1. DRUG PRESCRIPTION IN
HEPATIC PATIENTS
Prof. Maamoun Ashour

2. DRUGS & LIVER
Hepatotoxicity Interactions Side effects
Low efficacy expensive

3. DRUG HEPATOTOXICITY
 Any drug can cause liver problems

4. THE LIVER AND DRUG
Metabolism is the enzymatic conversion of one
chemical compound into another.
Most drug metabolism occurs in the liver.

5. 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.

6. 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common reason for a drug to be withdrawn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.

7. 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

8. 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

9. 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

10. 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)

11. 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)

12. ACUTE DOSE-DEPENDENT LIVER DAMAGE
 Drugs that may cause ACUTE DOSE-DEPENDENT
LIVER DAMAGE
 acetaminophen
 salicylates (doses over 2 grams daily)

13. DRUGS THAT MAY CAUSE ACUTE DOSE-INDEPENDENT LIVER DAMAGE
indomethacin isoniazid probenecid Para-
piroxicam pyrazinamide halothane aminosalicylic
diclofenac acid
naproxen
ibuprofen
Acebutolol quinine Phenytoin ketoconazole
atenolol quinidine valproic acid sulindac
metoprolol phenobarbital
diltiazem allopurinol cimetidine penicillins
verapamil ranitidine sulfonamides
tricyclic carbamazepine
antidepressants

14. ACUTE FATTY INFILTRATION OF THE LIVER
 adrenocortical steroids
 phenothiazines
 sulfonamides
 antithyroid drugs
 phenytoin
 tetracyclines
 isoniazid
 salicylates
 valproic acid
 methotrexate

15. DRUGS THAT MAY CAUSE CHOLESTATIC JAUNDICE
 oxacillin
 sulfonamides
 erythromycin
 amoxicillin/clavulanate
 Cloxacillin
 cephalosporins
 nitrofurantoin
 azathioprine

16. DRUGS THAT MAY CAUSE CHOLESTATIC JAUNDICE
 danazol
 griseofulvin
 enalapril
 captopril
 carbimazole

17. DRUGS THAT MAY CAUSE CHOLESTATIC JAUNDICE
 haloperidol
 ketoconazole
 mercaptopurine
 oral contraceptives
 tamoxifen
 methyltestosterone
 thiabendazole
 nifedipine

18. DRUGS THAT MAY CAUSE CHOLESTATIC JAUNDICE
 penicillamine
 phenothiazines
 tricyclic antidepressants
 cyclosporine
 anti-inflammatory drugs
 verapamil
 carbamazepine

19. DRUGS THAT MAY CAUSE LIVER GRANULOMAS (CHRONIC
INFLAMMATORY NODULES
allopurinol quinidine tolbutamide nitrofurantoi
gold chlorpromazi n
ne sulfonamide
s
penicillin
Diltiazem phenytoin Aspirin isoniazid
hydralazine carbamazepi phenylbutazo
ne ne

20. DRUGS THAT MAY CAUSE ACTIVE CHRONIC HEPATITIS
 methyldopa
 isoniazid
 nitrofurantoin

21. DRUGS THAT MAY CAUSE LIVER CIRRHOSIS OR FIBROSIS
 methotrexate
 terbinafine HCI (Lamisil, Sporanox)
 nicotinic acid

22. DRUGS THAT MAY CAUSE CHRONIC CHOLESTASIS (RESEMBLING
PRIMARY BILIARY CIRRHOSIS)
 chlorpromazine/valproic acid
(combination)
 imipramine
 thiabendazole
 phenothiazines
 phenytoin

23. DRUGS THAT MAY CAUSE LIVER TUMORS (BENIGN AND
MALIGNANT)
 anabolic steroids
 oral contraceptives
 thorotrast
 danazol
 testosterone

24. 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

25. 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.

26. 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.

27. DRUG INTERACTIONS
with
 Anticoagulants & antiplatelet
 in hep. Patients with:
 Ischemic heart diseases
 Thrombotic manifestations
 Atrial fibrillations

28. 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.

29. ANTICOAGULANTS
Many hepatic patients may need
anticoagulants for their cardiac ( AF) or
thrombotic manifestations.
Bleeding is a risk in these patients.

30. ANTICOAGULANTS
 Budd – Chiari Syndrome

31. 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.

32. DIURETICS
 Are mandatory In ascitic patients
 Many complications may develop:
 Muscle cramps
 Hypotension
 Gynecomastia

33. EXPENSIVE DRUGS
 Expensive Drugs

34. EXPENSIVE DRUGS
 Many drugs are expensive on individual
and national bases:
 Examples:
 Antivirals: Interferon, enticaver, gancyclovir.
 Vasopressors: Terlipressin, Somatostatin.
 Human albumin.
 Anti-tumors: Nexavar

35. 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.

36. 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.

37. 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.

38. 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.

39. NORADRENALIN VS TERLIPRESSIN
Data suggest that noradrenalin
is as effective and safe as
terlipressin in patients with HRS.

40. 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.

41. Drug Abuse

42. 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.

43. DISADVANTAGES OF DRUG ABUSE
 Possibility of hepatotoxicity
 Satisfaction of patients and doctors
 Financial burden on patients and
government.

44. 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.


45. 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.

46. 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.


47. 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)

48. 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.


49. 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.

50. 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.

51. SIDE EFFECTS OF DRUGS
Side effects of drugs

52. SIDE EFFECTS OF DRUGS
 Many drugs used to treat liver diseases
have side effects:
 Physicians should be aware of all
possible side effects:

53. SIDE-EFFECTS OF DRUGS
 Diuretics
 Immunosuppressive
 Antivirals
 Vasopressors
 B- blockers

54. 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.

55. VASOPRESSORS
 Ischemic manifestations are the most
serious.
 Before administration:
 ECG, is mandatory.
 sublingual nitrates may be given.

56. 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.

57. IMMUNOSUPPRESSIVE
 Corticosteroids when prescribed will be used
for long time.
 Blood sugar and blood pressure should be
controlled.

58. 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

59. 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.

60. UNCOMMON DRUGS
 Examples:
 D- pencilamine ( Artamine)

61. 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.

62. 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.

63. 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.

64. NEW ISSUES
 Interactions of new protease inhibitors:

65. 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.

66. 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.