GIT and Liver

1. Topics
2. Hepatitis
3. Alcoholic and NAFLD
4. Circulatory Disorders of the Liver
5. Tumors of the Liver
6. GIT Pharmacology
7. GIT Toxicology (Forensics)
 GIT and Liver Topics
Anatomy:
● Overview: structure and function of GIT
● Overview of blood supply and venous drainage of hepato-biliary system & macroscopic &
microscopic structure of Liver

Physiology:
● Overview: secretory, digestive, and absorptive function of the GIT
● Role of diet and nutrition/lifestyle modification

Biochemistry:
● Overview of dietary carbohydrates and glycemic index
● Overview of dietary fats & lipids, in relation to rancidity & per oxidation
● Overview of dietary proteins & nitrogen balance
● Nutritional energy balance
● Overview of bio-molecular function
● Differentiate between pre-hepatic, hepatic & post-hepatic causes of jaundice
● Nutrition care plan development & nutrition toxicology

Pathology:
● Pathogenesis of gastritis and peptic ulcer
● Tutorial: histopathology of gastric diseases
● Malabsorption syndrome (Celiac disease)
● Inflammatory bowel diseases
● Infective agents of dysentery & diarrhea
● Tutorial: stool DR and culture
● Enterocolitis and ischemic colitis
● Tumors of stomach
● Tumors of small & large intestine
● Tutorial: histopathology of intestinal tumors
● General features of hepatic disease (patterns of hepatic injury, hepatic failure, jaundice &
cholestasis)
 ● Hepatitis
● Alcoholic & non-alcoholic (NASH)
● Tumors of liver
● Cirrhosis & portal hypertension & circulatory disorders of liver
● Pathology of gallbladder
● Non-neoplastic disorders of exocrine function of pancreas

Medicine:
● GERD, esophagitis, Barrett’s, hiatus hernia
● Diagnosis and management of upper GI bleeding
● Causes, clinical presentation and management of malabsorption syndrome/ Celiac
disease
● Irritable bowel syndrome
● Acute gastroenteritis
● Clinical presentation and outline of management of hepatitis B and C
● Management of acute hepatitis & fulminant hepatic failure
● Ascites and concept of SAAG, hepatic encephalopathy & hepato-renal syndrome
● Liver abscess & tumors

Surgery:
● Clinical presentation and surgical management of IBD
● Management of intestinal obstruction (small & large bowel) & paralytic ileus
● Management of acute abdomen & peritonitis
● Management of CA esophagus and achalasia
● Management of gall bladder cancer
● Cholelithiasis – Presentation, Sequalae & Management
● Management of acute & chronic pancreatitis
● Perianal abscess; fistula-in-ano & hemorrhoids
● Surgical management of CA colon
● Abdominal trauma (primary and secondary survey pertaining to abdomen)
● TB abdomen
● Ventral hernias workup and management
● Management of obstructive jaundice & pancreatic tumor
● Management of acute abdomen & peritonitis
Pharmacology:
● Tutorial: effect of drug on the intestine of rabbit – preparation of Ach solution
● Proton pump inhibitors and H2 receptor antagonists
● Mucosal protective & Rx of H.Pylori
● Tutorial: treatment of peptic ulcer
● Emetics and antiemetics
● General management of Diarrhea & IBS
● Drugs used in Amebiasis
● Drugs used in constipation
● Management of hepatitis
● Pharmacological treatment of hepatitis B and C

Forensic Medicine:
● Tutorial: non-metallic irritants
● Traumatology
● Regional injuries
● Tutorial: metallic irritants -- arsenic
● Head and spinal cord injuries (regional injuries)
● Neck, chest, face, heart, and lung injuries
● Metallic irritants -- mercury
● Road traffic accidents
● Thermal injuries
● Metallic irritants -- lead
● Hepatic poison -- alcohol
● Copper
● Environmental trauma
● Toxicology -- irrespirable gases

Community Medicine
● Demography

Clinical Postings:
● History taking
● History taking in a surgical patient
● Surgery: general and physical examination in a surgical patient
 ● Peds – examination of respiratory system
● Abdominal examination
● Surgery: history and examination of an ulcer
● Surgery: examination of a swelling/lump (skin)
● Surgery: sterilization and disinfection
● Examination of an inguinoscrotal swelling

Skill Lab:
● Abdominal examination
● NG tube intubation

Pediatrics:
● Acute & chronic diarrheas
● Causes of vomiting, regurgitation/dysphagia in children; GERD
● Pediatric surgery: congenital and acquired causes & management of constipation
● Storage and metabolic disorders; acute hepatic failure/hepatitis
● Biliary atresia/cholestatic jaundice

