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78
Fig. 6.2: Endoscopic features of different types of ulcers: (A) Active spurting bleeding; (B) Active
oozing bleeding; (C) No active bleeding with visible vessel; (D) Broad adherent clot; (E) Haematin
covered flat spots; (F) No bleeding stigmata with clean base ulcer (Courtesy: Dr Deepak Gupta,
Gastroenterologist and Hepatologist, Navi Mumbai.)
Textbook of Pharmacotherapeutics
• Prostaglandins
• Antacids
Proton Pump Inhibitors
These are also called H+/K+-ATPase inhibitors. Drugs such as omeprazole, esomeprazole,
lansoprazole, rabeprazole and pantoprazole act by binding covalently and irreversibly
+/K+
with the H
-ATPase.
The proton pump inhibitors are pro-drugs which are weak bases and also acid
labile. These drugs have to be administered as enteric-coated granules inside capsule.
These drugs are most effective when given in the morning before breakfast. The drugs
are having short plasma half-life of approximately two hours but the duration of
action is long and lasts for 24 hours.
Adverse effects: Headache, fatigue, dizziness, diarrhoea, abdominal pain, nausea.
These drugs show interaction with other drugs like warfarin, phenytoin and
diazepam.
Sucralfate
This is a complex aluminium salt of sucrose octasulphate. It acts by forming a viscous
layer in the presence of gastric acid to create a protective barrier for the cells in the
stomach and duodenum. The other mechanism by which it shows its action is
enhancing prostaglandin synthesis stimulating mucus and bicarbonate secretion
helping mucosal defense and repair.
Gastrointestinal Disorders
79
Constipation is the most common side-effect of this drug. It should be avoided in
patients with chronic renal insufficiency. Hyperphosphataemia and gastric
bezoar formation are rare side-effects. Drug interactions, multiple doses per day
administration, time separation of sucralfate administration with meals makes its use
difficult.
Bismuth Compounds
Bismuth preparations show ulcer healing mechanism by acting as an antibacterial, as local gastroprotective agent and stimulating endogenous
prostaglandins.
Bismuth salts like bismuth subsalicylate and colloidal bismuth subcitrate do not
have any effect on secretion of gastric acid or neutralising it. The bismuth
preparations should be used with caution in aged patients and in case of patients
with renal problems. Bismuth subsalicylate may cause sensitivity of salicylate or
bleeding disorders. So, it should be used with caution in patients on salicylate
therapy. Liquid bismuth preparations may impart black colour to the tongue. Also,
these preparations impart black colour to the stools. Bismuth toxicity limits its longterm use.
H2 Receptor Antagonists
H2 receptor antagonists decrease gastric acid secretion by blocking the H2 receptors in
the gastric parietal cells. Agents are available on OTC basis. They are effective in
eradication of H. pylori, treatment of the duodenal ulcers and gastric ulcers,
maintenance treatment of ulcers, hypersecretory conditions, erosive and non-erosive
GERD and prevention of upper GI bleeding.
antagonists are safe and well tolerated. The uncommon side-effects include
H
2
hypertension, brady arrhythmias, tachyarrhythmias, atrioventricular conduction
abnormalities and cardiac arrest. Central nervous system effects seen are sedation,
dizziness and headache.
Examples of H
ranitidine.
receptor antagonists are cimetidine, famotidine and
2
Prostaglandins
Misoprostol is a synthetic prostaglandin which inhibits gastric acid secretion and acts
as a cytoprotective agent in higher doses. Adverse effect includes diarrhoea,
abdominal cramps, nausea, flatulence and headache. Misoprostol is contraindicated
in pregnant woman.
Antacids
The gastric acid is neutralised by antacids. Pepsin is inactivated and binding of bile
salts occurs. Aluminium containing antacid suppress H. pylori and enhances the
defence mechanism of mucosa. Antacids increase the mucosal prostaglandin levels,
stimulate mucus and bicarbonate secretion. Significant drug—drug interactions occur
with antacids. So, there should be a gap of about two hours between antacids and
other medications.
80
Textbook of Pharmacotherapeutics
KEY POINTS
• Peptic ulcer disease are ulcers which occur due to exposure of the GIT to acid for a particular
duration and concentration.
• The risk factors for peptic ulcer disease are Helicobacter pylori infection, stress and long-term use of NSAIDs.
• Mild epigastric pain, GI bleeding, perforation and obstruction are observed.
• Proton pump inhibitors, H
antacids are used in the treatment.
receptor antagonists, bismuth compounds, sucralfate, prostaglandins and
2
6.3 ALCOHOLIC LIVER DISEASE
A significant cause of liver disease is the chronic and excessive consumption of alcohol.
