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Textbook of Pharmacotherapeutics
BMI =
height in m
2
Pharmacological Management
• Bile acid sequestrants or bile acid resins
• Ezetimibe
• Niacin
• Statins
• Fibric acid derivatives or fibrates
• Omega-3 fatty acids or fish oils
Bile Acid Resins
These resins exchange anion for bile acids in the intestine. They act as sequestrants for
cholesterol and do not allow it to get absorbed, helping in its excretion. In order to
maintain the bile acid pool size, the liver utilises cholesterol for the formation of bile
acids. This leads to upregulation of LDL and lowering of LDL cholesterol in the blood
due to decreased hepatic intracellular cholesterol. There are three drugs used as bile
acid resins. They are colestipol, cholestyramine, and colesevelam. These drugs lower
total cholesterol and LDL levels moderately by 15 to 30%.
The side effects of bile acid resins include gastrointestinal effects. The gastrointestinal
side effects observed are constipation, abdominal pain, bloating, heartburn, belching,
and nausea.
Since they are not absorbed, there are no systemic side effects. Therefore, these
drugs are safe to be used in children and women of childbearing age who are pregnant,
lactating or may become pregnant. The disadvantage of these drugs is that they are
required in high quantities to show their effect. Around 6 to 7 tablets of the drugs may
be required to show a significant effect. The other disadvantage is that they may
interfere with the absorption of concurrent drugs. So, there should be a gap of at least
one hour before taking this drug, or 3 to 4 hours after taking it.
weight in kg
Ezetimibe
Cholesterol is present in the lumen of our small intestines in the form of dietary
cholesterol and bile. Ezetimibe acts on the brush border of the small intestine and
blocks the absorption of cholesterol from the GIT by binding with NPC
responsible for cholesterol uptake.
It is used in a dose of 10 mg/day. It decreases the LDL-C level by about 18%. It does
not affect the triglycerides and HDL cholesterol levels. It can be taken at any convenient
time by the patient with or without food. Ezetimibe as monotherapy or in combination
with lipid lowering drugs has not yet been documented to reduce the CHD incidences.
Ezetimibe is absorbed and can show its effects systemically like fatigue, back pain,
and arthralgia. The main side effects seen are on gastrointestinal tract such as
diarrhoea and abdominal pain.
Ezetimibe is used in statin intolerant cases. It can also be used with statins as it has
an additive effect. When combined with statins, monitoring of liver function tests is
recommended.
receptors
1L1
Disorders of Cardiovascular System
39
Niacin (Nicotinic Acid)
This is vitamin B, which is water soluble. This drug is effective in lowering the levels
of LDL-C and triglycerides and also nominally increasing HDL-C levels. Niacin is
available as immediate release, extended release, and sustained release tablets.
Immediate release niacin may lead to skin flushing.
Statins
Statins are also called HMG-Co-reductase inhibitors. They act on the enzyme HMGCoA to reversibly inhibit it during the formation of cholesterol. This is a rate-limiting
step in the formation of cholesterol in the body. As a result, the cholesterol level in the
body decreases.
The drugs used in the class of statins are lovastatin, simvastatin, atorvastatin,
fluvastatin, pravastatin, and rosuvastatin. Cerivastatin has been withdrawn because
of its effect of muscle toxicity.
These drugs reduce the blood LDL level. As the dose of statins are doubled, the
decrease in LDL level is approximately 6%. Also, triglyceride levels in the blood
decrease and HDL levels in the blood increase. As its dose is increased, atorvastatin
loses its capability to increase the HDL level.
Statins are given once a day after the determination of the perfect statin with its dose
for the patient. All statins are recommended once a day in the evening as it gives lower
LDL levels, with the exception of atorvastatin, which when administered at any time
of day gives the same result.
Side effects of statins include dyspepsia, headaches, fatigue, and muscle or joint
pains. Muscle symptoms associated with statin therapy include myopathy, myalgia,
myositis, and rhabdomyolysis. Myalgias, which are commonly seen in patients, may
be focal like leg cramps or non-specific like general fatigue. The risk factors for muscle
symptoms include advanced age, small body frame, presence of other diseases,
surgery period, hypothyroidism, and drug interactions. Determination of creatinine
kinase (CK) level can be utilised to understand the effect of statins on muscles.
