POLYMORPHISIMS: WHY
INDIVIDUAL DRUG RESPONSES
VARY
S.Ashwin kumar
Mims
Vizianagaram, AP
Single nucleotide polymorphisms
(SNPs)
• SNPs are single base pair
positions in genomic DNA
at which different
sequence al...
• SNPs are very
common in the
human
population.
• Between any
two people,
there is an
average of one
SNP every ~1250
bases.
• Mutation: difference in the DNA code that
occurs in less than 1% of population
–Often associated with rare diseases
• Po...
Factors Contributing to Interindividual
Variability in Drug Disposition and Action
• Age
• Race/ethnicity
• Weight
• Gende...
Factors that influence medication
effects
• Absorption
GIT
P-glycoprotein
• Drug metabolism
phase-1
phase-2 reactions
GIT
- Antacids-> alter stomach pHdecreases
ketoconazole absorption.
- GI transit time have a small role in drug
absorptio...
drug Absorption site remarks
Ketoconazole GI tract Acidic environment
improves absorption
cyclosporine PGP Affects bioavai...
P-GLYCOPROTEIN
• Is a membrane-bound transport protein affects
absorption in GIT.
• Functions as a part of first pass effe...
DRUG METABOLISM
process that facilitates drug clearance by
- Increasing solubility
- Prodrugs to their active drugs form
C...
PHASE-I REACTIONS
CYTOCHROME P-450 ENZYME SYSTEM OVERVIEW
• The cytochrome P-450 mono-oxygenase system
(CYP-450) is largely responsible for ...
CYTOCHROME P-450 ENZYME SYSTEM
NOMENCLATURE
Eg: CYP3A4
• Classified by amino acid similarities
– 1ST No. family number
– 2...
Drugs metabolized by various CYP isoforms
Isoform % of all drugs
metabolism
CYP3A4 40-45%
CYP2D6 20-30%
CYP2C9 10%
CYP2C19...
Polymorphisms –
• Approximately 40% of human CYP-dependent
drug metabolism is carried out by polymorphic
CYP enzymes.
• Th...
Importance- therapeutic index
Drug induced- inhibition or induction of
CYP isoforms
CYP-3A4 VARIABILITY
• Responsible for 40-50% of all phase-1 reactions
and accounts for up to 7% of GIT CYP activity.
• Is ...
CYP-2D6 VARIABILITY
• Shows significant pharmacological variation
and is integral in metabolism of numerous
medications es...
CYP-2C9 polymorphisms
• 10% drug metabolism.
• Although there have been over 100 SNP
identified, only 2 variants have been...
• CYP-2C9*3- role phenytoin induced cutaneous
adverse drug reactions.
• Warfarin is the most clinically significant
substr...
CYP2C19
• 5% of all drug
metabolism.
• PPI and numerous
anticonvulsants are
primarily substrates
metabolized.
CYP1A2 polym...
Dihydropyrimidine dehydrogenase(DPD)
• In metabolism of 5-FU.
• More than 80% of given drug is metabolised by
DPD.
• Defic...
Polymorphisms
• Many genetic variants in DPD gene have been
described, most common DPD*2A allele,
which leads to an enzyma...
PHASE-2 REACTIONS
P-GLYCOPROTEIN(permeability glycoprotein)
• Is an ATP-activated pump, increased attention
because of its...
Polymorphisms
• Identified in the multidrug resistance1(MDR1)
gene that encodes PGP.
• This decreased expression is associ...
THIOPURINE METHYLTRANSFERASE(TPMT)
• Is a catalyst for the metabolism and inactivation of
azathiopurine, 6-mercaptopurine(...
6-MMP
• is correlated with
azathiopurine-
induced
hepatoxicity.
• Decreased levels of
formation in TPMT
deficient
individu...
TPMT polymorphism
• normal allele homozygous TPMT*1high
activity(89-90% popl’tn)
• Mutant alleles TPMT*3C, *3A *2 dec...
