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HEPATOPROTECTIVE
AGENTS
Dr Priyank shah, Jr 1, Dept of pharmacology
1
Introduction
 Liver is one of the largest organs in human body and the
chief site for intense metabolism and excretion.
 It has a surprising role in the maintenance, performance
and regulating homeostasis of the body.
 It is involved with almost all the biochemical pathways to
growth, fight against disease, nutrient supply, energy
provision and reproduction.
2
3
Liver Toxicity
 The main causes of liver damage are
 The major cause in India is ethanol and it is suspected that more
than half of the cases of hepatotoxicity is caused by alcohol.
 Chemicals like carbon tetrachloride CCL4, phosphorous , aflatoxins,
chlorinated hydrocarbon etc
 Drugs i.e. DILI ( drugs induced liver injury )
 Autoimmune disorders
 Infections like viral hepatitis
4
Drugs
Liver Disease
Drug Metabolites
(the good, the bad and the ugly)
Drug Elimination
Drugs and the Liver
Drug-Drug
Interactions
LIVER
5
Drugs causing DILI
 Anti tuberculosis drugs
 All drugs causes
hepatotoxicity except
ethambutol
 Anti convulsant drugs
 Carbamazepine and
valproic acid
 NSAIDS
 Paracetamol , diclofenac ,
indomethacin , oxicam
group
 Anti microbials
 Dapsone , ketoconazole ,
Sulfonamides, anti
retrovirals
 Anaesthetics
 Enflurane , Isoflurane
 Miscellaneous drugs
 Disulfuram
 Flutamide
 Statins
 Labetlol
 Nicotinic acid
 Propylthiouracil
 OC pills
6
7
Clinical Presentations
Asymptomatic elevation in hepatic enzymes
No progress despite
Continued use of the
Medication.
(Drug tolerance)
•INH
•Phenytoin
•Chlopromazine
Progression to
Hepatic injury with
Continued use of the
medication
AST & ALT 3-5 times
Upper limit of normal
May progress to
Hepatic failure
8
Acute Hepatocellular Injury
by Drugs
 Characterized by
 Marked elevation in ALT and AST
 Normal or minimally elevated alkaline phosphatase
 Bilirubin variably increased-----›worse prognosis.
 Comprise 1/3 of all cases of fulminant hepatic failure in
the US.
 20% due to Acetominophen
 12%-15% due to other drugs
9
Acute Hepatocellular
Injury
 Alcohol
 AST is always 2-3 times higher than ALT
 AST remains less than 300 IU.
 ALT is almost always less than 100 IU.
 Towering elevation of ALT&AST(5000-10000 IU)
 Drugs (acetaminophen)
 Differential:
 Chemical toxins
 Toxic Mushrooms
 Shock liver
 Unusual with other causes of liver diseases including Viral
Hepatitis.
10
Mechanism of
Hepatotoxicity
11
Markers of Hepatotoxicity
 Aspartate Serum
Transferase (AST),
 Alanine Amino
Transferase (ALT),
 Alkaline Phosphatase
(ALP)
 Lactate dehydrogenase
(LDH)
 Total Bilirubin (TB)
 Total protein (TP),
 Triglycerides (TG)
 Gammaglutamyl
transferase (GGT) levels
12
13
14
Mechanism of hepatotoxicity
 Most of the hepatotoxic chemicals damage liver cells
mainly by inducing lipid per oxidation and other oxidative
damages in liver.
 By forming the reactive free oxygen radicals which
directly induces hepatotoxicity
 Increasing the apoptosis
 Reducing Glutathione stores an antioxidant of human
body
15
16
DILI
17
18
Hepatoprotective agents19
List of Hepatoprotective agents
20
 N acetylcysteine vitamins
 Penicillamine
 Anti oxidants melatonin
 cardiotropin 1 glutathione
 Herbal medications beta carotene
 S adenosyl methionine (SAM) many more
N acetyl cysteine21
Description
 N-acetyl derivative of L-
cysteine
 Pharmacologic category
 Antidote
 Mucolytic
22
Indications
23
 FDA labeled indications
 Acetaminophen (APAP) overdose
 Adjunctive mucolytic therapy
 Diagnostic bronchial studies
 Off-label use
 Prevention of contrast-induced nephrotoxicity
(CIN)
 Helicobacter pylori infection
Pathophysiology of APAP
Overdose24
 APAP primarily metabolized via Glucoronidation or
sulphation
 Secondary metabolism by CYP 450 system
 In OD, primary route saturated → CYP 450 system → NAPQI
production
 NAPQI converted to non-toxic form by glutathione
 In OD, glutathione stores consumed → excess NAPQI →
covalent binding to hepatocytes
25
26
 NAPQI causes
1. Protein binding cytoplasm loss /damage of protein
Apoptosis pro apoptotic factors
2. Formation ROS lipid peroxidation
Liver necrosis DNA damage
27
 N-acetylcysteine (NAC) has been used for several
decades and has proven to be the antidote of choice in
treating acetaminophen-induced hepatotoxicity.
 oral and intravenous NAC are equally efficacious in the
prevention of hepatotoxicity.
 An important factor in assessing the efficacy of NAC is
the timing of therapy initiation in relation to the ingestion.
 Pt should receive NAC within 8hours of APAP poisoning.
Metabolism of NAC
N-Acetylcysteine 12/2002
Society For Free Radical Biology and Medicine
Ercal & Gurer-
Orhan 28
Oral NAC administration
Extensive first-pass metabolism in
liver and intestine
3% of NAC
excreted in feces
Rapid absorption
LIVER
INTESTINE
NAC
deacetylation
cysteine
glutamate
Glutamylcystein
ee
+
glycine
GSH
+
GSH
synthase
glutamate-cysteine ligase
29
 N Acetyl cysteine
 Prevents hepatic injury primarily by restoring hepatic
glutathione
 N acetyl cysteine improves hemodynamics and
oxygen use,
 Decreases cerebral edema.
