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The drug therapy of The drug therapy of gastrointestinal, gastrointestinal,

hepatic, and billiary hepatic, and billiary disorderdisorder

azalia arif - fkuiazalia arif - fkui

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HematemesisHematemesis – vomiting of blood or altered – vomiting of blood or altered blood indicates bleeding proximal to blood indicates bleeding proximal to ligament of Trietzligament of Trietz

MelenaMelena – altered blood per rectum (>100 – altered blood per rectum (>100 mL mL blood required for one melenic stool), blood required for one melenic stool),

usually indicates bleeding of Treitz, usually indicates bleeding of Treitz, but may but may be as distal as ascending colon;be as distal as ascending colon;

pseudomelena pseudomelena may be caused by may be caused by ingestion ingestion of iron, bismuth, licorice, of iron, bismuth, licorice, beets, blueberries, beets, blueberries, charcoalcharcoal

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HematocheziaHematochezia – bright red or maroon rectal – bright red or maroon rectal bleeding, usually implies bleeding bleeding, usually implies bleeding

beyond beyond ligament of Trietz but may due ligament of Trietz but may due to rapid to rapid upper intestinal bleeding upper intestinal bleeding (>1000mL)(>1000mL)

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Ascites and edemaAscites and edema♣♣ accumulation of fluid within the accumulation of fluid within the peritoneal peritoneal cavity. Small amounts may cavity. Small amounts may be be asymptomatic; increasing amounts asymptomatic; increasing amounts cause cause abdominal distention and abdominal distention and discomfort, discomfort, anorexia, nausea, flank pain anorexia, nausea, flank pain and respiratory and respiratory distress distress

♣♣ retention of sodium and water occurs retention of sodium and water occurs in in chronic liver disease for variety of chronic liver disease for variety of reasonsreasons

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PathogenesisPathogenesis

contributing factors :contributing factors :- portal hypertension- portal hypertension- hypoalbuminemia- hypoalbuminemia- increase hepatic lymph formation- increase hepatic lymph formation- renal sodium retention - renal sodium retention secondary to secondary to

hyperaldosteronism, increase hyperaldosteronism, increase sympathetic sympathetic nervous activity (renin-nervous activity (renin-angiotensin angiotensin production)production)

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Initiating eventsInitiating events may be peripheral arterial may be peripheral arterial vasodilation triggered by endotoxin and vasodilation triggered by endotoxin and cytokines and mediated by nitric oxide;cytokines and mediated by nitric oxide; result in decrease “effective” plasma result in decrease “effective” plasma volume and activation of compensatory volume and activation of compensatory mechanisms to retain renal Na and mechanisms to retain renal Na and preserve preserve intravascular volume. intravascular volume.

In severe ascitesIn severe ascites, plasma atrial natriuretic , plasma atrial natriuretic factor levels are high but insufficient to factor levels are high but insufficient to cause natriuresiscause natriuresis

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Management of hepatic oedema and ascitesManagement of hepatic oedema and ascitesLow diet salt and diureticsLow diet salt and diuretics

salt salt ♠♠ usually moderate restriction (to usually moderate restriction (to 80 80 mmol/daymmol/day ♠♠ advising patient not to add salt to advising patient not to add salt to thei thei foodfood

diureticsdiuretics ♥♥ spironolactonespironolactone (100-400 mg/day), is (100-400 mg/day), is still a drug of choice still a drug of choice ♥♥ an aldosterone antagonistan aldosterone antagonist

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♥♥ if spironolactone not fully if spironolactone not fully effective, can effective, can be combined with be combined with furosemidefurosemide

care should be taken not care should be taken not produce tooproduce too

brisk diuresis brisk diuresis

precipitating acute electrolyte precipitating acute electrolyte disturbancesdisturbances

hepatic encephalopathyhepatic encephalopathy

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♪♪ Therapy should be monitored by :Therapy should be monitored by :- daily weighing- daily weighing- weight loss should be not > 0.5 kg/day- weight loss should be not > 0.5 kg/daywith ascites alone andwith ascites alone and > 1.0 kg/day if there is peripheral oedema> 1.0 kg/day if there is peripheral oedema

♪♪ If hypokalemia does not respond to If hypokalemia does not respond to spironolactone spironolactone add K supplement add K supplement

♪♪ In resistant ascites In resistant ascites large-volume large-volume paracentesis is requiredparacentesis is required

