Pharmacology: GI

Gastrointestinal Pharmacology ............................................................................................................................................... 2

Drugs and the Liver ................................................................................................................................................................. 9
 Gastrointestinal Pharmacology
Categories of drugs used for GI disorders:
 Peptic ulcer disease  Diarrhea
 Gastrointestinal motility disorders  Constipation
 Nausea/vomiting

Peptic Ulcer Disease

Gastric Acid production:
Inputs
 Neurologic input (Ach: muscarinic receptors)
o + acid, + mucous protection
 Gastrin (+ acid)
 Histamine (+ acid)
 Prostaglandins (+ mucous, - acid)

Roles of signals
1. Produce gastric acid
a. Parietal cell (H/K ATPase)
2. Help mucosa protect itself from acid
a. Superficial epithelial cell (HCO3- / mucous)

Drug strategies
 Acid neutralizing (antacids)
 Acid reduction (antisecretory)
 ↑ protection mucosal barrier (prostaglandin analogs)
 Eradicate H. pylori

Antacids
Mechanism of action: Clinical indications: (distant 3rd to H2RA / PPI for these)
 Basic compounds which neutralize HCl  Duodenal ulcers
 ↑ gastric intraluminal pH  GERD
 Inactivate pepsin, bind bile salts  Prophylaxis for stress ulcers

Pharmacokinetics
 Require frequent administration – rapid clearance is bad (want it to stay there)
 Caution in renal patients (cation absorption)

Pharmacokinetics Side effects

NaHCO3 very water soluble  rapidly cleared (bad) alkali & sodium load (bad for heart failure, etc)
CaCO3 rapid neutralization abdominal distension / belching
Mg alone is laxative (diarrhea)!
Combo Mg2+ / Al3+ slower absorption  longer neutralizing activity
 Al added to ↓ gut motility
Liquid is faster (doesn’t have to dissolve; ↑ surface area covered)
Product Al(OH)3 Mg(OH)2 CaCO3
Toxicities / interactions: change pH! Maalox quick

 Can interfere with absorption / bioavailability of other drugs dissolve
Mylanta  
 Can alter gastric motility (diarrhea / constipation)
Rolaids  
 Effects from cation absorption Tums-Ex 
Maalox TC  
Product names FYI, not for test Milk of Magnesia 
Acid reduction (antisecretory) therapies

H2 Receptor Antagonists (histamine congeners) (e.g. Ranitidine)

Mechanism of Action: H2 receptor antagonist (antisecretory acid reduction agent)
Effects: Competitive inhibition of histamine at H2 receptors (parietal cell)
 dose-dependent inhibition of gastric acid secretion by histamine & other secretagogues (H2 agonists)

Indications: Duodenal / gastric ulcers (treatment, recurrence of duodenal), acute & chronic GERD treatment.
 Inhibits basal acid secretion best (night / fasting), also physiologic acid secretion (feeding)
ranitidine
Administration: 1-2x/day
cimetidine
Pharmacokinetics: plasma peak 1-2h, mostly renal elimination, short half-life
famotidine
Toxicity:
 CYP450 INHIBITION (warfarin, theophylline, phenytoin)
 CNS confusion / somnolence
 Anti-androgen effects (esp. cimetidine) - gynecomastia, impotence (males), alactorrhea (females)

Other: cimetidine = Tagamet, ranitidine = Zantac, famotidine = Pepcid

Proton pump inhibitors (e.g. omeprazole)

Mechanism of Action: proton pump inhibitor (acid reduction - antisecretory therapy)

Effects:
 sufinyl group protonated in parietal cells (need acid)
 sulfenamide interacts covalently (irreversibly) with parietal cell H/K ATPase
 reduces daily acid production by 95%.

Selective Toxicity: Only acts where activated by acid (also, not on inactive proton pumps)
Indications:
 Peptic ulcers (esophagus, duodenum, stomach, esp. if H2RA unresponsive)
 erosive esophagitis from GERD
 Zollinger-Ellison syndrome

omeprazole Toxicity:
 Potential bacterial overgrowth of small bowel
 CYP450 inhibitor (watch out for phenytoin, diazepam, warfarin)
 ↑ risk of community acquired pneumonia (more bacteria; more chance of pneumonia on aspiration)
 ↑ risk of osteoporosis / fractures

Pharmacokinetics:
 Covalent bonding; long effects - days after drug disappears from plasma
o de novo synthesis of proton pumps required to increase acid production.
 Degraded by stomach acid (give enteric coating); metabolized by liver (need to adjust in liver failure)

Other: omeprazole (prilosec, zegerid), lansoprazole (prevacid), esomeprazole (nexium).

