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Textbook of Pharmacotherapeutics
by reducing the myocardial oxygen demand. Also, they cause coronary vasodilation,
leading to increased blood supply and in turn, oxygen supply to the myocardium, thus
relieving angina.
Nitrates help in preventing as well as treating acute anginal attacks.
Adverse effects: The main disadvantage of nitrates is the development of tolerance,
for which nitrate-free periods are helpful to reduce this effect. Throbbing headache,
dizziness, hypotension, light-headedness, facial flushing, and reflex tachycardia are
the other adverse effects seen with nitrate therapy.
Beta Adrenergic Blockers
Beta blockers help in the treatment of angina pectoris by reducing the myocardial
oxygen demand. These agents are effective in reducing the severity and frequency of
exertion induced angina attacks and also improve the survival of MI patients. Beta
adrenergic blockers cause a decrease in heart rate, arterial pressure, and myocardial
contractility, mainly during exercise. Decrease in chronotropy, inotropy, and arterial
pressure occurs only slightly at rest.
Adverse effects: Beta blockers may cause fatigue, depression, nightmares, reduced
exercise tolerance, sexual dysfunction, cold extremities, reduced left ventricular
function, impaired atrioventricular conduction, bradycardia, and intensification of
hypoglycaemia with oral hypoglycaemics and insulin. It may become necessary either
to reduce the dose of beta-blockers or stop the treatment if the side effects persist. The
dose has to be tapered over a period of two weeks in order to avoid the deterioration
of ischaemia on sudden discontinuation.
The beta-adrenergic blockers used are metoprolol, atenolol, labetalol, pindolol,
timolol, propranolol, bisoprolol, and carvedilol.
Calcium Channel Blockers
Calcium ion channels regulate the entry of extracellular calcium ions into smooth
muscles and cardiac muscles. These calcium ions act as triggers for contraction in the
muscular tissues. Calcium ion channel blockers, also called calcium channel
antagonists or calcium ion entry blockers, inhibit the entry of calcium ions. This leads
to negative inotropic, chronotropic, and dromotropic effects.
Calcium channel blockers may be classified into three classes based on their chemical structure
as well as their binding sites in the body:
1. Dihydropyridines, e.g. amlodipine, felodipine
• Short-acting drugs, e.g. nifedipine, nicardipine
• Medium acting drugs, e.g. nicardipine, isradipine
• Long-acting drugs, e.g. amlodipine, felodipine
2. Phenylalkylamines, e.g. verapamil
3. Benzothiazepines, e.g. diltiazem
Calcium channel blockers act via five major effects
• Peripheral vasodilation
• Coronary vasodilation
• Decreased myocardial contractility
Disorders of Cardiovascular System
29
• Reduced heart rate
• Slowing AV node conduction
Myocardial oxygen supply is increased by coronary vasodilation whereas
myocardial oxygen demand decreases as a result of peripheral vasodilation, decreased
myocardial contractility, reduced heart rate, and slowing of AV node conduction.
Adverse effects: Peripheral oedema, flushing, headache, and dizziness. Bradycardia
and AV block can occur with verapamil and diltiazem. Gastrointestinal adverse effects
like nausea, gastroesophageal reflux, and constipation may be seen.
Other Anti-anginal Agents
Ranolazine
Ranolazine is considered as a second-line agent for treatment of chronic angina. The
anti-ischaemic and antianginal effects of this drug are not fully understood. The adverse
effects are dizziness, headache, nausea, constipation, blurry vision, and confusion.
Ivabradine
Ivabradine is used for treating stable angina and heart failure in patients who cannot
tolerate beta blockers or are insufficiently responsive. This drug is a selective blocker
of HCN ion channels involved in the SA node. It acts by reducing the pacemaker
current, thereby reducing the heart rate. The antianginal effect is due to a decrease in
heart rate and, thereby, oxygen demand.
Adverse effects are on the eyes. This drug is contraindicated with concurrent
therapy with verapamil or diltiazem.
Nicorandil
Nicorandil is a nitrate ester of nicotinamide. It acts as an agonist on ATP-sensitive
potassium channels. It shows vasodilation both in arterial and venous vascular beds,
leading to a reduction in afterload and preload of the heart. It is used in patients with
stable coronary artery disease.
Adverse effects include headache, hypotension, and GI ulcerations.
