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Drugs and liver
Prof JH van Zyl 2010
01. Central role of liver in drug metabolism
02. Principal reactions in drug metabolism
03. Electron flow pathway in the microsomal drug-oxidizing system
04. Orphan nuclear receptors and drug metabolism
05. Genetic polymorphism of cytochrome P450 and acetylation
06. Consequences of drug biotransformation
07. Drug-drug interactions
08. Effect of cirrhosis on the plasma clearance of diazepam
09. Factors leading to decreased drug metabolism in aging
10. Primary mechanisms of impaired drug metabolism
11. Secondary mechanisms of impaired drug reactions
12. One of the outcomes of drug metabolism is the induction of liver injury
13. Drug-induced liver disease
14. Pathogenesis of drug-induced liver diseases
15. Mechanisms of acetaminophen toxicity
16. Mechanisms of isoniazid hepatotoxicity
17. Halothane hepatitis
18. Drug-induced fatty liver
19. Herbal preparations implicated in hepatotoxicity
20. Diagnosis of drug-induced liver disease
Management
1.
2.
3.
4.
5.
Isoniazid hepatitis incidence
Drug-induced fatty liver
Mechanisms of cholestasis
Herbal preparations implicated in hepatotoxicity
Antecedent liver injury and the use of potentially
hepatotoxic drugs
6. Diagnosis of drug-induced liver disease
7. Management of drug-induced liver disease
Learning Outcomes
1. Know what the liver does to drugs
2. Know how drugs affect the liver
3. Distinguish between the 2 types of drug induced liver
disease:
Drug induced hepatitis
vs
Liver toxins
4. Know what the levels are for “safe” alcohol usage
5. Know the effects of alcohol on the liver
6. Know how to recognise alcohol induced liver disease
Central role of liver in drug metabolism
Principal reactions in drug metabolism
Electron flow pathway in the microsomal drugoxidizing system
How does the liver affect drugs?
• Change from lipid-soluble to water-soluble
• Takes place in the intracellular space
FACTORS INFLUENCING HEPATIC UPTAKE OF
DRUGS
• Protein binding
• Blood flow
• Specific receptor or transport protein
FACTORS INFLUENCING HEPATIC UPTAKE OF
DRUGS
• Protein binding
• Weakly or strongly bound to protein
FACTORS INFLUENCING HEPATIC UPTAKE OF
DRUGS
• Blood flow
• Normal portal flow in man
= 1000-1200ml/min
• Reduced in cirrhosis
• 100% of blood in portal vein recovered from hepatic vein in
health and only 13% in cirrhosis( 87% via collaterals)
FACTORS INFLUENCING HEPATIC UPTAKE OF
DRUGS
• Specific receptor or transport protein
FACTORS INFLUENCING THE ACTIVITY OF DRUG
METABOLIZING ENZYMES
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•
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Genetic
Age
Drugs
Disease
FACTORS INFLUENCING THE ACTIVITY OF DRUG
METABOLIZING ENZYMES
• Genetic
• Slow and fast acetylation of INH
FACTORS INFLUENCING THE ACTIVITY OF DRUG
METABOLIZING ENZYMES
• Age
Table 6-18. Factors Leading to Decreased Drug Metabolism in Aging
Decreased liver blood flow
Decreased liver mass
Pseudo-capillarization
Decline in hepatic oxygenation?
FACTORS INFLUENCING THE ACTIVITY OF DRUG
METABOLIZING ENZYMES
• Drugs
• Warfarin and Phenytoin
FACTORS INFLUENCING THE ACTIVITY OF DRUG
METABOLIZING ENZYMES
• Disease
• In the metabolizing of the drug –
- Weaker?
- Stonger?
HOW DO DRUGS AFFECT THE LIVER?
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Increased load – Sulphonamides
Disordered metabolism- Anabolic Steroids
Hepatotoxins – C Cl4
Sensitivity
- Hepatitis - INH, Halothane
- Cholestatic – Phenothiazine
HEPATOTOXINS
• Exhibit a distinctive histological pattern for any given
hepatotoxin
• Is dose related
• Can be elicited in all individuals
• Are reproducible in laboratory animals.
