Nitrates

    Child-Pugh A+B Child-Pugh C
Isosorbide-5-mononitrate Safety safe safe
Dose no dose adjustment needed no dose adjustment needed
Nicorandil Safety no additional risks known no additional risks known
Dose no dose adjustment needed no dose adjustment needed
Nitroglycerin Safety no additional risks known no additional risks known
Dose no dose adjustment needed no dose adjustment needed
Isosorbide dinitrate Safety no additional risks known unknown
Dose (PO) use half of the normal dose no dosing advice possible (unknown)
Dose (IV) no dose adjustment needed no dose adjustment needed
Dose (SL) no dose adjustment needed no dose adjustment needed
Explanation

Nitrates are all metabolized by the liver but studies showed no or little alterations in    pharmacokinetics for isosorbide mononitrate and nicorandil in contrast to isosorbide dinitrate. No data on pharmacokinetics in cirrhotic patients are available for nitroglycerin. In safety studies side effects in patients with cirrhosis were comparable to healthy controls. However, patients with advanced cirrhosis are characterized by vasodilation which can be worsened by nitrates.

Information about the safety classification and the recommended actions can be found here.

Summary of literature

Considerations

In the past, nitrates were used as add-on treatment in portal hypertension. This is not common practice any more. In the following text the literature per nitrate is discussed.

One pharmacokinetic study (level 3) with isosorbide dinitrate in 7 cirrhotic patients (CTP unknown) was found. The AUC in cirrhotic patients was increased by approximately 139% after a single-dose. None of the cirrhotic patients complained of headache while most of the healthy controls did. Isosorbide dinitrate was used by 50 patients (CTP A/B/C 16/22/2, 10 unknown) in four studies about safety (level 3-4). In all these studies one or more patients suffered from a headache. It is classified as ‘no additional risks known’ in CTP A and B.  In patients with CTP A or B it is advised to use half of the normal dose if orally administered. For patients with CTP C it is classified as ‘unknown’ because of safety data from only 2 patients and no pharmacokinetic data.

The pharmacokinetics of isosorbide mononitrate have been studied in 9 cirrhotic patients CTP A/B 3/3 and 3 unknown) in two studies (level 3). No significant differences were found on pharmacokinetics between cirrhotic patients and healthy controls, except for a decrease in clearance (16-25%) in cirrhotics in one study. The authors consider this change not relevant because clearance value of cirrhotics were similar to those from healthy controls in other studies. There were 30 studies that partly assessed the safety of isosorbide mononitrate (level 1-4). In the largest meta-analysis 447 patients with cirrhosis using isosorbide mononitrate (CTP A/B/C 101/225/93) were included. Overall there were no serious adverse events related to ISMN treatment. Most reported adverse event related to ISMN was headache. We classified isosorbide mononitrate as ‘safe’ for CTP A/B/C cirrhosis. The dose-regimen of isosorbide mononitrate for patients with cirrhosis should remain the same as for patients with normal liver function.

Nicorandil is studied in one single-dose pharmacokinetic study (level 3) among 8 patients with cirrhosis (CTP unknown). No significant differences were found after intravenous administration of nicorandil between cirrhotic patients and healthy controls. After oral dosing, the AUC was significant lower (-37%) and the t1/2 was longer (+0.5 h). For patients with CTP A nicorandil is classified as ‘no additional risks known’ and CTP B and C are classified as ‘unknown’. Dose adjustment is not required in all CTP classes.

There was no pharmacokinetic study found with nitroglycerin. Nitroglycerin is a drug with a large first-pass effect and high hepatic extraction ratio (≈1) and is therefore not administered orally.  Safety of nitroglycerin was examined in 6 RCTs (level 2) and 5 clinical trials (level 3) among 298 patients with cirrhosis (CTP A/B/C n=48/152/78; rest unknown). Mainly mild adverse events (i.e. headache) occurred. Nitroglycerin is classified as ‘no additional risk known’ for CTP A/B/C.  After sublingual administration bioavailability can be increased, but no dose adjustment is advised because it is only used short-term during acute situations. After intravenous and transdermal administration it is possible that clearance is reduced, so after an initial dose, adjust maintenance dose according to dose-dependent adverse reactions.   