Revascularization Procedures/Mechanopharmacological Therapy
Two types of revascularization procedures are available. They are:
• Coronary artery bypass grafting (CABG)
• Percutaneous coronary interventions
Coronary artery bypass grafting
This is a surgical procedure in which the coronary artery stenosis is bypassed to
provide better coronary blood circulation (Fig. 2.1). In this, either the saphenous vein
from the leg is used for the bypass vessel or connection of the internal thoracic artery
beyond the coronary vessel is performed. There are chances of stenosis of the bypass
graft as well. The lifelong use of antiplatelet agents like aspirin or clopidogrel is given
to prevent thrombosis or occlusion.
Percutaneous coronary interventions (Fig. 2.2)
This is a less invasive technique involving atherectomy, laser angioplasty, and intracoronary stent implantation. Stent implantation involves using balloon dilatation to
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Textbook of Pharmacotherapeutics
Fig. 2.1: Coronary artery bypass grafting
Fig. 2.2: Percutaneous coronary interventions
place intracoronary stents. Coronary artery stents are made up of stainless steel
tubes and are inserted at the site of atherosclerotic plaque to decrease the rate of
restenosis. Newer techniques include drug eluting stents and biodegradable stents.
The drugs used in intravascular stents are paclitaxel, sirolimus, avarolimus, and
zatarolimus.
This procedure is usually used in patients with one or two vessel stenosis.
Angioplasty patients need to be given aspirin treatment to avoid thrombosis due to
the thrombogenic stents. Clopidogrel may be used in cases where aspirin is not
tolerated.
Disorders of Cardiovascular System
31
KEY POINTS
• Angina pectoris results from an imbalance between oxygen supply and oxygen demand in the heart.
• Angina pectoris is associated with single or multiple atherosclerotic coronary arteries and/or
vasospastic blood vessels.
• Organic nitrates, beta adrenergic blockers, calcium channel blockers and potassium channel
activators are used in the treatment.
• Revascularization techniques are available now.
MYOCARDIAL INFARCTION
Myocardial infarction (MI) or heart attack is a medical emergency where there is
necrosis of myocardial tissues. Prolonged ischemia or reduced blood supply to the
myocardial cells causes inadequate oxygen delivery which ultimately leads to necrosis
or cell death of myocardium.
Etiopathogenesis
The most common causative factor for the MI is atherosclerosis of coronary arteries
which narrows the lumen and ultimately restricts the blood supply. In rare cases,
coronary artery occlusion can also be caused by coronary emboli, congenital
abnormalities, coronary spasm, and some inflammatory diseases. The amount of
myocardial damage caused by coronary occlusion depends upon territory supplied
by affected vessel, extent of vessel occlusion, duration of coronary occlusion, and
demand for oxygen of the myocardium. The patients with previous history of MI,
coronary artery disease (CAD) or malignant arrhythmias are at highest risk of MI. Risk
factors for MI can be categorized as modifiable and non-modifiable factors. Nonmodifiable risk factors are increased age, male gender, and family history for MI.
Modifiable risk factors are cigarette smoking, diabetes mellitus, hyperlipidaemia,
hypertension, obesity, and physical inactivity. Cocaine abuse is also identified as a
possible causative factor for development of MI due to complete coronary closure in
absence of coronary atherosclerosis. In the morning hours, increased sympathetic
activity enhances platelet adhesiveness and coronary vasoconstriction. Also during
this time there is an alteration in the plasminogen inhibitor and plasminogen ratio,
making existent artherosclerotic plaques more vulnerable to rupture. Hence morning
hours are peak times for suffering acute myocardial infarction. Other precipitating
factors for MI include vasospasm, physical or emotional stress, haemorrhage, trauma,
respiratory failure, hypoglycaemia, and hypersensitive reactions.
Clinical Manifestations
Chest discomfort, i.e. oppressive, squeezing, crushing, burning pain or tightness,
expanding sensation or indigestion are most common complaints. Discomfort is
typically substernal which radiates to the neck, throat, jaw, shoulders and arms. It may
last from 30 minutes to several hours. The pain associated with MI may commence
when the patient is at rest, but does not subside with rest. Other rare presentations,
with or without pain, include sudden loss of consciousness, confused state of mind,
profound weakness, arrhythmia, or unexplained drop in arterial pressure. Blood
pressure fluctuations are common during MI.
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Textbook of Pharmacotherapeutics
Non-pharmacological Management
Continuous monitoring and prompt treatment to emergencies are required for
patients with suspected acute myocardial infarction in the intensive care unit or
coronary care unit. Administration of intramuscular drugs has to be avoided so there
is no interference in cardiac enzyme determination. The monitoring of vital signs,
body weight, bowel habits, diet, and pain relief is done.
