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Textbook of Pharmacotherapeutics
chemotaxis of inflammatory mediators and may inhibit release of inflammatory
neuropeptides which induce bronchoconstriction. They are normally referred for mild
persistent asthma as initial anti-inflammatory therapy in children.
Leukotriene modifiers: Leukotrienes are released from inflammatory cells in the
airway and interact with specific receptors. This leads to bronchoconstriction, airway
hyperresponsiveness, increased microvascular permeability leading to oedema,
leukocyte activation, eosinophilia, and enhanced mucus secretion. Leukotriene
modifiers block these leukotriene mediated effects. They are administered orally.
Zileuton, zafirlukast and montelukast are examples of this category of drugs.
Corticosteroids
• Systemic corticosteroids: These are reserved for severe persistent asthma and acute
exacerbations. Corticosteroids can inhibit microvascular leakage and reduction
in bronchial hyperresponsiveness. Prednisolone, methylprednisolone and
dexamethasone are commonly used corticosteroids.
• Inhaled corticosteroids: Inhaled corticosteroids are recommended for all patients
with persistent asthma and dosages are based on level of asthma severity.
Budesonide, beclomethasone, fluticasone and their salts are widely used to improve
inflammation and bronchial hyperresponsiveness characteristics of asthma. They
can be administered by using MDI (metered dose inhaler) and DPI (dry powder
inhalers).
KEY POINTS
• Asthma is characterized by airway inflammation and bronchoconstriction
• Asthma attack can be initiated with various triggers which can be avoided or controlled
• Pharmacological therapy includes use of bronchodilators and anti-inflammatory agents
• Patients’ education and encouragement is integral part of asthma therapy
3.2 COPD
Chronic obstructive pulmonary disease (COPD) is a condition in which partially
reversible airflow limitation is observed. The airflow restriction is usually progressive
and associated with an abnormal inflammatory response of the lungs to the noxious
particles or gasses. It covers several separate and distinct sets of pathological changes
including asthma, bronchitis and emphysema.
In asthma, narrowing of the airways is observed as a result of bronchial hyperreactivity,
excessive bronchial secretions, and airway inflammatory changes. Airflow obstruction
is normally reversible.
Chronic bronchitis can be defined as chronic or recurrent excess mucus secretion
into the bronchial tree.
Emphysema is abnormal permanent enlargement of the air spaces distal to the
terminal bronchioles along with destruction of its wall.
Aetiopathogenesis
The major risk factor associated with COPD is tobacco or cigarette smoking. Passive
smoking can also be associated with the development of COPD. Other contributing
Disorders of Respiratory System
Fig. 3.1:Fig. 3.1:
Fig. 3.1: Chronic bronchitis
Fig. 3.1:Fig. 3.1:
49
Fig. 3.2:Fig. 3.2:
Fig. 3.2: Emphysema
Fig. 3.2:Fig. 3.2:
factors could be environmental factors such as pollution and occupational exposure
to chemical fumes, irritants, dust or gasses. Exposure of the noxious particles leads to
inflammatory response in the lungs. Smokers have increased bronchial reactivity and
inflammation. Their ciliary function in the lungs is also depressed, which results in
decreased clearance of mucus and particles. Additional factors are age, gender and
genetic factors. Increasing age results in ventilatory impairment, most frequently
related to chronic smoking. Currently men are at high risk of developing COPD as
compared to women.
In COPD normal exchange of gases in the airway is impaired in several ways.
Peripheral airways get blocked with pathological increase in goblet cells (simple
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Textbook of Pharmacotherapeutics
columnar epithelial cells which secrete mucus) and in inflammatory cells in the airway
walls. Fibrosis also develops along with increased deposition of collagen in the air
walls. In emphysema as elastases destroy elastin, it results in dilation and destruction
of respiratory bronchioles and alveolar sacs and ducts. This leads to loss of alveolar
wall attachments and peripheral airway collapse. Hypoxia causes changes in
pulmonary vasculature. The inflammatory cells like macrophages and lymphocytes
get infiltrated on the vessel walls which lead to pulmonary hypertension. These
inflammatory cells release inflammatory mediators and cytokines. Over a period of
time the action of these mediators damages the lungs. It also has been observed that
imbalance between proteinases and antiproteinases leads to lung destruction.
