Liver Disease & Paracetamol Dosing

http://askdis.blogspot.com/2016/11/analgesics-used-in-hepatic-failure.html	Analgesia : In Hepatic Failure Paracetamol § In general, for long-term use in cirrhotic patients it is recommended to reduce dosing at 2 to 3 g/d. § Although such patients may eliminate paracetamol more slowly than patients without liver disease, repeated administration of the drug does not result in accumulation of hepatotoxic intermediate, NAPQI. § Furthermore, there is no evidence of increased CYP enzymes activity or reduced hepatocellular glutathione stores in patients with liver disease.
Can paracetamol (acetaminophen) be administered to patients with liver impairment? [Hayward et al 2016] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4833155/#!po=20.3704	Nevertheless, the conservative recommendations that followed the publication of the Watkins et al. 62 paper made by leading bodies of ‘at risk’ populations persist. For example, the American Liver Foundation recommended patients not exceed 3 g of paracetamol daily and the American Geriatric Society suggested no more than 2−3 g daily in older patients with hepatic insufficiency or a history of alcohol abuse. McNeil Laboratories self‐initiated packaging changes to recommend a 3 g daily maximum on their Tylenol products, and the FDA's pursuit to discourage prescribers from recommending products that contain more than 325 mg paracetamol per dosage unit is ongoing. It must be noted that these generalized recommendations may not be applicable to all patients, and sub‐therapeutic dosing may accelerate progression to stronger analgesics.
The Therapeutic Use of Analgesics in Patients With Liver Cirrhosis: A Literature Review and Evidence-Based Recommendations [Imani et al 2014]	Paracetamol is safe in patients with chronic liver disease but a reduced dose of 2-3 g/d is recommended for long-term use. Non-steroidal anti-inflammatory drugs (NSAIDs) are best avoided because of risk of renal impairment, hepatorenal syndrome, and gastrointestinal hemorrhage. Most opioids can have deleterious effects in patients with cirrhosis. They have an increased risk of toxicity and hepatic encephalopathy. They should be administrated with lower and less frequent dosing in these patients and be avoided in patients with a history of encephalopathy or addiction to any substance. Despite renal disease, in which the glomerular filtration rate is the metric used to guide dose adjustment, there is no reliable marker for liver disease severity and hepatic clearance that can be used as a guide for drug dosing. Though various tests like liver function test, indocyanine green clearance, megaxx, Child Pugh score, and MELD score are used for prediction of impaired liver function, they all lack the sensitivity to quantitate the specific ability of the liver to metabolize individual drugs. Thus the usefulness of these measures for dose adjustment purposes is imprecise. As a general rule, in patients with well-compensated cirrhosis and near-normal liver synthetic function (normal hepatic synthetic function, normal serum albumin, clotting factors and bilirubin), drug pharmacokinetics are unchanged or modified only to a small extent as compared to patients with decompensated cirrhosis with portal hypertension and significant synthetic dysfunction Paracetamol is commonly used as a first choice analgesic for different nociceptive acute or chronic pain and remains one of the safest available analgesics. However, the use of this drug in patients with hepatic disease is often avoided. This perception arose from awareness of hepatotoxic effect of paracetamol overdose and a lack of understanding its metabolic pathway in patients with liver disease. It is known that the majority of paracetamol is metabolized via the sulfation and glucuronidation pathways into nontoxic products which are then excreted via the urine. However, a small proportion (< 5%) is oxidized via CYP system, mostly CYP2E1, to a hepatotoxic intermediate, N-acetyl-p-benzoquinone imine (NAPQI), which is readily rendered nontoxic by conjugation to glutathione . Pharmacokinetic studies have indicated an increase in the elimination half-life (t ½) of paracetamol in patients with liver cirrhosis compared with healthy controls. Meanwhile, the plasma clearance of the drug was shown to be reduced in these patients (18-20). However, the t ½ of the drug or its plasma clearance has been found to be correlated with prothrombin time as well as the plasma albumin levels. The theoretical mechanisms of paracetamol-induced hepatotoxicity in chronic cirrhotic patients involves altered metabolism via CYP activity and depleted glutathione stores that cause accumulation of a hepatotoxic intermediate, NAPQI. However, available studies in these patients group have shown that although the half-life of paracetamol may be prolonged, CYP activity is not increased (potentially leading to a lesser degree of NAPQI formation) and glutathione stores are generally sufficient to avoid paracetamol hepatotoxicity (21). As a result, a number of studies claimed that concerns about administration of therapeutic doses of paracetamol in the cirrhotic patients are often inaccurate (21). Different available studies have evaluated the safety and efficacy of paracetamol administration in cirrhotic patients. It has been indicated that for short-term use or 1-time dosing, up to 4 g/d appears to be well tolerated for both healthy and cirrhotic individuals, using alcohol regularly (22, 23). This assumption is supported by a double-blind, crossover study of 20 patients with chronic liver disease (including 8 cirrhosis), who tolerated paracetamol at a dosage of 4 g/d for 13 days without adverse effects (21). In other survey conducted by Lucena et al. (24), paracetamol was safely used as a dosage of 3 g/d even in those with alcoholic cirrhosis. The findings of another case control study evaluating the