Testing methods for TPMT polymorphisms
• TPMT activity in erythrocytes
• DNA micro-array studies
Clinical application
i. T...
N-ACETYL TRANSFERASE (NAT2)
• Acetylates numerous xenobiotics making the
parent compound water soluble, thus
facilitating ...
Rapid acetylators
• homozygous for NAT2*4, NAT2*12 and NAT2*13.
• Require higher doses of medications to minimize
the lik...
GLUCOSE-6-PHOSPHATE DEHYDROGENASE
• Catalyses the first reaction in the pentose
phosphate pathway(PPP), leading to reducti...
In a study of 3166 Indian’s, g6Pd
deficiency is about 10.5%
Glutathione S-transferase(GST)
• Involved in detoxification of carcinogenic
derivatives of coal tar.
• 50% Europeans have ...
Folate pathway polymorphisms
• Methotrexate
- structural analouge of folic acid which competitively
inhibits dihydrofolate...
• Thymidylate synthase (TS) 5’-untranslated region (TS
5’-UTR 3R)
- This allele has been significantly linked with ADR in
...
• C677T polymorphism of MTHFR, observed in
8% of normal population, leads to a
thermolabile variant subsequently reducing ...
Severe cutaneous ADR and HLA
associations
• HLA-B*1502 & Carbamazepine (chinese)
- Drug induced SJS and TEN
- Not associated with hypersensitivity syndrome
• HLA-B*...
• Nevirapine (nnrti)
- HLA-B*3505 is predictor for all types of
nevirapine induced cutaneous drug
reactions(thai patients)...
Tests
a) CYP2D6 polymorphisms- DNA microarray
analysis
b) HLA polymorphisms- specific HLA typing
c) TPMT-
- phenotyping:- ...
d) G6PD
• Fluorescent spot test- enzyme activity in
erythrocytes
• Methemoglobin or nile blue sulfate reduction
G6PD studi...
• www.drug-interactions.com
HEPATOTOXICITY OF
DERMATOLOGIC DRUG THERAPY
Drugs and liver injury
• Drugs are estimated to be responsible for 10%
of cases of hepatitis in adults.
• 40-50% of hepati...
Hepatic drug metabolism
- Major site of metabolism for most drugs
- Overall goal of hepatic drug metabolism is to
convert ...
Biotransformation
• goal- lipophilic to hydrophilic
• Increased hydrophilicity --> excreted by either
renal or billiary ro...
Time period
• Majority occur between 15-90 days after the initiation
of therapy.
• Potentially serious hematologic drug re...
Outcome
• Most are completely reversible if detected
early(days/ few weeks)
• If detected relatively late, some are not fu...
Cellular and structural targets involved
with DILD
Cell or structure Category of reaction Representative drug
etiologies
H...
Risk Factors For Susceptibility to DILD
• Methotrexate
– Alcohol
– Obesity
– D.M
– Chronic hepatitis
– Renal insufficiency...
Drug specific risk factors
• Daily dose- retinoid hepatotoxicity.
• Cumulative dose- MTX induced liver disease.
Red flag ...
Major classification systems in DILD
1) Based on laboratory test abnormalities(LFT)
- hepatocellular:- elevated transamina...
3) Based on pathogenesis
- Toxic
- Idiosyncratic
a) metabolic- local toxic reactive
intermediates.
b) immunologic- neoanti...
Mechanisms of drug hepatoxicity
• Mainly by
- Idiosyncratic(majority, unpredictable))
- Toxic (dose dependent, predictable...
Metabolic targets involved with DILD
molecule consequence comments
Various proteins Neoantigen formation Reactive metaboli...
Hepatocellular Best diagnostic
test
Classic culprit Dermatology drugs
Hepatocellular AST & ALT Halothane Ketoconazole
Daps...
Dapsone and azathioprine
All physicians will do careful hematologic
monitering, whereas far fewer will routinely
check tra...
Diagnostic algorithm
1) Challenge- circumstances of the original drug course ,
drug timing/reputation, patient history or ...
