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88
Textbook of Pharmacotherapeutics
A person suffering from chronic iron deficiency anaemia may present the following rare
symptoms:
• Pica (a compulsive disorder when the affected person eats non-food items such as
ice, clay, paper, ash, or dirt), dysphagia, glossitis, stomatitis and koilonychia (nails
become spoon shaped).
Non-pharmacological Management
Prevention by diet:
High-risk patients may be given dietary supplements to correct the iron deficiency
before anaemia develops. The high-risk population includes children, adolescents,
women in general and pregnant women in particular, old people, alcoholics, and HIV
patients. Iron-rich diet helps to mitigate iron deficiency. Iron is available in haeme and
non-haeme forms in the diet. The haeme form of iron is present in red meat in the diet
and is readily absorbed by the duodenum. The non-haeme form of the iron present in
the vegetarian diet is absorbed with difficulty. The food rich in iron includes green
leafy vegetables, beetroot, dates, beans, apples, bananas, dry fruits such as dried
raisins.
Pharmacological Management
Oral iron therapy
Iron is available in ferrous and ferric forms. The ferrous form of iron is economical,
safe as well as an effective form of oral iron therapy. Ferrous sulphate, ferrous
gluconate and ferrous fumarate are used in tablet and syrup form. The elemental iron
present in the oral preparations is helpful in treatment of iron deficiency anaemia.
The standard treatment is ferrous sulphate 200 mg 2 to 3 times a day. It takes around
1 to 2 weeks for the haemoglobin level to rise by 1 mg/dl. The iron tablets should be
given on an empty stomach but the side-effects may be reduced by taking the drug
after meals. The disadvantage of this is that it reduces the absorption of iron from the
GIT.
Side effects are on the gastrointestinal tract. Nausea, vomiting, abdominal pain,
black stools and constipation may be seen.
Parenteral iron therapy
When iron is administered parenterally, it has no added advantage over oral therapy.
So, this therapy should be reserved for patients who cannot tolerate oral iron therapy
or show improper absorption of iron.
Iron dextran
This is a complex of ferric oxide and dextran. Once it is injected as intravenous infusion
or slow intravenous injection or by intramuscular injection, the iron dextran complex
is separated by the reticuloendothelial system in the body. Iron Dextran can also be
infused as total dose infusion (TDI). A test dose of 0.5 ml containing 25 mg should be
given before initiating the therapy to check for adverse reactions. Most reactions occur
during the initial administration and range from mild reactions to life-threatening
anaphylactic shock. The mild reactions are transient and may be seen as dyspnoea,
headache, nausea, vomiting, flushing, itching, urticaria, fever, hives, chest pain or
abdominal and back pain. Anaphylactic shock is characterised by respiratory and
Hematological Disorders
89
cardiovascular collapse. Drugs like epinephrine, diphenhydramine and corticosteroids
are used to treat anaphylactic shock. A patient who has not shown anaphylactic shock
during the test dose may even show it during therapy. The adverse systemic reactions
may be seen later after one or two days of iron dextran therapy as myalgias and
arthralgias.
Iron sucrose
This is a complex of ferric hydroxide and sucrose. Once administered, this complex is
dissociated in the reticuloendothelial system of the body. This is administered to
patients with kidney issues. The recommended doses of iron sucrose in dialysis and
non-dialysis kidney disease patients are different.
Ferric gluconate
The FDA approved sodium ferric gluconate complex in sucrose in the year 1999 for
the treatment of iron deficiency anaemia in patients undergoing haemodialysis and
receiving erythropoietin therapy. The recommended cumulative dose is 1000 mg over
dialysis sessions to achieve the desired haemoglobin level in the patient.
Red cell transfusion
This therapy may be required in patients who require immediate medical relief in
blood loss. Also, this transfusion therapy is reserved for patients with symptoms of
cardiovascular instability with anaemia.
Monitoring Iron Deficiency Therapy
The response to the iron therapy should be to treat the anaemia and in the long term
achieve proper iron stores in the body. Usually, the response to the iron therapy is
evident in one week by counting the number of reticulocytes in the blood. The rate of
increase of haemoglobin depends on the severity of anaemia.