Oxidative stress also leads to COPD.
Clinical Manifestations
Bronchitis begins with morning chronic cough with heavy sputum production.
Patients may feel fatigue and there will be decline in exercise tolerance. In emphysema
there will be minimal cough with minimal sputum production but the patient feels
dyspnoea. These patients are observed with prolonged expiratory efforts as a result
of airway obstruction. Weight loss may be observed in patients with primary
emphysema however chronic bronchitis patients are quite obese. Grunting sound can
also be heard during inspiration. Increase in the respiratory rate and wheezing sounds
in the bouts of airway obstruction are observed in both.
As the disease progresses other acute and chronic complications may develop. The
patient with predominant chronic bronchitis may experience repeated episodes of
respiratory failure. Further they may develop cor pulmonale and right-sided
congestive heart failure. The patients with COPD show decreased FEV1, decreased
FVC and increased residual volume in pulmonary function tests. FEV is forced
expiratory volume while FEV1 is the amount of air one can force from the lungs in one
second. FVC stands for forced vital capacity. It is the total amount of air exhaled
during the lung function test.
Non-pharmacological Management
Pulmonary Rehabilitation
Pulmonary rehabilitation can be achieved by following means:
• Advice and support to stop smoking
• Aerobic exercise training to improve exercise tolerance
• Relaxation techniques
• Breathing exercise training
• Counseling about their medicines, nutrition, self-management of the disease and
lifestyle changes
• Psychological support as COPD patients cannot participate much in social activities,
which makes them anxious, depressed and fatigued
Smoking cessation
Smoking is the major contributing factor in the development of COPD. To give up
smoking, requires self-motivation. Patients who smoke can be educated on the health
hazards of smoking and should be encouraged and motivated to quit smoking.
Smokers need both initial guidance from healthcare professionals and follow-up
Disorders of Respiratory System
51
support. In initial stages symptoms like coughing may increase after cigarettes are
stopped. In such cases there are chances of returning to the habit, hence close support
is required to avoid such return. Therapeutic help can also be provided to stop
smoking which includes nicotine replacement therapy (NRT), bupropion, varenicline.
Nicotine replacement can be achieved by various formulations such as patches, gums,
sublingual tablets, lozenges, inhalers and nasal sprays. Bupropion was originally
used as an antidepressant but proven effective in cessation of smoking, but it is
contraindicated in certain medical conditions and under the age of 18. Varenicline
reduces the symptoms of craving and withdrawal. Combination therapy of bupropion
and varenicline (with each other or with NRT) is not recommended.
Surgery
Lung volume reduction surgery (LVRS) is a surgical procedure where emphysematous
lung tissues are removed. This helps to maintain the same ventilatory pressure. The
other surgical option is lung transplantation but access to organ donors is the common
barrier for this.
Pharmacological Management
Aim of the treatment of COPD is preventing the disease progression, relieving
symptoms and improving patients’ quality of life.
Anticholinergic agents: First-line therapy for COPD starts with anticholinergic
agents. Anticholinergic drugs inhibit bronchoconstriction by preventing formation of
cyclic GMP. Atropine and its analogue, ipratropium bromide are commonly used by
inhalation route. Adverse effects associated with them are dry mouth, blurred vision,
tachycardia, bitter taste, cough and nausea.
Sympathomimetics: Sympathomimetics or -agonists are used to control dyspnoea
and improve exercise tolerance. These drugs cause airway smooth muscle relaxation
by activating adenyl cyclase and increasing levels of cAMP. Earliest -agonists like
ephedrine and isoproterenol are now replaced by newer, safer, -agonists such as
terbutaline, albuterol, bitolterol, salmeterol and pirbuterol, etc. They are highly
specific and show reduced adverse reactions. All of them are available for inhalation.
