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Textbook of Pharmacotherapeutics
bone fractures. Constipation can be avoided with a high-fibre diet and adequate
hydration. Support groups are an excellent source of educational, emotional, and
social support for such patients. Examples include the Parkinson’s Disease and
Movement Disorder Society of Mumbai and the Parkinson’s Disease Patient Welfare
Society of Kolkata.
Pharmacological Management
Levodopa: This has been the most effective drug in the treatment of Parkinson’s
disease. After entry into the peripheral circulation, levodopa crosses the blood–brain
barrier (BBB) where it is taken up by the dopaminergic neurons of the substantia nigra
and converted into dopamine by the enzyme dopa decarboxylase, which is then
released to act on dopamine receptors in the striatum.
Carbidopa is a reversible dopa decarboxylase inhibitor (DCI) that does not cross the
BBB. When administered in the absence of a DCI, levodopa undergoes significant
peripheral metabolism to dopamine, which is undesirable as dopamine cannot cross
the BBB.
Hence, levodopa is commonly used in combination with a DCI like carbidopa
or benserazide. The usual starting dose is 50 mg of levodopa with 12.5 mg of
carbidopa given 3 times a day. The dose is then gradually increased till maximum
benefit is achieved without serious toxicity; this may be 500–1000 mg daily in 3–4
divided doses. Carbidopa 75–100 mg per day is needed for maximum enzyme
inhibition.
Nausea, vomiting, anorexia, postural hypotension, and palpitations are some of the
early adverse drug reactions of levodopa. Behavioural and CNS effects occur during
prolonged treatment. Behavioural side effects include agitation, confusion,
restlessness, hallucinations, delusions, and depression. Parkinsonian patients suffer
from insomnia. The major drawback of long-term levodopa treatment is the
occurrence of dyskinesias involving involuntary choreiform movements and rapid
fluctuations in motor strength.
Dopamine agonists (DA) like bromocriptine are used even though they have limited
efficacy. About 1/3 of the patients have a good response to these drugs and may not
need levodopa for 3–5 years. Their disadvantage is that the patients do not have
fluctuations or dyskinesias till levodopa is added. However, with prolonged use, their
effect is reduced. Other dopamine agonists approved are pergolide, pramipexole, and
ropinirole.
Amantadine is used in patients with mild PD. It can also be used as an
adjunct in patients who cannot tolerate levodopa. Selegiline is an irreversible
enzyme inhibitor with relative selectivity for MAO-B. It is associated with a
delay in the need for levodopa, slowed disease progression, and extended
employability.
Entacapone and tolcapone are peripheral COMT inhibitors when given with
levodopa and DCI formulations are useful for reducing wear-off symptoms and total
daily levodopa intake.
Surgery: Thalamotomy, pallidotomy, and deep-brain stimulation with implanted
electrodes may benefit patients under 50 who suffer from severe symptoms
unresponsive to drug therapy.
Disorders of Central Nervous System
69
KEY POINTS
• Parkinson’s disease is the second most common degenerative disease after Alzheimer’s disease.
• It is characterised by tremors, rigidity, akinesia or dyskinesia, and postural instability.
• Non-pharmacological interventions include education, physical therapy, speech therapy, and nutrition.
• Levodopa-carbidopa combination is the most effective treatment for Parkinson’s disease.
5.3 ALZHEIMER’S DISEASE
Alzheimer’s disease is a chronic, progressive, degenerative non-psychiatric disorder
of the brain that leads to disturbances in thinking, memory, judgement, and
orientation. It is characterized by cognitive deficit and infirmity with no effect on
consciousness.
Aetiology
The aetiology of Alzheimer’s disease (AD) is unknown, but there is a genetic
predisposition. The major biochemical abnormality observed in AD is a reduction in
the enzyme choline acetyltransferase (any enzyme responsible for the synthesis of
acetylcholinesterase) in the cerebral cortex and hippocampus. This results in
decreased central cholinergic transmission, which has a strong correlation with a
decline in mental status scores and abnormal symptoms. There is a deficiency of other
neurotransmitters like somatostatin and norepinephrine in patients with AD. It is
believed that the deposition of -amyloid protein inside neuronal cells and
extracellularly causes synaptic dysfunction and neuronal cell death.
Pathogenesis
Two important histopathologic features of Alzheimer’s disease are an increase in
neuritic plaques and a high density of neurofibrillary tangles. Neuritic plaques are
small spheres containing amyloid -protein which is a fragment of abnormally
phosphorylated protein (APP). Overproduction of APP leads to a build-up of
-amyloid protein, which is toxic to neurons. Neurofibrillary tangles are abnormal
neurons containing bundles of paired helical filamentous structures wound around
each other in the cytoplasm. Due to abnormal chemical changes, the tau proteins
detach from microtubules and stick to other tau molecules, forming threads that
eventually join to form tangles inside neurons. These tangles interfere with nerve cell
functioning.