Transaminases
1-2 fold elevation-
- Reduce the drug dose and follow up the
transaminase values carefully.
Above 3- fold ...
• Hepatocyte integrity-
- Specificity- ALT/SGPT>AST/SGOT
- Greater sensitivity if both are ordered.
Periodic Liver biopsy-...
Thank you
Polymorphisims why individual drug responses vary
Polymorphisims why individual drug responses vary
Polymorphisims why individual drug responses vary
Polymorphisims why individual drug responses vary
Polymorphisims why individual drug responses vary
Polymorphisims why individual drug responses vary
Polymorphisims why individual drug responses vary
of 70

Polymorphisims why individual drug responses vary

ashwinsanapala
Published on: Mar 4, 2016
Published in: Health & Medicine      
Source: www.slideshare.net


Transcripts - Polymorphisims why individual drug responses vary

  • 1. POLYMORPHISIMS: WHY INDIVIDUAL DRUG RESPONSES VARY S.Ashwin kumar Mims Vizianagaram, AP
  • 2. Single nucleotide polymorphisms (SNPs) • SNPs are single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist wherein the least frequent allele has an abundance of 1% or greater. • SNPs are the most commonly occurring genetic differences.
  • 3. • SNPs are very common in the human population. • Between any two people, there is an average of one SNP every ~1250 bases.
  • 4. • Mutation: difference in the DNA code that occurs in less than 1% of population –Often associated with rare diseases • Polymorphism: difference in the DNA code that occurs in more than 1% of the population –A single polymorphism is less likely to be the main cause of a disease –Polymorphisms often have no visible clinical impact
  • 5. Factors Contributing to Interindividual Variability in Drug Disposition and Action • Age • Race/ethnicity • Weight • Gender • Concomitant Diseases • Concomitant Drugs • Social factors • GENETICS
  • 6. Factors that influence medication effects • Absorption GIT P-glycoprotein • Drug metabolism phase-1 phase-2 reactions
  • 7. GIT - Antacids-> alter stomach pHdecreases ketoconazole absorption. - GI transit time have a small role in drug absorption variability. Anticholinergics slow down transit times, crohn’s and ulcerative collitis can markedly increase transit times .
  • 8. drug Absorption site remarks Ketoconazole GI tract Acidic environment improves absorption cyclosporine PGP Affects bioavailability Mycophenolete mofitel GI tract Not to be given with Fe(inhibits absorption)
  • 9. P-GLYCOPROTEIN • Is a membrane-bound transport protein affects absorption in GIT. • Functions as a part of first pass effect by actively pumping the drugs out from cell, there by decreasing bioavailability. • High levels of PGP also found in liver and kidneys(drug elimination). • Decreased intestinal P-gp function –increased amount absorbed –increased plasma concentration
  • 10. DRUG METABOLISM process that facilitates drug clearance by - Increasing solubility - Prodrugs to their active drugs form Can be divided into two components a) phase -I : intra molecular modifications(reductases, oxidases, hydrolases) -create a site for attachment of larger polar side chains (in P-II rxn) b) phase-II: results in conjugation of drug with an endogenous substance by glucuronidase, sulphatase, acetylases, methylases. Despite what the nomenclature suggests, there is no order in which these reactions take place.