Also, the overload of iron usually seen in cases of haemochromatosis, haemosiderosis,
and thalassaemia should be monitored as iron toxicity may be acute or chronic.
KEY POINTS
• Iron deficiency anaemia is caused due to dietary iron deficiency, increased iron requirement
during growth years or pregnancy, malabsorption of iron and blood loss.
• 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.
• High-risk patients may be given dietary supplements to correct the iron deficiency before anaemia
develops.
• Oral iron therapy, parenteral iron therapy and red cell transfusion is used in treatment.
7.2 MEGALOBLASTIC ANAEMIA
Megaloblastic anaemia is classified under macrocytic anaemia. Megaloblastic
anaemias are a group of disorders characterised by the presence of abnormally sized
red blood cells caused by a deficiency of vitamin B
is an autoimmune disease caused by malabsorption of vitamin B
intrinsic factor.
or folic acid. Pernicious anaemia
12
due to a lack of
12
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Textbook of Pharmacotherapeutics
Physiologic importance of vitamin B
12
• Vitamin B12 is also known as cobalamin, a cobalt-containing vitamin which cannot
be synthesised by human tissue. It is an essential cofactor for several enzymatic
reactions in the body.
• Vitamin B
absorption may take place either by diffusion to some extent and/or by
12
binding to different binding proteins. Intrinsic factor secreted by the gastric cells
bind to the vitamin B
and helps in its absorption in the small intestine, mainly
12
ileum.
Physiologic importance of folate
The circulating form of folate is tetrahydrofolate. It is bound to plasma proteins and
helps in various metabolic processes of the body.
Aetiology
Vitamin B12 deficiency anaemia
• Deficiency of vitamin B12 occurs either due to inadequate dietary intake or improper
absorption of vitamin B
• Vitamin B
is present in foods derived from animal sources like dairy products,
12
eggs, meat, and fish. Inadequate dietary intake is the main cause of megaloblastic
anaemia in most Indians. Pernicious anemia, where a lack of intrinsic factor is seen,
is the main cause of megaloblastic anaemia in most Western countries.
Malabsorption may be seen in certain gastrointestinal conditions like gastrectomy,
removal of distal ileum, tropical sprue fish, tape worm infestation, coeliac disease,
lymphoma, gastric lesions, ileocolic fistula, anatomic blind loop intestinal structure,
intestinal stagnant loop syndrome, jejunal diverticulosis, Zollinger-Ellison syndrome,
Crohn’s disease, or achlorhydria. Use of certain drugs like proton pump inhibitors and
radiotherapy also cause malabsorption of vitamin B
Infants may develop megaloblastic anaemia at the age of six months when born to
severely cobalamin-deficient mothers and receiving mother’s milk containing low
cobalamin.
The drugs that induce vitamin B
proton pump inhibitors, biguanide hypoglycaemics, colchicine, and p-amino salicylic
acid. Alcohol and cholestyramine reduce the absorption of vitamin B
The daily requirement of vitamin B
3 to 5 mg of vitamin B
develop megaloblastic anaemia in these cases.
.
12
.
12
deficiency are neomycin, H2 receptor blockers,
12
.
12
is 1 to 3 μg/day. The body stores around
in case of proper vitamin B12 rich diet. It takes a few years to
12
12
Folate Deficiency Anaemia
Folate is available in normal diet like fruits, green vegetables, and yeast. It is a watersoluble vitamin, and heating the folate-rich food may lead to its destruction.
Inadequate folate intake or overutilisation of folate along with malabsorption are the
main causes of folate deficiency anaemia. Other causes include alcoholism, pregnancy,
enhanced metabolism, and interference in the metabolism or excretion by other
pharmacotherapeutic agents.
Malnutrition is one of the causes of folate deficiency. Malignancy leads to higher
cell division and thus requires more folate, e.g. in some cases of acute myeloid
leukaemia and myelodysplasia.