 It may involve scavenging of free radicals or changes
in hepatic blood flow
Adverse Reactions
 Oral
 Drowsiness
 Chills/fever
 Nausea / Vomiting
 Bronchospasm
 Rhinorrhea
 Unpleasant odor
 IV
 Anaphylactoid
reactions
 Vomiting
30
Penicillamine31
32
 Penicillamine is a degradation product of penicillin but
has no antimicrobial activity.
 It was first isolated in 1953 from the urine of a patient
with liver disease who was receiving penicillin.
Mechanism of action
33
 Penicillamine chelates several metals including copper,
lead, iron, and mercury, forming stable water soluble
complexes that are renally excreted.
 It also combines chemically with cystine to form a stable,
soluble, readily excreted complex.
 It may also have antifibrotic effects as it inhibits lysyl
oxidase, an enzyme necessary for collagen production.
34
 It also directly binds to collagen fibrils, preventing cross-
linking into stable collagen fibers.
 Penicillamine may have immunomodulatory effects and
has been demonstrated to reduce IgM rheumatoid factor
in humans with rheumatoid arthritis.
S Adenosyl Metheonine
(SAM)
35
Methionine & SAMe
 Methionine is an essential amino acid that is primarily
metabolized in the liver. SAM biosynthesis is the first
step in methionine metabolism in a reaction catalyzed by
methionine adenosyltransferase (MAT)
 In mammals, this reaction in the liver catabolizes nearly
half of the daily intake of methionine
 The liver is the main source of SAM biosynthesis and
metabolism, turning over nearly 8 gm per day in a
normal adult
 SAM is used in transmethylation reactions and is
converted to S-adenosylhomocysteine (SAH)
Hepatic methonine metabolism and
SAME biosynthesis
S Adenosyl Methionine
 SAM is the principal biological methyl donor required for
methylation of DNA, RNA, biogenic amines,
phospholipids, histones, and other proteins
 It is the precursor for synthesis of polyamines, which are
required for cell proliferation and the maintenance of cell
viability
 In the liver, SAM is a precursor for glutathione, a major
endogenous antioxidant that protects cells against injury
by scavenging free radicals.
 Thus, SAM deficiency can impair many vital functions of
liver, which render it susceptible to injury by toxic
agents, including alcohol
SAMe (S-adenosylmethionine)
 SAMe (S-adenosylmethionine) is the main methyl donor
group in the cell. MAT (methionine adenosyltransferase)
is the unique enzyme responsible for the synthesis of
SAMe from methionine and ATP
 SAMe is the common point between the three principal
metabolic pathways: polyamines, transmethylation and
transsulfuration that converge into the methionine cycle
 SAMe is now also considered a key regulator of
metabolism, proliferation, differentiation, apoptosis and
cell death
SAM functions as an
antioxidant
 Additionally, SAM functions as an antioxidant not only
because of its role as a precursor for GSH biosynthesis,
but also because of its capacity to interact directly with
reactive oxygen species
 Evidence to support this role comes from studies on the
capacity of SAM to diminish ischemia/ reperfusion
injuries in clinical trials during liver transplantation
 These studies demonstrated that SAM was more
effective than GSH in scavenging hydroxyl radicals and
in chelating iron ions to inhibit generation of these
radicals and, unlike GSH, SAM did not stimulate
formation of scavenging hydroxyl radicals at lower
concentrations
Other mechanisms
41
 Abnormal inflammatory cytokine metabolism is a major
feature of both alcoholic and non-alcoholic
steatohepatitis.
 Apoptotic cell death of hepatocytes is emerging as an
important mechanism contributing to the progression of
human liver diseases.
 SAM effectively reduces Apoptosis and inflammatory
cytokines.
Therapeutic potential of SAM in
ALD
 The therapeutic potential of SAM was tested in a 24-month randomized,
placebo-controlled, double-blind, multicenter clinical trial in patients with
alcoholic cirrhosis
 SAM treatment improved survival or delayed the need for liver
transplantation in alcoholic liver cirrhosis, especially those with less
advanced liver disease
 Mechanism of protection was not investigated in this trial, increased
hepatic concentrations of glutathione may have contributed to beneficial
effect of SAM
 This notion is supported by another study in which oral 1.2 g SAM/d for
6 months significantly increased hepatic glutathione concentrations in
ALD patients
 Authors evaluated whether SAMe infusion improved methionine
clearance in patients with stable ALD
Herbal medication43
List of herbal medication used in
hepatic diseases44
 Silybum marinum
 Eclipta alba
 Foeniculum vulgare
 Trigonella foenum graecum
 Jatropha curcas
 Garcinia mangostana Linn
 Chamomile capitula
Silybum marianum
45
 Silybum marianum, commonly known as ‘milk thistle’
(Family: Asteraceae/Compositae) is one of the oldest
and thoroughly researched plants in the treatment of
liver diseases.
 The extracts of milk thistle is being used as a general
medicinal herb from as early as 4th century B.C. and first
reported by Theophrastus.
 Silymarin, a single herbal drug formulation which is
mostly used in liver diseases amounts to about 240
million US dollars in Germany alone.
46
 Silymarin is a complex mixture of four flavonolignan
isomers, namely silybin, isosilybin, silydianin and
silychristin with an empirical formula C25H22O10
 Among the isomers silybin is the major and most active
component and represents about 60-70 per cent,
followed by silychristin (20%), silydianin (10%), and
isosilybin (5%).
 The structural similarity of silymarin to steroid hormones
is believed to be responsible for its protein synthesis
facilitatory actions
Mechanism of action
47
 Stimulation of protein synthesis:-
 Silymarin can enter inside the nucleus and act on RNA
polymerase enzymes resulting in increased ribosomal
formation.
