Pharmacology - II (Thakur Publication) (001-102)

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PHARMACOLOGY-II
B.Pharm, Semester-V
According to the syllabus based on ‘Pharmacy Council of India’
Dr. Pankaj Mishra

M.Pharm, Ph.D
Principal,
Keshlata College of Pharmacy,
Bareilly International University, Bareilly
Dr. Pragnesh Patani

M.Pharm. (Pharmacology), Ph.D., DIM.
Professor & Principal,
A-One Pharmacy College, SNME Campus,
Naroda, Ahmedabad
Dr. K. V. Otari
M.pharm, Ph.D (Pharmacology)
Professor & Principal,
Navsahyadri Institute of Pharmacy, Naigon, Dist. Pune
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Pharmacology-II
Edition 2019
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“Dedicated
to
my Beloved Parents,
Shri P. C. Mishra and Mrs. Geeta Mishra”
-Dr.Pankaj Mishra
“Dedicated to
My Loving Parents
Mr. V.M.Patani & Mrs. Amitaben Patani
&
Aaditya, Vishvam, Khushi, Purva,
Nishtha, Kavya & Prisha”
-Dr. Pragnesh Patani
“Dedicated
to
my Family and Friends”
-Dr. Kishor Vasant Otari
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Preface
It gives us immense pleasure to place before the B.Pharm Fifth Semester
pharmacy students the book on “Pharmacology-II”.
This book has been written strictly in accordance wi th the current syllabus
prescribed by Pharmacy Council of India, for B.Pharm students. Keeping in view
the requirements of students and teachers, this book has been written to cover all
the topics in an easy -to-comprehend manner within desired limits of th e
prescribed syllabus, and it provides the students fundamentals of pharmacology
of drugs used in cardiovascular, urinary, and endocrine systems, which are
required by them during their pharmaceutical career.
All efforts have been made to keep the text e rror-free and to present the subject
in a student friendly and easy to understand. However, any suggestions and
constructive comments would be highly appreciated and incorporated in the
future edition.
Please e-mail us at, thakurpublication@gmail.com
Website, www.tppl.org.in
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Acknowledgement
It gives me an immense pleasure to express my thankful gratitude to Professor
(Dr.) K.K. Maheswari, Professor (Dr.) S. D. Singh , MJP Rohilkhand
University Bareilly and Dr. Pushpendra Kanno jia, Principal BIU College of
Pharmacy, Bareilly International University, Bareilly for their constant
motivation and encouragement.
I also express my thanks toMr. Gaurav Tripathi and Ms. Neha Singh, Faculty of
Pharmacy, Keshlata College of Pharmacy Bareilly for their assistance and support.
I am also thankful to all staff members of Thakur Publication Pvt. Ltd.

especially, Ms. Tuhina Banerjee (Copy Editor) and Mr. Sharad Kushwaha
(Marketing Coordinator), for providing me an opportunity to be a part ofhis
t book.
Finally my greatest debt of gratitude is to my family members for being supportive

in times of stress and assisting with the tasks of manuscript preparation.
Dr.Pankaj Mishra
I bow in front of Lord Ganesha for all blessings he has conferred upon me. I am
always thankful for his words “for every loss God will give you something if you
look for it and work for it”. These words strengthen me throughout in writing of
this book.
I express my special thanks to Honorable Shri Narendrasinh Zala Sir

(Ex.MLA), Chairman, and Honorable Shree Dhavalsinh Zala (MLA,
Bayad -Malpur) Trustee of Divaba Education Trust, for providing me
excellent infrastructural and constant encouragement during completion of
this book.
At the outset, I take this opportunity to e xpress my sincere gratitude to

Dr. B. N. Suhagia Sir, Director, Faculty of Pharmacy, Dharamsinh Desai
University, Nadiad, Dr. J. K. Patel , Dean, Sakalchand Patel University and
Dr. A. K. Seth , Dean, Suandeep Vidyapeeth University, for their valuable
guidance, which made me to overcome the implications through proper planning
and execution. This boosted my confidence, enabled me to complete my
working, and morally supported me. His continuous encouragement, imposing
new ideas, keen interest served as a sou rce of constant inspiration during entire
tenure of my professional carrier.
I am honored to express my profound and deep sense of gratitude towards whole

Pharma fraternity especially associated with Gujarat Technological University,
Dr. N. R. Sheth (VC, GTU), Dr. C. N. Patel (Dean & BOG, GTU) for their
creative suggestion, helpful discussion and unfailing advice during writing this
book.
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Finally I wish to acknowledge the assistance given by the editorial and

publication team. I especially thank Thakur P ublication Pvt Ltd. and whole
team for offering us complete freedom to express my knowledge and thoughts
through this book.
-Dr. Pragnesh Patani
It is a moment of pleasure & pride to look back with a sense of contentment
during the course of book writing. Behind every success there are many efforts &
efforts are fruitful due to the hands making the passage smooth. I wish to thank
each one of them with all my heart, as the list is everlasting I attempted to
include most of them, if someone missed, I request to consider my innocence &
understand the limitations.
The way to accomplish my ambitions was shown by Dr. C. D. Upasani ,

