DRUG PRESCRIPTION IN HEPATIC PATIENTSProf. Maamoun Ashour
DRUGS & LIVERHepatotoxicity Interactions Side effects Low efficacy expensive
DRUG HEPATOTOXICITY Any drug can cause liver problems
THE LIVER AND DRUGMetabolism is the enzymatic conversion of one chemical compound into another. Most drug metabolism occurs in the liver.
THE LIVER AND DRUG The liver is the principal organ that is capable of converting drugs into forms that can be readily eliminated from the body.
HEPATOTOXICITY More than 900 drugs have been implicated in causing liver injury and it is the most common reason for a drug to be withdrawn from the market.
THE LIVER AND DRUG The reactions range from mild and transient changes in the results of liver function tests to complete liver failure with death of the host. Drugs may affect the liver adversely in more than one way. The use of these drugs requires careful monitoring of their effects on the liver during the entire course of treatment
DRUG INDUCED DISORDER CAN MIMIC ANY LIVER DISEASE ACUTE DOSE-DEPENDENT LIVER DAMAGE (resembling acute viral hepatitis) ACUTE DOSE-INDEPENDENT LIVER DAMAGE (resembling acute viral hepatitis) Drugs that may cause cholestatic jaundice
DRUG INDUCED DISORDER CAN MIMIC ANY LIVER DISEASE Drugs that may cause acute fatty infiltration of the liver. Drugs that may cause liver granulomas (chronic inflammatory nodules Drugs that may cause active chronic hepatitis Drugs that may cause liver cirrhosis or
DRUG INDUCED DISORDER CAN MIMIC ANY LIVER DISEASE Drugs that may cause chronic cholestasis (resembling primary biliary cirrhosis) Drugs that may cause damage to liver blood vessels. Drugs that may cause liver tumors (benign and malignant)
DRUG INDUCED LIVER PATHOLOGY acute hepatitis - cholestatic jaundice acute fatty infiltration of the liver. liver granulomas - active chronic hepatitis liver cirrhosis or fibrosis chronic cholestasis - damage to liver blood vessels. liver tumors (benign and malignant)
ACUTE DOSE-DEPENDENT LIVER DAMAGE Drugs that may cause ACUTE DOSE-DEPENDENT LIVER DAMAGE acetaminophen salicylates (doses over 2 grams daily)
DRUGS THAT MAY CAUSE ACUTE DOSE-INDEPENDENT LIVER DAMAGEindomethacin isoniazid probenecid Para-piroxicam pyrazinamide halothane aminosalicylicdiclofenac acidnaproxenibuprofenAcebutolol quinine Phenytoin ketoconazoleatenolol quinidine valproic acid sulindacmetoprolol phenobarbitaldiltiazem allopurinol cimetidine penicillinsverapamil ranitidine sulfonamidestricyclic carbamazepineantidepressants
ACUTE FATTY INFILTRATION OF THE LIVER adrenocortical steroids phenothiazines sulfonamides antithyroid drugs phenytoin tetracyclines isoniazid salicylates valproic acid methotrexate
DRUGS THAT MAY CAUSE CHOLESTATIC JAUNDICE oxacillin sulfonamides erythromycin amoxicillin/clavulanate Cloxacillin cephalosporins nitrofurantoin azathioprine
DRUGS THAT MAY CAUSE CHOLESTATIC JAUNDICE danazol griseofulvin enalapril captopril carbimazole
DRUGS THAT MAY CAUSE CHOLESTATIC JAUNDICE haloperidol ketoconazole mercaptopurine oral contraceptives tamoxifen methyltestosterone thiabendazole nifedipine
DRUGS THAT MAY CAUSE CHOLESTATIC JAUNDICE penicillamine phenothiazines tricyclic antidepressants cyclosporine anti-inflammatory drugs verapamil carbamazepine
DRUGS THAT MAY CAUSE LIVER GRANULOMAS (CHRONIC INFLAMMATORY NODULESallopurinol quinidine tolbutamide nitrofurantoigold chlorpromazi n ne sulfonamide s penicillinDiltiazem phenytoin Aspirin isoniazidhydralazine carbamazepi phenylbutazo ne ne
DRUGS THAT MAY CAUSE ACTIVE CHRONIC HEPATITIS methyldopa isoniazid nitrofurantoin
DRUGS THAT MAY CAUSE LIVER CIRRHOSIS OR FIBROSIS methotrexate terbinafine HCI (Lamisil, Sporanox) nicotinic acid
DRUGS THAT MAY CAUSE CHRONIC CHOLESTASIS (RESEMBLING PRIMARY BILIARY CIRRHOSIS) chlorpromazine/valproic acid (combination) imipramine thiabendazole phenothiazines phenytoin
DRUGS THAT MAY CAUSE LIVER TUMORS (BENIGN AND MALIGNANT) anabolic steroids oral contraceptives thorotrast danazol testosterone
DRUGS THAT MAY CAUSE DAMAGE TO LIVER BLOODVESSELS adriamycin mercaptopurine vincristine azathioprine methotrexate vitamin A (excessive doses) cyclophosphamide/cyclo-sporine (combination) oral contraceptives Anabolic steroids
HEPATOXICITY OF ANTITUBERCULOSIS DRUGS Most of antituberculous drugs causes hepat- toxicity. Combination of rifampicin and isoniazid increases hepatotoxicity. Effect of silymarin when combined with antituberculous drugs.