 This in turn hastens protein and DNA synthesis.
 This action has important therapeutic implications in the repair
of damaged hepatocytes and restoration of normal functions
of liver.
48
 Anti-inflammatory actions:
 The inhibitory effect on 5-lipoxygenase pathway resulting in
inhibition of leukotriene synthesis is a pivotal pharmacological
property of silymarin.
 Strong inhibitory effect on LTB4 but not on TNF alpha or on
prostaglandin formation
 In vivo study in mice treated with silymarin suggested that
parenteral exposure to silymarin results in suppression of T-
lymphocytes at low doses and stimulation of inflammatory
process at higher doses.
49
 Antifibrotic action:
 Liver fibrosis can result in remodeling of liver architecture
leading to hepatic insufficiency, portal hypertension and
hepatic encephalopathy.
 The conversion of hepatic stellate cells (HSC) into
myofibroblast is considered as the central event in
fibrogenesis.
 Silymarin inhibits HSC activation
 It also inhibits protein kinases and other kinases involved in
signal transduction and may interact with intracellular
signaling pathways.
50
 Drug and toxin related liver damage :
 Hepatocellular injury due to drugs seems to be the primary
event.
 This is rarely due to the drug itself and a toxic metabolite is
usually responsible.
 The drug metabolizing enzymes activate chemically stable
drugs to produce electrophilic metabolites.
 All this leads to reduction in glutathione stores, lipid
peroxidation, and membrane damage.
51
 Silymarin has a regulatory action on cellular and
mitochondrial membrane permeability in association
with an increase in membrane stability against
xenobiotic injury.
 prevent the absorption of toxins into the hepatocytes by
occupying the binding sites as well as inhibiting many
transport proteins at the membrane
52
 As an antioxidant :
 Free radicals, including the superoxide radical, hydroxyl
radical (.OH), hydrogen peroxide (H2O2), and lipid peroxide
radicals have been implicated in liver diseases.
 The cytoprotective effects of silymarin are mainly attributable
to its antioxidant and free radical scavenging properties.
 Silymarin can also interact directly with cell membrane
components to prevent any abnormalities in the content of
lipid fraction responsible for maintaining normal fluidity.
53
Adverse Drug Reactions
54
 Silymarin is reported to have a very good safety profile.
 Both animal and human studies showed that silymarin is
non toxic even when given at high doses (>1500
mg/day).
 gastrointestinal tract side effects like
 bloating, dyspepsia, nausea, irregular stool , diarrhoea
 It also produced pruritus, headache, exanthema,
malaise, asthenia, and vertigo.
Liv 52
55
 Key ingrediants
 The caper Bush ( Himsra)
 It contains p- methoxy benzoic acid which is a potent
Hepatoprotective. It prevents the elevation of malondialdehyde
(biomarker for oxidative stress)
 It also inhibits the elevation of ALT and AST
 Chicory (Kasani)
 Potent antioxidant
 It suppresses the oxidative degradation of DNA
56
 Mechanism of action
 Potent Hepatoprotective against chemical induced
hepatotoxicity
 It protects liver parenchyma and promotes hepatocellular
regenration
 It maintains cytochrome p450, hastens the early recovery
period and maintains functional integrity
 Rapid clearance of aldehyde and protects from alcohol liver
disease
57
 Side effects
 Only mild GI symptoms
 bloating,
 dyspepsia,
 nausea,
 irregular stool ,
 Diarrhoea
 When taken at prescribed dose it is totally side effects
free
As a supplementary therapy
Anti oxidants58
59
60
 The mechanism of free radical damage include
 ROS- induced peroxidation of polyunsaturated fatty acid
in the cell membrane bilayer, which causes a chain
reaction of lipid peroxidation, thus damaging the cellular
membrane and causing further oxidation of membrane
lipids and proteins.
 Subsequently cell contents including DNA, RNA, and
other cellular components are damaged.
Antioxidants
 Prevents the transfer of electron from O2 to
organic molecules
 Stabilizes free radicals
 Terminates free radical reactions
Cardiotrophin 163
64
 Phase I study in healthy volunteers completed
 Orphan Drug status granted for solid organ
transplantation and acute liver failure by FDA and EMA
 IP protection granted for liver diseases, and filed for
solid organs transplantation and kidney diseases
65
 Cardiotrophin 1 (CT-1) belongs to the IL-6 family of
cytokines.
 CT-1 receptor activation (gp 130-LIF-R) induce cell
survival through signal transduction mechanisms
mediated by Stat3, MAPK y PI3K.
 CT-1 is induced in the context of cell damage in several
tissues.
 Strong anti-apoptotic effects on hepatocytes.
 Reduce the cellular damage cause by ischemia/reperfusion.
 Decrease oxidative damage.
 Potent anti-inflammatory agent.
66
 Cardiotropin 1 has FDA and EMA orphan drug
designation for transplantation and acute liver failure.
 It has been granted for its use in hepatic regenration.
Vaccines67
HEPATITIS VACCINES
HEPATITIS A
Inactivated viral vaccine
Not given < 1 year
2 doses, 6 – 18 months apart
Combination Vaccine
Inactivated Hep – A + Recombinant Hep – B
3 doses, 0, 1 & 6 months, > 1 year older.