 No real increase in risk of carcinoid tumors (thought that chronic elevation of gastrin would increase ECL populations)
Protective mucosal barriers
Sulfated polysaccharides (e.g. sucralfate)
Mechanism of Action: improves protective mucosal barrier (protective to acid)
Effects:
 Activated by acid  viscous adherent gel binds electrostatically to (+) protein molecules in ulcer craters.
 Also inhibits pepsin and absorbs bile salts
Selective Toxicity: Activated by acid, works locally (not absorbed throughout body)

Indications: stress ulcers (prophylaxis), peptic ulcers, bile reflux (chemical gastritis - from duodenum to stomach)
sucralfate
Administration: Technically: should take on empty stomach (avoid binding to dietary protein / aluminum; also pH
increases after meal - less activation). In practice: usually take when you eat & at bedtime.

Pharmacokinetics: most of dose excreted unchanged in stool (works locally), aluminum accumulates with renal failure

Toxicity:
 Constipation, as an anion resin
 Binds other drugs (phenytoin, digoxin, theophyllin bioavailability reduced if given at same time)

Prostaglandin analogue (e.g. misoprostol)

Mechanism of Action: synthetic prostaglandin E1 analogue, increases protective functions of mucosal barrier
Effects:
 Antisecretory: inhibits basal, & nocturnal gastric acid secretion by direct action on parietal cells.
 Cytoprotective: increases production of gastric mucus and secretion of bicarbonate (epithelial cells)

misoprostol Indications: prevent gastric ulcers in patients on long term NSAIDs (COXi, so normal prostaglandins decreased!)
 Can use to treat constipation too!

Toxicity:
 Uterine contractions (abortifacent - DON'T USE in young women of reproductive age).
 Diarrhea, abdominal cramping

Eradication of H. pylori
 Gram-negative rod associated with gastritis, 60-95% of gastric ulcers / duodenal ulcers
o gastric adenocarcinoma & B-cell lymphoma too.
 Mechanism: ↓ antral D-cells  ↓ somatostatin  ↑ gastrin  ↑ acid production
 50% of world’s population infected, 15% of those develop duodenal ulcer

Treatment
 MULTIPLE ABX NEEDED: Single abx don’t work (lead to resistance!)
 ↑ effectiveness of pH-dependent abx (amoxicillin, clarithromycin) with PPI or H2-blocker
 Regimens: OAC (omeprazole + amoxicillin + clarithromycin); OMC (omeprazole + metronidazole + clarithromycin)
 10-14 days more effective than shorter courses
 Gastrointestinal motility disorders
Primary motor neuron in wall of gut controls motility

Receives input from:

Excitatory (↑ motility) Inhibitory (↓ motility)
 5HT3 serotonin receptor
 5HT4 serotonin receptor
 NANC (nonacetylcholine)
 ACh
 Dopamine

Mechanism of Action: 5-HT4 receptor activation (also dopamine antagonist and cholinergic agonist)
Effects: enhances smooth muscle propulsive contractionsof upper gut, accelerates gastric emptying (dopamine
normally slows things down; blocking it speeds things up).
 Also increases LES tone, has antiemetic effect (CNS dopamine antagonism)

Indications:
 gastroparesis(diabetic / idiopathic)
 GERD (increased LES tone, better gastric emptying)
metaclopramide
 nausea / vomiting

Pharmacokinetics: Half life increases in renal failure

Toxicity:
 somnolence, nervousness
 reversible extrapyramidal motor effects (Parkinson-like)
 irreversible tardive dyskinesia (inability to sit still / goes away with sleep)
Other: a.k.a. Reglan

Mechanism of Action: promotility agent; prostaglandin derivative; Cl channel agonist

Effects: Binds to ClC-2 channel on epithelial cell
 increased Cl & fluid secretion into gut lumen, softens stool and stimulates motility

Selective Toxicity: Acts at gut epithelium & works locally (fast metabolism; binds channels; doesn't get into blood)
Indications: Idiopathic chronic constipation, constipation-dominant IBS
lubiprostone
Pharmacokinetics: Negligible bioavailability; rapidly metabolized in gut epithelium
 no hepatic or CYP450 involvement
Toxicity:
 Nausea, diarrhea (too much of what you want)
 Headache, abdominal distension (more fluid into gut lumen)
 Flatulence