Alcoholic liver disease exists in three forms:
• Fatty liver
• Alcoholic hepatitis
• Cirrhosis
Most binge drinkers and chronic drinkers suffer from fatty liver. A small percentage
of heavy drinkers suffer from alcoholic hepatitis which is a precursor to cirrhosis.
Mortality of patients with alcoholic hepatitis concurrent with cirrhosis is high. There
is a paradox where alcohol being a direct hepatotoxin, only 10 to 20% of alcoholics
develop alcoholic hepatitis. There are other risk factors involved like gender, heredity,
immunity, nutrition and presence of other diseases.
Aetiopathogenesis
The development of alcoholic liver disease depends on the quantity and duration of
intake of alcohol. The pattern of drinking and role of type of beverage is not well
understood. There are other risk factors involved which lead to progression of hepatic
injury to fatty liver stage. The threshold for developing alcoholic liver disease is
greater than 60 to 80 g of alcohol per day for 10 years in men. Women on the other
hand develop similar liver injury by consuming 20 to 40 g of alcohol per day. Intake of
160 g of alcohol per day is associated with 25-fold increased risk of developing
alcoholic cirrhosis. The pathogenic process of development of liver disease with
alcohol has various factors like social, immunological and genetic.
An important comorbidity factor associated with alcoholic liver disease to cirrhosis
in chronic and excessive drinkers is the chronic infection with hepatitis C. Moderate
intake of 20 to 50 g of alcohol per day increases the risk of cirrhosis and hepatocellular
cancer with HIV infection.
Alcohol acts as a toxin for hepatic cells. The intake of alcohol causes a variety of
metabolic responses that influence the response of hepatic cells. In the past, it was
thought that malnutrition is the pathogenic mechanism but new theory has now
replaced it. Alcohol is metabolised by the liver which initiates a pathogenic process
involving production of toxic protein-aldehyde adducts, endotoxins, oxidative stress,
immunologic activity as well as pro-inflammatory cytokine release. There is an
interaction between intestinal and hepatic cells which aids the alcohol-mediated liver
injury. The tumour necrosis factor—TNF alpha and endotoxemia cause hepatocyte
apoptosis and necrosis. The stellate cell activation and collagen production cause
hepatic fibrogenesis. This fibrosis determines the derangement of liver on chronic
alcohol consumption.
Gastrointestinal Disorders
81
Clinical Manifestations
The clinical manifestations of alcoholic fatty liver are difficult to determine. The
clinical finding is hepatomegaly. Sometimes, fatty liver patients show right upper
quadrant discomfort, tender hepatomegaly, nausea, and jaundice. An accurate history
of drinking has to be found out in order to differentiate alcoholic fatty liver from nonalcoholic fatty liver. Standard questions are required to be answered to detect alcoholrelated problems. Alcoholic hepatitis shows many clinical features like fever, spider
nevi, jaundice, and abdominal pain which are seen in a number of patients. There are
many patients who are asymptomatic. Portal hypertension ascites or variceal bleeding
may occur in the absence of cirrhosis. Alcoholic cirrhosis patients show similar
symptoms as seen in other patients of cirrhosis.
Non-pharmacological Management
The treatment of alcoholic liver disease lies in the complete abstinence from alcohol
which improves the survival of the patient and exhibits potential for reversal of the
injury. The patients should consult alcohol counsellors and follow alcohol treatment
programmes. The nutritional and psychosocial state of the patient should also be
evaluated.
Liver transplantation can be evaluated only after a defined period of complete
alcohol abstinence. There are high rates of return to alcoholism after transplantation.
Also, a high rate of surgical mortality is seen following liver transplant.
Pharmacological Management
Glucocorticoids are administered in the treatment of alcoholic hepatitis with
discriminant factor >32 (discriminant factor determines the severity and prognosis of
alcoholic hepatitis). Prednisone 40 mg/day or prednisolone 32 mg/day is administered
to severe alcoholic hepatitis patients. The steroids are tapered after four weeks of
therapy.
The non-specific TNF inhibitor, pentoxifylline is considered as an alternative
therapy for severe alcoholic hepatitis.
KEY POINTS
• Alcoholic liver disease exists in three forms as fatty liver, alcoholic hepatitis and cirrhosis.
• The development of alcoholic liver disease depends on the quantity and duration of intake of alcohol.
• Fatty liver patients show right upper quadrant discomfort, tender hepatomegaly, nausea, and
jaundice.
• The treatment of alcoholic liver disease lies in the complete abstinence from alcohol.
• Glucocorticoids are administered in the treatment of alcoholic hepatitis.