Clinical Manifestations
Deterioration of short-term memory, impaired ability to learn new information or to
remember previously learned information, language dysfunction (aphasia), e.g.
difficulty finding words, increased difficulty with names and understanding what is
being said, impaired ability to carry out motor functions (dyspraxia), failure to
recognise or identify objects (agnosia), inability to draw and recognise two- or threedimensional figures are the main features. The patients may have difficulty driving,
using a telephone, and taking medications as prescribed. With progress in the disease,
there may be an increase in agitation, mood disturbances, delusions, and paranoia. The
disease leads to depression.
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Textbook of Pharmacotherapeutics
Non-pharmacological Management
There should be minimal changes in the patient’s environment. The items should be
labelled to make things simple for the patients as their memory is affected. Caregiver
training is important. Caregivers must understand the limitations of the patient’s
cognitive abilities and how that affects the patient’s behaviour. Incidents that can lead
to agitation should be minimized. Families must be educated about the progression of
the disease and the expectations of treatment. Alzheimer’s and Related Disorders
Society of India (ARDSI) provides services like caregiver meetings, counselling,
caregiver training, etc.
Pharmacological Management
There are two types of medications used to treat AD. The most frequently used
medications are symptomatic and used to control unwanted behavioural changes. The
other category is to slow disease progression, in which two cholinesterase inhibitors
have been approved to treat mild to moderate AD.
Symptomatic treatment: Antipsychotics such as risperidone or olanzapine are used
to treat agitation, hallucinations, and delusions. Sedating antidepressants like
trazodone can also be used for their calming effects. Hypnotics such as zolpidem and
temazepam may help treat insomnia. Anxiolytics such as clonazepam or lorazepam
are used for anxiety.
Cholinesterase inhibitors such as tacrine and donepezil are most extensively used
for the treatment of Alzheimer’s disease. They show a slight improvement in mental
status, a slowing of progression, and a reduction in behavioural changes. The side
effects include nausea, vomiting, insomnia, fatigue, and muscle cramps.
KEY POINTS
• Alzheimer’s disease is a chronic, progressive, degenerative non-psychiatric disorder of the
brain.
• It is characterized by cognitive deficit and infirmity with no effect on consciousness.
• Families must be educated about the progression of the disease and the expectations of
treatment.
5.4 STROKE
A stroke is defined as a focal neurological deficit due to a vascular lesion lasting longer
than 24 hours. When the blood supply to part of the brain is diminished, the brain
tissue is deprived of oxygen and nutrients. Within minutes, brain cells begin to die.
Pathophysiology
The common causes are:
• Arterial embolism from a distant site and subsequent brain infarction
• Atheromatous plaques within the carotid artery or vertebral artery
• Atheromatous arterial thrombosis within a cerebral vessel and subsequent brain
infarction
• Haemorrhage into the brain
• About 85% of the strokes are ischaemic and 15% are due to haemorrhages.
Disorders of Central Nervous System
71
Clinical Manifestations
Paralysis, numbness or weakness in the arm, face, and legs, especially on one side of
the body, difficulty speaking or understanding speech, confusion, slurring speech,
vision problems, such as trouble seeing in one or both eyes with vision blackened or
blurred, or double vision, difficulty walking, loss of balance or coordination,
dizziness, and severe, sudden headache with an unknown cause are the symptoms
of stroke.
Non-pharmacological Management
The following measures generally reduce the incidence of stroke:
• Treatment of hypertension
• Smoking cessation
• Active lifestyle
• Avoiding alcohol consumption
• Reduction in LDL cholesterol
• Anticoagulation in atrial fibrillation
Pharmacological Management
Antihypertensive therapy: Control of high blood pressure is the single most important
factor in primary stroke prevention.
Antiplatelet therapy: Aspirin (75 mg daily) reduces platelet aggregation, which
reduces further infarction after stroke. The combination of aspirin 75 mg and
dipyridamole 200 mg twice daily is the best combination for the long-term reduction
of further strokes.
Anticoagulants: Heparin and warfarin should be given when there is atrial
fibrillation.
Surgical procedures like internal carotid endarterectomy are used for patients
with internal carotid artery stenosis that narrows the arterial lumen by more than
70%.
Physiotherapy and speech therapy have an important role in the rehabilitation of
patients with stroke.