HEPATITIS B
rDNA – Yeast derived Vaccine
Adults – 10 -20 mcg IM at 0, 1, 6 months
< 10 yr – 5 – 10 mcg IM
95 % immunity till 40 yrs
Not contraindicated in pregnancy
For Immunodeficient :Recombivax HB(1 dose, 40g)
Engerix B (2 dose 20 g)
New Vaccines Status
• HBc VLP+ cochleates, nasal - Phase I
• HBV polyepitope vaccine - Phase I
• DNA coding for T-cell epitopes - Phase I
HEPATITIS C
No Vaccine yet available
New Vaccine Status
Vaccine Stage of
Development
Recombinant E1/E2 + MF59 subunit vaccine Phase I
Recombinant E1glycopro-tein subunit vaccine Phase II
HCcAg/E1/E2 VLPs Preclinical
Multiepitope synthetic peptides in virosomes Preclinical
Multigene recombinant Adenovirus Preclinical
Live recombinant MVA-NS3-NS4-NS5 antigens
vaccine
Preclinical
HEPATITIS E
New Vaccines Status
Vaccine Stage of Development
56 kD ORF-2 protein VLPs (baculovirus) Phase II/III
DNA vaccine (ORF-2) Preclinical
Evaluation of hepatoprotective
drugs
72
 In vitro metho
 Hepatocytes are isolated
and placed in HEPES (N-2-
hydroxyethylpiperazine – N-
2 ethanesulphonic acid)
 Hepatocytes are exposed to
test samples and toxins
CCL4, alcohol or
paracetamol.
 Degree of protection is
assesed by viability tests
(Trypan blue dye exclusion
method) and measurement
of enzymes levels.
 Ex vivo method
 After completion of in vivo
test, hepatocytes are
isolated and % of viable
cells and biochemical
parameters are determined
 Better correlated to clinical
models than in vitro or in
vivo
73
74
 Paracetamol model
 Ethanol model
 Ccl4 model
 Thioacetamide model
 D- galactosamine model
 Experimental rat
models
Future direction75
76
 Hepatotoxicity will remain clinical and
controlling significance.
 With increasing the incidence of hepatotoxicity
the need for new , potent and efficacious
Hepatoprotective agents arises.
NAC for anti TB hepatotoxicity
77
NAC for statins
78
79
 It also showed Hepatoprotective activity
against
 Carabamazepine
All in preclinical phase
 N-N dimethylformaide
 Anti retroviral agents
80
 Cannabinoids
 A very attractive target for modulating hepatic fibrosis.
 CB1 receptor – up regulated in myelofibroblast and promote
fibrosis
 CB2 receptor – antifibrotic but may amplify inflammation.
 As a result of these findings, CB1 antagonism is a more
promising strategy than CB2 agonism
81
 Rimonabant CB1 antagonist showed
 significant weight loss and improved metabolic function,
decreased triglycerides and improved insulin resistance.
 But it lead to increased neuropsychiatric complication so was
withdrawn from market.
 As a result, current efforts are directed towards CB1
antagonists that do not cross the bloodbrain barrier.
82
 Endothelin (ET1) receptor antagonist
 High levels of ET-1 and endothelin receptors are present
during cirrhosis.
 The blockade of ET-1 type A receptor and the
administration of vasodilators (prostaglandins E2 and
NO donor) exert an antifibrotic activity in rodents and in
humans also improves portal hypertension.
Hormones
83
 Adipokines
 Metabolic abnormalities are considered the ‘first hit’ of liver injury in
obesity-related liver disease, followed by oxidative stress and
inflammation.
 Leptin and its natural antagonist adiponectin are key adipokines
secreted by adipose tissue and stromal cells, especially HSC.
 Elevated leptin levels signal through their specific receptors to
promote fibrogenesis by JAK/STAT signalling.
 While adipokines are inversely related to body fat and inhibit
inflammation
 Gherlin ( a gut hormone) has also showed anti inflammatory activity
in rats
Tyrosine kinase receptors
inhibitors84
 Many proliferative cytokines, including PDGF, fibroblast
growth factor (FGF), and TGF-a signal through tyrosine
kinase receptors.
 Antagonism of pathways that mediate PDGF or VEGF
signals reduces HSC proliferation.
 Sorafenib, a multiple receptor tyrosine kinase inhibitor
approved for therapy in hepatocellular carcinoma,
targets the PDGF receptor and Raf/ERK signaling
pathways
85
86
References
87
 Manouchehr Khoshbaten et.al, N-Acetylcysteine Improves Liver Function in Patients with Non-
Alcoholic Fatty Liver Disease, Hepatitis Monthly 2010; 10(1): 12-16.
 Abajo F.J., Montero D., Madurga M., Garcia Rodriguez L.A. Acute and clinically relevant drug-
induced liver injury: a population based case–control study. Br J Clin Pharmacol. 2004; 58: 71–
80.
 Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004; 5: 836-847
 Taniguchi M, Takeuchi T, Nakatsuka R, Watanabe T, Sato K. Molecular process in acute liver
injury and regeneration induced by carbon tetrachloride. Life Sci 2004; 75: 1539-1549.
 Natalia A Osna, Hepatoprotective effects of S -adenosyl-L-methionine against alcohol- and
cytochrome P450 2E1-induced liver injury; World J Gastroenterol 2010 March 21; 16(11): 1366-
1376
 Lieber CS. S-adenosyl-L-methionine: its role in the treatment of liver disorders. Am J Clin Nutr
2002; 76: 1183S-1187S.
 S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. Pharmacol
Ther 1997; 73: 265-280
 www.dignabiotech.com
 Sharma SK, Ali M and Gupta J. Phytochemistry and Pharmacology, 2002; 2: 253-70.
 S. Luper, (1998).A review of plants used in the treatment of liver diseases: Part 1, Altren Med Rev
3: 410-421.