implication of paracetamol in patients with cirrhosis suggested no association between the occasional use of low dose paracetamol (2-3 g/d) and the acute decompensation of cirrhosis (25). Nonetheless, another study reported the elevation of aspartate aminotransferase (AST) levels in healthy adults, receiving 4 g/d for 14 days (26). Based on this finding, in 2006, the American Liver Foundation (ALF) issued recommendations that people not exceed 3 g/d of acetaminophen for any prolonged period of time (27). The ALF noted no issue with short-term use of 4 g/d. On the basis of data from different studies and with the new FDA guidelines in mind current recommendation for long-term acetaminophen use (> 14 days) in cirrhotic patients (not actively drinking alcohol) is for reduced dosing at 2 to 3 g/d (21, 28). Because of its proven safety profile (when given in recommended doses) and the lack of sedative effects and absence of nephrotoxicity, paracetamol is the preferred analgesic in patients with liver disease including cirrhosis. However, because paracetamol overdose is known as one of the most common cause of liver failure, it is not surprising that the majority of pain practitioners are not willing to prescribe it to patients with any form of liver disease.
Medicines Issues in Liver Disease https://www.ukmi.nhs.uk/NonCMS/conferenceDB2011/presentations/201102_01_Medicinesissuesinliverdisease.pdf	Paracetamol Use *  Use in mild hepatitis?   Yes (caution alcoholics) *  In cholestasis?    Yes *  In cirrhosis?    Yes, Suggest to reduce to TDS in severe decompensated cirrhosis *  In acute liver failure?    Yes – possibly reduce to TDS ; HOWEVER, NOT if cause of ALF is POD!
https://www.practicalpainmanagement.com/treatments/pharmacological/non-opioids/safe-usage-analgesics-patients-chronic-liver-disease-review	In 2006, the American Liver Foundation (ALF) issued recommendations that patients not exceed 3 grams a day of acetaminophen for any "prolonged period of time." They pointed to a study that reported aspartate aminotransferase (AST) levels were elevated in healthy patients receiving 4 grams per day for 14 days. The ALF noted no issue with short-term use of 4 gram dosing. Burns et al recommended that for patients with chronic active alcohol ingestion and cirrhosis, acetaminophen may be used at a maximum of 2 grams per day, which is one-half the recommended daily dose (well below toxicity levels). In addition, the 2013 American Chronic Pain Association stated that although the maximum recommended adult dose for acetaminophen is 4 grams per day, and 3 grams per day in older persons, patients can have asymptomatic elevations in liver enzymes at 2 grams per day of acetaminophen. Some healthcare professionals encourage patients to stay well below the 4 grams per day cutoff, even in patients without chronic liver disease or other concerns. In consideration of these findings, normal recommended doses of acetaminophen can be safely given for short-term use to patients who suffer from chronic stable liver disease (CSLD), provided they do not drink alcohol or take medications that could increase CYP activity. For long-term treatment, it is prudent to limit total daily dosing in CSLD patients to 2 to 3 grams per day, until additional studies can demonstrate safety. These patients were not shown to have elevated CYP450 level, nor significantly reduced glutathione levels. While it is true that these patients may metabolize acetaminophen more slowly than their healthy counterparts, no evidence of toxic accumulation has been seen to date.
UptoDate: Analgesic use in adult patients with advanced chronic liver disease or cirrhosis	·   Glutathione tissue stores needed to block formation of acetaminophen's toxic metabolite (NAPQI) are reduced in individuals with cirrhosis or malnutrition, thereby lowering the dose threshold of acetaminophen that can be safely administered each day. ·   Active alcohol consumption further reduces available glutathione stores. ·   Half-life of acetaminophen may be prolonged by up to 2-fold compared with healthy patients. ·   Acetaminophen is generally well tolerated in patients with chronic liver disease (CLD) or cirrhosis who do not consume alcohol, provided the total daily dose is limited to no more than 2 g/day. ·   For short-term or one-time use, a maximum total acetaminophen dose of up to 4 g/day may be considered in lower risk patients who do not consume alcohol and have CLD or early stage compensated cirrhosis. ·   Warn patients concerning acetaminophen content in combination prescription analgesics (eg, oxycodone-acetaminophen) and non-prescription (OTC) preparations. ·   Avoid use in patients with advanced CLD or cirrhosis who are actively consuming alcohol, malnourished, not eating, receiving multiple medications that undergo hepatic biotransformations, or any co-administered medication that is a potent inducer of hepatic enzymes.
Uptodate: Acetaminophen (paracetamol): Drug information	Note: Safety: Acetaminophen-induced hepatotoxicity, which can be life threatening, has been associated with doses >4 g/day. Although doses up to 4 g/day are generally well tolerated (Dart 2007; Krenzelok 2012; Larson 2007; Temple 2006; Whitcomb 1994), hepatotoxicity has been reported rarely at this dose limit (Amar 2007). Due to this risk, some experts recommend a lower maximum dose of 3 g/day in adults with normal liver function, particularly when used for longer durations (eg, >7 days) for pain (Chou 2019). Heavy alcohol use, malnutrition, fasting, low body weight, advanced age, febrile illness, select liver disease, and use of drugs that interact with acetaminophen metabolism may increase risk of hepatotoxicity; a lower total daily dose (eg, 2 g/day) or avoidance may be preferred (Hamilton 2019b; Hayward 2016; Larson 2007). When calculating total daily dose, confirm that all sources (eg, prescription, OTCs, combinations) are included.