Methylxanthines: Earlier theophylline was the mainstay of bronchodilator therapy
in COPD patients, but now it is used for its benefit in management of chronic COPD,
especially if bronchoconstrictive components can be identified. When it is given along
with anticholinergics, it produces additive bronchodilation.
Corticosteroids: In the treatment of COPD, inhaled corticosteroids have limited use
but still they are used frequently. Fluticasone and budesonide are potent drugs and
are available in convenient dosage form. Oral corticosteroids can improve baseline
FEV1 and subjective improvement in exercise tolerance and dyspnoea are also
reported.
Antibiotics and vaccine: The symptoms like increased dyspnoea, increased sputum
volume and sputum purulence (change in colour of sputum from uncoloured to
yellowish-green) indicates the use for antibiotic treatment. Other benefits are
improved clinical outcomes, fewer therapeutic failures and more rapid recovery of
lung function. Commonly prescribed antibiotics are doxycycline, ampicillin or
amoxicillin, cephalosporins and cotrimoxazole. Quinolones, clarithromycin or
azithromycin and -lactamase inhibitor combination drugs can also be used.
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Textbook of Pharmacotherapeutics
Vaccination with pneumococcal and influenzae virus vaccines are normally
recommended for high-risk patients.
Oxygen therapy: Oxygen therapy can be given to patients with severe chronic
hypoxemia, cor pulmonale and nocturnal or exercise induced hypoxemia. Oxygen can
be administered by devices that allow ambulation or fixed devices. Long term oxygen
therapy improves survival rate in patients.
Mucolytics/expectorants: Use of mucolytics is beneficial in stable COPDs, if chronic
cough is productive of sputum.
KEY POINTS
• COPD is obstructive lung disease comprising of asthma, bronchitis and emphysema
• Risk factors for COPD includes tobacco smoke, occupational dust, chemicals
• Management of COPD includes prevention of disease progression and symptomatic relief.
• Pulmonary rehabilitation and support to the patient for cessation of smoking helps in COPD
therapy
Disorders of Endocrine System
53
Disorders of
4
Endocrine System
4.1 DIABETES
Diabetes mellitus is the most common chronic endocrine disorder. It is a complex
syndrome that affects multiple organ systems. It is a spectrum of disorders that is
characterized by hyperglycemia.
Aetiopathogenesis
Aetiologically diabetes can be classified into two major types:
• Type I or IDDM (insulin dependent diabetes mellitus) and type II or NIDDM (noninsulin dependent diabetes mellitus)
• Type I diabetes is caused by destruction of insulin producing -cells of islets of
Langerhans, of pancreas which ultimately results in absolute insulin deficiency. It
is developed at a young age (below 30). Patient requires extrinsic insulin for his/
her survival. Hardly 5 to 10% of diabetes patients are of type I diabetes.
• Type II diabetes is more common above the age of 40. These patients have some
degree of insulin resistance with variable insulin secretion. They may survive without
insulin supplement, with the help of oral hypoglycemic agents and lifestyle
modifications.
Apart from this, rare etiology of diabetes also includes genetic defects, diseases of
exocrine pancreas, endocrinopathies, drug induced, due to infections, or sometimes
gestational diabetes.
Aetiology of diabetes is still not completely understood. Numerous factors are
associated with it. Few of them are:
• Obesity
• Increasing age
• Emotional stress
• Autoimmune -cells destruction
• Endocrine diseases
• Drugs
It has been observed in intensive research that most of the type I patients have
circulating antibodies, islet cell antibodies (ICA) and insulin autoantibodies (IAA)
before type I diabetes develops. It results in absolute insulin deficiency.
Many type II diabetic patients have excessive insulin secretion and are obese. Along
with this they also have hypertension, dyslipidaemia and impared fibrinolysis.
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Textbook of Pharmacotherapeutics
Collectively it is termed as metabolic syndrome X. These patients are at risk of
cardiovascular diseases and may develop long-term diabetic complications.