88

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Hepatoprotective agents

  • 1. HEPATOPROTECTIVE AGENTS Dr Priyank shah, Jr 1, Dept of pharmacology 1
  • 2. Introduction  Liver is one of the largest organs in human body and the chief site for intense metabolism and excretion.  It has a surprising role in the maintenance, performance and regulating homeostasis of the body.  It is involved with almost all the biochemical pathways to growth, fight against disease, nutrient supply, energy provision and reproduction. 2
  • 3. 3
  • 4. Liver Toxicity  The main causes of liver damage are  The major cause in India is ethanol and it is suspected that more than half of the cases of hepatotoxicity is caused by alcohol.  Chemicals like carbon tetrachloride CCL4, phosphorous , aflatoxins, chlorinated hydrocarbon etc  Drugs i.e. DILI ( drugs induced liver injury )  Autoimmune disorders  Infections like viral hepatitis 4
  • 5. Drugs Liver Disease Drug Metabolites (the good, the bad and the ugly) Drug Elimination Drugs and the Liver Drug-Drug Interactions LIVER 5
  • 6. Drugs causing DILI  Anti tuberculosis drugs  All drugs causes hepatotoxicity except ethambutol  Anti convulsant drugs  Carbamazepine and valproic acid  NSAIDS  Paracetamol , diclofenac , indomethacin , oxicam group  Anti microbials  Dapsone , ketoconazole , Sulfonamides, anti retrovirals  Anaesthetics  Enflurane , Isoflurane  Miscellaneous drugs  Disulfuram  Flutamide  Statins  Labetlol  Nicotinic acid  Propylthiouracil  OC pills 6
  • 7. 7
  • 8. Clinical Presentations Asymptomatic elevation in hepatic enzymes No progress despite Continued use of the Medication. (Drug tolerance) •INH •Phenytoin •Chlopromazine Progression to Hepatic injury with Continued use of the medication AST & ALT 3-5 times Upper limit of normal May progress to Hepatic failure 8
  • 9. Acute Hepatocellular Injury by Drugs  Characterized by  Marked elevation in ALT and AST  Normal or minimally elevated alkaline phosphatase  Bilirubin variably increased-----›worse prognosis.  Comprise 1/3 of all cases of fulminant hepatic failure in the US.  20% due to Acetominophen  12%-15% due to other drugs 9
  • 10. Acute Hepatocellular Injury  Alcohol  AST is always 2-3 times higher than ALT  AST remains less than 300 IU.  ALT is almost always less than 100 IU.  Towering elevation of ALT&AST(5000-10000 IU)  Drugs (acetaminophen)  Differential:  Chemical toxins  Toxic Mushrooms  Shock liver  Unusual with other causes of liver diseases including Viral Hepatitis. 10
  • 12. Markers of Hepatotoxicity  Aspartate Serum Transferase (AST),  Alanine Amino Transferase (ALT),  Alkaline Phosphatase (ALP)  Lactate dehydrogenase (LDH)  Total Bilirubin (TB)  Total protein (TP),  Triglycerides (TG)  Gammaglutamyl transferase (GGT) levels 12
  • 13. 13
  • 14. 14
  • 15. Mechanism of hepatotoxicity  Most of the hepatotoxic chemicals damage liver cells mainly by inducing lipid per oxidation and other oxidative damages in liver.  By forming the reactive free oxygen radicals which directly induces hepatotoxicity  Increasing the apoptosis  Reducing Glutathione stores an antioxidant of human body 15
  • 16. 16
  • 18. 18
  • 20. List of Hepatoprotective agents 20  N acetylcysteine vitamins  Penicillamine  Anti oxidants melatonin  cardiotropin 1 glutathione  Herbal medications beta carotene  S adenosyl methionine (SAM) many more
  • 22. Description  N-acetyl derivative of L- cysteine  Pharmacologic category  Antidote  Mucolytic 22
  • 23. Indications 23  FDA labeled indications  Acetaminophen (APAP) overdose  Adjunctive mucolytic therapy  Diagnostic bronchial studies  Off-label use  Prevention of contrast-induced nephrotoxicity (CIN)  Helicobacter pylori infection
  • 24. Pathophysiology of APAP Overdose24  APAP primarily metabolized via Glucoronidation or sulphation  Secondary metabolism by CYP 450 system  In OD, primary route saturated → CYP 450 system → NAPQI production  NAPQI converted to non-toxic form by glutathione  In OD, glutathione stores consumed → excess NAPQI → covalent binding to hepatocytes
  • 25. 25
  • 26. 26  NAPQI causes 1. Protein binding cytoplasm loss /damage of protein Apoptosis pro apoptotic factors 2. Formation ROS lipid peroxidation Liver necrosis DNA damage
  • 27. 27  N-acetylcysteine (NAC) has been used for several decades and has proven to be the antidote of choice in treating acetaminophen-induced hepatotoxicity.  oral and intravenous NAC are equally efficacious in the prevention of hepatotoxicity.  An important factor in assessing the efficacy of NAC is the timing of therapy initiation in relation to the ingestion.  Pt should receive NAC within 8hours of APAP poisoning.
  • 28. Metabolism of NAC N-Acetylcysteine 12/2002 Society For Free Radical Biology and Medicine Ercal & Gurer- Orhan 28 Oral NAC administration Extensive first-pass metabolism in liver and intestine 3% of NAC excreted in feces Rapid absorption LIVER INTESTINE NAC deacetylation cysteine glutamate Glutamylcystein ee + glycine GSH + GSH synthase glutamate-cysteine ligase
  • 29. 29  N Acetyl cysteine  Prevents hepatic injury primarily by restoring hepatic glutathione  N acetyl cysteine improves hemodynamics and oxygen use,  Decreases cerebral edema.  It may involve scavenging of free radicals or changes in hepatic blood flow
  • 30. Adverse Reactions  Oral  Drowsiness  Chills/fever  Nausea / Vomiting  Bronchospasm  Rhinorrhea  Unpleasant odor  IV  Anaphylactoid reactions  Vomiting 30
  • 32. 32  Penicillamine is a degradation product of penicillin but has no antimicrobial activity.  It was first isolated in 1953 from the urine of a patient with liver disease who was receiving penicillin.