6.4 INFLAMMATORY BOWEL DISEASES (CROHN’S DISEASE AND ULCERATIVE
COLITIS)
Inflammatory bowel disease, IBD, can be grouped into two major chronic inflammatory
disorders of the gastrointestinal tract:
• Ulcerative colitis
• Crohn’s disease
82
Ulcerative colitis affects mainly the colon and rectum whereas Crohn’s disease can
affect any part of the gastrointestinal tract. Both of these disorders have recurrent
episodes of acute inflammation and remission.
Textbook of Pharmacotherapeutics
Aetiopathogenesis
Several factors act as trigger factors but the causative agent of inflammatory bowel
disease (IBD) is not known.
According to a hypothesis, the non-pathogenic microflora in the colon can stimulate
an abnormal immune response. According to the autoimmune hypothesis, there is a
similarity between luminal antigen (luminal antigen is a modulator of gut function
and immunity) and epithelial cell proteins. So, the patient’s immune system attacks
and destroys intestinal epithelial cells. Genetic basis is considered to be present for
IBD. Also, gene mutations are associated with IBD.
Other proinflammatory antigenic agents considered as risk factors are thought to
be dietary, autoimmune, genetic and environmental factors. Intake of fatty food, fast
food, milk, refined sugars, fibres, chemical food additives, total protein and energy are
associated with IBD.
Smokers show a higher rate of Crohn’s disease. The clinical course of the disease
worsens with smoking. Though smoking does not initiate onset of ulcerative colitis
but causes deterioration of the condition. Certain medications like non-steroidal antiinflammatory drugs exacerbate IBD.
Stress may trigger a relapse in IBD.
Mycobacterium paratuberculosis has been considered to be a causative agent for Crohn’s
disease.
Clinical Manifestations
Ulcerative Colitis
The main symptoms of ulcerative colitis are bloody diarrhoea, passing of mucus,
abdominal pain with cramps, and tenesmus. Symptoms vary according to the severity
of the disease.
In acute severe disease, the patient may present with more than six bloody stools
per day, fever, tachycardia, and anaemia. The frequency of bloody stools is less than
six per day in case of moderately active disease. Proctitis patients show tenesmus,
rectal bleeding, and mucus discharge.
Extraintestinal complications of inflammatory bowel disease include effect on
joints, bones, skin, eyes, liver, and biliary duct. Anaemia and thromboembolic
complications are also seen.
Crohn’s Disease
The clinical symptoms of Crohn’s disease are dependent on the site of GIT. Diarrhoea,
abdominal pain and weight loss are the main symptoms.
Small Intestine Ileocecal and Terminal Ileum Disease
Patients show pain, diarrhoea, steatorrhoea, and bacterial growth proximal to a stricture
colitis. The symptoms seen are abdominal pain, profuse and frequent diarrhoea with or
without blood, weight loss, anorexia, nausea, tachycardia, anaemia and fever.
Gastrointestinal Disorders
Fig. 6.3: Endoscopic image of inflammatory bowel disease (Courtesy: Dr Deepak Gupta,
Gastroenterologist and Hepatologist, Navi Mumbai.)
83
Gastroduodenal and Oral Disease
These are rare conditions.
Stricture Crohn’s Disease
Patients present pain, vomiting and constipation.
Non-pharmacological Management
Many nutritional supplements are available to control remission in ulcerative colitis
and Crohn’s disease.
Deficiency of vitamins and minerals may occur because of malnourishment and
malabsorption. Fat malabsorption in Crohn’s disease contributes to low levels of fatsoluble vitamins like vitamin A, D and K. Low fibre diets help in reduction of
symptoms in Crohn’s disease. Certain cases may require a low lactose diet. Enteral
nutrition can be used in the form of elemental or polymeric diet. This therapy is used
in paediatrics as primary therapy. Enteral nutrition may help as an adjunct therapy in
IBD to restore the balanced nutritional state. Total parenteral nutrition (TPN) is used
in patients with IBD where internal nutrition is inadequate or not indicated. Some
patients are given concurrent enteral and parenteral feeding.
Patients with IBD use complementary and alternative medicines as well with
conventional drug treatment. This includes herbal medicines with special diets like
gluten-free dietary manipulations and other alternative medicines like homeopathy,
naturopathy, Tai chi, chiropractic treatment, massage and meditation. Flaxseed, garlic,
aloe vera, salmon oil, primrose oil, fenugreek, acidophilus, and slippery elm are useful
in patients with IBD.
Surgery
In case the drug therapy is ineffective in ulcerative colitis, then the patient has to
undergo surgery. Surgery is indicated in patients with other complications. Surgery
is a curative procedure in ulcerative colitis but not in Crohn’s disease as the condition
may recur elsewhere in the GIT.