Radiology:
● Recognition of normal & abnormal GIT structures
● Recognition of normal & abnormal hepatobiliary structures
 Hepatitis
• Hepatitis A is usually self-limited; vaccine is available
• Hepatitis B can cause:
o Acute hepatitis followed by recovery
o Non-progressive chronic hepatitis
o Progressive chronic hepatitis ending in cirrhosis
o Acute hepatic failure with massive liver necrosis (rare)
o Asymptomatic healthy carrier state
• Hep B is associated with hepatocellular carcinoma
• Vaccine against Hep B is present
• Age at the time of Hep B presentation is the best predictor for disease chronicity – the
younger the patient, the higher the chance of chronicity
• Hepatitis C RNA pol is low-fidelity, which gives rise to multiple genotypes. Within the
same person, closely related genetic variants of Hep C can exist; these are known as
quasispecies.
• In hep C, antibodies are formed against the E2 protein of the envelope. However, the
protein is encoded by the most variable region in the virus’ genome. This allows
emergent strains to escape antibodies, and this why there’s no vaccine for hepatitis C.
• Acute infection with hep C is often asymptomatic and missed. Chronic illness is the
hallmark of hepatitis C.
• Hepatitis C can induce insulin resistance, and is associated with metabolic syndrome.
• Hepatitis E is a zoonotic infection. Although it’s not related to chronic disease, chronic
disease can develop in immunocompromised (post-transplant or AIDS) patients.
• Hepatitis A, B, E, and D can cause fulminant hepatitis.
• The most common finding in symptomatic chronic hepatitis patients is fatigue.
• Morphology:
o Viral hepatitis morphology can mimic drug-induced and autoimmune hepatitis
morphology
o Acute and chronic hepatitis both invoke a lymphoplasmacytic infiltrate
o Acute hepatitis: portal inflammation is minimal – lobular hepatitis is common
(injury scattered throughout the lobule a.k.a spotty necrosis) – bridging necrosis
may occur in severe cases – hepatitis A infiltrate is especially rich in plasma cells.
o Chronic hepatitis: defining histological feature is a mononuclear portal infiltrate
– interface (between parenchyma and portal tract) hepatitis is seen – fibrosis of
portal tracts at first, and progression to cirrhosis later – ductular reactions are
seen – clinical assessment often requires biopsy
o Chronic Hepatitis B – ground-glass appearing cells – due to HBsAg filling the ER is
a diagnostic hallmark
o Chronic Hepatitis C – often should lymphoid aggregation and follicles and fatty
change of scattered hepatocytes
 Alcoholic and Non-Alcoholic Fatty Liver
Disease
Alcoholic liver disease:
o All changes begin in acinus zone 3 (closest to the central vein)
o Hepatic steatosis: even after moderate intake, liver cells accumulate fat droplets
– completely reversible with abstinence
o Alcoholic steatohepatitis: fat accumulating causes hepatocytes to burst
(ballooning) and die – Mallory-Denk bodies visible; these are made of
intermediate filaments in complex with proteins like ubiquitin; non-specific (also
seen in NAFLD) – neutrophils infiltrate the liver and surround ballooned
hepatocytes – presents acutely after heaving drinking, symptoms are non-
specific but can be those of acute liver failure – hepatorenal syndrome may
follow
o Alcoholic steatofibrosis: activation of stellate cells – fibrosis begins at central
vein – scar spreads out in chicken wire fence pattern (groups of hepatocytes
surrounded by fibrosis) – eventually, nodules develop and cirrhosis sets in –
continued use of alcohol leads to more subdivision of established nodules, which
leads to micronodular or Laennec cirrhosis – patient can develop hepatocellular
carcinoma
o Causes of alcoholic liver damage:
▪ Increased lipid synthesis due to increased NADH from alcohol metabolism
▪ Acetaldehyde damages cells by causing lipid peroxidation
▪ Alcohol impairs liver metabolism of methionine, reducing glutathione
synthesis and oxidative damage
▪ Alcohol causes release of bacterial endotoxin from gut into portal
circulation, which damages the liver

Non-alcoholic fatty liver disease:

o Defined by presence of hepatic steatosis in absence of alcohol consumption (less
than 20g ethanol/week)
o Non-alcoholic steatohepatitis (NASH) is used to denote overt symptoms of liver
damage like elevated aminotransferases – NASH increases the risk of
hepatocellular carcinoma
o NAFLD is closely associated with metabolic syndrome
o Hepatic steatosis arises from an overabundance of calories, and lack of exercise
o Fat laden cells are vulnerable to oxidative damage
o Mallory-Denk bodies and scar formation is seen
o Pathologic steatosis is defined as that involving more than 5% of hepatocytes
o NASH histology = alcoholic hepatitis histology; mononuclear cells more
prominent than neutrophils
o Fibrosis in NAFLD histology = alcoholic steatofibrosis
o Liver biopsy is the most reliable diagnostic tool for NAFLD/NASH
o CVS disease is a frequent cause of death in NASH patients due to association
with metabolic syndrome
o Goal of treatment is to reverse hepatic steatosis by correcting risk factors like
obesity, hyperlipidemia, and insulin resistance
 Circulatory Disorders of the Liver
Impaired Blood Flow into the Liver
Hepatic Artery Compromise:
• Intrahepatic branch thrombosis/compression – localized infarct – may be pale of
hemorrhagic
• Main hepatic artery blockage – doesn’t always produce ischemic necrosis – in
transplanted livers, necrosis of the biliary ducts occurs

