrial fibrillation with rapid ventricular response, atrial flutter, atrial tachycardias)
• ventricular arrhythmias (ventricular premature beats, non-sustained ventricular tachycardia, sustained ventricular tachycardia and ventricular fibrillation)
• secondary prevention of ventricular arrhythmias in patients with implantable cardioverter-defibrillators (ICD) 
• for resuscitation during cardiac arrest in patients with a shockable rhythm, after 3 shocks have been delivered.

Drug class and mechanism of action

Amiodarone is a class III antiarrhythmic agent. It blocks potassium channels within cardiac tissues, thus blocking outward flowing potassium currents. This influences the cardiac excitation process by prolonging the repolarisation time, action potential duration and refractory period. It also exerts effects on calcium channels, adrenergic receptors, and blocks sodium channels in the depolarised state, particularly the late sodium current. 

Adverse effects

Adverse effects of amiodarone will be subdivided into pulmonary toxicity, thyroid toxicity, cardiac toxicity, hepatoxicity, adverse ocular effects, and adverse dermatological effects.

Pulmonary toxicity

Pulmonary toxicity is one of the commonest adverse effects of amiodarone. Pulmonary toxicity may take several weeks to several years to develop. The most common form of pulmonary toxicity secondary to long-term exposure to amiodarone is chronic interstitial pneumonitis, the typical presentation of which is dyspnoea, dry cough, pleuritic pain, fever and weight loss. Other forms of pulmonary toxicity that have been demonstrated secondary to amiodarone therapy include:

• eosinophilic pneumonia
• organising pneumonia
• alveolar haemorrhage
• pulmonary nodules
• acute respiratory distress syndrome. 

The pathogenesis of pulmonary toxicity is thought to occur either through direct cytotoxicity, or via an indirect immune-mediated reaction (for further details see ‘Drug-induced interstitial lung disease’ section of this chapter). Risk factors include higher cumulative doses, higher daily doses, increased age and pre-existing lung disease. Treatment includes drug discontinuation and systemic corticosteroid therapy.

Thyroid toxicity

Thyroid toxicity may be the commonest adverse reaction to amiodarone. Again, higher individual doses and higher cumulative doses are risk factors. Pre-existing thyroid pathology and iodine intake influence the nature of thyroid dysfunction that occurs; both hypothyroidism and hyperthyroidism are seen as a result of amiodarone use. Their presentation is similar to non-iatrogenic hypo- and hyperthyroidism respectively, but the beta-blocking effect of amiodarone may make symptoms of hyperthyroidism harder to detect. The effects of amiodarone on thyroid function are due to both its iodine content and its intrinsic drug properties.

Intrinsic drug effects of amiodarone on thyroid function are as follows:

• inhibition of 5’-monodeiodination of thyroxine (T4) outer ring and resulting reduction in triiodothyronine (T3) production
• reduced T3-nuclear receptor binding due to direct blocking by amiodarone molecules and its metabolites, leading to diminished expression of certain genes involved in thyroid hormone production
• direct toxic effect on thyroid follicular cells causing a destructive thyroiditis.

The iodine-related effects of amiodarone are:

• development of goitre and hypothyroidism in patients with underlying Hashimoto’s disease, due increased iodine load and disruption of the normal mechanisms that inhibit iodine transport and thyroid hormone synthesis when iodine levels are raised
• increased thyroid hormone synthesis and thyrotoxicosis in patients with a nodular goitre containing regions of thyroid tissue that function autonomously.

Individuals with underlying Hashimoto’s thyroiditis or positive antithyroid antibodies are more likely to develop hypothyroidism secondary to amiodarone therapy. Those with underlying multinodular goitre or latent Graves’ disease are at risk of developing hyperthyroidism, as the excess iodine from amiodarone leads to increased thyroid hormone production. 