  • 11. PHASE-I REACTIONS
  • 12. CYTOCHROME P-450 ENZYME SYSTEM OVERVIEW • The cytochrome P-450 mono-oxygenase system (CYP-450) is largely responsible for catalysing phase1 reactions(70-80%). • Complex supergene family: at least 40 enzymes expressed in human tissues. • CYP1A2, 3A4, 2C9, 2C19, 2D6, 2E1 exert a major role in drug metabolism. • Enzymes are located on smooth endoplasmic reticulum of most cells, but are found in variable concentrations. • Hepatocytes have the greatest concentration of CYP enzymes. ARE RESPONSIBLE FOR THE METABOLIC ELIMINATION OF MOST DRUGS CURRENTLY USED IN MEDICINE
  • 13. CYTOCHROME P-450 ENZYME SYSTEM NOMENCLATURE Eg: CYP3A4 • Classified by amino acid similarities – 1ST No. family number – 2nd subfamily letter – Final number for each gene within the subfamily – asterisk followed by a number (and letter) for each genetic (allelic) variant o allele *1 is the normal function gene (wild allele) o CYP2D6*1a gene encodes wild-type protein CYP2D6*1
  • 14. Drugs metabolized by various CYP isoforms Isoform % of all drugs metabolism CYP3A4 40-45% CYP2D6 20-30% CYP2C9 10% CYP2C19 5% CYP1A2 5%
  • 15. Polymorphisms – • Approximately 40% of human CYP-dependent drug metabolism is carried out by polymorphic CYP enzymes. • This polymorphism expressed as variable enzyme activity, thus effecting metabolism of drugs. • Depending on enzyme activity, individuals designated as: -poor metabolisers(PM) -Intermediate metabolisers(IM) -Extensive metabolisers(EM) -Ultrarapid metabolisers(URM)
  • 16. Importance- therapeutic index
  • 17. Drug induced- inhibition or induction of CYP isoforms
  • 18. CYP-3A4 VARIABILITY • Responsible for 40-50% of all phase-1 reactions and accounts for up to 7% of GIT CYP activity. • Is co-expressed with P-glycoprotein in liver and intestine. • Despite little genetic variability between populations , there appears to be as much as 20 fold interindividual variability of enzyme activity. • CYP-3A4*1B appears to be the most common variant allele decreased activity.
  • 19. CYP-2D6 VARIABILITY • Shows significant pharmacological variation and is integral in metabolism of numerous medications especially psychiatric and cardiac medications. • almost 80 allelic variants. • 20-30% drugs are metabolised through this pathway.
  • 20. CYP-2C9 polymorphisms • 10% drug metabolism. • Although there have been over 100 SNP identified, only 2 variants have been shown to significantly reduce substrate affinity through inhibiting CYP activity. • Homozygote CYP-2C9*3/*3, comprising 0.5% of populations , is considered to have marked clinical significance with very low CYP-2C6 activity.
  • 21. • CYP-2C9*3- role phenytoin induced cutaneous adverse drug reactions. • Warfarin is the most clinically significant substrate. • Fluconazole inhibition of CYP-2C9 can result in markedly elevated levels of warfarin.
  • 22. CYP2C19 • 5% of all drug metabolism. • PPI and numerous anticonvulsants are primarily substrates metabolized. CYP1A2 polymorphism • Metabolize several antipsychotic medications and theophylline. • Environment and genetic factors are shown to influence the activity of CYP1A2. • Inducers- Tobacco, OCP,
  • 23. Dihydropyrimidine dehydrogenase(DPD) • In metabolism of 5-FU. • More than 80% of given drug is metabolised by DPD. • Deficiency of DPD have been reported to have severe neurotoxicity from 5-FU treatment. • Severe gastrointestinal and hematological toxicity reported with DPD deficient patient who applied it topically on scalp. Therefore contraindicated in DPD deficient patients.
  • 24. Polymorphisms • Many genetic variants in DPD gene have been described, most common DPD*2A allele, which leads to an enzymatically deficient DPD. • This allele is associated with 5-FU induced toxicity specially leucopenia and mucositis.
  • 25. PHASE-2 REACTIONS P-GLYCOPROTEIN(permeability glycoprotein) • Is an ATP-activated pump, increased attention because of its role in multidrug resistance, in particular to chemotherapeutic agents. • PGP involves pumping molecules from intracellular to extracellular spaces, countering the effects of passive diffusion, most notably in GIT, resultant decrease in net drug absorption.
  • 26. Polymorphisms • Identified in the multidrug resistance1(MDR1) gene that encodes PGP. • This decreased expression is associated with increased drug concentrations(digoxin). Importance- Significant overlap between PGP and CYP3A4, limiting assessment of PGP polymorphisms.