Portal Vein Obstruction and Thrombosis:

• Main manifestations – abdominal pain and esophageal varices that are prone to rupture
• Extra-hepatic obstruction is idiopathic in 1/3rd of the cases – other causes are:
o Intraabdominal sepsis
o Hypercoagulable disorders
o Trauma
o Pancreatitis or pancreatic cancer
o Hepatocellular carcinoma
o Cirrhosis
• Intra-hepatic obstruction – infarct of Zahn, which is an area of red-blue discoloration –
there’s no necrosis
• Small portal vein branch diseases – characterized by non-cirrhotic portal HTN with portal
fibrosis and obliteration of small portal vein branches – most common cause is
schistomiasis (eggs block the veins) – other causes are altogether called obliterative
portal venopathy

Impaired Blood Flow Through the Liver

• Most common cause – cirrhosis
• Other causes – sickle cell disease, DIC, eclampsia, metastatic tumor
• Can lead to massive necrosis and acute liver failure
• Peliosis hepatis – sinusoidal dilation due to impeded efflux of blood – blood-filled cysts
in the liver – seen in cancer, TB, post-transplant immunodeficiency, sex hormone
administration – lesions disappear after cause is removed
Hepatic Venous Outflow Obstruction
Hepatic Vein Thrombosis
• Budd-Chiari – obstruction of two or more hepatic veins – liver enlargement, pain, and
ascites – associated with polycythemia vera – liver is swollen with a tense capsule –
there’s centrilobular congestion and necrosis

Sinusoidal Obstruction Syndrome

• Seen after allogenic hematopoietic stem cell transplantation and in cancer patients
receiving chemotherapy
• Cause – toxic injury to the sinusoids – sloughed endothelium causes blockage
• Necrosis of perivenular hepatocytes – obliteration of terminal hepatic venules
• Usually diagnosed clinically, because biopsy is risky
• In stem cell transplant patients – anti-coagulation and ursodeoxycholate is beneficial

Passive Congestion and Centrilobular Necrosis

• Manifestations of systemic circulatory compromise
• Right-sided cardiac decompensation – congestion of centrilobular sinusoids
• Left-sided cardiac decompensation – hypoperfusion – centrilobular necrosis
• Combination of the above two – centrilobular hemorrhagic necrosis – live takes a
variegated mottled appearance – nutmeg liver
 Tumors of the Liver
Nodular Hyperplasia:
o Can arise in non-cirrhotic liver
o Usually due to alterations in blood supply
o Two types – focal nodular hyperplasia and nodular regenerative hyperplasia
o Focal nodular – arises in a normal liver as a solitary mass – pale mass with a
central stellate-shaped scar
o Nodule regenerative – denotes a liver completely transformed into nodules but
without fibrosis – can lead to portal hypertension

Benign neoplasms:
o Cavernous hemangiomas – most common benign liver tumor – made of vascular
channels in a bed of CT
o Hepatocellular adenomas
▪ Derived from hepatocytes
▪ May rupture, which is a surgical emergency
▪ Associated with oral contraceptives and anabolic steroids
▪ Cessation to exposure to sex hormones can lead to full regression
▪ Three subtypes
• HNF1a inactivated adenomas – fatty with no risk of malignant
transformation
• B-catenin activated adenomas – very high risk of malignant
transformation – should be resected
• Inflammatory adenomas – small but definite risk of malignant
transformation – have areas of fibrotic stroma, mononuclear
inflammation, ductular reaction, and telangiectatic vessels (other
adenomas are mainly made of hepatocytes)

