Other Drugs in GiT Treatment PDF

OTHER DRUGS USED IN THE TREATMENT OF GIT DISEASES At the end of this lecture, students should be able to determine  mechanism of actions, uses and adverse effects (if any) of  pancreatic enzyme supplements.  bile acid therapy for gallstones.  drugs used to treat variceal haemorrhage....

OTHER DRUGS USED IN THE TREATMENT OF GIT DISEASES At the end of this lecture, students should be able to determine  mechanism of actions, uses and adverse effects (if any) of  pancreatic enzyme supplements.  bile acid therapy for gallstones.  drugs used to treat variceal haemorrhage.  hepatoprotective agents. PANCREATIC ENZYME SUPPLEMENTS PANCREATIC ENZYME SUPPLEMENTS  In the case of exocrine pancreatic insufficiency.  Caused by cystic fibrosis, chronic pancreatitis, pancreatic resection (pancreatectomy).  Can impair fat and protein digestion and lead to steatorrhea (greasy stool), azotorrhea (excessive nitrogenous substance in feces and urine), vitamin malabsorption, and weight loss.  Constituents of pancreatic enzyme supplements;  Amylase, lipase and proteases  Two major types;  Pancreatin  Pancrelipase PANCREATIN  An alcohol-derived of hog pancreas with low concentrations of lipase and proteolytic enzymes.  No longer used because low efficiently than pancrelipase. PANCRELIPASE  Pancrelipase is an enrich preparation.  12 times the lipolytic activity and more than 4 times the proteolytic activity than pancreatin.  Available both non-enteric-coated and enteric-coated preparation.  Formulations – varying amounts of lipase, amylase, and protease PANCRELIPASE  Rapidly and permanently inactivated by gastric acid.  Non-enteric-coated preparation – given with acid suppression therapy (proton pump inhibitors or H2 antagonists)  Enteric-coated preparation are commonly used because no need acid suppression therapy  2006, FDA announced all products need approval. 3 enteric-coated capsules products are approved for used (Creon, Pancreaze, and Zenpep).  Taken with each meal and snack  Dosing should be individualized according to age, weight, the degree of pancreatic insufficiency and the amount of dietary fate intake of patient.  For patients with feeding tubes, microspheres may be mixed with enteral feeding prior to administration. PANCRELIPASE : ADVERSE EFFECT  Well tolerated  Pancreatic enzymes may cause oropharyngeal mucolitis, thus capsules should be swallowed not chewed.  Excessive dose – diarrhes and abdominal pain.  The high purine content of pancreas extracts may lead to hyperuricosuria and renal stones.  Several cases of colonic structures were reported in patients with cystic fibrosis who received high doses of pancrelipase with high lipase activity. BILE ACID THERAPY FOR GALLSTONES. BILE ACID THERAPY FOR GALLSTONES  Gallstones or cholelithiasis refers to presence or formation of gallstones in gallbladder or bile ducts.  Cholesterol gallstones develop when bile contains too much cholesterol and not enough bile salts. Incomplete and infrequent emptying of the gallbladder may cause the bile to become overconcentrated and contribute to gallstone formation.  Surgery: cholecystectomy has become the “gold standard” for treating symptomatic cholelithiasis. BILE ACID THERAPY FOR GALLSTONES  Nonsurgical treatment:  Only in special situations;  Small (< 5 - 10 cm) stones.  Non-calcified stones  Poor surgical candidates  Patient has a serious medical condition preventing surgery.  Elderly and infant  Oral dissolution therapy or bile acid therapy  URSODIOL (Ursodeoxycholic acid) and chenodeoxycholic acid.  Months or years of treatment may be necessary before all stones dissolve URSODIOL ; PHARMACOKINETICS  Half-life: 100 hours  10 mg/kg/day for 12-24 months  With long-term daily admin: constitutes 30-50% of the circulating bile acid pool  Absorbed, conjugated in liver with glycine or taurine, and excreted in the bile  undergoes extensive enterohepatic recirculation  Unabsorbed conjugated or unconjugated ursodiol (small amount): passes into the colon, where it is either excreted or undergoes dihydroxylation by colonic bacteria to lithocholic acid, a substance with potential hepatic toxicity. URSODIOL : PHARMACODYNAMICS  Decreases the cholesterol content of bile by reducing hepatic cholesterol secretion  Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissociation of gallstones.  Stabilize hepatocyte canalicular membranes, possibly through:  reduction in the concentration of other endogenous bile acids.  inhibition of immune-mediated hepatocyte destruction. URSODIOL: USES  Dissolution of small cholesterol and noncalcified gallstones.  Prevention of gallstones in obese patients undergoing rapid weight loss therapy.  1st line agent for treatment of early primary biliary cirrhosis. URSODIOL: ADVERSE EFFECTS  Free of serious adverse effects  Bile salt-induced diarrhea (uncommon)  Not associated with hepatotoxicity. Unlike its predecessor chenodeoxycholic acid. DRUGS USED TO TREAT VARICEAL HEMORRHAGE PORTAL HYPERTENSION  Most commonly occurs as a consequences of chronic liver disease.  Caused by increased blood flow within the portal venous system and increased resistance to portal flow within the liver.  Splanchic blood flow is increased in patients with cirrhosis due to low arteriolar circulating vasodilators and decreased vascular sensitivity to vasoconstrictors.  Intrahepatic vascular resistance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins, as well as reversible vasoconstriction of hepatic sinusoids and venules.  Consequences of portal hypertension: ascites, hepatic encephalopathy, development of portosystemic collaterals, especially gastric or esophageal varices.  