All information accessed on 18.02.2020

Dose of Acetazolamide in Hemodialysis (HD) Patient

https://www.aao.org/eyenet/article/acetazolamide-considerations-systemic-administrati American Academy of Opthalmology	Oral acetazolamide is 100 percent excreted unchanged, which means that the drug is eliminated through the kidneys and does not depend on metabolism for inactivation of the drug. Therefore, creatinine clearance (CrCl) directly influences the duration of action. Dosage adjustments in CKD. The following dosages are recommended for patients with renal compromise: If CrCl > 50 mL/min: Use full dose (250 mg four times a day or 500 mg extended-release capsule [e.g., Diamox Sequels] twice daily). If CrCl 10 to 50 mL/min: Use a half dose (250 mg twice daily). If CrCl < 10 mL/min: Do not give acetazolamide. If the patient is on hemodialysis: Use a half dose (250 mg twice daily). If the patient is on peritoneal dialysis: Use 125 mg daily.3-5 In patients with end-stage renal disease, oral acetazolamide has been found to reduce IOP only 50 percent as much as it does in healthy patients.
Micromedex	62.5 to 125 mg daily after dialysis; titrate to effect and toxicity
Medscape	20-50% Dialysable
Acetazolamide in Hemodialysis Patients: A Rational Use After Ocular Surgery [Roy et al. 1992]	250 mg STAT (loading dose), then 125 mg daily If prescribed for more than 4 days, plasma levels of acetazolamide should be measured
Acetazolamide Toxicity and Pharmacokinetics in Patients Receiving Hemodialysis [Schwennk et al. 1995]	62.5-125 mg/day would be approximate, titrated to effect, toxicity, and therapeutic drug monitoring (if available) The desired serum acetazolamide concentration range is 5-10 mcg/ml (total drug), which has been associated with maximum lowering of intraocular pressure," although some clinicians proposed a range of 15-20 mcg/ml for optimum long-term control of ocular hypertension
The Renal Drug Handbook (Third Edition, 2009)	Dose for CrCl < 10 mL/min: 250 mg daily HD: Unlike dialysability – 250 mg daily HDF (high flux): Unknown dialysability – 250 mg daily

Monitor for central nervous system toxicity, included fatigue, lethargy, and confusion

All information was accessed on 16.01.2020

Helicobacter pylori Infection

Initial Antimicrobial Therapy

Risk factors for macrolide (clarithromycin) resistance include:

**Prior exposure to macrolide therapy for any reason
**High local clarithromycin resistance rates ≥15 percent or eradication rates with clarithromycin triple therapy ≤85 percent

Bismuth quadruple therapy consists of bismuth subsalicylate, metronidazole, tetracycline, and a PPI given for 14 days. If tetracycline is not available, doxycycline (100 mg twice daily) may be substituted. Metronidazole resistance has a limited impact on eradication success rate in patients treated with bismuth quadruple therapy and can be overcome by increasing the dose, duration, or frequency of therapy.