Hematological Disorders
91
Malabsorption may occur in cases like sprue. Certain drugs which induce folate
deficiency by reducing absorption are alcohol, metformin, cholestyramine, sulphasalazine,
sulphamethoxazole, oral contraceptives, and some anticonvulsants. There are other
drugs which alter the metabolism and cause folate deficiency like methotrexate,
trimethoprim, triamterene, and pentamidine.
Folate deficiency occurs in stages and leads to megaloblastic anaemia.
The liver has a store of approximately 10 mg. The daily requirement of folate is
65 to 400 μg, which increases to 600 μg during lactation and pregnancy. The daily
dietary supply is important as there is degradation and excretion of folate every day.
Folate depletion leads to megaloblastic anaemia in about 6 months.
Clinical Manifestations
The general symptoms of anaemia are fatigue, paleness, difficulty in breathing, light
headedness, palpitations, increased heart rate, chest pain, and reduced mental
concentration. The specific features of megaloblastic anaemia are glossitis, angular
stomatitis, anorexia, constipation or diarrhoea, mild jaundice, sterility, fever, and
rarely skin pigmentation. Peripheral neuropathy, loss of hand coordination, tingling
sensation in extremities, depression, and spinal cord degeneration may be seen mainly
with vitamin B
deficiency.
12
Treatment
Identification of the cause of the underlying anaemia is the first step to prevent the
problems. Megaloblastic anaemia occurs either due to deficiency of vitamin B
or
12
folate. Administration of folate for the treatment of megaloblastic anaemia may help
in case of anaemia due to vitamin B
deficiency, but will not help in prevention of
12
neurological problems. So, it is important to identify the cause of megaloblastic
anaemia.
Dietary changes and supplemental therapy using vitamin B
orally, intranasally or
12
parenterally are the available options. Dietary changes help in patients with
malnutrition, vegetarian, vegan, and restricted diet but will not be helpful in cases of
malabsorption as pernicious anaemia.
Pharmacological Management
Oral Vitamin B12 Therapy
Most patients with vitamin B12 deficiency require lifelong replacement therapy.
Certain patients with underlying gastric or intestinal problems, if treated, find it
helpful in the correction of megaloblastic anaemia.
The usual oral dose of a vitamin B
therapy is not useful in cases of malabsorption.
B
12
supplement is 1 to 10 μg daily. But oral vitamin
12
Monitoring compliance and subsequent neurologic symptoms is important. The
therapeutic response for each patient should be determined.
Intranasal Vitamin B12 Therapy
Vitamin B12 intranasal administration is a recent advancement. Currently, Naso B
nasal spray is available in India, which contains methylcobalamin 500 μg. The nasal
spray is well tolerated.
12
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Textbook of Pharmacotherapeutics
Parenteral Vitamin B12 Therapy
Various regimens are available for the administration of parental vitamin B12. The
injection may be given by intramuscular or subcutaneous routes. Doses of 100 to
1000 μg of vitamin B
can be given. Usually, all regimens use frequent administration,
12
initially for correcting the deficiency and then injections every 1 to 3 months as lifelong
maintenance therapy. Two forms are available for administration: Cyanocobalamin
and hydroxocobalamin.
Adverse effects are rare and are documented as rashes, wheezing, or anaphylactic
shock. Preparations containing benzoyl alcohol as a preservative should be avoided
in infants due to its possible toxicity.
Monitoring
Response to the supplementation of vitamin B12 depends on the stage of deficiency.
Reticular cytosis occurs rapidly.
Folate Therapy
Folic acid is given in a dose of 5 to 15 mg per day. These doses are large and sufficient
for the patient to absorb the folic acid even in cases of malabsorption. Dietary
modifications are also advised along with folic acid. This will help the folate therapy
duration to be restricted to 6 months. In certain cases, like haemolytic anaemia, chronic
dialysis, or gluten-induced enteropathy, long-term treatment with folic acid may be
required. Parenteral folic acid treatment is generally not required.
Improvement in the health condition may occur after a short course of folic acid,
but the blood cells return to normal only after a longer duration of treatment.
Pregnant women are advised to take a daily dose of 400 μg to avoid neural tube
defects in the growing foetus. Also, this dosage will prevent any folate deficiency in
the later trimester of pregnancy. Actually, folate therapy is advised even before
conception.