Varices can rupture, leading to massive upper gastrointestinal bleeding DRUGS USED TO TREAT VARICEAL HEMORRHAGE  Several drugs are available that reduce portal pressure:  Somatostatin and Octreotide  Vasopressin and Terlipressin  Beta-receptor-blocking drugs SOMATOSTATIN AND OCTREOTIDE  Octreotide is long-acting analog of somatostatin  IV somatostatin (250 mcg/h) or octreotide (50 mcg/h)  Route: SC (half-life = 6-12 hours), IV (half-life = 1.5 hours)  Generally administered for 3-5 days  MOA; reduces portal blood flow and variceal pressure  Activity may be mediated through inhibition of release of glucogon and other gut peptides that alter mesenteric blood flow OCTREOTIDE; USES  1st line drug in variceal bleeding  Effective in promoting initial hemostasis from bleeding esophageal varices  Acromegaly is a disorder caused by excess growth hormone  Diarrhoea associated with metastatic carcinoid tumors. OCTREOTIDE; ADVERSE AFFECT  Common side effect :  Cardiac conduction disorder, gallbladder sludge and hyperglycemia  Other side effects  Cardiac arrhythmia  hypoglycemia VASOPRESSIN  Antidiuretic hormone which maintains serum osmolarity  Secreted by hypothalamus and stored in posterior pituitary  MOA: Potent vasoconstrictor  Splanchnic arterial vasoconstriction leading to reduced splanchnic perfusion and lowered portal venous pressure (IV, continuous infusion) VASOPRESSIN: USES  Before the advent of ocreotide: acute variceal hemorrhage  Acute GI bleeding form small bowel or large bowel vascular ectasias and diverticulosis to promote vasospasm VASOPRESSIN: ADVERSE EFFECT  Hypertension, myocardial ischemia or infarction, mesenteric infarction  Reduced by coadministration of nitroglycerin  Nausea, abdominal cramps and diarrhea (due to intestinal hyperactivity)  Retention of free water can lead to hyponatremia, fluid retention, and pulmonary edema TERLIPRESSIN  Vasopressin analog with similar efficacy  Never approved in US FDA; available in other countries.  Fewer adverse effects BETA-RECEPTOR-BLOCKING DRUGS  Non-selective beta blockers (propranolol and nadolol)  MOA  β1 blockade : reduce cardiac output  β2 blockade : splanchnic vasoconstriction caused by unopposed effect of systemic catecholamines on a receptors  Reduce portal venous pressure via decrease in portal venous inflow  Uses  Significantly reduce rate of recurrent bleeding HEPATOPROTECTIVE AGENTS HEPATOPROTECTIVE AGENTS  Liver has a role in the maintenance, performance and regulating homeostasis of the body.  The main causes of liver damage are  alcohol  chemicals like carbon tetrachloride, phosphorous, aflatoxins, etc  drugs like acetaminophen, sulfonamides, carbamazepine, etc  autoimmune disorders  infections like viral hepatitis. HEPATOPROTECTIVE AGENTS  Mechanisms of hepatotoxicity  Most of the hepatotoxic chemicals damage liver cells mainly by inducing lipid peroxidation 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.  Type of liver injury  Fatty liver, cholestasis, fibrosis and cirrhosis, necrosis, apoptosis, hepatitis, carcinogenesis. HEPATOPROTECTIVE AGENTS  N-acetylcycteine (NAC)  Herbal medication  E.g. Silymarin N-ACETYLCYSTEINE (NAC)  Derivative of L-cysteine  Brand name: acetadote, parvolex  Pharmacologic category:  Antidote  Mucolytic NAC; USES  FDA labelled indications  Acetaminophen / paracetamol or N-acetyl-para-aminophenol (APAP) overdose  Adjunctive mucolytic therapy  Diagnostic bronchial therapy  Off-label use  Prevention of contrast-induced nephrotoxicity  H. pylori infection ACETAMINOPHEN OVERDOSE NAC (MOA) AS ANTIDOTE  NAC is a precursor of glutathione, it increases the glutathione available for the conjugation of NAPQI.  NAC enhances sulphate conjugation of unmetabolized acetaminophen.  NAC also supplies thiol groups, which can directly bind with NAPQI in hepatocytes and enhances non-toxic sulfate conjugation for elimination.  NAC may involve in scavenging of free radicals or changes in hepatic blood flow NAC (ADVERSE EFFECT)  Oral  IV  Drowsiness  Anaphylactoid reactions  Chills/fever  Vomiting  Nausea / Vomiting  Bronchospasm  Rhinorrhea  Unpleasant odor SILYMARIN  Silybum marianum, commonly known as ‘milk thistle’ 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 centure 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  Silymarin is a complex mixture of four flavononolignan isomers, namely silybin (major), isosilybin, silydianin and silychristin with an empirical formula C25H22O10.  The structural similarity of silymarin to steroid hormones is believed to be responsible for its protein synthesis facilitatory actions. Katzung textbook: page MECHANISM OF ACTION  Stimulation of protein synthesis  Silymarin can enter inside the nucleus and act on RNA polymerase enzymes resulting in increased ribosomal formation.  Thus 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.  Anti-inflammation 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 MECHANISM OF ACTION  Antifibrotic action  Liver fibrosis can result in remodelling 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 inhibit HSC activation  It also inhibits protein kinase and other kinases involved in signal transduction and may interact with intracellular signalling pathways. MECHANISM OF ACTION  Drug and toxin related liver damage  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.  As an antioxidant  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. ADVERSE DRUG REACTION  Silymarin is reported to have a very good safety profile.  Both animal and human studies 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 pruritis, headache, exanthema, malaise, asthenia and vertigo. 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