KEY POINTS
• A stroke is defined as a focal neurological deficit due to a vascular lesion lasting longer than
24 hours.
• Paralysis, numbness or weakness in the arm, face, and legs are some of the symptoms.
• Control of high blood pressure is the single most important factor in primary stroke prevention.
5.5 MIGRAINE
Migraine is a paroxysmal disorder with attacks of headaches, nausea, vomiting,
photophobia, and malaise. There are episodes of unilateral or bilateral throbbing
headaches that are triggered by factors like food (chocolate, cheese), menstruation, or
stress. It is common among females.
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Textbook of Pharmacotherapeutics
Pathophysiology
The exact mechanism of migraine attacks is not known. It is believed that migraine
headaches are caused by vasodilation of meningeal blood vessels with stimulation of
trigeminal nerve endings, which release vasoactive neuropeptides within the
meninges. These peptides lead to vasodilation, mast cell degranulation, and vascular
leakage, resulting in neurogenic inflammation and pain. Calcitonin gene-related
peptide (CGRP), substance P (SP), and neurokinin A (NKA) are the mediators released
due to the stimulation of trigeminal nerves. CGRP causes vasodilation, whereas SP
and NKA cause vascular leakage and mast cell degranulation.
Clinical Manifestations
Prodrome, aura, attack, and postdrome are the four stages of migraine (not everyone
goes through all the stages). The changes that are observed one or two days before the
migraine are the prodromal symptoms, which include constipation, mood changes,
food cravings, neck stiffness, increased urination, or frequent yawning.
For some people, an aura might occur before or during migraines. Examples of
migraine auras include visual phenomena, such as seeing various shapes, bright spots
or flashes of light, pins and needles sensations in an arm or leg, weakness or numbness
in the face or one side of the body, or difficulty speaking.
During a migraine attack, there is throbbing pain, usually on one side but often on
both sides. There could be sensitivity to light and sound, as well as nausea and
vomiting. After a migraine attack (postdrome), the person feels drained and confused.
Non-pharmacological Management
Prevention of migraine attacks can be achieved by:
• Avoiding the precipitating factors like stress, loud noise, bright light, certain foods,
and hypoglycaemia.
• Using the right behavioural approach, in which the patient is educated about the
causes of attacks and their avoidance, and leading a healthy lifestyle.
Pharmacological Management
During an attack: Paracetamol (500 mg) or other analgesics like aspirin (300–600 mg)
should be given with an antiemetic like metoclopramide if required. Triptans (5-HT
agonists) like sumatriptan, zolmitriptan, and rizatriptan given orally, by subcutaneous
injection, or by inhalation, are highly effective in the treatment of acute attacks of
migraine. Ergotamine tartrate is also useful if given early.
Prophylaxis: Pizotifen, methysergide, and the tricyclic antidepressant amitriptyline
are effective for prophylaxis. Propranolol is used in patients with migraine attacks
related to stress.
KEY POINTS
• Migraine is a paroxysmal disorder with attacks of headaches, nausea, vomiting, photophobia, and malaise.
• Migraines are caused by vasodilation of meningeal blood vessels with stimulation of trigeminal
nerve endings.
• Prevention can be achieved by avoiding precipitating factors like stress, loud noise, bright light,
certain foods, and hypoglycaemia.
Gastrointestinal Disorders
73
Gastrointestinal
6
Disorders
6.1 GASTRO-OESOPHAGEAL REFLUX DISEASE
Gastro-oesophageal reflux disease (GERD) is defined as symptoms or complications
resulting from the refluxed stomach contents into the oesophagus or beyond into the
oral cavity including the larynx or lungs.
Aetiopathogenesis
Gastro-oesophageal reflux disease occurs mainly due to the abnormal reflux of gastric
contents from the stomach into the oesophagus oral cavity and maybe into the lungs.
Gastro-oesophageal reflux is associated with defective lower oesophageal sphincter
in certain cases.
Gastro-oesophageal reflux disease is classified as:
• Symptom based
• Tissue injury based
Abnormal reflux of gastric contents into the oesophageal, oral cavity or lungs may
lead to GERD. Oesophageal reflux is sometimes associated with low oesophageal
sphincter pressure.
Clinical Manifestations
Typical symptoms of symptom-based gastro-oesophageal reflux disease are
heartburn, regurgitation, belching, and reflux chest pain. Heartburn is the most
common symptom which is felt as a substernal sensation of warmth or burning rising
from the abdomen that may radiate to the neck.
Alarming symptoms indicative of complications of gastro-oesophageal reflux disease
such as Barrett’s oesophagus, oesophageal strictures, oesophageal adenocarcinoma
are dysphagia, odynophagia, bleeding, and weight loss.