Lifelong folate therapy may be required in patients with haemolytic anaemia.
KEY POINTS
• Megaloblastic anaemias are a group of disorders characterised by the presence of abnormally sized
red blood cells caused by a deficiency of vitamin B
• Deficiency of vitamin B
vitamin B
• Vitamin B12 is present in foods derived from animal sources like dairy products, eggs, meat, and
fish.
• Inadequate dietary intake is the main cause of megaloblastic anaemia in most Indians.
• Folate deficiency anaemia may occur due to malabsorption.
• Dietary changes and supplemental therapy using vitamin B12 orally, intranasally or parenterally
are the available options.
.
12
occurs either due to inadequate dietary intake or improper absorption of
12
or folic acid.
12
Infectious Disorders
93
8
Infectious Disorders
8.1 TUBERCULOSIS
Tuberculosis (TB) is a bacterial infection that has been considered a deadly disease
since the olden days. Robert Koch identified the tubercle bacillus as the cause of TB in
humans in the year 1882. Approaches to controlling the disease started after this
discovery.
The various steps included the development of a sanatorium to isolate the infectious
patients, pasteurisation of milk, and the development of the BCG (Bacillus CalmetteGuérin) vaccine. The discovery of anti-TB drugs started in the 1940s, which led to a
reduction in mortality.
According to estimates by the WHO, TB ranks 13th in the cause of death. World-
wide, 1.5 million people died from TB in the year 2020. It is the second-leading
infectious killer. But it is curable. TB is present in all countries and age groups. Eight
countries account for two-thirds of the TB load, with India leading the table, followed
by China, Indonesia, the Philippines, Pakistan, Nigeria, Bangladesh, and South Africa.
Ending the TB epidemic by 2030 is among the health targets of the UN Sustainable
Development Goals. [who.int Tuberculosis: 14th October 2021]
Aetiology
The causative agent of tuberculosis is mycobacteria, belonging to the family
Mycobacteriaceae and the order Actinomycetales. Mycobacteria tuberculosis complex
includes Mycobacterium bovis, Mycobacterium africanum, Mycobacterium pinnipedii and
Mycobacterium canetti. Out of these, Mycobacterium tuberculosis is the causative agent
in 99% of confirmed cases.
Mycobacteria are rod-shaped, non-spore forming, aerobic, slow growing bacteria.
They do not get stained easily, but once stained, they do not get decolourised. So, they
are classified as AFB or acid-fast bacteria.
Pathogenesis
Inhalation of droplet nuclei containing the causative microorganism Mycobacterium
tuberculosis leads to human-host interaction. The bacilli are expelled by the mucus and
ciliary mechanisms in the respiratory tract. About 10% of the bacilli reach the alveoli
of the lungs. This may lead to the development of infection depending on the
virulence of mycobacteria and the immunity of the person. Macrophages help in the
phagocytosis of the bacilli. In case the bacilli persist, they divide slowly, and lysis of
the macrophages leads to the release of the bacilli.
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Textbook of Pharmacotherapeutics
Two more immune responses are carried out by the host cell to inhibit the growth
of the bacilli. This balance host immune responses determine the development of the
form of the TB.
The lymphocytes and macrophages lead to the formation of granulomatous lesions,
also called tubercles. The lesions may undergo fibrosis, calcification, and heal. A few
other lesions may undergo progression.
The bacilli are transported to the regional lymph nodes during the early stages of
infection. The bacilli may spread to other parts of the body through the bloodstream
and lymphatic system. They divide in spleen, kidneys, bone, meninges, and apical
region of lungs.
Clinical disease is seen due to failure of control of mycobacterial replication
following initial infection (progressive primary TB) or when latent organisms
overcome immunological control of the host (reactivation TB).
Risk
1. People with comorbidities
2. HIV positive patients
3. Silicosis
4. Chronic renal failure
5. Haemodialysis
6. Malignancy of blood like leukaemia or lymphoma
7. Solid organ transplantation
8. Gastrectomy
9. Staying in areas with high TB incidence
10. Close contact with TB patients mainly with sputum smear positive pulmonary
TB
Clinical Manifestations
Tuberculosis is classified as pulmonary or extrapulmonary TB or both.