Based on Malaysia National Antibiotic Guideline (NAG) 2019, triple therapy is recommended as first line, where a PPI can be given with either two of the following antibiotics: amoxicillin / clarithromycin / metronidazole.

Concomitant therapy consists of a clarithromycin, amoxicillin, metronidazole and a PPI administered together. If concomitant therapy is used to treat H. pylori, the regimen should be continued for 10 to 14 days. The efficacy of concomitant therapy was decreased in patients with clarithromycin-resistant H. pylori infection but to a smaller degree as compared with clarithromycin triple therapy (90% vs 78%). In the meta-analysis carried out by Gisbert JP & Calvet X (2012), longer durations of therapy (7 to 10 versus 3 to 5) were associated with a trend toward higher cure rates.

Hybrid therapy consists of amoxicillin and a PPI for seven days followed by amoxicillin, clarithromycin, metronidazole, and a PPI for seven days. Hybrid therapy has been suggested as an alternative to clarithromycin triple therapy. However, the complexity of the treatment regimen has limited its use as a first-line regimen in the treatment of H. pylori. In contrast to patients who received clarithromycin triple therapy, clarithromycin resistance did not significantly impact eradication rates in patients treated with reverse hybrid therapy (96% vs 89%).

The 10-day clarithromycin-containing sequential therapy regimen consists of amoxicillin and a PPI for five days, followed by clarithromycin and nitroimidazole (eg, metronidazole) plus a PPI for five days. Given the complexity of the sequential therapy regimen and the lack of superiority to 14 day clarithromycin triple therapy in North America, clarithromycin-containing sequential therapy has not been uniformly endorsed by guidelines as a first-line therapy.

Regimen	Drug			Frequency	Duration (days)
Triple therapy	PPI (standard* or double dose)			BD	14
	Either two		Clarithromycin (500 mg)	BD
			Amoxicillin (1 g)	BD
			Metronidazole (500 mg)	BD
Bismuth Quadraple	PPI (standard dose*)			BD	10-14 (recom-mend 14)
	Bismuth subcitrate (120-300 mg) OR Bismuth subsalicylate (300mg)			BD
	Doxycyline (100 mg) OR Tetracycline (500 mg)			BD QID
	Metronidazole  (400 mg)			TDS
Concomitant Therapy	PPI (standard* or double dose)			BD	10-14
	Clarithromycin (500 mg)			BD
	Amoxicillin (1 g)			BD
	Metronidazole (400 mg)			BD
Sequential Therapy (Clarithromycin-based)	PPI (standard dose*) plus amoxicillin (1 g) for 5 days followed by:			BD	10 (total)
	PPI, clarithromycin (500 mg) plus metronidazole (400 mg) for an additional 5 days			BD
Hybrid Therapy (Clarithromycin-based)	PPI (standard dose*) plus amoxicillin (1 g) for 7 days followed by:			BD	14 (total)
	PPI, amoxicillin, clarithromycin (500 mg), plus metronidazole (400 mg) for an additional 7 days			BD
Levofloxacin-based Triple Therapy	PPI (standard dose*)			BD	10-14
	Levofloxacin (500 mg)			OD
	Either one	Amoxicillin (1 g)		BD
		Metronidazole (400 mg)		BD
Levofloxacin-based Sequential Therapy	PPI (standard dose*) plus amoxicillin (1 g) for 5-7 days followed by:			BD	10-14 (total)
	PPI BD, levofloxacin (500 mg OD), amoxicillin (1 g BD) plus metronidazole (400 mg BD) for an additional 5-7 days
Ofloxacin-based Therapy (available in Helicobacter Journal, based on a comparative trial – please note that the study used Tab Rabeprazole 20 mg BD)	PPI (standard dose*)			BD	14
	Ofloxacin (400 mg)			BD
	Amoxicillin (1 g)			BD

FDA: United States Food and Drug Administration; PPI: proton pump inhibitor.