The symptoms of tissue injury-based gastro-oesophageal reflux disease include
oesophagitis, strictures, Barrett’s oesophagus, oesophageal adenocarcinoma.
Extra-oesophageal and gastro-oesophageal reflux disease symptoms are chronic
cough, laryngitis, wheezing and asthma.
Non-pharmacological Management
Modification in lifestyle and anti-reflux surgery is recommended as non-pharmacological
treatment of gastro-oesophageal reflux disease. Earlier, endoscopic therapy and
endoluminal application of radiofrequency heat energy were used.
73
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Textbook of Pharmacotherapeutics
Fig. 6.1A to D: Endoscopic images of GERD (Courtesy: Dr Deepak Gupta, Gastroenterologist and
Hepatologist, Navi Mumbai)
Lifestyle Modifications
The approaches are eating smaller meals, sleeping after three hours of meals, avoiding
food and medication that exacerbate GERD, cessation of smoking, avoiding alcohol
and avoiding tight fitting clothes.
Obese patients are advised for weight loss programmes. There is an association
between body mass index, waist circumference and weight gain with the risk of
gastro-oesophageal reflux disease.
The lower oesophageal pressure decreases with a high fat meal. High-protein-low-
fat meal increases the lower oesophageal sphincter pressure thereby decreasing their
GERD symptoms and hence recommended. Certain foods like citrus juice, tomato
juice, coffee and pepper act as direct contact irritants to oesophageal mucosa. Hence,
these should be avoided. Chocolates decrease the lower oesophageal sphincter
pressure and should be avoided.
Medications that exacerbate GERD symptoms should be identified in patient
profiles. Certain medications act directly on the oesophagus mucosa as irritants and
others may decrease the lower oesophageal sphincter pressure. Alternative
therapies may be required if the condition of the patient worsens with the
medication.
Elevation of the head end of the bed is recommended for the patients. This helps
in decreasing the nocturnal oesophageal acid contact time.
Gastrointestinal Disorders
75
Smoking cessation helps as smoking can cause aerophagia, i.e. air swallowing
which leads to belching and regurgitation. Alcohol cessation also helps as alcohol
decreases the lower oesophageal sphincter pressure and may cause heartburn.
Interventional therapy: Anti-reflux surgery, endoscopic therapy and radiofrequency
ablation techniques may be used for the treatment of gastro-oesophageal reflux
disease.
Pharmacological Management
• Antacid and antacid-aligning acid products
• Non-prescription H
receptor antagonists and proton pump inhibitors
2
Antacids and Antacid-aligning Acid Products
Mild symptoms of gastro-oesophageal reflux disease can be controlled using antacids.
They provide immediate relief from symptoms and maintain the stomach pH greater
than four thereby decreasing the activation of pepsinogen to pepsin. This leads to
increase in lower oesophageal sphincter pressure.
Some antacid products are combined with alginic acid to form highly viscous
solution thereby acting as a protective barrier for the oesophagus.
Antacid dosages are difficult to derive, they have short duration of action and may
be required to be administered many times a day.
Non-prescription H2 Receptor Antagonists and Proton Pump Inhibitors
When taken prior to meals, H2 receptor antagonists like cimetidine, famotidine and
ranitidine are effective in decreasing the gastric acid secretion.
Proton pump inhibitors like esomeprazole, omeprazole, lansoprazole are used for
short-term treatment of heartburn.
Acid Suppression Therapy
Proton pump inhibitors: These drugs are used in the treatment of moderate to
severe gastro-oesophageal reflux disease. Proton pump inhibitor acts by blocking
+/K+
the creation of gastric acid by inhibiting the H
adenosine triphosphatase in the
gastric parietal cells. The gastric pH is maintained at greater than four and this effect
is long-lasting even during postprandial gastric secretion. The healing is seen in 4 to
8 weeks. So, drugs should be given 30 to 60 minutes prior to breakfast or before the
biggest meal of the day to maximise efficacy. The proton pump inhibitors get
degraded in acidic environment. So, it is formulated in the delayed release capsule
or tablet form. Examples are omeprazole, pantoprazole, rabeprazole, lansoprazole
and esomeprazole.
H2 Receptor Antagonists
Mild to moderate GERD can be treated with H2 receptor antagonists administered in
divided doses. Examples are cimetidine, famotidine, ranitidine, etc. H
antagonists have variable efficacy. The response to H
receptor antagonist is
2
dependent on severity of disease, dosage regimen and duration of therapy.