Hyperinsulinemia causes decrease in insulin receptors, reduced insulin binding or
postinsulin-receptor signaling defects.
Clinical Manifestations
Type I and type II diabetes have similar symptoms but may vary in intensity.
Symptoms of type I diabetes are severe and have faster onset of action. It includes:
• Polydipsia
• Polyphagia
• Weakness
• Weight loss
• Dry skin
• Ketoacidosis
• Hyperglycaemia associated with glycosuria, proteinaemia, blurred vision, tingling
or numbness of the extremities, slow healing skin infections, itching, drowsiness,
and irritability.
Non-pharmacological Management
Diabetes is a lifelong disease which can be controlled with proper education of patients
and adherence to the instructions given by the healthcare team members. Patients
should be educated on nutrition, physical activity, weight loss, smoking cessation and
limiting alcohol intake.
Diet
Dietary advice for diabetic patients includes:
• Regular meals with high-fiber containing food
• Choose low-fat dairy food
• Consume grilled, steamed or oven-baked food instead of frying or cooking with oil
or other fats
• Cut down on saturated fat, eat less butter, margarine, cheese
• Eat fresh fruits and vegetables every day
• Eat sugar-free or low-sugar products as it raises blood glucose levels quickly
• Consume less salt
• Drinking and smoking should be controlled
Physical Activity/Exercise
Physical activity/exercise has many health benefits, not only physical but also
psychological.
Exercise improves insulin sensitivity thereby facilitates glucose into the cells.
Exercise also penetrates glucose in muscle cells and allows its metabolism without
insulin. It also improves circulatory function, helps maintain normal body weight and
assists in breathing, digestion and metabolism.
Disorders of Endocrine System
55
Alcohol Restrictions
Alcohol can significantly alter blood glucose level. Pregnant women and patients with
a previous history of alcoholism should strictly avoid alcohol, if diagnosed with
diabetes. Other diabetic patients also restrict their alcohol consumption by considering
calorie content of the alcohol beverage. If consumed it should always be taken with
meals.
Long-term Diabetic Complications
Aetiology of macro- and microvascular complications is the same that arises from
atherosclerosis of the vessels which may lead to occlusion. Following are the risk
conditions commonly observed in diabetic patients:
• Macrovascular complications:
– Cardiovascular diseases
– Hypertension
• Microvascular complications:
– Retinopathy
– Nephropathy
– Peripheral neuropathy
• Micro- and macrovascular combined:
– Diabetic foot problems
However, these complications can be limited and sometimes prevented with early
diagnosis and good management of diabetes.
Pharmacological Management
Pharmacotherapy of diabetes includes insulin or oral hypoglycemic agents.
Insulin
All type I patients require insulin for their survival. Insulin may be categorized based
on its time activity profile as:
• Ultra-short acting
• Short acting
• Intermediate acting
• Long acting
Ultra-short acting insulin includes Humalog (insulin lispro) made by recombinant
DNA technology.
Short acting insulin includes semilente, regular and regular buffered insulin.
Regular and buffered insulin are clear and contain solubilized crystalline insulin.
Semilente is amorphous precipitate of insulin and zinc in the form of suspension. It
has slightly delayed onset and greater duration of action than regular insulin.
Intermediate acting insulins include NPH (neutral protamine hagedorn) and lente
insulin. NPH insulin contains suspension of zinc-insulin crystals and protamine. Lente
insulin is composed of a 30:70 mixture of semilente and ultralente.
The only long-acting insulin currently available is ultralente.
The most common adverse effects of insulin are hypoglycemia, lipohypertrophy,
and lipoatrophy.
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Textbook of Pharmacotherapeutics
Oral Hypoglycemic Agents
Five categories of the drugs can be used orally for type 2 diabetes patients.
