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Drugs for Hepatobiliary Disorders
Mustofa
Bagian Farmakologi & Terapi
Fakultas Kedoktteran UGM
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The liver and biliary system
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Pathophysiology
• Hepatocytes undergo pathological changes as a
result of the body's immune response to the virus.
• There is generalized inflammation with areas of
necrosis
• This leads to functional impairment of the liver
cells.
• There is Kuppfer cell hyperplasia (increase in
number of phagocytes)
• Disruption of structure and function leads to
obstruction of portal & hepatic blood flow.
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Hepatobiliary dysfunction
• Hepatitis : is an inflammation of the liver and may be caused
by viruses, bacteria, toxins, chemicals (including drugs).Type
include : hepatitis A, B and C
• Cirrhosis : a chronic disease of the liver marked by pathological
formation of widespread fibrosis (scarring) and degenerative
changes. Types include: Laennec’s (alcoholic), postnecrotic
(toxic), biliary (obstruction/infection), cardiac (severe ® sided
heart failure)
• Gall bladder disease : is several types of conditions that can
affect your gallbladder. They are commonly caused by
inflammation due to irritation of the gallbladder wall
(cholecystitis. This inflammation is often due to gallstones
blocking the ducts leading to the small intestine and causing
bile to build up.
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Hepatitis
H
epatitisA
H
A
V
oral-fecal
contam
inated
foodorw
ater
H
epatitisB
H
B
V
H
epatitisC
H
C
V
non-A
, non-B
bloodtransfusion
prim
arilyblood
IVdrugabuse
IVdrugexposure
sexual contact(low
)
*sexual contact
hem
odialysis, H
C
W
15-50days
(3w
eeks)
com
m
unicable
1-2w
kspsym
ptom
s
48-180days
(100days)
14-180days
fever, fatigue,
nausea, diarrhea,
anorexia, jaundice
R
U
Qpain
chronic
chronicprogressive
Sjogren's
cardio-renal
lym
phom
a
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Viral illness that may result in hepatitis
•
•
•
•
Cytomegalovirus
Epstein Barr virus
Herpes simplex
Varicella zoster causes multi system disease &
liver disease in immunosuppressed people
• Measles, Yellow fever (mosquito) Marbug &
Ebola viruses
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Manifestations
• Preicteric phase (before jaundice):
malaise, fever, nausea, vomiting,
diarrhea, anorexia, enlarged liver
and lymph nodes, electrolyte
imbalance, abdominal tenderness,
painful joints, fever.
• Icteric phase (jaundice): Jaundice,
pruritus, light-colored stools, brown
urine, malaise.
• Post-icteric phase: decrease in
fatigue, appetite returns to normal,
lab work normalizes, pain subsides
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Diagnosis of hepatitis – lab findings
Laboratory tests
  ALP, LDH, GGT, AST, ALT
  serum & urinary bilirubin
  serum albumin &
proteins
  Prothrombin time
  platelet count
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liver damage or
altered function
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Prevention
• Immune globulin (IG): prophylaxis for
family and friends exposed to HAV
• Hepatitis B immune globulin (HBIG);
individuals exposed to B virus
contaminated material.
• Vaccines: available for HAV & HBV –
recommended for people with
potential for exposure (HCPs and
people who travel to endemic areas)
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Prevention cont’d
• HAV & HAE : Good hand washing &
personal hygiene.
• HBV, HCV, HDV: careful handling of
needles/sharps, proper sterilization of nondisposable instruments, use of
condoms/refrain from multiple partners,
needle exchange programs.
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Immunisation
Active iummunisation by vaccination
• Hep A (Havrix®),
• Hep B (Engerix B®, H-B-vax II®),
• Hep A, Hep B (Twinrix®)
Passive immunisation
• pooled serum (high Ig titres) (HBIG)
Havrix active in 2 weeks, lasts about 1 year
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Booster2
Vaccine
Type of Route
Agent of Adm.