• Appear after a predictable and brief exposure
HEPATOTOXINS
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Carbon tetrachloride
Tetracycline
Aminita phalloides
Cytotoxic drugs
Methotrexate
Paracetamol
Arsenic
HEPATOTOXINS : PATHOLOGY
• Necrosis
• Fatty infiltration
• Little inflammation
HEPATOTOXINS : CLINICAL FEATURES
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Short latent period
Symptom of hepatitis without pre-icteric fever
Anorexia, nausea and vomiting
Jaundice
Hepatomegaly
SEVERE TOXIC HEPATITIS
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Intense abdominal pain
Haematemesis
Rapid decrease in liver size
Ascites, oedema
Bleeding tendency
Coma
Uraemia +/-
TOXIC HEPATITIS
• Treatment
- Gastric lavage
- Antidotes
Cysteamine for paracetamol
DRUG INDUCED HEPATITIS
• They cannot be produced in animals
• Only some individuals are at risk
• Severity or occurrence bears no relation to
amount consumed
• No relationship to the institution of therapy
• Histology varies
• Often fever, arthralgia, rash and eosinophilia
DRUG INDUCED HEPATITIS: TREATMENT
• Stop offending drug
• Do not rechallenge
• Value of corticosteroids uncertain
DRUG INDUCED HEPATITIS
• Patients with atopic allergy and a history of
antecedent reactions to other drugs are at risk
• A drug with other hypersensitivity reactions
will sooner or later produce hepatitis in others.
Orphan nuclear receptors and drug metabolism
Genetic polymorphism of cytochrome P450 and
acetylation
Table 6-9. Genetic Polymorphism of Cytochrome P450 and Acetylation
Enzyme
P450IID6
P450IIC
N-Acetyltransferase
(NAT)
Designation
Debrisoquine/sparteine
polymorphism
Mephenytoin
polymorphism
Acetylation (INH)
polymorphism
Antidepressants
Mephobarbital
Hydralazine
Hexobarbital
Phenelzine
Omeprazole
Procainamide
(Other drugs involved) Antiarrhythmics
β blockers
Codeine, neuroleptics
Dapsone
Sulfamethazine
Sulfapyride
Poor metabolism
(incidence)
Japanese
5%-10%
18%-23% 40%-70%
Chinese
0%-2%
15%-20% 10%-20%
Whites
5%-10%
2%-5%
Consequences of drug biotransformation
Drug-drug interactions
Effect of cirrhosis on the plasma clearance of
diazepam
Factors leading to decreased drug metabolism in
aging
Table 6-18. Factors Leading to Decreased Drug Metabolism in Aging
Decreased liver blood flow
Decreased liver mass
Pseudo-capillarization
Decline in hepatic oxygenation?
Primary mechanisms of impaired drug metabolism
Secondary mechanisms of impaired drug reactions
One of the outcomes of drug metabolism is the
induction of liver injury
Drug-induced liver disease
Table 6-4. Drug-induced Liver Disease: General Characteristics
Hepatotoxicity
*
Predictable
Unpredictable
Incidence
High
Low
Reproducible in animals
Usually
No
Dose-dependent
Yes
Rarely
Example
Acetaminophen
Diphyenylhydantoin
*
Metab olic idiosyncrasy, presumab ly related to formation of toxic metabolite(s) under genetic control.
Hypersensitivity idiosyncrasy, presumably related to immune reaction, ? to metab olite.
Pathogenesis of drug-induced liver diseases
Mechanisms of acetaminophen toxicity
Mechanisms of isoniazid hepatotoxicity
Halothane hepatitis
Drug-induced fatty liver
Table 6-32. Agents Producing Drug-induced Fatty Liver
Macrovesicular
Methotrexate
Allopurinol
Halothane
Isoniazid
α-Methyldopa
Microvesicular
Tetracycline
Valproic acid
Ibuprofen
Pirprofen
Amineptine
Tianeptine
Salicyclic acid
Tamoxifen
Herbal preparations implicated in hepatotoxicity
Table 6-41. Herbal Preparations Implicated as Possible Hepatotoxins*
Common
names
Scientific
names
Possible toxic
component
Hepatic disorder
Cancer, arthritis ,
bruis es , diarrhea,
eczem a, colds ,
bronchitis , m ens trual
cramps , amenorrhea,
venereal diseas e,
"blood purifier", em etic,
antis eptic, diuretic
Nordihydroguaiaretic
acid (DNGA) and other
related compounds
Acute and s ubacute
hepatitis
Tonic, to rem ove "toxic
products of pregnancy"
in neonates
Unknown
Unconjugated
hyperbilirubinem ia
Folk uses
Chaparral
Larrea tridentata
(Creos ote
bus h,
greas ewood,
governadora)
Larrea divaricata
Chines e herbs
Coptis s enes ia
Chuen-Lin