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SpironolactoneSpironolactone♠♠ antagonist aldosteroneantagonist aldosterone (aldosterone causes Na (aldosterone causes Na retention), directly increases Na+ retention), directly increases Na+ excretion and excretion and decreases Kdecreases K++ secretion in distal convulated tubule secretion in distal convulated tubule♠♠ indikasiindikasi : use with thiazides for edema, cirrhosis : use with thiazides for edema, cirrhosis hepatis, and nephrotic syndrome hepatis, and nephrotic syndrome♠♠ S.E S.E : hyperkalemia, Na and water depletion: hyperkalemia, Na and water depletion♠♠ given orallygiven orally, excreted unchanged in kidney, can , excreted unchanged in kidney, can be used in patients with hepatic insufficiencybe used in patients with hepatic insufficiency♠♠ C.I :C.I : anuria, substantial renal insufficiency, anuria, substantial renal insufficiency, hyperkalemia. Avoid in diabeticshyperkalemia. Avoid in diabetics

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FurosemideFurosemide♣♣ inhibits chloride reabsorption in thick inhibits chloride reabsorption in thick

ascending loop of Henle. High loss of ascending loop of Henle. High loss of KK++ in in urineurine♣♣ indications :indications : prefered diuretics in prefered diuretics in patients patients with low GFR and hypertensive with low GFR and hypertensive

emergencies. Also edema, emergencies. Also edema, pulmonary pulmonary edema, and to mobilize edema, and to mobilize large volume of large volume of fluid. fluid.

♣♣ S.E :S.E : hyponatremia, hypokalemia, hyponatremia, hypokalemia, hyperglycemia, hyperuricemia, hyperglycemia, hyperuricemia,

hypocalcemia, ototoxicity, hypocalcemia, ototoxicity, hypomagnesemia, hypomagnesemia, hypochloremic hypochloremic alkalosis, hypovolemiaalkalosis, hypovolemia

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Hepatic encephalopathyHepatic encephalopathya state of disordered CNS function associated a state of disordered CNS function associated with with severe acute or chronic liver severe acute or chronic liver disease; may disease; may be be acute and reversible or chronic and acute and reversible or chronic and progressiveprogressive

PrecipitantPrecipitant- GI bleeding (100 mL= 14-20 gr of protein)- GI bleeding (100 mL= 14-20 gr of protein)- azotemia- azotemia- constipation- constipation- high-protein meal- high-protein meal- hypokalemic alkalosis- hypokalemic alkalosis- CNS depressant drugs (- CNS depressant drugs (benzodiazepin andbenzodiazepin and barbiturate)barbiturate)- - hypoxia, sepsishypoxia, sepsis

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TreatmentTreatment♣♣Remove precipitantRemove precipitant♣♣Reduced blood anemia by decreasing protein Reduced blood anemia by decreasing protein

intakeintake♣♣Enema /cathartics to clear gutEnema /cathartics to clear gut♣♣Lactulosa (converts NH3 to NH4Lactulosa (converts NH3 to NH4++, produces , produces

diarrhea, alters bowel flora) 30-60 mLdiarrhea, alters bowel flora) 30-60 mL♣♣In refractory cases : add In refractory cases : add neomycinneomycin 0,5-1 gr bid 0,5-1 gr bid♣♣FlumazenilFlumazenil, benzodiazepine antagonist, may , benzodiazepine antagonist, may

have a role in management of hepatic have a role in management of hepatic encephalopathy precipitated by benzodiazepine encephalopathy precipitated by benzodiazepine useuse

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NeomycinNeomycin♪♪ aminoglycoside antibioticsaminoglycoside antibiotics♪♪ bactericidal inhibitors of protein bactericidal inhibitors of protein synthesissynthesis♪♪ clinical use :clinical use : to reduce g.i.t flora to reduce g.i.t flora preoperativelypreoperatively to reduce amonia-producing to reduce amonia-producing bacteria bacteria in patients with hepatic in patients with hepatic coma coma ♪♪ S.E :S.E : nephrotoxic, topical nephrotoxic, topical dermatitis dermatitis♪♪ ph’kinetics :ph’kinetics : topical, not well absorbed topical, not well absorbed systemically systemically

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FlumazenilFlumazenil- antagonist benzodiazepinantagonist benzodiazepin- action action blocks many of the action of blocks many of the action of

benzodiazepin benzodiazepin

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Acute bleeding from gastro-oesophageal Acute bleeding from gastro-oesophageal varicesvarices♪♪ acute variceal bleeding is a medical acute variceal bleeding is a medical emergencyemergency♪♪ blood losses should be placed immediatelyblood losses should be placed immediately♪♪ the diagnosis should be confirmed as soon the diagnosis should be confirmed as soon as possible endoscopyas possible endoscopy♪♪ octreotideoctreotide reduces bleeding from varicesreduces bleeding from varices♪♪ sclerotherapy is the treatment of choice sclerotherapy is the treatment of choice