Mechanism of Action: promotility agent: antagonizes dopamine receptor

Effects: Dopamine receptor usually inhibits primary motor neuron in gut wall, slowing gastric motility.
domperidone  nhibiting dopamine receptor leads to more contractility.
Indications: like metaclopromide (gastroparesis, GERD, nausea / vomiting)
Selective Toxicity: does not cross BBB (no somnolence/extrapyramidal motor effects!)

erythromycin Mechanism of action: Promotility agent; macrolide; stimulates GI motility by agonizing motilin receptor

Things not to use:

 Tegaserod: MI, cerebrovascular accidents
 Cisapride: arrhythmias
 Nausea / Vomiting

 Emetic center in medulla

 CTZ: Chemoreceptor-trigger zone (area postrema) is key
o Note: M = muscarinic receptors

Why vomit?
 Get rid of toxins (smell, sense, etc)
 Protective: Less delicious to lions if you vomit all over yourself

Triggers:
 Motion (inner ear)  Local irritants
 Sensory input  Memory, fear
(via higher centers)  Gagging
 Blood-borne emetics

Receptors: lots of redundancy / overlap

 Simplified here (basics) – but dopamine, serotonin, histamine, acetylcholine are key!
Serotonin (5-HT3) Dopamine (D2) Histamine (H3)
Motion sickness (inner ear) 
Gagging   
Local irritants (chemo, radiation, bacteria, viruses) 

By knowing where these things work, you can figure out what medicine will be useful for which condition
 Note: don’t use serotonin antagonist for motion sickness – not involved in that pathway!

Mechanism of Action: antiemetic (serotonin receptor blocker)

Effects: blocks serotonin effect receptors in CNS (chemo-receptor trigger zone, nucleus tractus solitarius of
vagus nerve); may block vagal afferents in GI tract

Indications:
 Chemotherapy-induced nausea, nausea from upper GI irradiation
odansetron  hyperemesis of pregnancy
(zofran)  postoperative nausea
 NOT MOTION SICKNESS (no serotonin in that pathway)

Administration: once/day (antiemetic effect lasts long after drug cleared)

Pharmacokinetics: well absorbed from gut, CYP450 metabolism in liver (decrease dose in liver dysfunction)
Toxicity: Generally well tolerated: constipation, diarrhea, headache, light-headedness, minor EKG changes (not
clnically significant); financial toxicity ($$$!)

Others
Type Examples Blocks Special Indications
Phenothiazines Dopamine @ CTZ Motion sickness
prochlorperazine
Histamine, ACh too (better than ondansetron: anti-histamine / antiAch)
metaclopramide Dopamine @ CTZ
Prokinetics
domperidone (prokinetics)
promethazine  Post-op emesis
Antihistamines Histamine
diphenhydramine  Motion sickness
Anticholinergics scopolamine Muscarinic Ach receptor Motion sickness
activates cannabinoid Stimulates appetite too (AIDS pts)
Cannabinoids dronabinol
receptors in vomiting center?  Expensive!
 Diarrhea / Constipation: Overview
Key concepts:
 Fluid content = principal determinant of stool volume, consistency (usually 75-80% stool wt is H2O)
 Extent of fluid absorption by gut parallels transit time
o Faster transit  less fluid absorption (less time to absorb fluid)  diarrhea
o Slower transit  more fluid absorption (more time to absorb fluid) constipation

Numbers
 9L presented to small intestine each day (2 from diet, 7 from secretions)
 Making solid stool: conserves water & better bowel control
 Colon: can absorb 4-5 L /day (so it can pick up some slack if ↓ small bowel absorption)

Diarrhea:
Intraluminal agents
Put things into payload delivered to colon that absorb water (hygroscopic agents)

Hydroscopic agents Absorb excess water (↓ water content of stool) psyllium (Metamucil)
Bile salt binders Bind excess bile salts to avoid colon secretion cholestyramine (Questran)
Unknown mechanism, but bismuth has antisecretory,
Bismuth compounds bismuth subsalicylate (Pepto-Bismol)
anti-inflammatory, antimicrobial effects