Pulmonary Tuberculosis
The symptoms and signs of tuberculosis are:
• Cough for more than three weeks, which is initially non-productive and later with
purulent sputum
• Fever with night sweats
• Weight loss
• Anorexia
• Weakness and tiredness
• Haemoptysis may be seen in cases of severe pulmonary TB.
Extrapulmonary Tuberculosis
Disseminated or extrapulmonary TB may occur at sites other than the lungs, like
lymph nodes, pleural cavity, urinary tract, bones, joints, spine, peritoneum,
pericardium, or meninges.
Infectious Disorders
95
Drug-resistant TB
MDR TB, also known as multi-drug resistant TB, is caused by bacteria resistant to at
least isoniazid and rifampicin, which are considered the most effective anti-TB drugs.
XDR TB (extensive drug resistant TB) is caused by mycobacteria resistant to isoniazid
and rifampicin as well as to any fluoroquinolones and any of the anti-TB injectable drugs
used in second-line treatment of TB like amikacin, kanamycin, or capreomycin.
The mechanisms by which resistance develops in TB are as shown in Table 8.1.
Table 8.1: Mechanisms of mycobacterial resistance
Mycobacterial resistance
1 Thick waxy hydrophobic cell wall prevents entry of drugs
2 Drugs affecting metabolic processes cannot act on dormant mycobacteriae
3 Enzyme alteration leads to blocking conversion of prodrug to active form (pyrazinamide,
isoniazid)
4 Target protein structure alteration prevents drug recognition (rifamycin, ethambutol,
streptomycin, fluoroquinolones, macrolide)
5 DNA repair genes mutations lead to multiple drug resistance
6 Drug expelled from bacteria before it reaches target (streptomycin, ethambutol, isoniazid)
7 Lowering of pH makes the drug inactive (streptomycin)
Non-pharmacological Management
Prevention and Patient Counselling
Use of vaccine
Bacillus Calmette-Guérin (BCG) vaccines are live attenuated strains of M. bovis. The
route of administration for the BCG vaccine is the intradermal method. This vaccine
was first introduced to humans in the early 1920s. The efficacy of vaccines varies and
ranges from 0 to 80%.
In India, the BCG vaccine is included in the national immunisation schedule and is
administered to neonates at birth.
Patient education
Patient counselling helps in reducing the transmission rates of TB and helps in the
complete treatment of TB patients.
TB requires treatment with the help of combination therapy, which includes three
or more drugs. Also, the treatment lasts for a long duration, consisting of a minimum
of six months of combination therapy. This leads to many cases of non-adherence and
noncompliance by the patients. Some patients stop the medication after a few months
as they start feeling better. This leads to the development of resistance. All the patients
need to be advised to complete the full course of the medicine and that discontinuing
the course midway may lead to the development of resistance in bacteria and the
development of MDR TB and XDR TB. Also, the infectious TB patients should be
advised to take the medicine every day at a particular time, as missing a dose may lead
to the development of resistance.
All these issues need to be addressed by the healthcare provider.
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Textbook of Pharmacotherapeutics
Counselling tips should also include information regarding the harmless discolouration
of body fluids, including urine, by rifampicin. Oral contraceptive pills for women
should be avoided during rifampicin treatment and for eight weeks afterwards as it
reduces the effectiveness of hormonal contraceptives. Patients should be advised to
consult the physician in case of any changes in vision during ethambutol therapy.
Pharmacological Management
The development of anti-TB agents started with streptomycin during the 1940s; later,
isoniazid and para-amino salicylic acid were combined with streptomycin in the
regimen.
The current treatment for TB uses a combination of agents in order to eliminate all
forms of mycobacteria (extracellular organisms) from the sputum, decrease infectivity,
and destroy slow dividing organisms within macrophages and granulomas. The
treatment regimen consists of two months of the initial phase and the next four months
of the continuation phase.
The drugs used for the treatment of TB are divided into:
• First-line drugs: Examples, isoniazid, rifampicin, pyrazinamide, ethambutol.