Malignant tumors:
o Hepatoblastoma – most common liver tumor of early childhood
o Hepatocellular carcinoma
▪ Chronic liver disease is the most common setting for its emergence
▪ Most important underlying factors – viral infections (Hep B, C) and toxins
(alcohol, aflatoxin)
▪ Metabolic diseases like hemochromatosis and metabolic syndrome also
increase the risk of HCC
▪ Most common mutations – activation of B-catenin and inactivation of p53
▪ Precursor lesions:
 • Adenoma
• Large cell change
• Small cell change
• Dysplastic nodules – often detected in cirrhosis – can be low-
grade and high-grade – high-grade are the most important
primary pathway of HCC emergence in viral hepatitis and alcoholic
liver disease
▪ Morphology:
• May present grossly as:
o Unifocal mass
o Multifocal widely distributed nodules
o Diffuse infiltrative cancer
• Metastasizes via blood – lung is a common site
• Can invade the portal vein (portal HTN), IVC, or the right side of
the heart
• Fibrolamellar carcinoma – single, large tumor with fibrous bands
coursing through it – it’s a subtype of HCC
▪ Symptoms, diagnosis, and treatment
• Symptoms – ill-defined abdominal pain, malaise, fatigue,
hepatomegaly – cause hypoglycemia (high metabolic activity) and
erythrocytosis (produce EPO) – can cause Budd-Chiari syndrome
• Diagnosis – a-fetoprotein is raised but is an insensitive screening
test – most valuable tool for diagnosis is imaging – but remember,
the definitive diagnosis of cancer is made by biopsy
• Treatment – small tumors can be surgically removed with good
outcomes – radiofrequency ablation is used for local control of
large tumors – chemoembolization can also be used
o Cholangiocarcinoma
▪ Second most common primary malignant liver tumor after HCC
▪ Malignancy of biliary tree
▪ Risk factors:
• Liver flukes
• Chronic inflammation of bile ducts
• Hep B, C, and NAFLD
• Most are sporadic
▪ Can be intra- or extrahepatic
▪ Klatskin tumor – extra-hepatic cholangiocarcinoma at the junction of left
and right hepatic ducts
 ▪ Extra-hepatic tumors are small at the time of diagnosis because they
rapidly cause symptoms of obstruction – they arise as firm gray nodules
within the duct
▪ Cholangiocarcinoma is adenocarcinoma and produces mucin
o Metastasis
▪ More common than primary liver cancers
▪ Common sites where they come from are – colon, breast, lung, and
pancreas
o Hepatic angiosarcoma
▪ Associated with PVC and arsenic
 GIT Pharmacology
The vomiting reflex:
• Vomiting center is located in the medulla oblongata.
• Vomiting center contains muscarinic receptors -- stimulation triggers the emetic reflex.
• CTZ (chemoreceptor trigger zone) -- also located near the medulla.
o gets triggered by chemicals
o contains -- D2 and 5 HT3 receptors
o when stimulated, stimulates the vomiting center
o is outside the BBB
• Motion sickness:
o Initiated by the inner ear
o Vestibulocochlear nerve brings signals to the vestibular nuclei
o Vestibular nuclei contain H1 and muscarinic receptors
o Vestibular nuclei pass signals to CTZ, which stimulates the vomiting center
• Vomiting can also result due to signals from higher brain centers -- cerebrum
o Emotional factors
o Pain
o Repulsive sight or smell
o Signals stimulate the vomiting center
• Vomiting can also occur from things happening in the stomach
o Stomach has EC cells -- release serotonin in response to cytotoxic agents
o Stimulates 5 HT 3 receptors on vagus nerve
o Information goes to the vomiting center
• Vomiting reflex (caused by signals from the vomiting center):
o LES relaxes
o Diaphragm and abdominal muscles contract
o Intra-abdominal pressure rises
o Autonomic changes -- tachycardia, increased salivation and peristalsis
o Epiglottis closes
o Vomiting happens!

Antiemetics
• Anti-emetics target the following receptors:
o Area postrema (CTZ)– 5HT3, D2, M1
 o Stomach/small intestine – 5HT3
o Solitary tract nucleus – 5HT3, D2, M1, H1
o Cerebellum – H1, M1
• Give anti-emetics to treat vomiting caused by:
o Chemotherapy
o Post-irradiation
o Surgery
o Pregnancy
o Motion sickness
• Weak tea, carbonated drinks, Gatorade and pedialyte (children) can also treat vomiting
• 8 categories of anti-emetics:
o Dopamine antagonists (phenothiazines, butyrophenones, benzamides,
benzimidazole)
o Anti-histamines
o Anti-cholinergics (scopolamine aka Hyoscine)
o Benzodiazepines
o Serotonin antagonists (ondansetron)
o Glucocorticoids
o Cannabinoids
o Miscellaneous
• Phenothiazines – prototype is chloropromazine, can produce symptoms like
hypotension, sedation, and Parkinsonism (extrapyramidal syndrome), which limits their
use.
• Dopamine antagonists are not effective in motion sickness induced vomiting.
• Ondansetron is a selective 5-HT3 blocker, which blocks 5-HT released by EC cells in the
gut after administration of cytotoxic drugs. Also works in the CTZ.
• Cannabinoids are moderately effective against emetogenic chemotherapy, and
probably act on vomiting center. Hallucinations, disorientation, and vertigo are side
effects. Their use is limit to patients refractory or intolerant to other anti-emetic agents.
• H1 receptor antagonists and anticholinergics are mainly used for prevention of motion
sickness. Hyoscine aka scopolamine (anti-muscarinic) is the drug of choice, and it blocks
conduction in vestibular apparatus. Anti-motion sickness drugs should be taken 0.5 to 1
hour before the journey, once sickness starts, it is difficult to control. H1 receptor
antagonists are also used in suppressing chemo-induced vomiting in addition to D2
antagonists and help reduce their extra-pyramidal side effects. Anti-muscarinic drugs
reduce side effects of metochlopramide. Main side effects include dryness of mouth,
urine retention, and mydriasis.
 • Benzodiazepines have low anti-emetic effects and prevent anticipatory emesis which
accompanies chemotherapy.
• Dexamethasone (glucocorticoid) has moderate anti-emetic effects and probably works
by reducing peritumoral inflammation and PG production. Should be avoided in
psychotic and diabetic patients.
• Vomiting in pregnancy sometimes results from pyridoxine deficiency, so pyridoxine (B6)
should be given.