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TerlipressinTerlipressin is given in a single IV dose of 2 is given in a single IV dose of 2 mg,mg,repeated every 4-6 hour until repeated every 4-6 hour until bleeding stop bleeding stop or or

VasopressinVasopressin is given by IV infusion over 20 min is given by IV infusion over 20 min in in a dose of 20 i.u in 100 mL of 5% a dose of 20 i.u in 100 mL of 5% dextrose dextrose

PropranololPropranolol is effective in preventing primary is effective in preventing primary bleeding from varicesbleeding from varicesthe dose of propranolol for this the dose of propranolol for this conditionis 40-160 mg b.dconditionis 40-160 mg b.d

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Portal hypertensionPortal hypertension♪♪ an increase in portal vein pressure an increase in portal vein pressure due to due to anatomic or functional anatomic or functional obstruction to blood obstruction to blood flow in the portal flow in the portal venous systemvenous system

♪♪ normal vein pressure is 5-10 mmHgnormal vein pressure is 5-10 mmHg

♪♪ Indicators of portal hypertension are :Indicators of portal hypertension are :- intraoperative portal vein pressure > 30 cm - intraoperative portal vein pressure > 30 cm salinesaline- intrasplenic pressure of > 17 mmHg- intrasplenic pressure of > 17 mmHg- wedged hepatic vein pressure of > 4 mmHg - wedged hepatic vein pressure of > 4 mmHg above IVC (inferior vena cava)above IVC (inferior vena cava)

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ConsequenciesConsequencies1. increased collateral circulation between 1. increased collateral circulation between high-high-pressure pressure portal venous system and low portal venous system and low pressure systemic venous pressure systemic venous systemsystem

2. increased lymphatic flow2. increased lymphatic flow

3. incresed plasma volume3. incresed plasma volume

4. ascites4. ascites

5. splenomegaly, possible hypersplenism5. splenomegaly, possible hypersplenism

6. protosystemic shunting (including hepatic 6. protosystemic shunting (including hepatic encephalopathy)encephalopathy)

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TreatmentTreatment♠♠ ccontrol of acute bleedingontrol of acute bleeding♠♠ IV vasopressinIV vasopressin up to 0.1-0.4 U/min until up to 0.1-0.4 U/min until bleeding is controlled for 12-24 hour (50-80% bleeding is controlled for 12-24 hour (50-80%

success rate) than stop or taper;success rate) than stop or taper;♠♠ add add nitroglycerinnitroglycerin up to 0.6 mg SL, can be up to 0.6 mg SL, can be

given IV or transdermal patch to prevent given IV or transdermal patch to prevent coronary or renal vasoconstrictioncoronary or renal vasoconstriction

♠♠ maintain systolic BP > 90 mmHgmaintain systolic BP > 90 mmHg♠♠ octreotideoctreotide 50-259 mcg bolus + 50-250 mcg 50-259 mcg bolus + 50-250 mcg

IV IV infusion infusion as effective as vasopressin with as effective as vasopressin with fewer serious complicationfewer serious complication

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VasopressinVasopressin- antidiuretic hormone – polypeptideantidiuretic hormone – polypeptide- potent arterial vasoconstrictorpotent arterial vasoconstrictor- IV in continous infusion IV in continous infusion splanchnic splanchnic

arterialarterialvasoconstrictionvasoconstriction

lead to reduced splanchnic arteriallead to reduced splanchnic arterialperfusion and lowered portalperfusion and lowered portalvenous pressurevenous pressure

- prior to advent octreotide - prior to advent octreotide vasopressin vasopressin commonly use to treat acute variceal commonly use to treat acute variceal hemorrhagehemorrhage

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- adverse effects :adverse effects : - hypertension- hypertension- myocardial ischemia / infarction- myocardial ischemia / infarction- mesenteric infarction- mesenteric infarction- nausea, vomitus, abd. cramps, diarrhea- nausea, vomitus, abd. cramps, diarrhea

may be reduced by coadministered ofmay be reduced by coadministered ofnitroglycerinnitroglycerin

- - antidiuretic effectsantidiuretic effects water retention water retention

hyponatremia, fluid retentionhyponatremia, fluid retentionpulmonary edemapulmonary edema