Hepatitis A
Inactiva Intramus One dose
ted
cular
(administer at least
virus
2–4 weeks before
travel to endemic
areas)
At 6–12 months
for long-term
immunity
Hepatitis B
Inactive Intramus Three doses at 0, 1,
viral
cular
and 6 months
antigen,
recombi
nant
Not routinely
recommended
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Primary
Immunization
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Vaccine indication
Hepatitis A
1. Travelers to hepatitis A endemic
areas
2. Homosexual and bisexual men
3. Illicit drug users
4. Chronic liver disease or clotting
factor disorders
5. Persons with occupational risk
for infection
6. Persons living in, or relocating
to, endemic areas
7. Household and sexual contacts
of individuals with acute
hepatitis A
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Hepatitis B
1. For all infants
2. Preadolescents,
adolescents, and young
adults
3. Persons with occupational,
lifestyle, or environmental
risk
4. Hemophiliacs
5. Hemodialysis patients
6. Postexposure prophylaxis
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Drug therapy
• Alpha interferon
• α-interferon 2a
• α-interferon 2b
• Antivirals
• Entecavir
• Tenofovir
• Lamivudine
• Adefovir
• Telbivudine
• Immune globulin
• Vaccines
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Interferons (INF)
• Low molecular weight proteins
produced by mammalian cells in
response to viral infections
• 3 classes of interferon
• IFNα (produced by lymphocytes)
• IFNβ (produced by fibroblasts)
• IFNγ (produced by lymphocytes)
• Interferons are host-species specific
• Can be produced by recombinant
genetic techniques
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General actions of IFN
• Induction of gene transcription;
Inhibits cellular growth, alters the
state of cellular differentiation,
interferes with oncogene expression,
alters cell surface antigen expression,
increases phagocytic activity of
macrophages, and augments
cytotoxicity of lymphocytes for target
cells
• Reduction in risk of progression to
cirrhosis, hepatocellular carcinoma,
and liver-related death in long-term
responders of interferon
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Pharmacokinetics of IFN2
• Distribution : Vd 0.223-0.748 L/kg
• Metabolism: Primarily renal, filtered through
glomeruli and undergoes rapid proteolytic
degradation during tubular reabsorption
• Bioavailability: IM 83%; SQ 90%
• Half-life elimination: IV 3.7- 8.5 hours (mean 5 hours)
• Time to peak, serum: IM, SQ: 6 - 8 hours
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Adverse effects IFN2α
• Flu-like Symptoms: Fatigue, myalgia/arthralgia, fever, chills,
asthenia, sweating, leg cramps and malaise,
• Central and Peripheral Nervous System: Headache, dizziness,
paresthesia, confusion, concentration impaired and change in taste
or smell,
• Gastrointestinal: Nausea/vomiting, diarrhea, anorexia, abdominal
pain, flatulence, liver pain, digestion impaired & gingival bleeding,
• Psychiatric: Depression, irritability, insomnia, anxiety and behavior
disturbances,
• Pulmonary and Cardiovascular: Dryness or inflammation of
oropharynx, epistaxis, rhinitis, arrhythmia and sinusitis
• Skin: Injection site reaction, partial alopecia, rash, dry skin or
pruritus, hematoma, psoriasis, cutaneous eruptions, eczema &
seborrhea.
• Other: Conjunctivitis , menstrual irregularity and visual acuity
decreased.
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Entecavir (nucleoside analaogue)
• Mechanism of actions : inhibits HBV replication at
three different steps i.e. the priming of HBV DNA
polymerase; the reverse transcription of the negative
strand HBV DNA from the pregenomic RNA, and the
synthesis of the positive strand HBV DNA
• Indictions: indicated for the treatment of chronic
hepatitis B virus infection, decompensated
cirrhosis /recurrent hepatitis B after, liver
transplantation, lamivudine-refractory HBV,
adefovir-resistant HBV
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Entecavir (cont’d…)
Pharmacokinetics/efficacy and use
• not recommended for anyone less than 16 years old.
• stomach (at least 2 hours after a meal and at least 2
hours before the next meal).
• primarily eliminated by the kidneys
• Dose 0.5 mg orally once daily or 1 g if with resistance
Durability of response/outcomes: 24 weeks after
seroconversion and 48 weeks treatment :
• suppression of serum HBV to undetctable levels in 39%,
• normalizaiton of ALT 79%,
• seroconversion 77%
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Entecavir (cont’d…)
Adverse effects:
• headache, tiredness, dizziness, and nausea.
Exacerbations of hepatitis after discontinuation of
treatment.
• Lactic acidosis: muscle pain and weakness, dyspnea,
fast or uneven heart rate, nausea, vomiting,
stomach pain, and numbness
• severe liver symptoms such as nausea, stomach
pain, low fever, loss of appetite, dark urine, claycolored stools, jaundice and severe hepatomegaly
with steatosis
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Tenofovir
• Mechanisms of actions : nucleotide analogue, first
approved for the treatment of HIV infection and
approved 2008 for HBV
• Tenofovir is structurally similar to adefovir.