  • 33. Mechanism of action 33  Penicillamine chelates several metals including copper, lead, iron, and mercury, forming stable water soluble complexes that are renally excreted.  It also combines chemically with cystine to form a stable, soluble, readily excreted complex.  It may also have antifibrotic effects as it inhibits lysyl oxidase, an enzyme necessary for collagen production.
  • 34. 34  It also directly binds to collagen fibrils, preventing cross- linking into stable collagen fibers.  Penicillamine may have immunomodulatory effects and has been demonstrated to reduce IgM rheumatoid factor in humans with rheumatoid arthritis.
  • 36. Methionine & SAMe  Methionine is an essential amino acid that is primarily metabolized in the liver. SAM biosynthesis is the first step in methionine metabolism in a reaction catalyzed by methionine adenosyltransferase (MAT)  In mammals, this reaction in the liver catabolizes nearly half of the daily intake of methionine  The liver is the main source of SAM biosynthesis and metabolism, turning over nearly 8 gm per day in a normal adult  SAM is used in transmethylation reactions and is converted to S-adenosylhomocysteine (SAH)
  • 37. Hepatic methonine metabolism and SAME biosynthesis
  • 38. S Adenosyl Methionine  SAM is the principal biological methyl donor required for methylation of DNA, RNA, biogenic amines, phospholipids, histones, and other proteins  It is the precursor for synthesis of polyamines, which are required for cell proliferation and the maintenance of cell viability  In the liver, SAM is a precursor for glutathione, a major endogenous antioxidant that protects cells against injury by scavenging free radicals.  Thus, SAM deficiency can impair many vital functions of liver, which render it susceptible to injury by toxic agents, including alcohol
  • 39. SAMe (S-adenosylmethionine)  SAMe (S-adenosylmethionine) is the main methyl donor group in the cell. MAT (methionine adenosyltransferase) is the unique enzyme responsible for the synthesis of SAMe from methionine and ATP  SAMe is the common point between the three principal metabolic pathways: polyamines, transmethylation and transsulfuration that converge into the methionine cycle  SAMe is now also considered a key regulator of metabolism, proliferation, differentiation, apoptosis and cell death
  • 40. SAM functions as an antioxidant  Additionally, SAM functions as an antioxidant not only because of its role as a precursor for GSH biosynthesis, but also because of its capacity to interact directly with reactive oxygen species  Evidence to support this role comes from studies on the capacity of SAM to diminish ischemia/ reperfusion injuries in clinical trials during liver transplantation  These studies demonstrated that SAM was more effective than GSH in scavenging hydroxyl radicals and in chelating iron ions to inhibit generation of these radicals and, unlike GSH, SAM did not stimulate formation of scavenging hydroxyl radicals at lower concentrations
  • 41. Other mechanisms 41  Abnormal inflammatory cytokine metabolism is a major feature of both alcoholic and non-alcoholic steatohepatitis.  Apoptotic cell death of hepatocytes is emerging as an important mechanism contributing to the progression of human liver diseases.  SAM effectively reduces Apoptosis and inflammatory cytokines.
  • 42. Therapeutic potential of SAM in ALD  The therapeutic potential of SAM was tested in a 24-month randomized, placebo-controlled, double-blind, multicenter clinical trial in patients with alcoholic cirrhosis  SAM treatment improved survival or delayed the need for liver transplantation in alcoholic liver cirrhosis, especially those with less advanced liver disease  Mechanism of protection was not investigated in this trial, increased hepatic concentrations of glutathione may have contributed to beneficial effect of SAM  This notion is supported by another study in which oral 1.2 g SAM/d for 6 months significantly increased hepatic glutathione concentrations in ALD patients  Authors evaluated whether SAMe infusion improved methionine clearance in patients with stable ALD
  • 44. List of herbal medication used in hepatic diseases44  Silybum marinum  Eclipta alba  Foeniculum vulgare  Trigonella foenum graecum  Jatropha curcas  Garcinia mangostana Linn  Chamomile capitula
  • 45. Silybum marianum 45  Silybum marianum, commonly known as ‘milk thistle’ (Family: Asteraceae/Compositae) is one of the oldest and thoroughly researched plants in the treatment of liver diseases.  The extracts of milk thistle is being used as a general medicinal herb from as early as 4th century B.C. and first reported by Theophrastus.  Silymarin, a single herbal drug formulation which is mostly used in liver diseases amounts to about 240 million US dollars in Germany alone.
  • 46. 46  Silymarin is a complex mixture of four flavonolignan isomers, namely silybin, isosilybin, silydianin and silychristin with an empirical formula C25H22O10  Among the isomers silybin is the major and most active component and represents about 60-70 per cent, followed by silychristin (20%), silydianin (10%), and isosilybin (5%).  The structural similarity of silymarin to steroid hormones is believed to be responsible for its protein synthesis facilitatory actions
  • 47. Mechanism of action 47  Stimulation of protein synthesis:-  Silymarin can enter inside the nucleus and act on RNA polymerase enzymes resulting in increased ribosomal formation.  This in turn hastens protein and DNA synthesis.  This action has important therapeutic implications in the repair of damaged hepatocytes and restoration of normal functions of liver.
  • 48. 48  Anti-inflammatory actions:  The inhibitory effect on 5-lipoxygenase pathway resulting in inhibition of leukotriene synthesis is a pivotal pharmacological property of silymarin.  Strong inhibitory effect on LTB4 but not on TNF alpha or on prostaglandin formation  In vivo study in mice treated with silymarin suggested that parenteral exposure to silymarin results in suppression of T- lymphocytes at low doses and stimulation of inflammatory process at higher doses.