Opiods
Mechanism of Action: opiod antimotility/antisecretory agent
Effects:
 ↑ fluid absorption, ↓ fluid secretion, ↓ motility (↑ transit time)
 ↓ longitudinal muscle activity (propulsion), ↑ segmentation activity (non-propulsive)
Indications: diarrhea (but not treating underlying cause)
loperamide
Pharmacokinetics: doesn't penetrate CNS in normal doses. loperamide is 40-50x more potent as anti-diarrheal than
morphine; quick onset affter oral dosing, peak 3-5h, half life 11h, hepatic metabolism

Toxicity: sedation and paralytic ileus with overdose

Other: aka Imodium

Constipation
General mechanisms of action
 Retain intraluminal fluid (osmotic / hydrophilic mechanisms)
 ↓ net absorption of fluid
 Motility effects:
o Inhibit segmenting (nonpropulsive) contractions
o Stimulate propulsive contractions

Stool softeners (emollients)

Mechanism of Action: emollient (stool softener) - anionic detergent
docusate sodium
Effects: lowers surface tension of stool (permits penetration of water, fats)
(colace)
Indications: used more for hard stools than constipation
Bulk-forming laxatives
Mechanism of Action: Hydrophilic compounds that hold water in stool
 might inhibit absorption of bile acids (stimulate H2O secretion by colon) too

Indications: used more for irritable bowel syndrome than for constipation

Mg salts
Most commonly used agents; hypertonic > isotonic for efficacy

Mechanism of action:
 Mg poorly absorbed  ↑ intraluminal osmolarity  ↑ water retention by stool
 Maybe ↑ CCK secretion (↑ bowel motility, secretion)

Stimulant cathartics
Direct effects on enterocytes, enteric neurons, muscle.

Mechanism of action: induce low grade inflammation in small bowel & colon!
 Inflammation  ↑ fluid, electrolytes  ↑ intestinal motility

Examples
 Bisacodyl
 Anthraquinones (senna)
Mechanism of action: Anthraquinone laxatives; "stimulant" cathartic (laxative)
Effects: induce low grade inflammation in small bowel & colon!
 Inflammation  ↑ fluid, electrolytes ↑ intestinal motility
Administration: not for daily use (see below)

senna Toxicity:
 melanosis coli (dark colon - reversible)
 "CATHARTIC COLON" (years of laxative abuse; becomes dilated & ahaustral; neurons lost & muscularis propria
atrophies - bowel function lost!)

Other: aloe, cascara are also anthraquinone laxatives

 Castor oil
o from castor plant bean
o stimulates fluid / electrolyte secretion in 1-3 hrs
o unpleasant taste, can be toxic to intestinal epithelium / enteric neurons

Nonabsorbable sugars
 If not absorbed by small intestine, can reach colon (metabolized to osmotically active organic FAs)
 Osmotic effect of FAs  fluid secretion, ↑ motility
 Examples: lactulose, glycerin, sorbitol, mannitol, lactose (if lactase deficient)
 Drugs and the Liver
Hepatic Drug Metabolism

Basic idea: both phase I and phase II want to make nonpolar

compounds more polar (easier to eliminate)

Phase I metabolism:
 Oxidation rxns catalyzed by CYP450 enzymes
(membrane-bound, have substrate specificity)
 Electrons transferred: substrate  ferric iron  O2
 NADPH serves as co-substrate (NADPH  NADP+)
 Some products are highly electrophilic; react with cellular metabolites

Phase II metabolism:
 Conjugation with UDP-glucuronic acid, glutathione, sulfate, amino-acids
 Catalyzed by several different transferases
 Substrate-specific (both endogenous & exogenous substrates: drugs)
 Almost all products are non-toxic, water-soluble

For polar compounds

 Low molecular wt drugs (<300) drugs are excreted by kidneys  urine
 High molecular wt drugs (> 300) are excreted into bile  stool

Phase III (transport)

 Transport proteins on cannalicular membrane: facilitate movement of conjugates into bile
 P-glycoprotein (Pgp) is a product of MDR-1 gene; can be induced by substrates for CYP3A4

IMPORTANT Definitions
Systemic clearance = hepatic clearance for drugs metabolized ONLY in the liver
Instrinsic clearance (Clint): clearance that depends on enzymatic metabolism (hepatic)
Extraction ratio (E): fraction of drug that is metabolized by “first pass” through the stomach / liver after oral ingestion

Relationship between hepatic clearance and blood flow

Equation Explanation Implication
𝑭=𝟏−𝑬 oral bioavailability = 1 - extraction ratio ↓ extraction ratio  ↑ oral bioavailability
𝑪𝒍𝒉𝒆𝒑𝒂𝒕𝒊𝒄 = 𝑸 × 𝑬 Hepatic clearance = flow x extraction ratio ↑ blood flow or ↑ extraction ratio = ↑ clearance!