• In vitro studies showed that tenofovir and adefovir
are equipotent.
• Because tenofovir appears to be less nephrotoxic, the
approved dose is much higher than that of adefovir,
300 mg versus 10 mg daily.
• This may explain why tenofovir has more potent
antiviral activity in clinical studies
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Tenofovir (cont’d..)
 Efficacy in Various Categories of Patients.
1. HBeAg-positive and negative patients
2. Lamivudine-refractory HBV-greater reductions
than adefovir
3. Adefovir-resistant HBV-shares cross-resistance
• Adverse Events. Tenofovir has been reported to
cause Fanconi syndrome, renal insufficiency as well
as osteomalacia and decrease in bone density.
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Adefovir dipivoxil
• Mechanism of actions : an acyclic nucleotide analog with
activity against human hepatitis B virus (HBV).
• Indications : 12 years of age and older with evidence of active
viral replication and either evidence of persistent elevations in
ALT or AST or histologically active disease.
• Pharmacokinetics:
• Taken with or without food
• Bioavailability is about 59%. Cmax is about 18.4 ng/mL, and
Tmax is about 1.75 h.
• Distribution: Up to 4% is protein bound.
• Efficacy :
• HBeAg positive and negative chronic hepatitis B
• Children (under trial but not yet approved for use)
• Lamivudine resistant hepatitis B- if no improvement,
alternative regimens
• Dose: 10 mg daily 1 to 2 yrs
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Adefovir dipivoxil (cont’d..)
• Metabolism : Adefovir dipivoxil (prodrug) is rapidly converted
to adefovir (active).
• Elimination : The terminal elimination half-life is
approximately 7.48 h; is renally excreted
• Adv effects : asthenia, headache, abdominal pain, diarrhea,
nausea, dyspepsia, flatulence, increased
creatinine,hypophosphatemia; exacerbations of hepatitis
(ALT elevations 10 times the upper limit of normal or greater)
occurred in up to 25% of patients after discontinuation
• Durability of response and outcome: Seroconversion
maintained in 91% of pts on longer durations but for HBeAg
negative pts. Only 8% of pts had sustained viral suppression
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Lamivudine
• Mechanism of actions : a synthetic nucleoside analogue;
incorporation of the monophosphate form into viral DNA by
HBV reverse transcriptase results in DNA chain terminationinhibition of DNA synthesis
• Pharmacokinetics :
• Absorption and Bioavailability: rapidly absorbed after oral
administration. May be administered with or without food.
• Distrbution : Binding of lamivudine to human plasma proteins
is low (<36%) and independent of dose
• Excretion : 12 h at 71 %
• No significant differences were observed in AUC∞ or total
clearance for lamivudine or zidovudine when the 2 drugs
were administered together.
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Lamivudine (cont’d…)
• Efficacy
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Telbivudine
 Mechanism of actions : L-nucleoside analogue
 telbivudine is more potent than lamivudine in suppressing
HBV replication.
 However, telbivudine is associated with a high rate of
resistance and telbivudine-resistant mutations are crossresistant with lamivudine.
 Therefore, telbivudine monotherapy has a limited role in the
treatment of hepatitis B.
 Uses:
1. HBeAg positive pts – 1 to 2 yrs
2. HBeAg negative pts. -1 to 2 yrs
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Telbivudine (Cont’d…)
• Adverse effects : cases of myopathy and peripheral
neuropathy have been reported. Peripheral
neuropathy appears to be more common when
telbivudine was used in combination with pegIFN.
• Dose: 600 mg daily
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Emtricitabine (Emtriva, FTC)
• Potent inhibitor of HIV and HBV replication. FTC has
been pproved for HIV treatment as Emtriva (FTC only)
and as Truvada (in Combination with tenofovir as a
single pill).
• Because of its structural similarity with lamivudine
(3TC), treatment with FTC selects for the same
resistant mutants.
• Adverse effects: headache, diarrhea, indigestion, joint
pain, unusual dreams, depression, trouble falling
asleep or staying asleep, numbness, burning, or
tingling in the hands, arms, feet, or legs, runny nose
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Clevudine
• Mechanism of actions: nucleoside analogue
• Durable viral suppresion up to 24 wks after
withdrawal of treatment
• Adverse effects: myopathy in posts treated longer
than 24 wks; typically onset after 8 mos;
mitochondrial toxicity
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Cirrhosis
• Cirrhosis represents the end stage of chronic liver
disease in which the normal architecture of the liver is
replaced by fibrous septa that encompass
regenerative nodules of hepatic tissue.