  • 27. THIOPURINE METHYLTRANSFERASE(TPMT) • Is a catalyst for the metabolism and inactivation of azathiopurine, 6-mercaptopurine(6-MP) and thioguanine. • Function- converting 6-MP to active methyl mercaptopurine(6MMP) nucleotides and converting thioguanine to inactive metabolites. • decreased activity results in increased 6- thioguanine levels, leading to increased toxicity(myelosuppression)
  • 28. 6-MMP • is correlated with azathiopurine- induced hepatoxicity. • Decreased levels of formation in TPMT deficient individuals. • Therefore, deficient individuals are at lower risk of developing hepatotoxicity.
  • 29. TPMT polymorphism • normal allele homozygous TPMT*1high activity(89-90% popl’tn) • Mutant alleles TPMT*3C, *3A *2 decreased activity • Heterozygous expression along with TPMT*1 – results in intermediate TPMT activity(10-11%). • Low to no TPMT activity0.3%{decreased hepatotoxicity & increased myelosuppression}
  • 30. Testing methods for TPMT polymorphisms • TPMT activity in erythrocytes • DNA micro-array studies Clinical application i. TPMT*1(normal)– 2 to 2.5ml/kg/day (standard dose) ii. Heterozygous with one mutant allele - dose reduced by 15-50%. iii. Two mutant alleles – recommended that not to be treated; if must, @ dose reduced by 90%.
  • 31. N-ACETYL TRANSFERASE (NAT2) • Acetylates numerous xenobiotics making the parent compound water soluble, thus facilitating drug elimination. • 25 allelic variants of NAT2 gene have been identified. • Enzyme activity often reported as rapid, intermediate, or slow (analogous to EM,IM,PM).
  • 32. Rapid acetylators • homozygous for NAT2*4, NAT2*12 and NAT2*13. • Require higher doses of medications to minimize the likelihood of treatment failure. Intermediate acetylators NAT2*5, *6, *7, *14 Slow acetylators • More likely to develop toxic adverse effects, including drug induced lupus - procainamide and hydralazine neuropathy –isonaizd TEN – sulfonamides • Have increased risk certain solid tumors and for some IgE-mediated food allergies seen in children
  • 33. GLUCOSE-6-PHOSPHATE DEHYDROGENASE • Catalyses the first reaction in the pentose phosphate pathway(PPP), leading to reduction of NADP to NADPH. • NADPH plays important role in reducing glutathione, which plays pivotal role preventing cell damage by oxidative stress. • Since erythrocytes lack mitochondria, the PPP is the only source of NADPH, thus making erythrocytes sensitive to oxidative stress, resulting in hemolysis.
  • 34. In a study of 3166 Indian’s, g6Pd deficiency is about 10.5%
  • 35. Glutathione S-transferase(GST) • Involved in detoxification of carcinogenic derivatives of coal tar. • 50% Europeans have low to absent activity owing to the presence of the GSTM1-null genotype. • Hence , when these individuals are treated with topical coal tar have a greater mutagen exposure.
  • 36. Folate pathway polymorphisms • Methotrexate - structural analouge of folic acid which competitively inhibits dihydrofolate reductase (DHFR). - Also directly inhibits thymidylate synthase(TS) - Influences the activity of methylene tetrahydrofolate reductase(MTHFR), which converts homocysteine to methonine. - The adverse drug reactions have been associated with polymorphisms of TS and MTHFR.
  • 37. • Thymidylate synthase (TS) 5’-untranslated region (TS 5’-UTR 3R) - This allele has been significantly linked with ADR in psoriasis patients taking MTX when folic acid is not administered. - associated with a poor therapeutic response to MTX. - Lower risk for 5-FU induced ADR. • TS 5’-UTR 6 bp deletion allele has also been associated with increased MTX-induced toxicity , including up to an 8-fold increase of developing elevated ALT transaminase levels in absence of folic acid supplementation.
  • 38. • C677T polymorphism of MTHFR, observed in 8% of normal population, leads to a thermolabile variant subsequently reducing its activity to about 30% of wild type. • This has been associated with an increased risk of discontinuing MTX because of elevation in liver enzymes.