In parts of the world where individuals tend to be iodine-replete, amiodarone induced hypothyroidism is more common than hyperthyroidism; however, in regions that are iodine-deficient, the opposite is true. Patients with hypothyroidism can be treated with thyroid hormone replacement and may be able to continue on amiodarone therapy, while those with hyperthyroidism may require cessation of amiodarone and treatment with an alternative antiarrhythmic medication; endocrinologist input is also required in the management of amiodarone-induced hyperthyroidism.

Cardiac toxicity

Cardiotoxic effect	Mechanism
Excessive bradycardia and atrioventricular (AV) block	Predominantly due to calcium channel blocking effect of amiodarone
QT prolongation	Prolongation of the QT interval is an expected effect of amiodarone; in very rare instances, this can lead to pro-arrhythmia. Exact mechanisms are not known; more likely to occur in concurrence with other factors contributing to prolonged QT interval (hypokalaemia, hypomagnesaemia, use of other QT-prolonging drugs).
Interaction with implantable cardioverter-defibrillators (ICDs)	Causes slowing of ventricular rate which may prevent ventricular tachycardia recognition by device; amiodarone metabolite (desethylamiodarone) increases defibrillation threshold at higher doses.

Table 9: Cardiac Toxicity

Hepatotoxicity

Around one quarter of patients demonstrate a transient rise in serum aminotransferase levels after amiodarone is initiated. A much smaller proportion of patients (around 3%) develop symptomatic hepatitis, which may progress in some circumstances to cirrhosis, and liver failure. A rise in bilirubin and clinical jaundice can also be seen with amiodarone use. The hepatic effects of amiodarone are believed due to both direct hepatotoxicity of the drug, and idiosyncratic effects of its metabolites.

Adverse ocular effects

The two main ocular effects of amiodarone to be aware of are corneal micro-deposition and optic neuropathy. 

Corneal microdeposits are present in most patients on long-term amiodarone treatment and rarely affect vision, or produce only mild effects. They occur due to secretion within tears produced by the lacrimal gland, and accumulate on the corneal surface at the junction of the lower third and upper two thirds of the cornea, in a pattern resembling cat’s whiskers. Visual acuity is not affected, but a minority of patients may complain of halos around lights, visual blurring or photophobia. 

Optic neuropathy can occur secondary to amiodarone therapy and cause unilateral or bilateral visual loss. It has the potential to progress to permanent blindness, and therefore cessation of amiodarone therapy and treatment with an alternative antiarrhythmic drug is advised where possible in the event of this adverse drug effect. More evidence is required to determine whether this effect is related to the duration of amiodarone therapy.

Warfarin

Indications

Warfarin is used for its anticoagulation properties for the prevention or treatment of thromboembolic disease. Those conditions in which it may be used include: 

• prosthetic heart valves 
• antiphospholipid syndrome
• atrial fibrillation (AF)
• venous thromboembolism including deep vein thrombosis and pulmonary embolism. 

Note that in the settings of AF and venous thromboembolic disease, direct oral anticoagulants (DOAC) are the preferred drug to achieve anticoagulation due to reduced bleeding risk (particularly relevant in older adults) and reduced need for international normalised ratio (INR) monitoring. There are some situations, however, when warfarin may be chosen, for example due to lower cost, liver or renal impairment, extremes of body weight, patient preference, and availability of and familiarity with reversal agents.

Drug class and mechanism of action

Warfarin is a vitamin-K antagonist. It is a coumarin derivative which produces its anticoagulant effects by inhibiting the hepatic vitamin K epoxide reductase complex. Inhibition of this complex results in decreased levels of vitamin K in its reduced form, which normally acts as a cofactor for gamma-carboxylation of vitamin K-dependent clotting factors (II [prothrombin], VII, IX and X), and proteins C and S. These vitamin-K dependent clotting factors therefore cannot function to promote haemostasis, as they cannot bind calcium and phospholipid membranes.

