Drug prescription in hepatic patients

DRUG PRESCRIPTION IN HEPATIC PATIENTS

Prof. Maamoun Ashour

DRUGS & LIVER

Hepatotoxicity Interactions Side effects

Low efficacy expensive

DRUG HEPATOTOXICITY

Any drug can cause liver problems

THE LIVER AND DRUG

Metabolism 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More than 900 drugs have been implicated in causing liver injury and it is the most common reason for a drug to be withdrawn from the market.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


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 fibrosis


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 DAMAGE

indomethacin piroxicam diclofenac naproxen ibuprofen

isoniazid pyrazinamide

probenecid halothane

Para-aminosalicylic acid

Acebutololatenolol metoprolol

quinine quinidine

Phenytoinvalproic acid phenobarbital

ketoconazole sulindac

diltiazemverapamil

allopurinol cimetidineranitidine

penicillins sulfonamides

tricyclic antidepressants

carbamazepine

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


danazol griseofulvin enalapril captopril carbimazole


haloperidol ketoconazole mercaptopurine oral contraceptives tamoxifen methyltestosterone thiabendazole nifedipine


penicillamine phenothiazines tricyclic antidepressants cyclosporine anti-inflammatory drugs verapamil carbamazepine

DRUGS THAT MAY CAUSE LIVER GRANULOMAS (CHRONIC INFLAMMATORY NODULES

allopurinol gold

quinidine chlorpromazine

tolbutamide

nitrofurantoin sulfonamides penicillin

Diltiazemhydralazine

phenytoin carbamazepine

Aspirinphenylbutazone

isoniazid

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 BLOOD VESSELS

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 INTERACTIONS

with 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.

ANTICOAGULANTS

Budd – Chiari Syndrome

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

Expensive Drugs

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.


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.


Data 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.

Drug Abuse

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

Side effects of drugs

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.

UNCOMMON DRUGS

Examples: D- pencilamine ( Artamine)

PENICILLAMINE ( ARTAMINE)

Penicillamine is a chelating agent used in the treatment of Wilson's disease.

Its use relies on its binding to accumulated copper and elimination through urine.


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.


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.

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Drug prescription in hepatic patients