  • 49. 49  Antifibrotic action:  Liver fibrosis can result in remodeling of liver architecture leading to hepatic insufficiency, portal hypertension and hepatic encephalopathy.  The conversion of hepatic stellate cells (HSC) into myofibroblast is considered as the central event in fibrogenesis.  Silymarin inhibits HSC activation  It also inhibits protein kinases and other kinases involved in signal transduction and may interact with intracellular signaling pathways.
  • 50. 50  Drug and toxin related liver damage :  Hepatocellular injury due to drugs seems to be the primary event.  This is rarely due to the drug itself and a toxic metabolite is usually responsible.  The drug metabolizing enzymes activate chemically stable drugs to produce electrophilic metabolites.  All this leads to reduction in glutathione stores, lipid peroxidation, and membrane damage.
  • 51. 51  Silymarin has a regulatory action on cellular and mitochondrial membrane permeability in association with an increase in membrane stability against xenobiotic injury.  prevent the absorption of toxins into the hepatocytes by occupying the binding sites as well as inhibiting many transport proteins at the membrane
  • 52. 52  As an antioxidant :  Free radicals, including the superoxide radical, hydroxyl radical (.OH), hydrogen peroxide (H2O2), and lipid peroxide radicals have been implicated in liver diseases.  The cytoprotective effects of silymarin are mainly attributable to its antioxidant and free radical scavenging properties.  Silymarin can also interact directly with cell membrane components to prevent any abnormalities in the content of lipid fraction responsible for maintaining normal fluidity.
  • 53. 53
  • 54. Adverse Drug Reactions 54  Silymarin is reported to have a very good safety profile.  Both animal and human studies showed that silymarin is non toxic even when given at high doses (>1500 mg/day).  gastrointestinal tract side effects like  bloating, dyspepsia, nausea, irregular stool , diarrhoea  It also produced pruritus, headache, exanthema, malaise, asthenia, and vertigo.
  • 55. Liv 52 55  Key ingrediants  The caper Bush ( Himsra)  It contains p- methoxy benzoic acid which is a potent Hepatoprotective. It prevents the elevation of malondialdehyde (biomarker for oxidative stress)  It also inhibits the elevation of ALT and AST  Chicory (Kasani)  Potent antioxidant  It suppresses the oxidative degradation of DNA
  • 56. 56  Mechanism of action  Potent Hepatoprotective against chemical induced hepatotoxicity  It protects liver parenchyma and promotes hepatocellular regenration  It maintains cytochrome p450, hastens the early recovery period and maintains functional integrity  Rapid clearance of aldehyde and protects from alcohol liver disease
  • 57. 57  Side effects  Only mild GI symptoms  bloating,  dyspepsia,  nausea,  irregular stool ,  Diarrhoea  When taken at prescribed dose it is totally side effects free
  • 58. As a supplementary therapy Anti oxidants58
  • 59. 59
  • 60. 60  The mechanism of free radical damage include  ROS- induced peroxidation of polyunsaturated fatty acid in the cell membrane bilayer, which causes a chain reaction of lipid peroxidation, thus damaging the cellular membrane and causing further oxidation of membrane lipids and proteins.  Subsequently cell contents including DNA, RNA, and other cellular components are damaged.
  • 61.
  • 62. Antioxidants  Prevents the transfer of electron from O2 to organic molecules  Stabilizes free radicals  Terminates free radical reactions
  • 64. 64  Phase I study in healthy volunteers completed  Orphan Drug status granted for solid organ transplantation and acute liver failure by FDA and EMA  IP protection granted for liver diseases, and filed for solid organs transplantation and kidney diseases
  • 65. 65  Cardiotrophin 1 (CT-1) belongs to the IL-6 family of cytokines.  CT-1 receptor activation (gp 130-LIF-R) induce cell survival through signal transduction mechanisms mediated by Stat3, MAPK y PI3K.  CT-1 is induced in the context of cell damage in several tissues.  Strong anti-apoptotic effects on hepatocytes.  Reduce the cellular damage cause by ischemia/reperfusion.  Decrease oxidative damage.  Potent anti-inflammatory agent.
  • 66. 66  Cardiotropin 1 has FDA and EMA orphan drug designation for transplantation and acute liver failure.  It has been granted for its use in hepatic regenration.
  • 68. HEPATITIS VACCINES HEPATITIS A Inactivated viral vaccine Not given < 1 year 2 doses, 6 – 18 months apart Combination Vaccine Inactivated Hep – A + Recombinant Hep – B 3 doses, 0, 1 & 6 months, > 1 year older.
  • 69. HEPATITIS B rDNA – Yeast derived Vaccine Adults – 10 -20 mcg IM at 0, 1, 6 months < 10 yr – 5 – 10 mcg IM 95 % immunity till 40 yrs Not contraindicated in pregnancy For Immunodeficient :Recombivax HB(1 dose, 40g) Engerix B (2 dose 20 g) New Vaccines Status • HBc VLP+ cochleates, nasal - Phase I • HBV polyepitope vaccine - Phase I • DNA coding for T-cell epitopes - Phase I
  • 70. HEPATITIS C No Vaccine yet available New Vaccine Status Vaccine Stage of Development Recombinant E1/E2 + MF59 subunit vaccine Phase I Recombinant E1glycopro-tein subunit vaccine Phase II HCcAg/E1/E2 VLPs Preclinical Multiepitope synthetic peptides in virosomes Preclinical Multigene recombinant Adenovirus Preclinical Live recombinant MVA-NS3-NS4-NS5 antigens vaccine Preclinical
  • 71. HEPATITIS E New Vaccines Status Vaccine Stage of Development 56 kD ORF-2 protein VLPs (baculovirus) Phase II/III DNA vaccine (ORF-2) Preclinical
  • 73.  In vitro metho  Hepatocytes are isolated and placed in HEPES (N-2- hydroxyethylpiperazine – N- 2 ethanesulphonic acid)  Hepatocytes are exposed to test samples and toxins CCL4, alcohol or paracetamol.  Degree of protection is assesed by viability tests (Trypan blue dye exclusion method) and measurement of enzymes levels.  Ex vivo method  After completion of in vivo test, hepatocytes are isolated and % of viable cells and biochemical parameters are determined  Better correlated to clinical models than in vitro or in vivo 73
  • 74. 74  Paracetamol model  Ethanol model  Ccl4 model  Thioacetamide model  D- galactosamine model  Experimental rat models
  • 76. 76  Hepatotoxicity will remain clinical and controlling significance.  With increasing the incidence of hepatotoxicity the need for new , potent and efficacious Hepatoprotective agents arises.