• Second-line drugs: These reserve drugs have a higher level of toxicity and a lower
level of efficacy. Examples are streptomycin, capreomycin, amikacin, para-amino
salicylic acid, cycloserine, and fluoroquinolones.
First-line Agents
Isoniazid
Also called nicotinic acid hydroxide, INH is the first-line most widely used drug
against TB. The advantages of this drug are that it is bactericidal in nature, relatively
non-toxic, economical, and well absorbed when given orally or parenterally. INH is
available in various dosage forms like tablets, syrups, and parenterals given as
intravenous or intramuscular injections.
The adverse reactions of isoniazid are hepatitis, peripheral neuritis, aplastic
anaemia, GI effects, hypersensitivity of skin, and CNS toxicity like hallucinations and
convulsions.
Rifamycins
Rifamycins are a group of broad-spectrum antibiotics consisting of rifampicin,
rifabutin, and rifapentine.
Rifampicin is a bactericidal for Mycobacterium tuberculosis as it shows synergism
with INH. Rifampicin is available in the form of capsules and an aqua solution as a
parenteral.
The adverse reactions of rifampicin are effects on the functioning of the liver, skin
reactions, gastrointestinal reactions, thrombocytopenic purpurea, fever, and chills. It
also imparts a reddish-orange colour to body fluids and urine.
Pyrazinamide
Pyrazinamide is a bactericidal drug against mycobacteria in an acidic pH. It is a
synthetic pyrazine analogue of nicotinamide. Pyrazinamide has been added to the
initial therapy of tuberculosis treatment along with INH and rifampicin.
Infectious Disorders
The adverse reactions are anorexia, nausea, flushing, hepatitis, vomiting, arthralgia,
hyperuricaemia, dysuria, and skin hypersensitivity.
97
Ethambutol
Ethambutol is a bacteriostatic anti-TB agent. This is a synthetic agent which interferes
with the mycobacterial cell wall formation. It is usually targeted towards actively
dividing tubercle bacillus.
The adverse reactions of ethambutol include optic neuritis, headache, gastrointestinal
intolerance, hyperuricaemia, and arthralgia.
Second-line Agents
Streptomycin
Streptomycin was the first drug introduced for the treatment of tuberculosis. It is an
aminoglycoside bactericidal in an alkaline medium. It acts by inhibiting protein
synthesis. The route of administration recommended is intramuscularly, as it is poorly
absorbed from the GIT. An intravenous route is another alternative.
The major toxic effect of streptomycin is ototoxicity, mainly affecting the body
balance, resulting in vertigo and ataxia. Hearing loss may also occur. Other side effects
include hypersensitivity, fever, and kidney dysfunction.
Capreomycin, Kanamycin, and Amikacin
These are injectable aminoglycoside antibiotics that are used in combination
with other anti-TB drugs. The adverse reactions are ototoxicity and kidney
dysfunction.
Para-amino Salicylic Acid
Para-amino salicylic acid (PAS) is a structural analogue of para-amino benzoic acid
(PABA). It is a tuberculostatic agent. The usual dose of PAS in adults and children is
150 mg/kg orally. The adverse effects of PAS are related to the gastrointestinal tract,
like nausea, vomiting, anorexia, diarrhoea, and epigastric pain.
Ethionamide
Ethionamide is an oral agent used in the second-line treatment of tuberculosis. It is
given in a daily dose of 15 to 20 mg/kg with a maximum dosage of 1 g per day.
The common side effects include anorexia, nausea, and vomiting. Other adverse effects
are arthralgia, impotence, photosensitivity, dermatitis, hepatitis, hypothyroidism, and
metallic taste in the mouth.
Cycloserine
Cycloserine acts by inhibiting the synthesis of the bacterial cell wall. It is available in
250 mg capsules. The usual adult dose is 10 to 15 mg/kg per day, given in two divided
doses. The common adverse effects are headache, psychosis and seizures.
Fluoroquinolones
Levofloxacin, moxifloxacin and gatifloxacin exhibit activity against Mycobacterium
tuberculosis and may be used in drug resistant TB.