Adverse effects

Bleeding

In reducing the risk of thrombosis, warfarin simultaneously increases the risk of bleeding. Whilst warfarin technically doesn’t itself cause bleeding, in the incidence of a damage to a blood vessel wall, haemostasis is impaired as a result of warfarin therapy, leading to increased likelihood of significant haemorrhage.  Factors which increase the risk of bleeding in patients treated with warfarin include supratherapeutic INR, older age, prior bleeding, and comorbidities such as pre-existing bleeding disorders, diabetes, hepatic pathology, renal pathology and malignancy. Bleeding risk can be mediated by careful selection of the most suitable anticoagulation therapy taking into account individual patient factors; close INR monitoring and careful dose adjustment as required; thorough counselling regarding adherence; and addressing modifiable risk factors such as hypertension, renal and hepatic disease, falls prevention, and limiting use of drugs increasing bleeding risk (such as antiplatelets and interacting medications). The treatment of supratherapeutic INR and/or bleeding in patients taking warfarin may be managed by the administration of vitamin K, prothrombin complex concentrate, and in some situations, tranexamic acid, dependent on the severity of bleeding and the INR value.

Skin necrosis

Skin necrosis may be seen and is most likely within the first few days following initiation of warfarin anticoagulation, particularly when larger doses are used. It occurs most commonly on the trunk, digits, penis, and breast tissue. The mechanism is believed to be due to a reduction in protein C levels. 

Cholesterol embolization

Cholesterol embolization is a rare complication of warfarin use. It occurs due to embolization of cholesterol crystals and presents as dark purple mottling of the soles of the feet and the lateral aspects of the toes. It has been referred to as ‘blue toe syndrome’. 

Vascular calcification

Studies have demonstrated that coronary, femoral and aortic artery calcification increases in a significant proportion of patients taking warfarin therapy, and that this increases duration of therapy increases. However, there is no evidence to suggest that there is an associated increased risk of related clinical events (myocardial infarction, stroke, or peripheral vascular disease).

Teratogenicity

Warfarin has a dose-related teratogenic effect. It carries the highest risk during the 6th and 12th weeks of gestation. Most commonly, teratogenic effects manifest as abnormalities of cartilage and bone development, for example chondrodysplasia punctata (causing calcific stippling of cartilage and other soft tissues surrounding bony articulations) and hypoplasia of the limbs. The mechanism for these effects is unclear.

Glucocorticoid therapy

Indications

Glucocorticoid therapy may take the form of systemic (intravenous or oral), topical, inhaled, or intraarticular therapy. This section will focus specifically on the adverse effects of systemic therapy. The indications for glucocorticoid therapy are numerous, but in general it is used for autoimmune, allergic, and inflammatory diseases; it may also be used to establish a diagnosis of Cushing’s syndrome, and to treat adrenal insufficiency. Examples of glucocorticoids include prednisolone, prednisone, methylprednisolone, dexamethasone, triamcinolone, and betamethasone.

Mechanism of action

Glucocorticoids are hormones released as a physiological response to stress (primary stress hormones). Adrenal glucocorticoid release is under the control of the hypothalamic-pituitary-axis (HPA). Synthetic derivatives of glucocorticoid hormones are used to treat a wide range of inflammatory and immune disorders. Glucocorticoid molecules act via the intracellular glucocorticoid receptor (GR) found within a variety of tissues, with different tissues showing variability in responses to GR binding due to differences in GR variants. GRs are activated as a result of glucocorticoid molecule binding, and subsequently up- or downregulate the expression of many genes via direct DNA binding. GRs also function via non-genomic pathways, which are poorly understood. The effects of exogenous glucocorticoid administration result largely from either suppression of the HPA, or the development of iatrogenic Cushing’s syndrome.