The patients have to take bedrest during the first 24 hours after the event so that
the myocardial oxygen consumption is less. Also, it helps in preventing extension of
infarction during the recovery process. Movement with in bed, exercises and personal
hygiene can be started in few days.
Liquid diet is advised for the first day in recovery phase. A patient can start with
step II diet consisting of low saturated fat and cholesterol after discharge from
hospital. If the LDL cholesterol level after diet therapy is high then drug therapy has
to be started to reduce it.
Patients at risk for suffering myocardial infarction and their family members should
be counselled about the urgent need for healthcare help immediately at the onset of
symptoms. All the symptoms related to the disorder should be told to the patient and
the family members on each visit.
Public awareness campaigns may help the society in increasing the knowledge
about the signs and symptoms of myocardial infarction.
Pharmacological Management
Oxygen
Oxygen administered as a supplement helps in reducing the burden of ischaemia.
It is administered at the rate of 4 L per minute by nasal cannula or mask for first 24
to 48 hours. In case 90% or more oxygen saturation is not attained, then
endotracheal intubation and positive airway pressure mechanical ventilation has
to be used.
Analgesics
Drugs like morphine, meperidine, and nalbuphine may be used in acute
myocardial infarction. The drug of choice is morphine except in patients with
hypersensitivity.
Nitrates
Organic nitrates like nitroglycerin and nitroprusside decrease the preload and
afterload by venodilation and arteriodilation respectively. Nitrate reduces myocardial
oxygen demand. Nitroglycerin decreases the systemic vascular resistance and
myocardial wall tension. It improves blood flow to the myocardium. It is given
sublingually but contraindicated in right ventricular infarct or marked bradycardia.
The side effects of nitroglycerin include reversible hypotension, bradycardia,
hypoxaemia, methemoglobinaemia, and headache.
Antiplatelet Agents
Aspirin inhibits platelet aggregation by irreversible acetylation of cyclooxygenase.
Administration of low doses of aspirin is advised to all patients of MI.
Disorders of Cardiovascular System
33
Heparin
Heparin is administered after thrombolytic therapy to prevent coronary artery reocclusion. The risk of reocclusion is high immediately after thrombolysis. Side effects
of heparin include haemorrhage and thrombocytopenia. Heparin is contraindicated
in haemorrhage, uncontrolled hypertension, blood dyscrasias, active bleeding or in
major surgery.
Thrombolytic Agents
Thrombolytic agents can be used in patients with acute myocardial infarction to save
cardiac muscles. This reduces mortality and prevents electrical instability and left
ventricular dysfunction. Intravenous streptokinase is given at a dose of 1.5 million IU
over a period of 30 to 60 minutes. In order to reduce allergic risk, patients may be
given diphenhydramine and hydrocortisone intravenously before streptokinase
infusion. Patients are given full dose heparin for 24 to 72 hours after streptokinase
administration.
Administration of streptokinase within the first hour of symptom onset gives
maximum myocardial salvage in acute myocardial infarction and ST segment
elevation. Bleeding is the major concern with thrombolytic agents.
The other classes of drugs useful in myocardial infarction include blockers.
KEY POINTS
• Myocardial infarction (MI) or heart attack is a medical emergency where there is necrosis of
myocardial tissues.
• The most common causative factor for myocardial infarction is atherosclerosis of coronary arteries
which narrows the lumen and thereby restricts the blood supply.
• Chest discomfort is typically sub-sternal which radiates to the neck, throat, jaw, shoulders and arms
in MI. It may last from 30 minutes to several hours.
• Continuous monitoring and prompt treatment to emergencies are required for patients with
suspected acute myocardial infarction.
• Pharmacological treatment includes administration of oxygen, analgesics, nitrates, antiplatelet
agents, heparin and antithrombolytic agents.
2.3 HYPERLIPIDAEMIA
Hyperlipidaemia can alternately be called dyslipidaemia, which refers to unhealthy
levels of any type of lipid in humans. This is a disorder of lipoproteins.
Dyslipidaemia is one of the major factors contributing to cardiovascular disorders,
which needs special attention.
Dyslipidaemia, which usually presents itself as hyperlipidaemia, can be controlled
by diet and lifestyle changes. But if non-pharmacological methods are inadequate for
its control, then drugs like statins need to be administered to keep hyperlipidaemia
under check.