• Although cirrhosis usually is associated with:
– Alcoholism
– Viral hepatitis
– Toxic reactions to drugs and chemicals
– Biliary obstruction
– Metabolic disorders that cause the deposition of
minerals in the liver:
• Hemochromatosis (i.e., iron deposition)
• Wilson’s disease (i.e., copper deposition)
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Cirrhosis
• The manifestations of cirrhosis are variable, ranging from
asymptomatic hepatomegaly to hepatic failure. Often there are no
symptoms until the disease is far advanced.
• The most common signs and symptoms of cirrhosis are:
– Weight loss (sometimes masked by ascites)
– Weakness
– Anorexia
– Diarrhea frequently is present, although some persons may
report constipation
– Hepatomegaly
– Splenomegaly and thrombocytopenia
– Bleeding caused by decreased clotting factors; Jaundice
– Abdominal pain because of liver enlargement or stretching of
Glisson’s capsule
– The late manifestations of cirrhosis are related to portal
hypertension and liver failure
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Gallstones disease
 80% : cholesterol
stones
 Major risk factor
• Obesity
• Female sex hormones
• Bile acid
malabsorption
• High calorie diet
• Demographic
characteristics:
Northern European,
North and South
America, American
Indians, family history
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 20 % : pigment/calcified
stones.
 Calcium-bilirubinate
major risk factors:
• Chronic hemolysis
• Alcoholic cirrhosis
• Biliary infection
• Age
• Demographic
characteristics:
Far East > West,
rural > urban
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Pathophysiology of cholesterol gallstones
• Genetic or metabolic predisposition
• Supersaturation of bile with cholesterol
(hepatobiliary cholesterol vs. bile acids or lecithin)
• Nucleation and crystal growth
• Development of macroscopic stones (poor
gallbladder emptying)
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Treatment
Treatment depends upon presence of symptoms, likelihood
of complications, morbidity of complications (or treatment)
and cost
Treatment options currently available in U.S.:
1. Cholecystectomy (routine vs laparoscopic)
2. Gallstone dissolution with bile acids (slow
dissolution)
 Chenodeoxycholic acid (CDC or Chenodiol)
 Ursodeoxycholic acid (UDC or Ursodiol)
3. Contact dissolution
 Methyl tert-butyl ether (MTBE)
 Monooctanoin (common bile duct stones)
4. Extracorporeal shock wave (lithotripsy) (ECS)
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Gallstone dissolution with bile acids
(Chenodiol, Ursodiol)
• Bile acid dissolution is useful only for cholesterol
gallstone
• CDC and UDC act by:
a) Depressing secretion of cholesterol into bile (low
cholesterol-solubility capacity due to hydrophilic
property) - Major effect
b) Expands the bile acid pool and increases bile
acid secretion - Minor effect
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Chenodiol (CDC)
• Approved by FDA in 1983
• Criteria for treatment:
cholesterol stones, small stones,
functioning gallbladder, thin patient
• Contraindications for treatment:
pigment stones, calcified stones, large (> 1.5 cm)
stones, liver disease, pregnancy
• Optimal dosage and duration:
15 mg/kg day for up to two years.
• Results:
13.5% complete dissolution at two years,
40% partial dissolution at two years;
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Chenodiol (CDC)
• Recurrence rate of 10%/yr
• low dose CDC does not prevent recurrence.
• Predictors of successful dissolution:
floating stones on OCG; less than 3 stones;
less than 1.5 cm diameter; high plasma cholesterol;
weight < 100% of ideal body weight
• Complete dissolution in ideal setting: 60-90%
• Complications:
diarrhea (33%); increased plasma cholesterol by 20 mg/dl;
increased liver enzyme (AST)
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Ursodiol (UDC)
•
•
•
•
Approved by FDA in 1988
Criteria for treatment and efficacy: same as CDC
Optimal dosage and duration: 10-13 mg/kg/day
Advantages:
no hepatotoxicity; no alteration in plasma cholesterol;
no diarrhea.
• Stone recurrence may be prevented with low dose UDC
• Ursodiol has replaced CDC as bile acid of choice for gallstone
dissolution
• Combination CDC-UDC regimens have been used with
comparable safety to UDC alone
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