(Huang-Lien,
Ma Huang)
Coptis japonicum
Yin-Chen
Antem es ia
s coparia
Neonatal jaundice
Unknown
Potential kernicterus
Com frey
Sym phytum
officinate
Fatigue, abdom inal
pain, allergy
Pyrrolizidine alkaloids
Venoocclus ive
dis ease
Germ ander
Teucrium
cham aedrys
Weight control, bitter
tonic, appetizer,
choleretic, antis eptic
Furano neoclerodane
deterpenoids
Revers ible acute
hepatitis , fatal
m assive hepatic
necros is
Gordolobo
Verbas cum
thaprus , senecio
longilobus ,
gnaphalium
m acounii
Pyrrolizidine alkaloids
Potential for
venoocclus ive
dis ease
Mis tletoe
Vis cum album ,
phoradendron
flaves cens
Infertility, as thm a,
epileps y, aphrodisiac
Hepatitis with
β-Phenylethylamine,
piecemeal necros is
tyram ine, acetylcholine,
and dis tortion of
propionylcholine
lobular architechture
Senna
Cass ia
angus tifolia,
cassia acutifolia
Laxative or cathartic
Senos ides , rhein
anthron
Skullcap
Scuttelaria
galericulata
Sedative,
anticonvuls ant
Hepatitis with
centrilobular and
bridging necros is
Valerian
(garden
heliotrope)
Valerian
officinalis
Sedative, hypnotic,
s pasm olytic,
hypotensive
Hepatitis with
piecemeal necros is ,
chronic aggressive
hepatitis with fibros is
*
Hepatitis
Herb al teas vary widely in com position and m ay contain several potential toxins often containing
pyrrolizidine alkaloids from Senecio, Sym phytum , Crotalaria, or Heliotropum . Intrauterine dam age may also
result from m aternal consum ption of these concoctions. Bab ies may develop toxic liver disease from
consum ing herbal beverages or milk from mothers tak ing toxin-containing herb al drink s.
Isoniazid hepatitis incidence
Mechanisms of cholestasis
Antecedent liver injury and the use of potentially
hepatotoxic drugs
Table 6-9. Antecedent Liver Injury and the Use of Potentially Hepatotoxic Drugs
Lower dose in hepatically metabolized dose-dependent hepatotoxins
Consider drug binding in plasma and drug-drug interactions
Consider pharmacodynamic effects ie, sedatives and NSAIDs in cirrhotics)
No basis for avoiding unpredictable hepatotoxins, ie, no increased frequency of drug-induced liver disease*
However, greater risk of increased severity of combined liver disease
Thus, need for good baseline liver tests, monitoring of early therapy, and vigilance
*
In patients with chronic hepatitis C, there may be a higher incidence of hepatotoxicity to antituberculous and
antiretroviral (ritonavir) medications, as well as chemotherapy regimens.
Diagnosis of drug-induced liver disease
Table 6-45. Diagnosis of Drug-induced Liver Disease
High index of suspicion
Careful history of drug intake
Compatible temporal sequence
Short duration of drug use
Clinical/laboratory profile consistent with known pattern (ie, hepatocellular, cholestatic) of drug injury
Use of drug combinations (ie, isoniazid/rifampin/alcohol/acetaminophen) known to predispose to drug
toxicity
Age compatible with particular drug toxicity (ie, > 40 for isoniazid; < 20 for valproic acid)
Systemic manifestations (ie, fever, rash, eosinophilia, multisystem involvement)
Liver biopsy consistent with drug-induced injury (not necessarily specific and not always needed)
Exclusion of other causes
Improvement (clinical/laboratory) after cessation of drug use; usually significant fall in transaminases in 2-4
wk for hepatocellular injury, slower with cholestasis
Rechallenge (almost never indicated)
Management of drug-induced liver disease
Table 6-11. Management of Drug-induced Liver Disease
Prompt cessation of suspected drug use
*
Specific antidote (ie, N-acetylcysteine for acetaminophen
Supportive therapy for liver disease (ie, management of complications/transplant)
Corticosteroids offer no proven benefit but may be tried in patients with hypersensitivity (vasculitis) not
responding to drug withdrawal
Liver transplantation for fulminant hepatic failure (acute liver failure)
*
Clinical and biochemical monitoring may permit early discontinuation of drug use. The frequency and
cost/benefit of biochemical monitoring is presently under discussion and requires more study.