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NitroglycerinNitroglycerin♠♠ actions :actions : reduces cardiac preload by reduces cardiac preload by reducing reducing venous tone venous tone blood blood pooling in the pooling in the periphery periphery♠♠ indications :indications : antianginal antianginal♠♠ S.E :S.E : hypotension and rebound hypotension and rebound tachycardia, tachycardia, bradycardia , cerebral bradycardia , cerebral ischemia, ischemia, contact dermatitis, aggravation contact dermatitis, aggravation of of peripheral edemaperipheral edema♠♠ ph’kinetics :ph’kinetics : SL, transdermal, topical, SL, transdermal, topical, ♠♠ interactions :interactions : alcohol, antihypertensive alcohol, antihypertensive agents, and vasodilators agents, and vasodilators increase increase risk of orthostatic risk of orthostatic hypotension hypotension

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PropranololPropranolol- block - block ββ1 and 1 and ββ2 adrenergic receptors2 adrenergic receptors- - indication :indication : cardiosuppression in acute MI cardiosuppression in acute MI and unstable angina and unstable angina- - S.E :S.E : transient hypertension due to transient hypertension due to antagonism of antagonism of ββ2 receptors (which 2 receptors (which dilate dilate large arteries) and reflex large arteries) and reflex response to response to decreased c.o, decreased c.o, bronchospasmbronchospasm- PO, good CNS penetration- PO, good CNS penetration more severe more severe S.ES.E- - C.I :C.I : severe diabetes, bradycardia, partial severe diabetes, bradycardia, partial heart block, heart failure, asthma, heart block, heart failure, asthma, emphysemaemphysema

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OctreotideOctreotide- analog somastatin - analog somastatin

- 45x more potent than somatostatin in - 45x more potent than somatostatin in inhibiting GH releaseinhibiting GH release- - also useful for the acute control of also useful for the acute control of bleeding bleeding from esophageal varices, given from esophageal varices, given for 3-5 daysfor 3-5 days- - in patient with cirrhosis & portal in patient with cirrhosis & portal hypertension, IV somatostatin or octreotide hypertension, IV somatostatin or octreotide (50 mcg/day) reduces portal blood flow & (50 mcg/day) reduces portal blood flow & variceal pressurs variceal pressurs mech of action ??? mech of action ???

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OctreotideOctreotide

- action may be mediated through - action may be mediated through inhibitioninhibition of glucagon release and other gut of glucagon release and other gut peptidespeptides

alter mesenteric blood flowalter mesenteric blood flow- very costly- very costly- - adverse effects :adverse effects : nausea, vomiting, nausea, vomiting, abdominal cramps, sinus tachycardia abdominal cramps, sinus tachycardia (25%), (25%), conduction disturbances (10%)conduction disturbances (10%)- billiary sludge and gallstone may occur - billiary sludge and gallstone may occur after after 6 months of use 6 months of use 20-30% pats 20-30% pats

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Chronic active hepatitisChronic active hepatitis- chronic viral hepatitis (h v types B and C),- chronic viral hepatitis (h v types B and C),involves a chronic immune inflammatory involves a chronic immune inflammatory response response asymptomatic asymptomatic cirrhosis with cirrhosis with complication complication hepatocellular carcinoma hepatocellular carcinomaTreatment Treatment interferon-interferon-αα - chronic hepatitis B, interferon may - chronic hepatitis B, interferon may eliminateeliminatecould be combined with could be combined with lamivudinlamivudin- in chronic hepatitis C, interferon plus - in chronic hepatitis C, interferon plus ribavirin ribavirin give response to 50% of patientsgive response to 50% of patients

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Drug treatment in gallstoneDrug treatment in gallstone mostly cholesterol stonesmostly cholesterol stones pathogenesis is not clearly understoodpathogenesis is not clearly understood chenodeoxycholic acid (10-15 chenodeoxycholic acid (10-15

mg/kg/day) mg/kg/day) and and ursodeoxycholic acid ursodeoxycholic acid (8-10 mg/kg/day) (8-10 mg/kg/day) with long term with long term treatment (3 months or treatment (3 months or more) dissolve more) dissolve stonesstones

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Drug and the liverDrug and the liver many drugs can cause hepatic damage many drugs can cause hepatic damage ((table)table)

ParacetamolParacetamol- liver damage associated with paracetamol - liver damage associated with paracetamol overdose overdose is due to the formation of hepatotoxic is due to the formation of hepatotoxic metabolite metabolite N-acetyl-p-benzoquinoneeimineN-acetyl-p-benzoquinoneeimine

accumulate and bind to liver cell accumulate and bind to liver cell irreversible damageirreversible damage- liver damage can be prevented by providing - liver damage can be prevented by providing acetylcysteineacetylcysteine