Anti-diarrheals
• According to WHO, diarrhea = 3 or more loose or liquid stools per day
• Acute diarrhea has a sudden onset, lasts from3 days to 2 weeks and is self-limiting. Can
be bacterial, viral, drug-induced, nutritional, protozoal.
• Chronic diarrhea lasts for more than 3 weeks, and is associated with other symptoms
like nausea, vomiting, loss of appetite, and weakness. Causes include tumors, diabetes,
Addison’s disease, hyperthyroidism, irritable bowel syndrome.
• Oral rehydration therapy is immediately started after onset of diarrhea until diarrhea
resolves, often spontaneously.
• ORS – NaCl, KCl, Sodium citrate, Glucose dissolved in one liter of water.
• Glucose is included in ORS because it facilitates sodium absorption in the gut via the
SGLT1 symporter.
• Citrate/bicarbonate corrects acidosis caused by loss of alkali in stool.
• ORS is isotonic.
• 5 categories:
o Adsorbents
o Anticholinergics
o Intestinal flora modifiers
o Opiates
o Opiate-related agents
• Adsorbents coat GI walls and bind to causative agents or toxins which are then
eliminated through stool. E.g. bismuth subsalicylate, activated charcoal. Adsorbents are
not used for more than 2 days. Side effects: increased bleeding time, heating loss, blue
gums.
• Anticholinergics slow peristalsis, e.g. belladonna alkaloids, atropine. Contraindicated in
patients with diarrhea caused by organisms which penetrate the GI mucosa e.g.
salmonella.
 • Intestinal flora modifiers e.g. cultures of lactobacillus work by production of lactic acid
and favor establishment of aciduric bacteria and suppress growth of diarrhea-causing
bacteria.
• Opiates decrease bowel motility e.g. codeine.
• Opiate related agents include loperamide and diphenoxylate and decrease GI motility.
Not used on children under 2 years of age and with those bacteria which penetrate GI
mucosa e.g. bacterial entercolitis caused by salmonella and shigella, and with
pseudomembranous colitis associated with broad-spectrum antibiotic use.

• Loperamide and diphenoxylate are both analogues of meperidine, and activate

presynaptic opioid receptors in the enteric nervous system. This inhibits acetylcholine
release and decreases persastalsis.

• These drugs can cause toxic megacolon.

• Loperamide is an OTC drug, while diphenoxylate is a prescription drug because

diphenoxylate can cross the BBB and cause CNS opioid effects and dependence.

• Octreotide: inhibits many GIT hormones, reduces intestinal fluid secretion and slows GI
motility. It also induces a reduction of portal and splanchnic blood flow.

• Drugs used in Irritable Bowel Syndrome:

o Anti-spasmodics -- treat pain and spasms -- classified into antimuscarinics (e.g.

hyoscine) and smooth muscle relaxants (e.g. mebeverine)

o do not give anticholinergics to patients with glaucoma or prostatic hyperplasia

o In IBS-D: Antibiotics (Rifaximin), antimotility agents, and serotonin antagonists

o In IBS-C: laxatives, chloride channel activators, serotonin agonists, Guanylate