For low extraction drugs, Clhepatic = Clint (hepatic clearance is ≈ the intrinsic clearance)
 The rate of clearance depends mostly on how the enzymes are working (increasing flow won’t really help)

Drugs with E close to 1 (high extraction)
LOW oral bioavailability
IV drug levels will be higher than PO if same dose
(IV skips 1st pass metabolism)
Drugs with low E (low extraction)
HIGH oral bioavailability
IV drug levels will be the same as PO
Variables that affect hepatic drug clearance
Intrinsic clearance
Hepatic blood flow Drug binding to plasma
(activity of drug-metabolizing enzymes)
 Interactions with other drugs and alcohol Drugs with high E are flow limited
(inhibition, induction)  1st pass effect! Only free drug is active
 Liver disease, Nutrition, Gender, Genetics Heart failure, shunts (e.g. TIPS) affect flow

Pharmacokinetics
 Polymorphisms exist for CYP450 isozymes
 May account for toxicity of certain drugs (e.g. isoniazide) – why do some get idiosyncratic drug rxns?
 Influence rates of elimination
Drugs & Cirrhosis
Low-extraction drugs
(e.g. antipyrine)
 For drugs that are oxidized by CYP450, the activity of enzymes decreases in advanced cirrhosis
o No drop-off until severe cirrhosis: flow doesn’t play a big role
 Hepatic clearance and intrinsic clearance decrease in parallel! (ClHep ≈ Clint)
o Enzyme activity is the key player!

High-extraction drugs
(e.g. lidocaine)
 For high E drugs, systemic clearance is normally dependent on flow (Q), not on Clint

In cirrhosis, blood isn’t all flowing through liver (portal hypertension, porto-hepatic shunting, etc)
 Intrinsic clearance becomes driving factor (how much can your enzymes work?)
 ↑ oral bioavailability: can now give lidocaine orally
o Need to lower oral doses (or would wind up with higher levels of drug)
o E.g. Propranolol: high extraction in liver; need to give less in cirrhosis
st
 (normally a lot gets cleared on 1 pass; not anymore!)

Basically: in cirrhosis, there’s “no such thing as a high extraction drug” anymore!
 ↓ flow through liver, so intrinsic clearance becomes more important

Cirrhosis: summary
 ↑ oral biovailability of drugs with high extraction ratio
 ↓ elimination of drugs metabolized by CYP450 in advanced cirrhosis
 ↓ binding (↓ serum protein) so ↑ “free drug” too!

Predictors of drug metabolism in cirrhosis

No “creatinine” for the kidney
 No correlation with AST / ALT / alk phos
 Weak correlation with albumin / PT
 Modest correlation with Childs-Pugh score
 But the good thing is that it takes severe liver damage to affect CYP450s

Recommendations for use of drugs in pts with cirrhosis

 Drugs eliminated by glucuronidation are less affected than those that are oxidized by CYP450
o Glucuronidation is pretty much intact, even in severe liver disease
 Oral administration of highly extracted drugs may lead to very high levels
 Dosing drugs w/ narrow therapeutic index should be modified in pts with advanced liver disease
 Drug-Induced Liver Damage
 Liver is major target for serious adverse affects
 Drugs are major cause of fulminant hepatic failure & frequent cause of undiagnosed liver dz
 Some drugs may be more toxic in individuals with underlying liver disease
 DILD is most common reason for post-marketing withdrawal of medications

DILD is histologically diverse:

 Hepatocellular necrosis, chronic hepatitis, steatohepatitis, granulomas, fibrosis, cholestasis, liver tumors, more!
 Some drugs have signature findings; others can cause different histology in different pts

Classification of DILD
Intrinsic hepatotoxins Idiosyncratic hepatotoxins
 Usually dose-related  Not always dose-related
 Short interval between ingestion / evidence of toxicity  Host factors play important role in risk
 Same type of injury across spectrum of individuals  Different reactions in different individuals
 Reproducible in animal models  Not reproducible in animal models

Idiosyncratic drug reactions: subclassification

Metabolic idiosyncrasy Immunologic idiosyncrasy
 Metabolism of drugs triggers “anti-stress” / anti-oxidant  Genetically determined
defense mechanisms in cells  Pt’s own immune response plays key role
 Responses / metabolism differs in pts; leads to toxicity  Aspects of hypersensitivity displayed, E.g. drug-induced lupus