  • 39. Severe cutaneous ADR and HLA associations
  • 40. • HLA-B*1502 & Carbamazepine (chinese) - Drug induced SJS and TEN - Not associated with hypersensitivity syndrome • HLA-B*5801- Allopurinol induced severe cutaneous ADR. • Abacavir hypersensitivity - HLA-B*5701(severe and fatal) - HLA-DQ3, HLA-DR7
  • 41. • Nevirapine (nnrti) - HLA-B*3505 is predictor for all types of nevirapine induced cutaneous drug reactions(thai patients). - HLA-DRB1*0101 hepatitis, fever, and rash, but not with isolated rash. - ADR occur more frequently in patients with higher pre-treatment CD4 levels - Therefore, it is now recommended that it should be avoided with CD4 count women- >250/microL men- >400/microL
  • 42. Tests a) CYP2D6 polymorphisms- DNA microarray analysis b) HLA polymorphisms- specific HLA typing c) TPMT- - phenotyping:- measures enzyme activity in peripheral RBC lysates. - Genotyping:- DNA microarray, PCR, prometheus TPMT genetics - genetic allele testing.
  • 43. d) G6PD • Fluorescent spot test- enzyme activity in erythrocytes • Methemoglobin or nile blue sulfate reduction G6PD studies • G6PD genotyping e) Thymidylate synthase • Genotyping of 5’UTR repeats f) GSTM1- PCR analysis
  • 44. • www.drug-interactions.com
  • 45. HEPATOTOXICITY OF DERMATOLOGIC DRUG THERAPY
  • 46. Drugs and liver injury • Drugs are estimated to be responsible for 10% of cases of hepatitis in adults. • 40-50% of hepatits in adults over 50yrs of age. • 25% of fulminant hepatitis. • Liver failure, when drug induced on an idiosyncratic basis, is fatal 75-80% of the time.
  • 47. Hepatic drug metabolism - Major site of metabolism for most drugs - Overall goal of hepatic drug metabolism is to convert pharmacologically active relatively lipophilic drugs into inactive relatively hydophilic metabolites(biotransformation) and conversion of reactive metabolic intermediates to more stable molecular compounds (detoxification). - Reasonable balance between the two process keeps liver away from toxicity.
  • 48. Biotransformation • goal- lipophilic to hydrophilic • Increased hydrophilicity --> excreted by either renal or billiary routes. Detoxification • Goal- To avoid local or distant damage from reactive intermediates(electrophilic compounds) during biotranformation. These systems are adequate to allow safe drug administration without significant risk to liver.
  • 49. Time period • Majority occur between 15-90 days after the initiation of therapy. • Potentially serious hematologic drug reactions have a much more gradual onset. within 15 days after cessation - Marked improvement(mostly) - may lead to hepatocellular toxicity, hypersensitivity syndrome and cholestasis type reactions. Occurs over years- Steatosis progressing to fibrosis is much slower
  • 50. Outcome • Most are completely reversible if detected early(days/ few weeks) • If detected relatively late, some are not fully reversible. • Delayed diagnosis - Death - liver failure requiring transplantation - severe fibrosis or cirrhosis. LOSS OF SOME DEGREE OF LIVER FUNCTION IS INDEFINITE
  • 51. Cellular and structural targets involved with DILD Cell or structure Category of reaction Representative drug etiologies Hepatocytes Hepatocellular necrosis Ketoconazole, minocycline Bile ducts, bile canaliculi Cholestasis Erythromycin Endothelial cells, sinusoids Veno-occlusive Very high dose cyclophosphimide Ito cells Steatosis-> fibrosis methotrexate
  • 52. Risk Factors For Susceptibility to DILD • Methotrexate – Alcohol – Obesity – D.M – Chronic hepatitis – Renal insufficiency • INH – HBV,HCV,HIV – Alcohol – Older age – Female • Sulfonamide – HIV – Slow acetylator – Genetic defect in defense • Anticonvulsants – Genetic defect in detoxification • Acetaminophen – Alcohol – Fasting – INH • Valproate – Young age – Anticonvulsants • Diclofenac – Female – Osteoarthritis • Rifampicin – Slow acetylators – INH • Pyrazinamide – Slow acetylators – INH
  • 53. Drug specific risk factors • Daily dose- retinoid hepatotoxicity. • Cumulative dose- MTX induced liver disease. Red flag signs in prescribing recently released medications - Presence of significant number of patients in clinical trails with mild elevation in LFT. - Report of even 1-2 deaths from drug hepatoxicity in clinical trails or very soon after drug’s release.