Certain drugs alter the statin metabolism through the CYP3A4 pathway. The drugs
may inhibit the metabolic enzymes mildly like erythromycin, diltiazem, and
grapefruit juice, or may be potent inhibitors like itraconazole, ritonavir, cyclosporine,
and amiodarone. Also, there are certain drugs that act as metabolic inducers like
rifampicin, carbamazepine, and phenobarbital. These drugs should be avoided with
statin therapy in order to avoid its side effects.
Statins are contraindicated in patients with hepatitis and elevated liver function
tests. The liver function tests have to be monitored after commencing the statin
therapy. If the transaminase values AST and ALT increases to greater than thrice of
normal values the statin therapy needs to be reduced or discontinued.
Other pharmacological effects of statins include endothelial function improvement,
inhibition of prothrombotic forces, immunosuppression, atherosclerosis plaque
stabilisation (slowing atherosclerosis progression), and an anti-inflammatory effect.
It is observed that the CRP values are lowered with statin therapy.
Statin combinations: Lovastatin and extended-release niacin combination.
Simvastatin is available with ezetimibe in a fixed dose combination.
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Textbook of Pharmacotherapeutics
Fibrates
These are fibric acid derivatives. They mainly lower the triglyceride levels. They also
act on LDL to reduce it by 20% and increase HDL by approximately 10 to 20%. The
fibrates act as agonists of peroxisome proliferative activated receptors (PPAR) alpha
subtype. Example is gemfibrozil.
Omega-3 Fatty Acids
The long chains of polyunsaturated fatty acids (PUFA) are useful in the treatment of
hypercholesterolaemia. These polyunsaturated fatty acids are present in fish oils and
flaxseeds. The most widely used contents are eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA).
The omega-3 fatty acids are linked to fewer cardiovascular events. They are found
to lower serum triglycerides concentrations by 25 to 30%, reduce platelet aggregation,
and cause arrhythmia and sudden death. The side effect of these is the fishy aftertaste.
KEY POINTS
• Hyperlipidaemia or dyslipidaemia, a disorder of lipoproteins, refers to unhealthy levels of any type
of lipid in humans.
• The primary cause includes genetic predisposition, and secondary causes include diet, the
presence of other diseases, and certain medications.
• The symptoms range from no symptoms to chest pain, sweating, palpitation, anxiety, shortness of breath,
loss of consciousness, difficulty in movement, difficulty in speech, pain in the abdomen, and sudden death.
• Bile acid sequestrants, ezetimibe, niacin, statins, fibrates and omega-3 fatty acids are used for the treatment.
2.4 CONGESTIVE HEART FAILURE
Congestive heart failure, also known as heart failure, happens when the heart muscles
fail to pump blood as efficiently as it should.
Heart failure patients may be classified into two categories:
• Heart failure with systolic dysfunction (depressed EF), and
• Heart failure with preserved diastolic dysfunction (preserved EF)
(EF means ejection fraction which is a volume of fluid ejected out of a heart chamber)
According to public health estimates, approximately 60% of the world's heart
diseases are accounted for in India. It is considered a silent epidemic in India.
Aetiology
Heart failure occurs due to two main reasons:
• Hypertension, and
• Coronary artery disease.
The reasons for systolic dysfunction include:
• Decrease in left ventricular ejection factor
• Idiopathic cardiomyopathies
• Viral infections
• Genetic
• Valvular diseases
Disorders of Cardiovascular System
41
• Hypertension
• Coronary artery disease
• Alcohol
• Certain drugs like antineoplastics and immunomodulating agents
The reasons for diastolic dysfunction include:
• Increased LVEF
• Hypertension
• Ageing
• Coronary artery disease
• Valvular diseases of heart
• Cardiomyopathies like amyloidosis
• Genetic issues
Pathogenesis
The development and progression of heart failure with depressed ejection factor from
the ventricle may occur due to an index event. This index event may be abrupt or
develop slowly. Heart failure patients may be asymptomatic for a long time, ranging
from a few months to several years. The actual reason for the patients being
asymptomatic is not yet known and is still under study.
There are various compensatory mechanisms when the heart starts failing. The compensatory
mechanisms may be listed as follows.
1. Activation of the renin angiotensin aldosterone system
2. Activation of the adrenergic nervous system
3. Increased myocardial contractility
4. Activation of vasodilator molecules
Genetic factors, gender, the environment, and age may influence these compensatory
mechanisms. The adaptive changes occurring in the myocardium are referred to as LV
remodelling.
Patients with heart failure are classified by doctors into various classes depending
on their ability to perform physical work without showing the signs and symptoms.