WHAT WE SHOULD DO Drug history is mandatory in all hepatic patients. Monitoring of liver functions in patients receiving hepatotoxic drugs. Avoidance of unnecessary drugs and chemicals.
DRUG INTERACTIONSwith Anticoagulants & antiplatelet in hep. Patients with: Ischemic heart diseases Thrombotic manifestations Atrial fibrillations
PRESCRIPTION OF ANTIPLATLETS Clopedogril and aspirin are frequently prescribed in patients with ischemic heart diseases. Many of these patients have liver diseases which may be associated with thrombocytopenia and manifestations of bleeding tendency. What is the decision of the hepatologist and the cardiologist.
ANTICOAGULANTS Many hepatic patients may need anticoagulants for their cardiac ( AF) or thrombotic manifestations. Bleeding is a risk in these patients.
B- BLOCKERS B blockers is used to lower portal hypertension. In advanced cases of LCF when systemic blood pressure comes down: B- blockers become a problem. When to give sympathomimetics B blockers aggravate impotence in hepatic patients.
DIURETICS Are mandatory In ascitic patients Many complications may develop: Muscle cramps Hypotension Gynecomastia
EXPENSIVE DRUGS Many drugs are expensive on individual and national bases: Examples: Antivirals: Interferon, enticaver, gancyclovir. Vasopressors: Terlipressin, Somatostatin. Human albumin. Anti-tumors: Nexavar
ALTERNATIVES TO EXPENSIVE DRUGS We should search for and evaluate alternative cheap drugs. Examples: Human plasma as alternative to albumin in hypoalbuminea. Norepinephrine as alternative to glypressin HRS.
NORADRENALIN VS TERLIPRESSIN IN PATIENTS WITH HEPATORENAL SYNDROME Treatment of hepatorenal syndrome (HRS) is based on vasoconstrictors. Terlipressin is the one with the soundest evidence. Noradrenalin has been suggested as an effective alternative.
NORADRENALIN VS TERLIPRESSIN Noradrenalin (0.1-0.7 microg/kg/min) and albumin. Treatment is administered until HRS reversal or for a maximum of two weeks.
NORADRENALIN VS TERLIPRESSIN Reversal of HRS was observed in 7 out of 10 patients (70%) treated with noradrenalin and in 10 of 12 patients (83%) treated with terlipressin, p=ns. Treatment led in both groups to a significant improvement in renal and circulatory function. No patient developed signs of myocardial ischemia.
NORADRENALIN VS TERLIPRESSINData suggest that noradrenalin is as effective and safe as terlipressin in patients with HRS.
PLASMA VS ALBUMIN Fresh frozen plasma is superior as it contains coagulation factors. Controlled studies are required to clarify the advantages and disadvantages of both.
ABUSE OF DRUGS Liver supports are widely prescribed in Egypt for many reasons: Failure of antiviral drugs to achieve satisfactory cure. Contribution of non- specialized and non- medical persons in treatment of liver diseases. Influence of drug companies.
DISADVANTAGES OF DRUG ABUSE Possibility of hepatotoxicity Satisfaction of patients and doctors Financial burden on patients and government.
SILYMARIN RCT: Silymarin (Milk Thistle) does not affect hepatic disease in patients with hepatitis C unsuccessfully treated with interferon Reference: JAMA. 2012; 308(3):274-282 Date published: 18/07/2012 16:50 Summary by: Sheetal Ladva Despite, limited and conflicted evidence on silymarin, an extract of milk thistle, it is commonly used by patients to treat chronic hepatic disease.
STUDY DESIGN The Silymarin in NASH and C Hepatitis (SyNCH) study was a randomised, double-blind, placebo-controlled multicentre trial which evaluated the safety and efficacy of silymarin for treating chronic hepatitis C virus (HCV) infection among patients previously unsuccessfully treated with interferon (IFN)–based treatment.