Types of Lipoproteins
• Very low-density lipoprotein (VLDL)
• Intermediate-density lipoprotein (IDL)
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Textbook of Pharmacotherapeutics
• Low-density lipoprotein (LDL)
• High density lipoprotein (HDL)
The density of lipoprotein depends on the amount of lipid per particle. These
lipoproteins have various functions, like acting as carrier molecules for various
substances in the human body like cholesterol, triglycerides, and fat-soluble
vitamins.
Dyslipidaemia means low levels of HDL or elevated levels of LDL, total cholesterol,
or triglycerides. Table 2.1 gives the classification of cholesterol.
Table 2.1: Classification of cholesterol
Triglycerides
Less than 150 mg/dL Desirable
150–199 mg/dL Borderline high
200–499 mg/dL High
500 mg/dL and above Very high
HDL-Cholesterol
Less than 40 mg/dL Major risk factor for heart disease
60 mg/dL and above Offers some protection against heart disease
LDL-Cholesterol
Less than 100 mg/dL Desirable
100–129 mg/dL Above optimal
130–159 mg/dL Borderline high
160–189 mg/dL High
190 mg/dL and above Very high
Total Cholesterol
Less than 200 mg/dL Desirable
200–239 mg/dL Borderline
240 mg/dL and above High
Aetiology
Hyperlipidaemia may occur due to primary or secondary causes.
The primary cause includes genetic predisposition, and secondary causes include
diet, the presence of other diseases, and certain medications.
The screening of hypercholesterolaemia is done by determining the plasma levels
of cholesterol, triglycerides, LDL-C, and HDL-C measured after a 12-hour overnight
fasting.
Disorders of Cardiovascular System
35
Types of Hyperlipidaemia
Primary hyperlipidaemia:
• Familial hypercholesterolaemia
• Polygenic hypercholesterolaemia
• Familial combined hyperlipidaemia
• Familial chylomicronemia
• Familial hypertriglyceridemia
Secondary hyperlipidaemia may result due to:
• Alcoholism
• Diabetes
• Cushing's syndrome
• Renal failure
• Cholestasis
• Nephrotic syndrome
• Hypothyroidism
• Drugs like beta blockers, thiazides, steroids, and antiretrovirals.
The LDL receptor activity gets affected in the case of hyperlipidaemia. Primary
hyperlipidaemia (familial hypercholesterolaemia) requires compulsory use of drugs,
otherwise it may cause morbidity and mortality in early life. The genetic factor
includes either homozygous or heterozygous receptor abnormality.
A heterozygous receptor abnormality is a single mutation for LDL receptor activity.
Due to this, only half of the LDL receptors are active. This leads to twice the normal
cholesterol levels.
A homozygous receptor abnormality is a double mutation in LDL receptor activity
that leads to almost no functional LDL receptor. We further see extremely high
cholesterol values of up to 1000 mg/dL. Cardiovascular heart disease may develop in
the first two decades of life in this case.
Secondary hyperlipidaemia may result in patients who are already suffering from
diseases like diabetes mellitus, hypothyroidism, Cushing's syndrome, obstructive
liver disease, and nephrotic syndrome. Alcoholism may also contribute to high
cholesterol levels.
In this case, correction of the underlying disease should be attempted first, as this
helps in normalisation of cholesterol levels before giving any medication for
hyperlipidaemia.
Pathophysiology
Cholesterol is a lipid obtained from dietary sources as well as synthesised endogenously.
It, along with triglycerides and lipid molecules, circulates in the body in various forms
like LDL, HDL, IDL, and VLDL.
LDL accounts for 60 to 70% of total circulating cholesterol in the body. Excess LDL
leads to its oxidation and gets deposited in the vascular endothelium of artery walls,
where it becomes cytotoxic and starts the process of atherosclerosis. HDL cholesterol
accounts for 20 to 30% of the circulating cholesterol in the body. It is considered a good
cholesterol because it acts as a reverse transport for cholesterol. This means it accepts
cholesterol from peripheral tissue and takes it to the liver and kidney where it is
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Textbook of Pharmacotherapeutics
metabolised and excreted out of the body. The LDL forms 10 to 15% of circulating
cholesterol and is mainly made up of triglycerides. The triglycerides are derived from
dietary fat and an excess of carbohydrates in the liver.