* Standard dosing of orally administered proton pump inhibitors include:
## Lansoprazole 30 mg twice daily;
## Omeprazole 20 mg twice daily;
## Pantoprazole 40 mg twice daily;
## Rabeprazole 20 mg twice daily; or;
## Esomeprazole 20 mg twice daily or 40 mg once daily (NAG 2019: 20 mg BD).

• Some North American guidelines do not support the use of sequential therapy.
• Hybrid therapy has not been universally endorsed as an option for first-line therapy.
• In patients with risk factors for macrolide resistance, clarithromycin-based therapy should be avoided.
• Generally UptoDate doses oral metronidazole as 500 mg. This is converted to 400 mg to suit availability in Malaysia, based on adaptation of dosing in Malaysia National Antibiotic Guideline (2019).
• Doses are for adults with normal renal function. Dose adjustment is warranted in patients with renal impairment for certain antibiotics (eg, levofloxacin, rifabutin, clarithromycin if end-stage disease).

Should we test for treatment success after H. pylori eradication therapy?

Whenever H. pylori infection is identified and treated, testing to prove eradication should be performed using a urea breath test, fecal antigen test or biopsy based testing at least 4 weeks after the completion of antibiotic therapy and after PPI therapy has been withheld for 1–2 weeks. (Strong recommendation; Low quality of evidence).

Salvage Therapy

(persistent H. pylori Infection)

• In patients with persistent H. pylori infection, the choice of antibiotic therapy should be guided by the patient’s initial treatment regimen, the use of other antibiotics, and the presence of relevant antibiotic allergies. Antibiotics included in the initial regimen should generally be avoided. However, amoxicillin can be reused as resistance rarely develops.
• American College of Gastroenterology (ACG) 2017: Bismuth quadruple therapy or levofloxacin salvage regimens are the preferred treatment options if a patient received a first-line treatment containing clarithromycin. [Selection of best salvage regimen should be directed by local antimicrobial resistance data and the patient’s previous exposure to antibiotics]
• Bismuth quadruple therapy should be used for 14 days when used as salvage regimen.
•  Levofloxacin-based triple therapy has demonstrated efficacy as a salvage regimen in patients who have failed initial clarithromycin triple therapy and/or bismuth quadruple therapy.
•  High dose dual therapy with amoxicillin and proton pump inhibitor (PPI) for 14 days is a salvage treatment option, particularly in patients in whom dual metronidazole/clarithromycin resistance or levofloxacin resistance is suspected.

• Culture with antibiotic sensitivity testing should be performed to guide antibiotic treatment in patients who have failed two prior treatment regimens.
• Compliance with medications should also be reinforced.
• UptoDate reserve the use of rifabutin-containing regimens for patients with ≥3 previous antibiotic failures (PPI-amoxicillin-rifabutin regime, 10 days duration).

Regimen	Drug		Frequency	Duration (days)
Bismuth Quadraple	PPI (standard dose*)		BD	10-14 (recom-mend 14)
	Bismuth subcitrate (120-300 mg) OR Bismuth subsalicylate (300mg)		BD
	Doxycyline (100 mg) OR Tetracycline (500 mg)		BD QID
	Metronidazole  (400 mg)		TDS-QID
Concomitant Therapy	PPI (standard* or double dose)		BD	10-14
	Clarithromycin (500 mg)		BD
	Amoxicillin (1 g)		BD
	Metronidazole (400 mg)		BD-TDS
Levofloxacin-based Triple Therapy	PPI (standard dose*)		BD	14
	Levofloxacin (500 mg)		OD
	Either one	Amoxicillin (1 g)	BD
		Metronidazole (400 mg)	BD
High-dose dual therapy	PPI (standard* to double dose)		TDS-QID	14
	Amoxicillin (1 g TDS or 750 mg QID)
Rifabutin-based Triple Therapy	PPI (standard dose*)		BD	10
	Rifabutin (300 mg)		OD
	Amoxicillin (1 g)		BD

References:

1. UptoDate [online]: Treatment regimens for Helicobacter pylori.
2. UptoDate algorithm [online]: Initial approach to antibiotic treatment for Helicobacter pylori infection.
3. UptoDate algorithm [online]: Approach to antibiotic treatment in patients with persistent Helicobacter pylori infection.
4. Pharmaceutical Services Dision, Malaysia. National Antibiotic Guideline (2019).
5. Chey WD et al. American College of Gastroenterology (ACG) Clinical Guideline: Treatment of Helicobacter pylori Infection. Am J Gastroenterol 2017; 112:212–238.