Adverse effects

Cardiovascular 

At higher doses, glucocorticoids promote fluid retention. Patients with pre-existing cardiac and renal disease are at particular risk of this effect. Hypertension is also seen, again particularly in those on higher-dose therapy, and is present in 20% of patients diagnosed with iatrogenic Cushing’s syndrome. Patients receiving glucocorticoid therapy are at higher risk of myocardial infarction, angina, stroke, transient ischaemic attack, and heart failure. The risk of developing atrial fibrillation, atrial flutter, and sudden cardiac death is also reportedly higher in patients receiving glucocorticoids.

Endocrine /metabolic 

Hyperglycaemia is a notable metabolic effect of patients receiving glucocorticoid therapy. The effect is dose-related. In patients without pre-existing diabetes, the largest increase is seen in postprandial blood glucose levels; a less marked increase is also demonstrated in fasting glucose levels. The development of diabetes mellitus as a result of glucocorticoid therapy in patients with previously normal glucose tolerance is rare. In patients with pre-existing diabetes, an increase in blood glucose levels, and thus challenging diabetic control, may be seen. Patients with early previously undiagnosed diabetes or impaired glucose tolerance may develop diabetic ketoacidosis or hyperglycaemic hyperosmolar state. The mechanism by which glucocorticoids result in hyperglycaemia is believed to be attributable to a combination of factors, including receptor functions, increased hepatic gluconeogenesis, and reduced uptake of glucose in adipose tissue. 

A second endocrine effect of glucocorticoids is inhibition of the HPA, with abrupt withdrawal of exogenous glucocorticoid leading to acute adrenal insufficiency and associated hypotension and/or shock. Additional features such as weakness, nausea, vomiting, anorexia, fever and confusion are commonly seen in the event of adrenal crisis.  Thus, a tapering regimen is recommended in patients receiving glucocorticoids for greater than 2 weeks.

Bone

Glucocorticoid use is associated with reduction in bone mineral density leading to osteoporosis. The risk of osteoporotic fracture is also increased. This effect is a result of both increased bone resorption through stimulation of osteoclast proliferation and differentiation, and reduced bone formation as a result of inhibition of osteoblast development. Vertebral fractures are the most common. These phenomena of osteoporosis and fractures are most often seen in the first few months of treatment with glucocorticoids. Osteonecrosis is also seen with high-dose steroid use. The mechanism for this is unclear but one proposed theory is that glucocorticoids stimulate an increase in circulating lipids which result in microembolism within arterial supply to bones.

Muscle

Occasionally, myopathy is seen as a result of glucocorticoid therapy. This manifests as painless proximal weakness in the upper and lower limbs. The pathogenesis of this relates to both catabolic and anti-anabolic effects of glucocorticoids, likely mediated through muscle glucocorticoid receptors. 

Gastrointestinal 

The main gastrointestinal (GI) side effects of glucocorticoids are gastritis, ulcer formation, and gastrointestinal bleeding. This risk is significantly increased when glucocorticoids are used concurrently with non-steroidal anti-inflammatory drugs (NSAIDs). Further possible GI effects include gastrointestinal tract perforation, hepatic steatosis and even cirrhosis. There is mixed evidence as to whether they may cause acute pancreatitis; some studies suggest that the underlying disease for which glucocorticoids are indicated, for example systemic lupus erythematosus (SLE), is in fact the causative factor making this more likely in patients taking glucocorticoids.

Neuropsychiatric 

Psychiatric and cognitive effects seen include emotional lability, mania, hypomania, depression, psychosis confusion, delirium, and memory impairment. These tend to be dependent on glucocorticoid dose and duration of therapy. Older patients are particularly at increased risk of particular mood and memory disturbances, including depression, mania and hypomania, confusion, delirium and memory impairment. ‘Steroid dementia’ is a term given to a phenomenon whereby severe memory impairment develops in smaller group of patients (approximately 1%), which may persist for up to 11 months following cessation of treatment. Often reported are also disturbances in sleep, which results particularly from evening doses which disrupts the normal diurnal pattern of endogenous cortisol release. 