Cyclase - C agonists

Anti-acids
• Weak bases which react with HCl. They increase pH and therefore decrease pepsin
activity. Pepsin doesn’t work at a pH greater than 4.
• More effective in duodenal ulcers than in gastric ulcers
• H2 antagonists and PPIs are preferred over antacids in GERD
• Magnesium and aluminum antacids reduce bioavailability of iron, tetracyclines,
benzodiazepines, phenothiazines, NSAIDs, ranitidine, phenytoin, and vitamin A
• Calcium antacids reduce absorption of tetracyclines
• Antacids increase elimination of phenobarbitone and salicylates and decrease
elimination of amphetamine, ephedrine, quinidine, mecamylamine
• Non-systemic antacids
o Make a protective film over gastric lining
o Water insoluble and not absorbable
o In stomach, cations react with HCl to form chlorides which react with
bicarbonates in small intestines and inhibit their absorption.
▪ Aluminum Hydroxide
● Slow acting, and slow down gastric emptying
● Stimulate mucus production
● Prevent phosphate absorption
● Constipation is main side-effect, which is overcome by adding
magnesium antacids. Megaldrate = complex hydroxymagnesium
aluminate
▪ Calcium Carbonate
● Quick acting
● Rebound hyper-secretion present
● Decreases phosphate absorption
● Side-effects include belching, flatulence, and nausea due to CO2
release and milk-alkali syndrome
▪ Magnesium Trisilicate
● Slow acting, but prolonged action
● Becomes gelatinous and forms a covering over ulcers
● Side-effects include mild diarrhea and CNS depression in renal
failure patients
▪ Magnesium Hydroxide
● Quick acting
● Has osmotic effects so causes diarrhea
• Systemic antacids
o Soluble and easily absorbable
o Decrease acidity but cause systemic alkalosis due to bicarbonate absorption
▪ Sodium Bicarbonate
● Rebound hyper-secretion
● May produce milk-alkali syndrome in large doses
● CO2 release causes side-effects like distention which is harmful
for patients approaching perforation of an ulcer.
Peptic Ulcer and GERD Drugs
• Triple therapy used to treat H.pylori induced ulcers and includes:
o A proton-pump inhibitor (PPI)
o Amoxicillin
o Clarithromycin
• H2-receptor antagonists – competitive blockers
o Histamine normally stimulates Gs protein in parietal cells which then activates
protein kinase which then activates H/K pump. ACh and gastrin increase calcium
levels to activate protein kinase. PGE2 stimulates Gi protein.
o The four drugs are cimetidine, ranitidine, famotidine, and nizatidine.
o Cimetidine was the first H2 antagonist but its use is limited due to its side-
effects.
o Use of these agents has decreased as PPIs have taken over.
o Treat H.pylori associated ulcers well, but NSAID induced ulcers should be treated
using PPIs.
o Can also be used to treat acute stress ulcers but again, PPIs are preferred.
o GERD is treated with PPIs because:
▪ H2 antagonists work in only 50% of patients with GERD
▪ H2 antagonists need at least 45 minutes for their effects
▪ Antacids work only temporarily
o Side effects:
▪ Only cimetidine has anti-androgenic effects; it causes gynecomastia and
galactorrhea
▪ Cimetidine inhibits cytochrome P450 enzymes thereby interferes with
metabolism of drugs like warfarin, phentoyin, and clopidogrel.
▪ All H2 antagonists reduce efficacy of drugs which require an acidic
environment for absorption.
• PPIs
o Bind to H/K pumps
o All have “prazoles” at the end of their names
o Omeprazole, esomeprazole, and lansoprazole are available over-the-counter for
treatment of GERD
o Are taken as pro-drugs with an acid-resistant covering, are absorbed in the
alkaline duodenum and then are taken to parietal cells where they are converted
to active drugs which form a stable covalent bond with H/K pumps. (Since the
bond is stable, PPIs have a long duration of action.)
o Superior to H2 antagonists in acid suppression and ulcer treatment
 o PPIs require active proton pumps to work, therefore, if an H2 antagonist is being
taken alongside a PPI, it should be taken well after the PPI.
o All PPIs are effective orally, and should be taken 30 to 60 minutes before the
largest meal of the day.
o Side effects:
▪ Omeprazole and esomeprazole inhibit CYP2C19 and reduce the
effectiveness of clopidogrel
▪ If used for more than 1 year, fractures are a risk
▪ Prolonged acid suppression may reduce absorption of vitamin B12
▪ Calcium carbonate absorption is impaired with increased gastric pH, so
supplementation with calcium citrate given
▪ Diarrhea and Clostridium difficile colitis (some bug which also causes
diarrhea)

• Prostaglandins
o PGE normally inhibits gastric acid production and stimulates mucus and
bicarbonate production.
o Misoprostol (PGE1 analog) is used to treat NSAID induced ulcers.
o Misoprostol should not be given in pregnancy since it can cause uterine
contractions and miscarriage.
o PPIs are still preferred for NSAID ulcers.

• Mucosal protective agents

o Sucralfate = aluminum hydroxide plus sucrose
▪ binds normal and necrotic mucosa to form complex gels and thus creates
a physical barrier between the ulcer and acid.
▪ Effective for duodenal ulcers and not for gastric ulcers
o Bismuth subsalicylate – coats and protects ulcers, reduces pepsin activity, and
increases mucus secretion
▪ Also a component of the quadruple therapy for peptic ulcers

Drugs for Constipation

● may cause electrolyte imbalances when used chronically
● users run the risk for dependence
● Irritants and stimulants:
a. Senna -- oral; causes bowel evacuation within 8 to 10 hours; useful for treating
opioid-induced constipation
 b. Bisacodyl -- acts directly on the nerve fibers of the colon
c. Castor oil -- broken down to ricinoleic acid, which is very irritating to the
stomach and increases peristalsis; avoid in pregnancy because it can induce
uterine contractions
● Bulk laxatives:
a. form gels in the large intestine
b. retain water and distend the gut to cause peristalsis
c. examples are methylcellulose and psyllium seeds
d. can cause obstruction in immobile patients
● saline and osmotic laxatives:
a. magnesium citrate/hydroxide -- nonabsorbable; hold water to disten the
intestine and cause peristalsis
b. polyethylene glycol -- used in colonic lavage solutions to prepare the gut for
procedures like endoscopy
c. lactulose -- cannot be broken down; reaches colon and is converted into
bacterial products, which retain water to distend the colon and cause peristalsis;
also used to treat hepatic encephalopathy
● stool softeners:
a. soften the stool and ease its passage
b. examples are docusate sodium/calcium
c. take days to become active -- so used as prophylactic treatment, not in acute
cases
d. should not be taken with mineral oil because they increase the risk of its
absorption
● lubricant laxatives:
a. mineral oil and glycerine
b. mineral oil can be aspirated and cause lipoid pneumonia -- so should be taken
upright
● chloride channel activators:
a. lubiprostone
b. activate chloride channels to increase fluid secretion
c. used in the treatment of chronic constipation because it doesn’t lead to
dependency and has minimal drug-drug interactions
 GIT Toxicology