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Isoniazid (INH)Isoniazid (INH) -- long term treatment with INH can cause long term treatment with INH can cause liver damage (± 15%) liver damage (± 15%) - a small number - a small number chronic active hepatitis chronic active hepatitis - liver damage cause by metabolite- liver damage cause by metabolite - INH - INH acetylisoniazid acetylisoniazid

acetylhydarzine acetylhydarzine reactive metabolite reactive metabolite

bind to liver protein bind to liver protein cause liver cause liver damagedamage

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Drug that can cause intrahepatic cholestasisDrug that can cause intrahepatic cholestasis(table)(table)

chlorpromazine chlorpromazine hypersensitivity hypersensitivity reactionreaction

it starts with week 1-4; fever, chills, itching, it starts with week 1-4; fever, chills, itching, nausea and vomiting due to nausea and vomiting due to

conjugation of conjugation of the drug metabolite with the drug metabolite with liver cell proteinsliver cell proteins

cholestatic jaundice cholestatic jaundice oral contraseptive, oral contraseptive, estrogen and corticosteroidsestrogen and corticosteroids

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HepatoprotectiveHepatoprotectivemany plants have hepatoprotective effectsmany plants have hepatoprotective effects

1.1. Milk thistleMilk thistle ( (Silybum marianum)Silybum marianum)- alkaloids from the seed (silymarin, - alkaloids from the seed (silymarin, silychristin and silydianin)silychristin and silydianin)- inhibit the entrance of toxins and block - inhibit the entrance of toxins and block toxin-binding site through alteration of toxin-binding site through alteration of the the liver cell’s outer membrane liver cell’s outer membrane- - silymarinsilymarin increases gluthatione increases gluthatione production production by the liver, intestines and by the liver, intestines and stomachstomach Gluthation is used for detoxification cells Gluthation is used for detoxification cells in in the liver the liver

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- - silybininsilybinin decreases hepatic and decreases hepatic and mitochondrial mitochondrial glutathione oxidation glutathione oxidation induced by iron induced by iron overload and is a mild overload and is a mild chelator of ironchelator of iron

- - silymarinsilymarin stimulate RNA polymerase I in stimulate RNA polymerase I in the the cell nucleus of the hepatocytescell nucleus of the hepatocytes

increase of ribosomal protein synthesis andincrease of ribosomal protein synthesis andthe regenerative activity of the liverthe regenerative activity of the liver

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LicoriceLicorice (Glycyrrhiza glabra) (Glycyrrhiza glabra)

antiviral/antifungal effectsantiviral/antifungal effects- - glycyrrhizinglycyrrhizin supresses the secretion of supresses the secretion of hepatitis B virus (HBV) surface antigen hepatitis B virus (HBV) surface antigen (HbsAg) (HbsAg) in patients with HBV in patients with HBV- the compound is thought to bind to - the compound is thought to bind to hepatocytes at a concentration able to modify hepatocytes at a concentration able to modify the expression of HBV-related antigens on the the expression of HBV-related antigens on the hepatocytes ans suppress sialylation of HbsAg hepatocytes ans suppress sialylation of HbsAg- glycyrrhizin stimulates interferon gamma - glycyrrhizin stimulates interferon gamma produced by T-cells for an antiviral effect produced by T-cells for an antiviral effect against influenza virus infection against influenza virus infection

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- - C.I :C.I : - chronic hepatitis- chronic hepatitis- cholestatic diseases of the liver- cholestatic diseases of the liver- severe renal insuficiency- severe renal insuficiency- diabetes- diabetes- arrhythmia- arrhythmia- hypertension- hypertension- hypertonia- hypertonia- hypokalemia and pregnancy- hypokalemia and pregnancy

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CurcumaCurcuma (Curcuma xanthorrhizia) (Curcuma xanthorrhizia) - root contains curcuminoids - root contains curcuminoids curcumin curcumin- approve by Commission E :- approve by Commission E :

- liver and gall bladder complains- liver and gall bladder complains- loss of appetite- loss of appetite

- in Indonesia it has long been used for - in Indonesia it has long been used for liver liver and gallbladder complaintsand gallbladder complaints- it should not be administered if there is - it should not be administered if there is a bile a bile duct blockage.duct blockage.

colic can occur when the patient colic can occur when the patient suffers suffers from gallstonesfrom gallstones

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