84
Textbook of Pharmacotherapeutics
Patient Education
Psychosocial therapy is important with concurrent pharmacological treatment. All
patients should be informed regarding their condition and medication. The patients
need to continue taking prescribed therapy even in times of remission of the disease.
Pharmacological Management
There is no treatment available for inflammatory bowel disease as its exact cause is
unknown. The following drugs are used to keep the conditions of ulcerative colitis and
Crohn’s disease in long periods of remission.
• 5-amino salicylic agents
• Corticosteroids
• Immunosuppressants
• Antimicrobials
5-Amino salicylic acid (5-ASA) agents
These agents are useful in inducing remission both in ulcerative colitis and Crohn’s
disease. Sulphasalazine is used to treat mild to moderate ulcerative colitis, Crohn’s
ileocolitis and colitis. The adverse effects of sulphasalazine are headache, anorexia,
nausea, vomiting, rashes, fever, hepatitis, agranulocytosis, hypersensitivity,
pneumonitis, pancreatitis, worsening of colitis, and reversible sperm abnormalities.
Newer sulphur-free aminosalicylate preparations can be used to deliver increased
amounts of 5-ASA to the affected site of GIT. Olsalazine, balsalazide, claversal,
asacol, pentasa are the examples of aminosalicylates.
Topical mesalamine enemas are used in mild to moderate distal ulcerative colitis
and Crohn’s disease. Mesalamine suppositories are used in the treatment of proctitis.
Corticosteroids
Corticosteroids can be administered by intravenous, oral or topical routes. Corticosteroids,
when administered continuously or by intermittent intravenous infusion, helps in the
remission of severe active ulcerative colitis or Crohn’s disease within 7 to 10 days.
Examples are methylprednisolone, hydrocortisone.
Oral corticosteroids are useful in the treatment of IBD patients. Prednisone may be
administered orally in doses of 40 to 60 mg per day for ulcerative colitis. Clinical
improvement is seen within 30 days. Many patients show steroid dependency as they
show recurrent symptoms during dose tapering or just after withdrawal.
Topically, corticosteroids are given as enema, rectal foams, and suppositories.
Topically administered rectal corticosteroids are effective for mild to moderate distal
ulcerative colitis. Retention enemas are administered at bedtime so that the drug
remains in contact with the inflamed mucosa overnight. Remission occurs usually
within 2 to 3 weeks after which an alternate night schedule may be used for another
two weeks.
Side-effects of corticosteroids are moon face, acne, sleep and mood disturbances,
dyspepsia, hypernatraemia, hypokalaemia, osteoporosis and increased infection risk.
Budesonide
Budesonide is given orally as enteric-coated controlled release dosage form which
releases the drug slowly into the distal ileum and ascending colon.
Gastrointestinal Disorders
85
Immunomodulators
Azathioprine, 6-mercaptopurine, methotrexate, and cyclosporin are some immunosuppressants used in steroid and aminosalicylate unresponsive cases. Azathioprine is
a prodrug which is metabolised to 6-mercaptopurine by the liver. It probably acts by
inhibiting purine ribonuclease synthesis and in turn, inhibiting lymphocyte function.
Side effects include flu-like symptoms, headache, myalgia, nausea and diarrhoea.
Methotrexate
Low dose regimen of methotrexate is used effectively in chronic active cases of Crohn’s
disease. A dose of 15 to 25 mg is administered the same day each week either orally or
parenterally. Methotrexate is a folic acid antagonist reserved for patients not
responsive to or intolerant of azathioprine or 6-mercaptopurine.
Adverse effects include nausea, vomitting, diarrhoea and stomatitis. More serious
effects seen are hepatotoxicity, bone marrow suppression and pneumonitis.
Methotrexate is teratogenic. So, it has to be administered with care.
Anti-TNF antibody
Infliximab and adalimumab are the biologic agents used for IBD.
Infliximab is a human monoclonal antibody to TNF alpha used for the treatment of
severe active Crohn’s disease with or without fistulae and ulcerative colitis. This is
used for patients who are unresponsive to other treatments, resistant to steroids, or
surgery is inappropriate. Infliximab is administered as intravenous infusion in a dose
of 5 mg/kg over a period of two hours. This is repeated after two weeks if clinical
response is shown by the patient. A maintenance dose of 5 mg/kg is administered
every eight weeks.
Side effects include effects on normal immune responses, headache, dizziness,
nausea, rash, raised liver function tests, abdominal pain, and fatigue.