Phosphorus

• White (crystalline) phosphorus (turns yellow) and is highly poisonous. Gives off fumes that glow
with a pale-yellow color – phosphorescence. Red (amorphous) phossy is inert unless
contaminated with white.
• MOA – protoplasmic poison – diminishes cellular metabolism (necrobiosis).
• Causes increased fat deposition in the liver and decreased glycogen deposition. Also causes
necrosis of the bone.
• Acute poisoning sx – burning sensation; garlic taste in the mouth; vomited matter and diarrhea
are luminous in the dark. Jaundice and distension of the abdomen due to liver necrobiosis. In
later stages, liver shrinks (acute yellow atrophy).
• Tx – oily and fatty substances contraindicated (increase phossy absorption). Wash stomach with
potassium permanganate, which acts as a chemical antidote.
• PM findings – stomach and bowel contents may be luminous and body might smell of garlic. If
death is delayed, fatty degeneration and hemorrhages are seen internally. Subendocardial
hemorrhages in the left ventricle are common.
• Preserve viscera in saturated solution of salt – phossy can be detected in putrefied bodies too.
• Chronic poisoning is characterized by phossy jaw – osteomyelitis of mandible with multiple
sinuses discharging foul smelling pus.

Iodine

• MOA – direct action on cells by precipitating proteins.

• Sx – if swallowed, signs are of corrosive poisoning. If inhaled, edema of glottis leads to death
from asphyxia.
• Tx – wash stomach with starch solution. Demulcents are useful. Sodium thiosulfate can be given
orally. Tracheostomy if inhaled.

Bromide

• MOA – displaces chloride from plasma cells and depresses CNS.

• One sign of chronic bromide poisoning is bromide acne – a rash that affects shoulder and the
face.
• Tx – sodium chloride orally is the best antidote. In unconscious patients, give normal saline.
Arsenic

• Arsenous oxide or white arsenic is tasteless and very poisonous.

• MOA – combines with sulfhydryl enzymes and interferes with metabolism.
• One use of arsenic is in rat poisons.
• Acute poisoning sx – GIT disturbances; nausea and burning pain in the stomach; vomiting and
retching; diarrhea and tenesmus; rice water stools tinged with blood; if death is delayed,
patient becomes weaker and might die of HF.
• Tx – wash stomach with warm water and then give ferric oxide as an antidote. Do not give
alkalis as they increase absorption. Tx systemic effects by IM BAL (dimercaprol).
• PM findings – body is dehydrated; stomach has appearance of red velvet; petechial
hemorrhages under the endocardium of the left ventricle.
• Chronic poisoning has 4 stages
o GIT disturbances – NVD
o Catarrhal – cold symptoms
o Skin rashes – nettle rash; rain drop pigmentation; white band crossing the nails
o Nervous problems – tingling of hands and feet; muscle weakness affecting foot
extensors; headache; drowsiness; heart failure
• Tx chronic poisoning – IV sodium thiosulfate; BAL
• PM findings – retards decomposition and preserves tissues. Hair must be preserved along with
their bulbs and nails should be used as whole. Traces of poison found in urine and feces – shaft
of lower end of femur should be preserved.
• Radiopaque material is found on abdominal X-rays.
• Popular agent for homicide – children might ingest by chewing paint that contains arsenic.
Mercury

• Causes poisoning if finely divided and ingested, inhaled, or rubbed into skin.
• MOA – combines with SH groups.
• Acute poisoning sx – highest concentration found in kidney; a metallic taste is felt; burning
sensation and pain in the abdomen; nausea and vomiting; collapse; urine contains blood and
albumin.
• Tx – if no vomiting, emetics/lavage with sodium formaldehyde sulphoxylate; egg albumin can be
given; BAL for removal from tissues; cuprimine (penicillamine derivative) is effective.
• PM appearances are those of corrosive poisoning – mouth has diffuse greyish white escharotic
appearance.
• Chronic poisoning aka hydragyrism
o Excessive salivation
o Loosening of teeth
o Inflamed gums
o Blue-black line on gums
o Ulcers near nails/knuckles
o Nephritis
o Mercuria lentis – discoloration of eye lens capsule is an early sx
o Erethism – personality change – shyness, irritability; hatter’s shake (a coarse intentional
tremor that affects the hands, arms, and tongue).
o Tx – belladonna for salivation; IM BAL; sodium hyposulphite for dermatitis.
Lead