Frequency of idiosyncratic drug reactions: broad range

o INH, others: more common (5-20/1k) but rarely prescribed
o Amoxicilin / clavulanic acid: more rare (.5-3 / 100k) but widely prescribed, so see more often!
o Minocycline: rare (1-10/10k) but really serious
 How often you see the reaction depends on frequency of Rx and probability of reaction
Clinical Spectrum of DILD
Hepatocellular injury Intrahepatic cholestasis Mixed hepatocellular /
(acute necrosis, chronic hepatitis) cholestatic injury
ALT ↑↑ (2-3x ULN) Minor changes ↑↑ (2x ULN)
Alk phos Minor changes ↑↑ (2x ULN) ↑↑ (2xULN)
ALT/alk phos ratio ↑↑ (> 5) ↓ (<2) Between 2 and 5

↑ risk for serious reactions

 Age  Genetic factors  Underlying liver dz (HCV /
 Gender  Obesity EtOH)
 Dose

Metabolic Hypersensitivity Syndrome

A.K.A. DRESS (drug reaction with eosinophila & systemic symptoms)

Features: hypersensitivity!
 Fever, rash, oral ulcers, lymphadenopathy, arthritis
 Cytopenias, eosinophilia
 Genetic susceptibility, family history
 ↑ risk in immunosuppressed (counterintuitive)
o HIV/AIDs, SLE, corticosteroids (e.g. TMP-SMX in AIDS)
Pathogenesis: Reactive Metabolite Hypothesis

 Most drug metabolism occurs within liver

 Phase 1 pathways (cytochrome P450s) produce oxidized, sometimes highly
reactive metabolites
 Can form enzyme – drug adducts; hypersensitivity rxn against these
 Can block MDR transport at bile canaliculi
 Reactive metabolites can bind to cellular macromolecules  cell injury
 Reactive metabolites also trigger apoptosis / release of cytokines

Case examples:

Drug-induced acute liver failure

 Drugs account for more that 50% of ALF
o 40% due to acetaminophen toxicity (55% unintentional)
o 13% due to idiosyncratic DILD
o 8% HBV, 4% HAV
o Survival lowest in those with idiosyncratic DILD

 Severe, but usually don’t need liver transplant

Acetaminophen toxicity
Histology: damage is mostly around terminal hepatic venule

Pathogenesis:
Note: APAP = n-acetyl-p-aminophenol = “acet-amino-phen”!

At normal therapeutic doses

 90% Phase II metabolism
o acetaminophen  either sulfate / glucuronide form, excreted

 10% phase I metabolism to NAPQI (CYP450 2E1)

o nasty effects (apoptosis, cytokines, binds macromolecules)
o Can normally be avoided by GSH addition  excretion

In acetaminophen overdose
 ↑ APAP  ↑ NAPQI produced  deplete GSH  can’t get rid of
NAPQI  more bad stuff happens (↑ *NAPQI+)

With ethanol ingestion too

 Ethanol processed by CYP450 2E1 & induces CYP450 2E1 too!
 ↑ CYP450 2E1  ↑ conversion of APAP to NAPQI  more toxicity!

Treatment: give N-acetyl cystine (restore GSH levels depleted by acetaminophen toxicity)

Diagnosis of drug-induced liver damage

 High index of suspicion
 Timing: of onset / resolution of sx / signs of liver disease in relation to drug ingestion
 Re-challenging is not a good idea ( can be hazardous)
 Exclude other possible disorders (DILD often mimics other liver diseases)
Management of drug-induced liver damage
 Stop drug delivery
 Don’t use generalized corticosteroids
 N-acetylcysteine helps APAP toxicity; may be of benefit for other drug reactions

Prevention of drug-induced liver damage

 Advise pts of signs / sx of liver disease
 Investigate anyone who becomes symptomatic on new drug
 Careful adherence to dosage guidelines (e.g. methotrexate, acetaminophen)
 Avoid deleterious drug combos
 Monitor LFTs (only for selective drugs: INH, etretinate, minocycline, or in those with ↑ risk factors: HCV)

Summary
• Most drugs are metabolized in liver
• Advanced liver disease affects hepatic drug elimination, particularly for those drugs that are oxidized by P450
• Drug induced liver damage most often related to metabolism of drugs to reactive metabolites that cause liver injury
• Host factors are important determinants of both metabolism and toxicity (idiosyncratic)