Mood disorders in glucocorticoid use typically take the form of a sense of euphoria, hypomania, mania, or anxiety within the first few days. Symptoms are more severe in higher-dose therapy. In longer-term therapy, depression is more commonly seen. Psychosis may be seen, but this is almost exclusively seen in patients on long term therapy and high doses (at least 20mg prednisolone per day). These patients tend to respond well to antipsychotic medication. An increased risk of suicide is reported in patients taking glucocorticoids, in particular in younger patient groups (however absolute risk is low). 

Rarer reported neuropsychiatric effects include pseudotumour cerebri, panic disorder and akathisia.

Ophthalmic

The main ophthalmic effects of glucocorticoids are cataract and glaucoma. Cataracts occur in patients on long-term therapy and this is a dose-related effect. Most commonly they are posterior subcapsular cataracts and are usually seen bilaterally. 

Raised intraocular pressure occurs more commonly in patients using topical steroid therapy (i.e. eye drops, and dermatological use on the eyelids and in the periorbital region) but it can also be seen with systemic therapy, particularly in long term use. While the pathogenesis is not certain, it is believed to be a result of reduced drainage through the trabecular meshwork. 

More rarely, lid swelling and exophthalmos can be seen in association with glucocorticoid use.

Dermatologic 

Skin thinning and bruising are commonly seen and can occur even with low daily doses of glucocorticoid use. The prevalence of these features has been shown to increase with higher doses. 

Cushingoid features of central obesity, moon facies and buffalo hump can be seen within the first two months of glucocorticoid use, but the prevalence again increases with increasing dose and duration of therapy. While the prevalence of Cushingoid features shows a linear effect with relation to dose, weight gain shows a threshold effect, with no significant change in weight seen below 5mg per day or above 7.5mg per day of prednisolone. 

Acne, facial erythema, striae, and hirsutism are additional dermatologic effects seen in association with glucocorticoid use.

Immune 

There is a dose-related increase in the risk of infection with glucocorticoid use. Infectious pathogens are typically common bacteria, viruses and fungi. This is mediated via effects on both innate and acquired immunity. The main mechanisms of glucocorticoid effects on the immune system are via its direct effects on DNA, which result in:

• increased production of anti-inflammatory gene products (e.g. I-kappa-B-alpha, interleukin-1 receptor II)
• blocking the effects of pro-inflammatory genes (e.g. interleukin-1 alpha and beta) 
• inhibition of cytokine synthesis. 

Clinical features of infection may be masked by glucocorticoid use, making it more difficult to detect, as a result of inhibition of cytokine release and dampened inflammatory response.

Haematologic 

Glucocorticoid therapy induces a leukocytosis, which is largely a neutrophilia. This results from a reduction in the adherence of neutrophils to the vascular endothelium, and increased mobilisation of granulocytes from the bone marrow.

Anti-epileptic drugs

Antiepileptic drugs (AEDs) form a group of drugs that encompasses a wide range of medications which fall into several discrete classes of drugs. The drug classes have differing pharmacological properties and mechanisms of action, and hence differing side effect profiles. Here, some of the commonest mechanisms of action of AEDs will be reviewed, then some of the more commonly used AEDs and their side effect profiles will be discussed individually. 

Mechanisms of action

AEDs may be classified on the basis of their mechanism, although it should be noted that several drugs exert their effects via multiple mechanisms; furthermore, for some specific drugs the mechanism is unknown.

Drugs which block sodium currents

The most common mechanism via which AEDs act is via voltage-gated sodium-channel inhibition. Voltage-gated sodium channels contribute to the generation and propagation of action potentials in neurons. Sodium channels in the brain have roles within both inhibitory interneurons and excitatory neurons. When neurons are hyperpolarised, voltage-gated sodium channels are closed (resting); during depolarisation they open; and they close again and become inactivated in the period after depolarisation. The action of most AEDs which influence voltage-gated sodium channels results from binding when the channel is in the inactivated state, thus prolonging the period of inactivity and delaying the transition from the inactivated state to the resting state. Prolongation of this inactivated state inhibits high-frequency repetitive firing of action potentials. This inhibition of repetitive firing acts to inhibit seizure-related neuron firing.