Cholesterol metabolism and transport involves two pathways—the endogenous
and exogenous pathways. The exogenous system involves metabolism and transport
of chylomicrons and their remnants. These are absorbed from the intestine through
the lymphatic system and reach the general circulation. Here, they are broken down
by protein lipase into chylomicron remnants and free fatty acid. The free fatty acid is
taken up by the muscles and other tissues where they are utilised as an energy source.
The chylomicron remnants are available for uptake by the liver and are incorporated
into bile salts.
The endogenous pathway involves transport of cholesterol and triglycerides in the
form of VLDL, LDL, and HDL. The VLDL secreted by the liver into the bloodstream
undergoes hydrolysis by vascular lipoprotein lipase into ideal and ultimately LDL
particles. The LDL particles transport cholesterol to various body tissues where they
interact with LDL receptors and are available for cellular uptake of cholesterol. The
LDL particles are used for steroid synthesis and the formation of cell membranes.
Excess LDL gets deposited outside the cell and in the blood vessels, where it starts the
process of atherosclerosis.
It is now known that the LDL particles are of different densities and diameters. The
shift to a smaller diameter and higher density occurs in metabolic syndrome and/or
type two diabetes. These lesser diameter and denser LDL particles are associated with
a higher risk of cardiovascular diseases as they get oxidised faster and get deposited
in the arterial wall to start the atherosclerotic process.
Clinical Manifestations
Most patients are asymptomatic. They show clinical evidence of disease after many years.
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.
There may be no signs seen to abdominal pain, pancreatitis, peripheral polyneuropathy,
and high blood pressure. BMI maybe greater than 30 kg/metre square.
Increased serum cholesterol levels, specifically LDL cholesterol, are associated with
an increased risk of coronary heart disease.
Non-pharmacological Therapy
Diet, foods, additives, weight loss, exercise, and smoking cessation form the
therapeutic lifestyle changes (TLC) for hyperlipidaemia. Goals are set under
therapeutic lifestyle changes that need to be reviewed after six weeks approximately.
In case the goals are not achieved, changes are made in the TLC and again reviewed
after about six weeks.
Diet: Diet modification is considered an important point in the management of
dyslipidaemia. Patients should be guided regarding the foods that should be included
in the diet and the ones to be avoided. Processed foods should be avoided, and fresh
fruits and vegetables should form part of the diet. Patients need to be cautioned
against the use of high saturated fats. The following table shows the types of fats
present in various types of edible oils.
Disorders of Cardiovascular System
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Fatty Acid Composition of Fats and Oils from Plant and Animal Origin
Containing high saturated fats
• Ghee (clarified butter)
• Butterfat
• Cocoa butter
• Coconut oil
• Palm oil
• Palm kernel oil
High in monounsaturated fats and low in saturated fats
• Olive oil
• Canola oil (rapeseed)
• Peanut oil (groundnut)
High in polyunsaturated fats and low in saturated fats
• Sunflower oil
• Safflower oil
• Corn oil
• Soya bean oil
The widely used diet plan for lowering LDL-C (low density lipoprotein-
Cholesterol) is 'Step I diet' developed by the NCEP and AHA. Patients mostly show
approximately 10% reduction in serum LDL-C levels on following this diet. Table 2.2
gives the diet recommendations to lower the blood cholesterol.
Table 2.2: Recommended diet modifications to lower blood cholesterol
Products to be included in diet Products to be excluded from diet
Fresh fruits and vegetables Processed food
Fish, poultry without skin, shellfish Fatty cuts of meat
Rice, whole grains like wheat, rye, multigrain cereals Commercial products containing high-fat
Low-fat milk, buttermilk, yogurt, cheese Whole milk and dairy products, ice cream
Unsaturated vegetable oils Butter, oil rich in saturated fat
Seeds and nuts Coconut
Egg whites Egg yolks
Foods and additives: Certain types of food and additives help in lowering the
serum LDL-C level. Salad dressings and spreads contain plant stanol and sterol esters
interfere with the absorption of cholesterol, thereby reducing its level. The addition of
psyllium, soy proteins, red yeast rice, certain whole grains, and omega-3 fatty acids
rich foods to the diet helps in reducing cholesterol.
Weight loss and exercise: Obesity or fat around the waist should be controlled if
present. Aerobic exercises help in increasing the activity of lipoprotein lipase, thereby
helping reduce plasma triglyceride levels and increase HDL-C levels. There are added
benefits of regular exercises and weight reduction such as maintaining hypertension
and diabetes among scores of other benefits.