STUDY DESIGN A total of 154 subjects with serum alanine aminotransferase (ALT) levels of 65 U/L or greater were randomised to 420-mg silymarin, 700-mg silymarin (both doses higher than normal doses used), or matching placebo administered three times per day for 24 weeks. The primary efficacy measure was serum ALT level of 45 U/L or less (normal range) or less than 65 U/L, provided this was at least a 50% reduction from baseline values.
RESULTS The following findings were reported: • Two subjects in each treatment group met the primary outcome measure (3.8% [95% CI, 0.5% to 13.2%] for placebo, 4.0% [95% CI, 0.5% to 13.7%] for 420-mg silymarin, and 3.8% [95% CI, 0.5% to 13.2%] for 700-mg silymarin; P ≥ 0.99). • There was no statistically significant difference in the mean decline in serum ALT activity at the end of treatment across the three groups (mean decline, −4.3 [95% CI, −17.3 to 8.7] U/L for placebo, −14.4 [95% CI, −41.6 to 12.7] U/L for 420-mg silymarin, −11.3 [95% CI, −27.9 to 5.4] U/L for 700-mg silymarin; p=0.75)
RESULTS There were no statistically significant differences in HCV RNA levels (mean change, 0.07 [95% CI, −0.05 to 0.18] log10 IU/mL for placebo, −0.03 [95% CI, −0.18 to 0.12] log10 IU/mL for 420-mg silymarin, 0.04 [95% CI, −0.08 to 0.16] log10 IU/mL for 700-mg silymarin; P =0.54) or quality-of-life measures.
ADVERSE EVENTS The adverse event profile of silymarin was comparable with that of placebo. The most frequent adverse events were gastrointestinal symptoms, reported in 12% of participants receiving any silymarin dose compared with 5% receiving placebo.
SILYMARIN DID NOT SIGNIFICANTLY REDUCE ALT The authors concluded that higher doses of silymarin did not significantly reduce serum ALT levels more than placebo in participants with chronic HCV infection unsuccessfully treated with interferon-based therapy.
SIDE EFFECTS OF DRUGS Many drugs used to treat liver diseases have side effects: Physicians should be aware of all possible side effects:
SIDE-EFFECTS OF DRUGS Diuretics Immunosuppressive Antivirals Vasopressors B- blockers
ANTIVIRALS Interferon and ribavirin have many side- effects especially on the hematological system. Depression and activation of auto immune diseases are among many other complications. Pregnancy should be postponed until 6 months after end of tt.
VASOPRESSORS Ischemic manifestations are the most serious. Before administration: ECG, is mandatory. sublingual nitrates may be given.
DIURETICS Muscle cramps are common, gyncomastia is frequent but electrolyte disturbances and HRS are serious Follow up with: Na. K. and creatinine should be monitored.
IMMUNOSUPPRESSIVE Corticosteroids when prescribed will be used for long time. Blood sugar and blood pressure should be controlled.
GLUCOCORTICOIDS Those receiving glucocorticoids were almost 7 times more likely to commit or attempt suicide, more than 5 times more likely to develop delirium, more than 4 times more likely to develop mania, and almost twice as likely to develop depression than those with the same underlying conditions who did not receive the medications
GLUCOCORTICOIDS Steroid-treated patients do not always know that the neuropsychiatric symptoms that they are experiencing are induced by the treatment. They may, think that they are induced by the underlying disease.
PENICILLAMINE ( ARTAMINE) Penicillamine is a chelating agent used in the treatment of Wilsons disease. Its use relies on its binding to accumulated copper and elimination through urine.
PENICILLAMINE ( ARTAMINE) It is also used to reduce cystine excretion in cystinuria Penicillamine is used as a form of immunosuppression to treat rheumatoid arthritis unresponsive to conventional therapy.
PENICILLAMINE ( ARTAMINE) Artamine should be taken on an empty stomach at least one hour before meals and two hours after food has been eaten. Artamine has a high incidence of severe reactions therefore patients should be constantly monitored for any untoward reactions.
NEW ISSUES Interactions of new protease inhibitors:
STATINS AND HCV PROTEASE INHIBITORS When taken together with the affected statins, HIV and HCV protease inhibitors can boost the blood level of the statins, which in turn can lead to myopathy. One of the most serious forms of myopathy is rhabdomyolysis, which can damage the kidneys, possibly resulting in kidney failure and death.
ANTIPLATELET THERAPY Antiplatelet therapy is critical for the prevention of cardiovascular events in patients with or at risk for cardiovascular disease; however the reduction in thrombotic events comes at the price of bleeding, particularly upper gastrointestinal (GI) bleeding. Therapies to minimize these risks include proton pump inhibitors (PPIs) but there is a lot of confusion around the impact of PPIs on the efficacy of various antiplatelet agents.