  • 54. Major classification systems in DILD 1) Based on laboratory test abnormalities(LFT) - hepatocellular:- elevated transaminases - Obstructive:- elevated ALP, GGT and bilirubin values - Mixed:- combination of both (either type over time commonly becomes ‘mixed’) 2) Based liver histology - Steatosis(fatty liver) - Fibrosis to cirrhosis - Granulomatous - Veno-occlusive
  • 55. 3) Based on pathogenesis - Toxic - Idiosyncratic a) metabolic- local toxic reactive intermediates. b) immunologic- neoantigens
  • 56. Mechanisms of drug hepatoxicity • Mainly by - Idiosyncratic(majority, unpredictable)) - Toxic (dose dependent, predictable) - Idiosyncratic DILD • Well accepted hypothesis:- Reactive electrophilic intermediates with defective cellular detoxification systems
  • 57. Metabolic targets involved with DILD molecule consequence comments Various proteins Neoantigen formation Reactive metabolites induce a change in structure or conformation CYP proteins Neoantigen formation CYP especially vulnerable , due to proximity to reactive metabolites DNA Apoptosis or necrosis results in cell death Lipids Lose membrane integrity Result of lipid peroxidation by reactive metabolites
  • 58. Hepatocellular Best diagnostic test Classic culprit Dermatology drugs Hepatocellular AST & ALT Halothane Ketoconazole Dapsone Minocycline Azathioprine Acitretin MTX Hypersensitivity AST, ALT & eosinophil count Phenytion Dapsone Minocycline Azathioprine Sulfonamides Cholestasis ALP GGT Bilirubin(direct) Chlorpromazine Rifampin Erythromycin TMP/SMX Steatosisfibrosis Liver biopsy Transaminases MTX Acetretin(rarely)
  • 59. Dapsone and azathioprine All physicians will do careful hematologic monitering, whereas far fewer will routinely check transaminase levels, another is the very ‘delayed’ discovery of the potential for minocycline to induce hepatotoxicity (an isolated findings) or DHS.
  • 60. Diagnostic algorithm 1) Challenge- circumstances of the original drug course , drug timing/reputation, patient history or prior reactions to the drug in question 2) Dechallenge- expected improvement after the drug is discontinued 3) Rechallenge- only when it is essential to know the responsible drug with certainty and the reaction pattern is a relatively low-risk adverse effect from drugs. 4) Exclusion- other non-drug etiologies for the same adverse effect. ‘Dechallenge’ and ‘exclusion’ steps are appropriate for virtually all patients with a 2-3 fold elevation of transaminase values.
  • 61. Transaminases 1-2 fold elevation- - Reduce the drug dose and follow up the transaminase values carefully. Above 3- fold elevation(critical)- - Prompt indefinite discontinuation of the drug or drugs likely to be responsible, unless an alternative etiology for this elevation is uncovered.
  • 62. • Hepatocyte integrity- - Specificity- ALT/SGPT>AST/SGOT - Greater sensitivity if both are ordered. Periodic Liver biopsy- psoriasis patients on long term MTX therapy. In rhematology, patients with RA and on MTX ; repeated elevations of transaminases i.e elevetions in 5 of 9 tests performed every 6 weeks, over a year or albumin levels <3 gm% are the published standard of care to indicate a need for a liver biopsy.
  • 63. Thank you

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