Examples: 

• Phenytoin
• Carbamazepine
• Lamotrigine
• Oxcarbazepine
• Lacosamide
• Topiramate

Drugs which block calcium currents

AEDs may also act to inhibit voltage-gated calcium channels. There are two ways in which this effect may inhibit seizure activity; first, through inhibition of T-type calcium channels, which are normally involved in the generation of oscillatory neuronal activity in thalamo-cortical pathways, and are of particular benefit in the treatment of absence seizures; second, via inhibition of neuronal N- and P/Q type calcium channels, thus reducing the release of glutamate into the synapse.

Examples:

• Ethosuximide
• Valproate
• Gabapentin
• Pregabalin

Drugs which enhance GABA-ergic chloride currents

GABA is an inhibitory neurotransmitter acting on GABAA and GABAB receptors. GABAA receptors mediate neuronal excitability through tonic and phasic inhibition. Phasic inhibition refers to the modulation of transient, rapidly degrading currents, while modulation of longer-lasting, slowly degrading currents is known as tonic inhibition. GABAergic AEDs act by enhancing inhibitory activity; this is through a variety of effects, including allosteric binding to GABAA which increasing the affinity of GABA binding, increasing the concentration of synaptic GABA, and prolonging the duration and/or increasing the frequency of chloride channel activation that occurs as a result of GABAA activation.

Examples:

• Valproate
• Benzodiazepines
• Vigabatrin
• Topiramate

Drugs which block glutamatergic currents

Glutamate is an excitatory neurotransmitter. Glutamate binds to postsynaptic receptors and hence increase cationic conductance and promote neuronal depolarisation. Although few AEDs act exclusively at glutamate receptors, several exert some of their action via this pathway by blocking receptor binding and blocking excitatory glutamatergic activity. Several AEDs also exert an inhibitory effect on neuronal firing through inhibition of presynaptic glutamate release. This effect is a result of blockade of sodium and calcium channels.

Examples: 

• Topiramate
• Levetiracetam
• Phenobarbital

Specific AEDs and their associated adverse effects

Benzodiazepines

• Sedation
• Withdrawal seizures with abrupt cessation
• Ataxia
• Dysarthria
• Depressed mood
• Behavioural changes / aggression

Carbamazepine

• Bone marrow suppression
• Toxic epidermal necrolysis (TEN) or Stevens-Johson Syndrome (SJS)
• Hyponatraemia
• Rash
• Fluid retention
• Nausea and vomiting
• Diarrhoea

Phenytoin / fosphenytoin 

• Gingival hyperplasia 
• Rash – rarely SJS / TEN
• Increase in body hair
• Reduced bone mineral density
• Folate deficiency 
• Confusion 
• Diplopia
• Ataxia 
• Peripheral neuropathy
• Sexual dysfunction

Valproate

• Nausea and vomiting
• Ecchymosis
• Weight gain
• Metabolic syndrome 
• Thrombocytopenia
• Subclinical hypothyroidism
• Polycystic ovarian syndrome 
• Teratogenic effects 
• Acute liver injury
• Acute pancreatitis
• Hyperammonaemic encephalopathy

Ethosuximide

• Sleep disturbance
• Sedation
• Nausea and vomiting 

Gabapentin

• Sedation
• Ataxia
• Weight gain
• Risk of respiratory depression in overdose and concurrent opioid administration

Pregabalin

• Sedation
• Ataxia
• Dizziness 
• Increased body habitus
• Fluid retention
• Diplopia 
• Weakness 
• Tremor
• Mood disturbance