Antibiotics
Metronidazole is used for Crohn’s disease associated with the colon. It is given in
doses of 15 to 20 mg/kg/day in three divided doses for several months. The sideeffects are nausea, metallic taste, and peripheral neuropathy with prolonged
administration.
KEY POINTS
• Inflammatory bowel disease, IBD, can be grouped into ulcerative colitis and Crohn’s disease.
• Ulcerative colitis affects mainly the colon and rectum whereas Crohn’s disease can affect any part
of the gastrointestinal tract.
• Both of these disorders have recurrent episodes of acute inflammation and remission.
• Stress may trigger a relapse in IBD.
• Many nutritional supplements are available to control remission in ulcerative colitis and Crohn’s
disease.
• There is no treatment available for inflammatory bowel disease as its exact cause is unknown.
• The drugs which are used to keep the conditions of ulcerative colitis and Crohn’s disease in long
periods of remission are 5-amino salicylic agents, corticosteroids, immunosuppressants and
antimicrobials.
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Textbook of Pharmacotherapeutics
7
Hematological
Disorders
Anaemia
Anaemia is a haematological condition in which there is deficiency of
haemoglobin in the blood along with reduction in the number of erythrocytes
(RBCs). Anaemia is a global issue which affects young children and pregnant
women. According to the studies, almost half of India’s population of women
and children are anaemic.
Erythropoiesis
This is a process of formation of RBCs which occurs in the bone marrow. The
pluripotent cells present there undergo multiple stages of differentiation and
maturation to form reticulocytes and in turn erythrocytes. Various nutrients like iron,
vitamin B
hormone released by the cortex of kidneys, helps in regulation of formation of
erythrocytes.
Every day, approximately 2 × 1011 erythrocytes enter the blood circulation. The lifespan
of erythrocytes is 120 days and then they are broken down by the reticuloendothelial
cells present in the spleen. Haemoglobin is made up of two parts: haeme and globin.
After the breakdown of RBCs, the iron from the haeme part is sent to the bone marrow
for reuse.
and folic acid are required during erythropoiesis. Erythropoietin, a
12
Normal Values
The normal values of haemoglobin and erythrocytes are given in Table 7.1.
Table 7.1: Normal values of haemoglobin and erythrocytes
Normal value of Male Female
Haemoglobin (in g/dl of blood) 14–17 12–16
Erythrocytes (in million/cu mm of blood) 5–6.5 4–5.5
The function of RBCs is to carry oxygen from the heart to all parts of the body in the
form of oxyhaemoglobin. It carries carbon dioxide from all parts of the body to the
lungs for excretion in the form of carboxyhaemoglobin.
Anaemia results in a decrease in oxygen carrying capacity of blood.
86
Hematological Disorders
87
Aetiology
The low levels of haemoglobin may be due to two reasons:
• Loss in haemoglobin due to loss of RBCs or destruction of RBCs.
• Reduced synthesis of haemoglobin due to lack of nutrients or malfunctioning of
bone marrow.
Types of Anaemia
The different types of anaemia are:
1. Iron deficiency anaemia
2. Aplastic anaemia
3. Megaloblastic anaemia
4. Haemolytic anaemia
5. Sideroblastic anaemia
6. Sickle-cell anaemia
7.1 IRON DEFICIENCY ANAEMIA
Iron deficiency anaemia is a major health concern in India.
Aetiopathogenesis
Following are the causes of iron deficiency anaemia:
• Dietary iron deficiency
• Increased iron requirement during growth years or pregnancy
• Malabsorption of iron
• Blood loss.
Dietary iron deficiency: The daily requirement for iron varies from 0.5 mg in
infants to 2.5 mg in adults. The requirement increases to approximately to 5 mg in case
of pregnant women.
The reasons for deficiency of iron include inadequate income, starvation, vegetarian
diet, and dieting.
Increased iron requirement during growth years or pregnancy: Defective intake
or poor diet during the growth years in children or adolescents as well as in pregnant
women may lead to iron deficiency anaemia.
Malabsorption of iron: Malabsorption of iron may occur in gastrectomy and in
conditions like coeliac disease also known as gluten enteropathy.
Blood loss: Blood loss may occur due to bleeding in the gastrointestinal tract or during
menstrual cycle. There may be blood loss due to intestinal hookworm infestation.
Clinical Manifestations
In general, an anaemic patient shows fatigue, lethargy, breathlessness due to exertion,
palpitations, oedema, dizziness, tachycardia, chest pain, worsening cardiac failure and
loss of mental concentration.
The symptoms of iron deficiency anaemia include delays in general development,
central nervous system disturbances in behaviour, impairment in work capacity,
preterm delivery and delivery of low-birth weight babies.