Tables 2.3 and 2.4 show the classification of patients based on their ability to perform
physical work and objective assessment, respectively.
Table 2.3: Classification based on ability to perform physical work
Class Classification of patients with cardiac disease based on ability to perform physical work
Class I Not showing any symptoms like fatigue, dyspnoea, palpitations, or angina while
performing simple physical tasks
Class II Not showing any symptoms at rest but showing fatigue, palpitation, dyspnoea, or angina
symptoms during ordinary physical tasks
Class III Showing symptoms of fatigue, palpitation, angina or dyspnoea with less than simple
ordinary physical tasks, but they are comfortable at rest
Class IV Resulting in symptoms of heart failure even at rest and the symptoms getting elevated with
physical activity
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Class Objective assessment
A No objective evidence seen in patients. The patients are comfortable during simple physical
activities as well as at rest
B Minimal objective evidence of cardiovascular disease. Mild symptoms while performing
simple physical tasks. The patients are comfortable at rest
C Objective evidence of moderate cardiovascular disease. Patients show marked symptoms
during simple physical activities. Person is comfortable only at rest
D Objective evidence of severe cardiovascular disease. The patient shows severe symptoms
even at rest
Textbook of Pharmacotherapeutics
Table 2.4: Objective assessment
Clinical Manifestations
Heart failure leads to reduced cardiac output, thereby reducing the oxygen supply to
the muscles. Fatigue is experienced due to this. Dyspnoea and orthopnoea may also
occur.
The postural change in the lying down position may cause pressure on the
diaphragm, leading to congestion in the lungs. This leads to shortness of breath where
the patient feels the need to get propped up or sit or stand to facilitate breathing. Sleep
is further disturbed due to increased urine production (nocturia).
Patients with heart failure may have a reduced supply of blood to the brain, leading
to confusion. Reduced blood supply to the kidneys may lead to renal failure.
Abdominal distension, nausea, anorexia, and abdominal pain may also be seen along
with hepatomegaly.
The pulmonary oedema in acute heart failure patients may be life-threatening. The
sputum may become bloody and red due to leakage of blood from the capillaries.
Severe dyspnoea may lead to cyanosis and shock.
Guidelines for contacting healthcare personnel:
• Difficulty in breathing especially if it does not feel better when the physical activity
is stopped
• Shortness of breath at rest
• Experiencing cough persistently
• Lethargic to do routine activities
• Swelling or oedema in lower extremities of body
• Abrupt weight gain in a week
• Lack of concentration
• Pain in abdomen
• Nausea
• Chest pain
• Dizziness while changing posture
• Irregularity in heartbeat or arrhythmia
• Any side-effects of medicines
• Emergency may include severe chest pain, severe shortness of breath, fainting or
coughing out pink, frothy sputum.
Disorders of Cardiovascular System
43
This list is a guideline and may not include all the problems associated with heart
failure to seek urgent medical advice.
Non-pharmacological Management
General measures include treatment of hypertension and coronary artery disease,
which are the main contributors to the development of heart failure.
Other comorbidities like diabetes mellitus, issues related to sleep disorder and
breathing should be treated. Serum lipid levels should be kept under control and body
weight should be maintained. Patients are advised to quit smoking and limit alcohol.
Myocardial valve replacement has to be performed to treat the valvular disorders in
patients. A pacemaker may be required in the cases of bradycardia patients.
Furthermore, precipitating factors like systemic infection, pulmonary embolism,
hypercalcaemia, anaemia, and hyperthyroidism should be treated properly.
There is a wide variation in the exercise capacity of patients. Each patient should
receive individual attention for cardiac rehabilitation. Generally, regular moderate
exercise is advised.
Patient education regarding nutrition and medication, along with family members,
is important in the management of CHF.
The sodium intake in India is approximately 11 g per day, which is higher than the
WHO recommendation of about 5 to 7 g per day.
Higher sodium intake leads to acute decompensation and may require higher doses
of diuretic which is considered undesirable.
Fluid restriction of less than 2 litres per day has to be considered for patients of
severe heart failure.
Certain prescription and non-prescription medications are known to exacerbate
heart failure. Beta blockers, certain calcium channel blockers like diltiazem, verapamil,
and certain antiarrhythmic drugs may worsen pre-existing heart failure. Nonsteroidal
anti-inflammatory drugs (NSAIDs) may cause fluid retention thereby leading to
kidney failure. Sympathomimetic agents which may be in certain cold medications,
herbal medicines or nutraceuticals should be avoided.