Pharmacokinetic data

  • Absorption: Nitrates are well absorbed after oral administration but the bioavailability varies per nitrate. Isosorbide mononitrate and nicorandil are not subjected to a significant first-pass effect and therefore have a high bioavailability (F>75%). Isosorbide dinitrate undergoes extensive first-pass metabolism and has a bioavailability of around 20-30%. Nitroglycerin is also subject to extensive first-pass metabolism and is therefore not orally administered. After transdermal use, bioavailability is 70% and after oromucosal administration 39%.
  • Distribution: Nitrates are not extensively bound to plasma proteins (fb <60%). The volume of distribution of nitrates is around 0.6 - 4 L/kg.
  • Metabolism: All nitrates are metabolized in the liver by denitration in inactive metabolites except for isosorbide dinitrate. Isosorbide dinitrate is metabolized in the liver to active metabolites: isosorbide-5-mononitrate and isosorbide-2-mononitrate.
  • Elimination: All nitrates are mainly excreted in urine. Isosorbide mononitrate is for 50% excreted in the urine and also for 25% excreted in faeces. The elimination half-life varies among nitrates. Nitroglycerin has a very short half-life (2-4 min) and isosorbide mononitrate and isosorbide dinitrate half-lives are somewhat longer, 30-60 min. respectively 4.5 hours. The elimination of nicorandil is biphasic: a fast phase with a half-life of approximately 1 hour of 96% of the plasma concentration and a slow phase with a half-life of 12 hours.
  • Pharmacokinetic studies:
  • Isosorbide dinitrate (ISDN): In one single-dose study plasma concentrations of ISDN after oral administration were higher in 5 out of 7 patients (CTP unknown) than the control subjects. The AUC increased with 139% in cirrhotic patients.
  • Isosorbide mononitrate (ISMN): In two single-dose studies pharmacokinetics of ISMN P.O. and I.V. administration were examined. One study found no significant differences in the AUC, Cmax, t1/2 and Vd between the patients (CTP A/B) and the controls. The only statistical difference was found in clearance, a decrease of 16% for oral ISMN and 25% for I.V. ISMN in cirrhotic patients. This was not considered to be relevant since clearance values of cirrhotics were similar to clearance values of healthy controls in other studies. The other was a small study where no differences in plasma concentration of ISMN has been found between the two groups (CTP A/B). The group sizes were too small to perform a statistically analysis.
  • Nicorandil: One single-dose study measured a significant decrease in AUC (- 37%) and a prolonged t1/2 of 0.5 hour in cirrhotic patients for nicorandil P.O. Decrease of absolute bioavailability (-19%) was not statistically significant. In nicorandil I.V. differences in clearance, volume of distribution and t1/2 were not significant.
  • Nitroglycerine: no study was conducted.

Safety data

Most of the safety data studied nitrates in combination with beta-blockers as add-on therapy for portal hypertension. Therefore, sometimes it is hard to distinguish side effects per drug. The use of nitrates as add-on therapy in portal hypertension is not common practice anymore. In general, patients with advanced cirrhosis are characterized by vasodilation which can be worsened by nitrates.

Isosorbide dinitrate (ISDN): two clinical trials looked at safety of ISDN in cirrhotic patients. In two patients ISDN induced hypotension, bradycardia and nausea. In one patient the dosage of ISDN was decreased because of headache. One case study found slight and transient headaches during the first days of treatment in all patients with ISDN. In the pharmacokinetic single dose study no side effects were reported in the group with cirrhotics, while in the control group most subjects did complain of headache.

Isosorbide mononitrate (ISMN): in three meta-analyses and two systematic reviews ISMN was investigated as add on medication in combination with a beta-blocker and compared with an endoscopic procedure or a beta-blocker as monotherapy. Adverse events (AEs) rates were higher in the groups with ISMN but none of the AEs were fatal. In two systematic reviews the difference in AEs between the groups were not statistically significant. 21 RCTs and one clinical trial investigated the safety ISMN as add-on treatment. One RCT examined ISMN as monotherapy on safety vs. placebo. ISMN was also investigated on safety in two pilot studies. Overall, there were no reports of serious AEs in the groups with ISMN medication. Most of the reported AEs in the studies were headache, dizziness, hypotension and bradycardia. One RCT mentioned fatigue and loss of libido at two patients. The AEs were resolved over time, with decreasing the dose or discontinuing ISMN.

Nitroglycerin: in 6 RCTs the safety of nitroglycerin was examined in cirrhotic patients. In three trials (mild) headache occurred in about one third of the patients using nitroglycerin. One study reported bradycardia, tachycardia and hypertension and another study noted palpitation without headache in patients with nitroglycerin. In one RCT there was no significant difference between the groups in overall adverse effects associated with therapy. Five clinical trials also looked at safety of nitroglycerin in cirrhotics. In three trials side effects as increase of pulse rate, palpitation without headache and hypotension were observed. The other two trials found no side effects during the study.

Nicorandil: no safety studies were found for nicorandil in cirrhotic patients.