Lacosamide

• PR interval prolongation on electrocardiogram (ECG) – therefore caution advised in patients with pre-existing conduction disease and other medications which may enhance this effect
• Nausea and vomiting
• Ataxia
• Vertigo 

Topiramate

• Cognitive impairment
• Sedation
• Fatigue
• Weight loss 
• Mood disturbance
• Metabolic acidosis
• Renal calculi 
• Reduced bone mineral density
• Ophthalmological effects including acute angle closure glaucoma and acute myopia

Lamotrigine

• Nausea 
• Dizziness 
• Sedation 
• Rash, including risk of TEN/SJS
• Cardiac arrhythmias 
• Drug reaction with eosinophilia and systemic symptoms (DRESS) (rare) 
• Haemophagocytic lymphohistiocytosis (rare) 
• Disseminated intravascular coagulation (rare) 

Levetiracetam

• Acute behaviour disturbance or psychosis
• Sedation 
• Dizziness 
• Predisposition to upper respiratory tract infections

Phenobarbital

• Sedation
• Mood disturbance 
• Behavioural change
• Reduced bone mineral density
• Palmar fascia thickening 
• Frozen shoulder 
• Teratogenic effects

Oxcarbazepine

• Sedation 
• Vertigo
• Hyponatraemia
• Headache
• Rash – rarely SJS, TEN
• Anaphylaxis / angioedema (rare) 
• Pancytopenia / agranulocytosis

Vigabatrin

• Sedation
• Headache
• Dizziness
• Depressed mood
• Increased body habitus 
• Hypersensitivity reactions
• Irreversible visual field defects

First generation anti-psychotic drugs

Antipsychotic medications, used in the treatment of acute psychosis, chronic schizophrenia, bipolar disorder and treatment-resistant depression, are divided into two classes: first-generation (or “typical”) antipsychotics, and second-generation (or “atypical) antipsychotics. 

First- and second-generation antipsychotics differ both in their mechanism of action, and in their side effect profile; however, it should be noted that there exist significant areas of overlap with regards to adverse drug effects between the two classes. Furthermore, individual drug types exhibit differences in their side effect profiles when compared with other members of the same antipsychotic class. Generally speaking, first-generation antipsychotics (FGAs) are more likely to cause extra-pyramidal side effects (EPSEs) and tardive dyskinesias than second-generation antipsychotics (SGAs). While metabolic disturbance is more typically associated with SGAs than FGAs, emerging evidence suggests this in fact occurs in both classes with similar frequency.

Mechanism of action

The primary mechanism of action of FGAs is thought to be via neuronal dopamine-2 (D2) receptor antagonism; activity at muscarinic, histaminergic, 5-HT2a and alpha-1 receptors is also seen.

Examples

• Haloperidol
• Fluphenazine
• Perphenazine 
• Pimozide
• Thiothixene
• Chlorpromazine
• Thioridazine