• Sulphonylureas
• Biguanides
• -glucosidase inhibitors
• Thiazolidinediones
• Meglitinides
Sulphonylureas
Sulphonylureas exert both pancreatic and extrapancreatic effects but are useful only
in patients who have intact and functioning -cells. It increases insulin secretion
directly and decreases glucagon release. It also increases insulin receptor binding
affinity thereby increasing post receptor action and decreasing hepatic insulin
extraction, e.g. tolbutamide, chlorpropamide, glibenclamide, glipizide, glimepiride,
gliclazide
Biguanides
They reduce hepatic glucose production and glycogen metabolism in the liver and
enhance insulin-mediated glucose uptake by skeletal muscles, e.g. metformin
Metformin is the only biguanide widely used for diabetic patients. It is more useful
in overweight patients as it does not cause weight gain. In fact, loss of small amounts
of weight is observed in some patients. In the initial stage of treatment with metformin,
adverse effects like abdominal bloating, nausea, intestinal cramping and diarrhoea are
observed, but they subside with continued use.
-glucosidase Inhibitors
-glucosidase along with -amylase causes hydrolysis of complex carbohydrates.
Acarbose, which is a -glucosidase and -amylase inhibitor, reduces the rate of
carbohydrate metabolism and subsequent glucose absorption, thereby lowering
postprandial glucose excursion in diabetic patients. Acarbose is particularly effective
in patients with postprandial hyperglycemia.
Thiazolidinediones
Thiazolidinediones also known as glitazones, are insulin sensitizers which lower
glucose level by enhancing insulin action and reducing insulin resistance. It is mainly
active on skeletal muscles, liver and heart. Common example is pioglitazone, but it is
associated with weight gain and oedema. It should not be used in patients with preexisting heart failure.
Meglitinides
Meglitinide, also known as a postprandial glucose regulator, is an insulin releasing
agent. They have more rapid onset and short duration of action than sulphonylureas.
Adverse effects of meglitinide include hypoglycemia, visual disturbances, abdominal
pain, diarrhoea, constipation, nausea, vomiting and rarely hypersensitivity reactions,
e.g. repaglinide, nateglinide.
Disorders of Endocrine System
57
Combination Therapy
It has been observed in clinical studies that, if antidiabetic drugs are substituted, there
will be no increase in therapeutic effect. In fact, in many cases, glycemic control is
compromised. Hence combination therapy is more beneficial in type 2 diabetic
patients. Insulin requirement may be reduced when combined with oral agents like
sulphonylureas, acarbose, metformin, troglitazone and repaglinide.
KEY POINTS
• Diabetes is a common endocrine disease characterized by hyperglycemia
• Excessive secretion of insulin causes decrease in insulin receptors, their binding with insulin
• Insulin is required to treat type I diabetes while type II diabetes can be managed with oral
hypoglycemic agents alone or in combination
• Along with medicines, patient counseling also plays important role in diabetes management
4.2 THYROID DISORDERS—HYPO- AND HYPERTHYROIDISM
Thyroid is a small endocrine gland weighing around 20 grams or more in normal
adults and situated at the root of the throat. It is butterfly shaped and has two lobes. It
traps iodine from plasma and synthesises, stores and releases two hormones:
Triiodothyronine (T3) and tetraiodothyronine (T4). T4 is also called thyroxin. TSH
(thyroid stimulating hormone/thyrotropin) which is secreted by the anterior pituitary
gland and stimulates thyroid to synthesize and secrete T3 and T4. Hypothalamus,
which is a part of the CNS and not a gland, produces TRH, i.e. thyrotropin releasing
hormone that regulates release of TSH. When circulating levels of T3 and T4 go down,
release of TRH and TSH get initiated which in turn increases iodide (ionic state of
iodine) trapping and consequently synthesis of thyroid hormones. As feedback of
increasing levels of thyroid hormones TRH and TSH shuts off and prevents further
synthesis of thyroid hormones.
Hypothyroidism
Hypothyroidism is the condition where there is deficiency of thyroid hormones.
Thyroid cannot produce and release sufficient hormones. It is characterized by
decreased metabolism of all body systems.
Fig 4.1: Regulation of thyroid hormones