Pharmacological Management
• Diuretics
• ACE inhibitors
• Angiotensin II receptor blockers
• Beta blockers
• Digoxin
• Nitrates
Diuretics
Diuretics are useful in cases of retention of water and salt, which leads to volume
expansion and, thereby, congestion. Thiazide diuretics like metalozone are used. Loop
diuretics, which act on the loop of Henle, are also recommended. Examples of loop
diuretics are furosemide and bumetanide.
Potassium sparing diuretics, which are considered weak diuretics, act on the
terminal part of the distal convoluted tubule. Examples include spironolactone,
triamterene, and amiloride.
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Textbook of Pharmacotherapeutics
ACE Inhibitors
ACE inhibitors act by blocking the conversion of angiotensin I to angiotensin II, which
is a potent vasoconstrictor. Examples are captopril, enalapril, lisinopril, quinapril, and
ramipril. The ACE inhibitor therapy should be started at a low dose and gradually
increased. The main side effects are hypotension and cough.
Angiotensin II Receptor Blockers
Angiotensin II receptor blockers are also called ARBs. These drugs act by blocking the
effect of angiotensin II. The adverse effects are symptomatic hypertension and
hypokalaemia.
Beta Blockers
Beta blockers were thought to be contraindicated in congestive cardiac failure earlier.
It was included in the treatment only in the late 1990s in stable patients. Examples are
metoprolol and carvedilol.
Digoxin
Digitalis glycosides have been used in the treatment of CHF. Digoxin is a positive
inotropic agent. It acts by releasing calcium within the myocardium and thereby
increasing the contractility of cardiac muscles.
The adverse effects include nausea, vomiting, confusion, and visual disturbances.
Nitrates/Hydralazine
Nitrates cause venodilation and reduce the symptoms of pulmonary congestion.
Nitrates are used in combination with arterial vasodilators such as hydralazine.
KEY POINTS
• Heart failure occurs when the heart muscles fail to pump blood as efficiently as it should.
• Heart failure occurs due to hypertension or coronary artery disease.
• Heart failure leads to reduced cardiac output, thereby reducing the oxygen supply to the muscles.
• Fatigue and dyspnoea is experienced due to this.
• Pharmacological management includes administration of diuretics, ACE inhibitors, angiotensin
receptor blockers, beta blockers, digoxin and nitrates.
Disorders of
3
Respiratory System
3.1 ASTHMA
Asthma is a chronic inflammatory disorder of the airways. It involves many cells and
cellular elements such as mast cells, eosinophils, T-lymphocytes, macrophages,
neutrophils and epithelial cells. Inflammatory symptoms are usually associated with
airflow obstruction and increased airway response to stimuli. Obstruction is often
reversible.
Aetiopathogenesis
Asthma is a complex disease; its etiology is characterised by airway hyperresponsiveness
and bronchoconstriction. Hyperresponsiveness is an increased tendency of the airway
to respond to the stimuli or triggers which results in asthma attack. Bronchoconstriction
is narrowing of airways which lead to airflow obstruction. The common triggers for
asthma attack are mentioned in Table 3.1.
Table 3.1: Common triggers for asthma attack
Stimuli/triggers Examples
Allergens Pollen grains, house dust mite, pet animals’ dander, saliva or excretory
products
Industrial chemicals Paints, resins, sprays
Drugs Penicillins, ibuprofen, aspirin
Food Nuts, few fishes, dairy products, food colorants
Environmental pollutants Traffic fumes, cigarette smoke
Occupational triggers Wood, grain or cotton dust, cereal grains
Miscellaneous Cold air, emotional upset, exercise, stress, swimming pool chlorine
Bronchial hyperresponsiveness is an exaggerated bronchoconstrictive response to
stimuli. Mechanism by which inflammatory cells and their mediators promote airway
hyperresponsiveness is not yet clear but the degree of hyperresponsiveness can be
measured and it is related to disease severity and medication needs.
Mast cells are important in initiating inflammatory response. Allergens when
exposed, binds to immunoglobulin E (IgE)-bound high affinity receptors on the
surface of mast cells, and releases various immediate acting mediators such as
45
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Textbook of Pharmacotherapeutics
histamine, leukotriene, prostaglandins and platelets activating factor (PAF) to cause
immediate bronchoconstriction. Several long acting mediators such as eosinophil,
neutrophil chemotactic factor, tumor necrotic factor and cytokines are also released
which promote airway inflammation. For developing chronic airway inflammation
along with mast cells, macrophages, eosinophils and T-lymphocytes are also
important. PAF causes accumulation of eosinophils within the airways and mucosal
oedema which results in airway plugging. All these pathological changes lead to
respiratory symptoms.