Adverse effects

• Extrapyramidal side effects (EPSEs) 
  • Akathisia – motor disturbance resulting in restlessness, an urge for constant movement, often accompanied by visibly excessive movements
  • Parkinsonism – rigidity, tremor, bradykinesia, cogwheeling, hypomimia 
  • Acute dystonias – this refers to involuntary contraction of a muscle group or groups, which is frequently distressing to the patient. Examples include oculogyric crisis, torticollis, opisthotonos and laryngospasm (which may be fatal without appropriate and swift management). 
• Tardive dyskinesias
  • This refers to involuntary, repetitive movements, which may involve the tongue, lips (e.g. lip-smacking), jaw, trunk, and limbs. ‘Writhing’ movements of the torso, limbs or tongue may be seen
  • Often of little concern to the patient
  • Long-term disability or cosmetic deformity may occur if not addressed.
• Metabolic complications – includes weight gain, hyperlipidaemia, diabetes mellitus and cardiovascular sequelae.
• Neuroleptic malignant syndrome – the characteristic features are muscle rigidity, altered mental status, fever and dysautonomia. Rhabdomyolysis may occur. The aetiology is unclear but a previous episode of neuroleptic malignant syndrome appears to be the biggest risk factor. 
• QT prolongation / sudden cardiac death – haloperidol, chlorpromazine and thioridazine are associated with particularly increased risk of QT prolongation. The increased incidence of sudden cardiac death seen with FGAs is attributed to prolonged QT interval. Baseline ECG and annual monitoring of the QT interval is recommended. 
• Anticholinergic side effects – such as dry mouth, urinary retention, constipation, and blurred vision; particularly seen in association with chlorpromazine and thioridazine. 
• Postural hypotension – seen most with chlorpromazine and thioridazine. The mechanism is believed to be secondary to alpha-adrenergic receptor antagonism.
• Agranulocytosis – FGAs carry a very small risk of agranulocytosis, the development of which may be fatal. It has been reported with the use of chlorpromazine, fluphenazine and thioridazine.
• Hyperprolactinaemia – this may present with menstrual cycle abnormalities, galactorrhoea, and sexual dysfunction. It occurs secondary to dopamine inhibition, hence reducing the dopaminergic inhibition of prolactin release from the anterior pituitary gland.

Other side effects of FGAs include falls, seizures, increased mortality, sexual dysfunction, retinitis pigmentosa, and cholestatic jaundice.

Second generation anti-psychotic drugs

Mechanism of action

The main mechanism of action of SGAs is via serotonin 5HT2A receptor binding and dopaminergic D2/D3 binding.

Examples 

• Aripiprazole
• Clozapine 
• Olanzapine
• Paliperidone 
• Quetiapine
• Risperidone

Adverse effects 

• Metabolic syndrome – risk appears highest with clozapine and olanzapine. 
• EPSEs – although the risk is reduced with SGAs as compared with FGAs generally, among SGAs risperidone carries the highest risk of EPSEs. This is more commonly seen at higher doses. 
• Tardive dyskinesias – this is substantially less likely to occur with SGAs than with FGAs. Of the SGAs, risperidone and aripiprazole carry relatively higher risk, while quetiapine carries a lower risk, and clozapine use is not associated with tardive dyskinesias. 
• QT prolongation / sudden cardiac death – may be seen with quetiapine, risperidone and olanzapine 
• Myocarditis / cardiomyopathy – such cardiac complications have been reported with clozapine use and are thought to result from a hypersensitivity reaction. 
• Postural hypotension – this is believed to occur secondary to alpha-adrenergic receptor antagonism and is seen across the SGAs with varying frequencies. 
• Hyperprolactinaemia – risperidone is one of the SGAs most strongly linked to hyperprolactinaemia; in contrast, this is rarely seen with clozapine, aripiprazole or quetiapine.  
• Neuroleptic malignant syndrome – while most strongly linked to FGAs, neuroleptic malignant syndrome has also been demonstrated with SGA use.
• Agranulocytosis – this is a well-recognised side effect of clozapine. Following initiation of clozapine, weekly monitoring of the differentiated white cell count should be performed for 18 weeks; two-weekly for up to 12 months after initiation; then monthly thereafter. 
• Hypersensitivity syndrome – drug reaction with eosinophilia and systemic symptoms (DRESS) has been reported with SGA use.
• Anticholinergic side effects – most commonly seen with clozapine, although note that clozapine may more commonly cause sialorrhoea than dry mouth.

Other side effects include cataract, seizures, sedation, sexual dysfunction, falls, increased mortality, and hypothyroidism.

The National Institute for Health and Care Excellence (NICE) recommends monitoring of multiple parameters during antipsychotic therapy, including:

• Weight
• Waist circumference
• Pulse
• Blood pressure
• Serum lipid levels
• Fasting glucose levels or HbA1c
• Adherence
• Development of movement disorders
• Symptomatic or behavioural changes
• Other reported side effects.

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