• 10x more toxic when inhaled than when ingested

• MOA – affects a lot of enzymes like SH groups and heme synthesis (ALAD) enzymes; causes
widespread organ dysfunction.
• Sx include
o Lead colic
o Sideroblastic anemia
o Brain edema – headaches, clumsiness, seizures, coma; motor neuron dysfunction
o Nephropathy and interstitial nephritis leading to gout aka saturnine gout
o Impairs GH release in children leading to abnormalities of bone growth
• Acute poisoning is very rare and mimics arsenic poisoning, except diarrhea is replaced with
constipation and stools are black.
o Tx – wash stomach with magnesium/sodium sulfate followed by ample washings with
plain water; EDTA and penicillamine can chelate it
o PM – colon contains blackened stool
• Chronic poisoning is very common. Sx are
o Facial pallor – especially around the mouth
o Anemia with basophilic stippling of RBCs (bluish dotted cytoplasm)
o Colic
o Burtonian line – bluish-black line on the gums
o Lead palsy – foot and wrist drop
o Encephalopathy – insomnia, visual blurring, headache
o Renal damage
o Infertility and menstrual disorders; abortion
o Tx if severe or enceph present – BAL; EDTA, which is the specific chelator for lead
▪ If mild, edetate IM
o It’s also important to remove exposure and decontaminate the patient with whole
bowel irrigation (using polyethylene glycol) if the presentation is remote or lavage if
presentation is acute
• Children who lick walls, toys painted with lead can get poisoning

Copper

• Salts are poisonous

• MOA – inhibits enzymes
• Acute poisoning sx – burning sensation; green/blue vomit which will turn deep blue if
ammonium hydroxide is added; uremia; jaundice in severe cases
• Tx – stomach wash with potassium ferrocyanide; albumins to form insoluble albuminate;
penicillamine, BAL, or EDTA can be given
• PM findings – blue/green gastric mucosa
• Chronic poisoning can lead to a green line at the base of the gums and Wilson’s disease;
bronzed diabetes
• Copper is sometimes added to veggies to keep their green color and accidental poisoning can
occur here.
Ethanol

• Has a fruity odor and sweetish burning taste

• MOA – depresses CNS (initially might activate is as inhibitory neurons are depressed)
• The major pathway of ethanol metabolism is the alcohol dehydrogenase pathway.
• Seven stages of intoxication are sobriety, euphoria, excitement, confusion, stupor, coma, and
death.
• McEwan’s sign
o Seen in acute intoxication
o Pinching the skin of face and neck dilates the constricted pupils momentarily
• Most crimes happen during stage 3 and 4 of intoxication.
• Chronic poisoning
o Alcoholic dementia – gradual physical, mental, and moral deterioration
o Delirium tremens
▪ Excitement and hallucinosis that lasts 3-4 days due to cerebral edema and
increased ICP
▪ Can be due to an unusual bout of drinking or sudden withdrawal (after 3-5 days
of withdrawal)
▪ Hallucinations are usually visual.
▪ The person is considered insane and is not responsible for his actions.
▪ Treated with sedatives like chlorpromazine and glucose and thiamine.
o Korsakoff’s syndrome
▪ Psychotic personality with amnesia and confabulations
▪ Tx with thiamine
o Acute hallucinosis
▪ Chiefly auditory hallucinations and delusions of persecution
▪ Patient can become homicidal/suicidal, so admit to the hospital and treat as
delirium tremens.
o Wernicke’s encephalopathy
▪ Due to thiamine def.
▪ Patient has nystagmus, ophthalmoplegia, and unsteady gate
o Other things that can happen include hepatitis, pancreatitis, gastritis, cardiomyopathy.
• Tx of acute poisoning – dextrose IV; activated charcoal; thiamine
• Tx of chronic poisoning – wean the patient off slowly; carbamazepine can be given to control
delirium tremens; disulfiram for aversion therapy (given orally only)
• CSF or vitreous humor should always be preserved in a patient with alcoholic poisoning; blood
samples must be taken from a peripheral vein; the preservative used should be saturated
solution of common salt.
• Chronic alcoholism is the commonest cause of sexual jealously crimes.
• PM findings – alcoholic smell, shrinkage of grey matter; fatty/cirrhotic liver
• A fine lateral nystagmus is a very strong indicator of alcoholic intoxication.
Methanol

• MOA – leads to the generation of formaldehyde and formic acid, which mediate damage.
Formic acid can lead to severe metabolic acidosis.
• Signs – intestinal contraction is diagnostic – intestines look like a thick pipe with a very narrow
lumen.
• Tx – stomach wash with sodium bicarb only within 2-4 hours of ingestion; ethanol is the
antidote; sodium bicarb for acidosis.
• Preserve viscera in saturated solution of salt.
• Poisoning usually occurs when an alcoholic cant find alcohol and resorts to methanol, which is
found in antifreeze, paint removers, and varnishes.