Clinical Manifestations
Asthma can be presented in a number of ways. The common manifestations are:
• Shortness of breath (dyspnoea)
• Wheezing (a high-pitched noise due to turbulent air flow through a narrowed
airway)
• Cough
• Sputum production
• Chest tightness
Objective signs are:
• Reduced air flow
• Increased airway resistance
• Reduced conductance
• Hyperinflation of the lungs
In acute obstructed patients:
• Tachypnoea
• Tachycardia
• Retractions
• Cyanosis
• Hypoxemia
Asthma is often predominated with nocturnal symptoms. Allergies, atopic
dermatitis, rhinitis and sinusitis are common symptoms. These symptoms may be
episodic, continuous, or continuous with episodic exacerbation and can occur
seasonally, perennially or perennially with seasonal exacerbation. Based upon clinical
features asthma can be classified as mild intermittent, mild persistent, moderate
persistent and severe persistent. Details can be referred in Table 3.2.
Table 3.2: Classification of asthma severity
Type of asthma Symptoms Nocturnal symptoms Pulmonary function
Mild intermittent NMT twice a week NMT twice a month Normal
Mild persistent More than twice a week At least twice a month Normal
but not daily
Moderate persistent Daily At least a week Abnormal
Severe persistent Continuous Frequent Abnormal
Disorders of Respiratory System
47
Non-pharmacological Management
Prevention and control of allergens and other stimuli which triggers asthma is the
important part of successful asthma therapy. Patients should be counseled to adhere
with consistent environmental control to achieve maximum benefits of therapy. The
patients who have intolerable adverse effects from drug therapy or cannot avoid
exposure to allergens can be treated with immunotherapy, i.e. subcutaneous
administration of standardized allergen extract. Patients with coronary heart disease,
severe hypertension, severe asthma or severe atopic dermatitis should not receive
immunotherapy as it may increase risk of life-threatening consequences. Along with
this patient’s education on following points is also required.
• Basic facts about asthma
• Mode of action of medicines
• Training on appropriate use of device
• Environmental control measures
• Appropriate use of rescue plan and medicines
Pharmacological Management
The drugs used for asthma are classified as bronchodilators and anti-inflammatory
agents. Further they can be categorised as:
1. Quick-relief medication: Short acting inhaled
-agonist, anticholinergic and short
2
term use of systemic corticosteroids.
2. Long term control medications: Inhaled and systemic corticosteroids, cromolyn,
nedocromil, long acting
-adrenergic agonist: -adrenergic agonists are potent bronchodilators. They can
-agonist, methylxanthines, and leukotriene modifiers.
2
be classified as short-acting drugs such as albuterol, bitolterol, metaproterenol,
pirbuterol, terbutaline and long-acting drugs such as salmeterol, formoterol. They can
be given orally, subcutaneously or by inhalation. Inhalation is the preferred route as
for oral administration. The dose should be higher to consider first pass metabolism
and intravenous route is associated with potential life-threatening adverse effects.
Theophylline: Theophylline is the primary drug from the methylxanthine
category. It is a strong bronchodilator and also has modest anti-inflammatory or
immunomodulatory effects. As compared to
-adrenergic agonists, theophylline is a
2
weaker bronchodilator but it can inhibit bronchospasm induced by various stimuli
including histamine, methacholine, exercise, etc. It can be administered orally,
intravenously and rarely rectally. By inhalation route it does not have an anti-asthma
effect.
Anticholinergic drugs: When compared with
-adrenergic agonists, anticholinergic
2
drugs do not produce maximum bronchodilation, but they have longer duration of
action. They are nonselective competitive antagonists at muscarinic receptors.
Atropine sulphate is now replaced by ipratropium bromide which is a quaternary
amine for nebulization.
Anti-inflammatory agents: Cromolyn and nedocromil are the drugs of choice as
anti-inflammatory agents. Cromolyn and nedocromil act by various mechanisms
including inhibiting the IgE-mediated release of mediators from mast cells,
eosinophils, alveolar macrophages, neutrophils and monocytes. They can also inhibit