  • 77. NAC for anti TB hepatotoxicity 77
  • 79. 79  It also showed Hepatoprotective activity against  Carabamazepine All in preclinical phase  N-N dimethylformaide  Anti retroviral agents
  • 80. 80  Cannabinoids  A very attractive target for modulating hepatic fibrosis.  CB1 receptor – up regulated in myelofibroblast and promote fibrosis  CB2 receptor – antifibrotic but may amplify inflammation.  As a result of these findings, CB1 antagonism is a more promising strategy than CB2 agonism
  • 81. 81  Rimonabant CB1 antagonist showed  significant weight loss and improved metabolic function, decreased triglycerides and improved insulin resistance.  But it lead to increased neuropsychiatric complication so was withdrawn from market.  As a result, current efforts are directed towards CB1 antagonists that do not cross the bloodbrain barrier.
  • 82. 82  Endothelin (ET1) receptor antagonist  High levels of ET-1 and endothelin receptors are present during cirrhosis.  The blockade of ET-1 type A receptor and the administration of vasodilators (prostaglandins E2 and NO donor) exert an antifibrotic activity in rodents and in humans also improves portal hypertension.
  • 83. Hormones 83  Adipokines  Metabolic abnormalities are considered the ‘first hit’ of liver injury in obesity-related liver disease, followed by oxidative stress and inflammation.  Leptin and its natural antagonist adiponectin are key adipokines secreted by adipose tissue and stromal cells, especially HSC.  Elevated leptin levels signal through their specific receptors to promote fibrogenesis by JAK/STAT signalling.  While adipokines are inversely related to body fat and inhibit inflammation  Gherlin ( a gut hormone) has also showed anti inflammatory activity in rats
  • 84. Tyrosine kinase receptors inhibitors84  Many proliferative cytokines, including PDGF, fibroblast growth factor (FGF), and TGF-a signal through tyrosine kinase receptors.  Antagonism of pathways that mediate PDGF or VEGF signals reduces HSC proliferation.  Sorafenib, a multiple receptor tyrosine kinase inhibitor approved for therapy in hepatocellular carcinoma, targets the PDGF receptor and Raf/ERK signaling pathways
  • 85. 85
  • 86. 86
  • 87. References 87  Manouchehr Khoshbaten et.al, N-Acetylcysteine Improves Liver Function in Patients with Non- Alcoholic Fatty Liver Disease, Hepatitis Monthly 2010; 10(1): 12-16.  Abajo F.J., Montero D., Madurga M., Garcia Rodriguez L.A. Acute and clinically relevant drug- induced liver injury: a population based case–control study. Br J Clin Pharmacol. 2004; 58: 71– 80.  Taub R. Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 2004; 5: 836-847  Taniguchi M, Takeuchi T, Nakatsuka R, Watanabe T, Sato K. Molecular process in acute liver injury and regeneration induced by carbon tetrachloride. Life Sci 2004; 75: 1539-1549.  Natalia A Osna, Hepatoprotective effects of S -adenosyl-L-methionine against alcohol- and cytochrome P450 2E1-induced liver injury; World J Gastroenterol 2010 March 21; 16(11): 1366- 1376  Lieber CS. S-adenosyl-L-methionine: its role in the treatment of liver disorders. Am J Clin Nutr 2002; 76: 1183S-1187S.  S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. Pharmacol Ther 1997; 73: 265-280  www.dignabiotech.com  Sharma SK, Ali M and Gupta J. Phytochemistry and Pharmacology, 2002; 2: 253-70.  S. Luper, (1998).A review of plants used in the treatment of liver diseases: Part 1, Altren Med Rev 3: 410-421.
  • 88. 88

Editor's Notes

  1. NAC is a derivative of the amino acid cysteine. It is classified as a mucolytic and an antidote.
  2. It is FDA approved as an antidote for APAP overdose, as adjunctive therapy for respiratory conditions, and as a mucolytic for diagnostic bronchial studies. The off-label uses are for the prevention of contrast-induced nephropathy and as An adjunct in the treatment of H. pylori infections
  3. The most important adverse reactions to the inhalation are bronchospasm and n/v. Asthmatic patients are at higher risk of developing bronchospasm. Approximately 10 – 20 % of patients receiving NAC will have an anaphylactoid reaction to the IV form and patients with asthma are at a higher risk. These reactions are most commonly seen w/in 30 – 60 minutes of starting the infusion. If the reaction is just flushing, the infusion should continue, however if other symptoms are present such as rash, hypotension, or shortness of breath, the NAC infusion may be interrupted until the symptoms are adequately treated. [If they return or progress, stop NAC and consider calling the poison control center’s APAP over dose line for health care providers 1-800-525-6115] Treatment of anaphylactoid reactions: Diphenhydramine 1mg/kg IV up to 50 mg Cimetidine 5 mg/kg up to 300 mg Oral ephedrine 0.5 mg/kg up to 25 mg