The common adverse effects are headache, dizziness, fatigue and diarrhoea or
constipation.
receptor
2
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Textbook of Pharmacotherapeutics
Promotility Agents
These agents can be used as an adjunct to acid suppression in patients with known
motility defect.
Metoclopramide
This is a dopamine antagonist which increases the lower oesophageal sphincter
pressure. It also helps in faster gastric emptying. Metoclopramide provides
symptomatic relief to GERD patients.
Combination Therapy
Combination of acid suppression agent, a promotility agent or mucosal protectant
may help in GERD therapy.
Maintenance Therapy
Relapse is seen in patients with GERD when medication is withdrawn. Therefore, a
long-term maintenance treatment is needed. Drug of choice for maintenance therapy
in patients with moderate or severe GERD disease or other complications is a proton
pump inhibitor. Table 6.1 shows the recommendations for pharmaceutical care in
GERD.
Table 6.1: Recommendations for pharmaceutical care
S. No Assessment of the patient’s condition to determine if patient directed therapy is appropriate
1 Patient history: All drugs being taken by the patient is noted
2 Counselling of patient on lifestyle modifications to improve symptoms
3 Appropriate drug therapy recommended
4 Effectiveness of acid suppression therapy after 8 to 16 weeks assessed
5 Alternative therapy, if necessary, recommended
6 Adverse drug reactions, allergies, drug interactions evaluated
7 Patient educated regarding compliance of therapeutic regimen, lifestyle modification, etc.
KEY POINTS
• Gastro-oesophageal reflux disease is defined as symptoms resulting from the refluxed stomach
contents into the oesophagus or into the oral cavity including the larynx or lungs.
• Gastroesophageal reflux disease is of two types—symptom-based and tissue injury based.
• Heartburn, regurgitation, belching, and reflux chest pain are seen as symptoms.
• Lifestyle modifications may help control the symptoms.
• Pharmacological treatment includes antacid and antacid-aligning acid products, H
antagonists and proton pump inhibitors.
receptor
2
6.2 PEPTIC ULCER DISEASE
An ulcer is a disruption in the integrity of the gastric or duodenal mucosa >5 mm size
up to sub-mucosa layer leading to local defect due to inflammation.
Gastrointestinal Disorders
77
Peptic ulcer disease are ulcers which occur due to exposure of the GIT to acid for a
particular duration and concentration.
Aetiopathogenesis
The risk factors for peptic ulcer disease are Helicobacter pylori infection, stress and longterm use of NSAIDs. The less common risk factors are Zollinger-Ellison syndrome,
viral infections, radiation therapy and chemotherapy.
H. pylori is a Gram-negative bacterium which is micro-aerophilic and urease
producing; commonly found in the stomach or duodenum. H. pylori is transmitted
person to person by faecal-oral route. People who acquire H. pylori are usually of lower
social economic status. It may get transmitted within the household. It also depends
on the country of origin. H. pylori infection may increase complications of GIT and
chances of development of peptic ulcer disease.
Non-steroidal anti-inflammatory drugs have been linked to peptic ulcer disease.
The dose, duration of use and type of NSAIDs may affect the ulcers.
Other risk factors include hypersecretory conditions in the stomach where large
quantities of gastric acid may affect the body’s normal defence mechanisms. Smoking
and genetic factors are also considered as risk factors for peptic ulcer disease.
The risk factors combined with the caustic effects of gastric acid and pepsin disrupts
the normal GI mucosa.
Clinical Manifestations
Mild epigastric pain is observed. There are certain life-threatening acute upper
gastrointestinal complications like GI bleeding, perforation and obstruction. Other
symptoms include burning sensation in the GIT, vague discomfort, cramping
and feeling full. Nocturnal pain usually between midnight and 3 am may awaken the
patient due to discomfort.
The symptoms vary from patient to patient and even in different seasons. Episodes
of discomfort may be continuous for few weeks and then pain-free period may be
there. Hard belching, bloating, nausea, vomiting and anorexia are seen.
The signs of peptic ulcer disease are weight loss associated with nausea, vomiting
and anorexia. Complications include ulcer, bleeding, perforation, penetration and
obstruction.
Non-pharmacological Management
Peptic ulcer disease patients should eliminate smoking, use of non-steroidal antiinflammatory drugs including aspirin, and psychological stress. The patients should
also avoid spicy food, caffeine and alcohol that cause dyspepsia and exacerbate the
symptoms of ulcers.
New technique of endoscopic procedures like use of mechanical clips, coagulation
forceps and burnout methods are being utilized.
Pharmacological Management
• Proton pump inhibitors
receptor antagonists
•H
2
• Bismuth compounds
• Sucralfate