Professor & Principle SNJB’s College of Pharmacy, Chandwad. His time-to-time
encouragement, excellent guidance & valuable suggestion s made me capable to
bring this book at excellence. I am thankful to Dr. K. R. Mahadik , Dr. R. V.
Shete, Dr. K. S. Jain, Dr. Thakurdesai P. A., Dr. R. J. Patil, Dr. K. S.
Charak, Prof. Mrs. Sarita Gaikwad for their constant encouragement, valuable
guidance and support. I thank to the Management of Navsahyadri Education
Society’s Navsahyadri Institute of Pharmacy, Naigaon (Nasrapur), Pune for
facilitating this book completion. I express my profound appreciation towards my
students, colleagues, teaching & non-teaching staff.
-Dr. K.V. Otari
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Syllabus
Module 01 10 Hours
Pharmacology of Drugs Acting on Cardio Vascular System
 Introduction to hemodynamic and electrophysiology of heart.
 Drugs used in congestive heart failure
 Anti-hypertensive drugs.
 Anti-anginal drugs.
 Anti-arrhythmic drugs.
 Anti-hyperlipidemic drugs.
Module 02 10Hours
Pharmacology of Drugs Acting on Cardio Vascular System
 Drug used in the therapy of shock.
 Hematinics, coagulants and anticoagulants.
 Fibrinolytics and anti-platelet drugs.
 Plasma volume expanders.
Pharmacology of Drugs Acting on Urinary System
 Diuretics.
 Anti-diuretics.
Module 03 10 Hours
Autocoids and Related Drugs
 Introduction to autacoids and classification.
 Histamine, 5-HT and their antagonists.
 Prostaglandins, Thromboxanes and Leukotrienes.
 Angiotensin, Bradykinin and Substance P.
 Non-steroidal anti-inflammatory agents.
 Anti-gout drugs.
 Antirheumatic drugs.
Module 04 08 Hours
Pharmacology of Drugs Acting on Endocrine System
 Basic concepts in endocrine pharmacology.
 Anterior Pituitary hormones- analogues and their inhibitors.
 Thyroid hormones- analogues and their inhibitors.
 Hormones regulating plasma calcium level- Parathormone, Calcitonin and Vitamin
-D.
 Insulin, Oral Hypogl ycemic agents and glucagon.
 ACTH and corticosteroids.
Module 05 07 Hours
Pharmacology of Drugs Acting on Endocrine System
 Androgens and Anabolic steroids.
 Estrogens, progesterone and oral contraceptives.
 Drugs acting on the uterus.
Bioassay
 Principles and applications of bioassay.
 Types of bioassay
 Bioassay of insulin, oxytocin, vasopressin, ACTH, d -tubocurarine, digitalis,
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histamine and 5-HT. *
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Contents
Module 1 1.3.4. Angiotensin Converting 28
Chapter 1: Pharmacology of Drugs Enzyme (ACE) Inhibitors
Acting on CVS 1.3.4.1. Mechanism of Action 28
1.1. Cardiovascular System 15 1.3.4.2. Therapeutic Uses 28
1.1.1. Introduction 15 1.3.4.3. Adverse Effects 29
1.1.2. Hemodynamics 15 1.3.4.4. Individual Drugs 29
1.1.3. Electrophysiology of Heart 16 1.3.5. Angiotensin II Receptor 30
1.2. Drugs Used in Congestive 17 Antagonists
Heart Failure 1.3.5.1. Mechanism of Action 30
1.2.1. Introduction 17 1.3.5.2. Therapeutic Uses 30
1.2.2. Classification 17 1.3.5.3. Adverse Effects 31
1.2.3. Cardiac Glycosides 17 1.3.5.4. Individual Drug - Losartan 31
1.2.3.1. Mechanism of Action 18 1.3.6. Ganglion Blockers 31
1.2.3.2. Pharmacokinetics 18 1.3.6.1. Mechanism of Action 31
1.2.3.3. Pharmacological Actions 19 1.3.6.2. Therapeutic Uses 31
1.2.3.4. Therapeutic Uses 20 1.3.6.3. Adverse Effects 31
1.2.3.5. Adverse Effects 20 1.3.7. Adrenergic Drugs 32
1.2.3.6. Drug Interactions 20 1.3.7.1. Centrally Acting 32
1.2.3.7. Contraindications 21 Sympatholytic Drugs
1.2.3.8. Treatment of Digitalis 21 1.3.7.2. Adrenergic Neuron 33
Toxicity Blockers
1.2.4. Bipyridines 22 1.3.7.3. Sympatholytics 34
1.2.4.1. Mechanism of Action 22 (Adrenergic Receptor
1.2.4.2. Therapeutic Uses 22 Blockers)
1.2.4.3. Adverse Effects 22 1.3.8. Calcium Channel Blockers 37
1.2.5. β-Adrenergic Agonists 22 1.3.8.1. Classification 37
1.2.5.1. Mechanism of Action 22 1.3.8.2. Mechanism of Action 37
1.2.5.2. Therapeutic Uses 23 1.3.8.3. Therapeutic Uses 37
1.2.5.3. Adverse Effects 23 1.3.8.4. Adverse Effects 38
1.2.6. Diuretics 23 1.3.8.5. Individual Drugs 38
1.2.6.1. Mechanism of Action 23 1.3.9. Vasodilators 38
1.2.6.2. Therapeutic Uses 23 1.3.9.1. Mechanism of Action 38
1.2.6.3. Adverse Effects 23 1.3.9.2. Therapeutic Uses 39
1.2.7. Angiotensin Antagonists 24 1.3.9.3. Adverse Effects 39
1.2.7.1. Mechanism of Action 24 1.3.9.4. Individual Drugs 39
1.2.7.2. Pharmacological Actions 24 1.4. Anti-Anginal Drugs 40
1.2.7.3. Therapeutic Uses 24 1.4.1. Introduction 40
1.2.7.4. Adverse Effects 24 1.4.2. Classification 41
1.2.8. β-Adrenoceptor 24 1.4.3. Organic Nitrites & Nitrates 41
Antagonists 1.4.3.1. Mechanism of Action 41
1.2.9. Vasodilators 24 1.4.3.2. Therapeutic Uses 42
1.3. Anti-Hypertensive Drugs 25 1.4.3.3. Adverse Effects 42
1.3.1. Introduction 25 1.4.3.4. Individual Drugs 42
1.3.2. Classification 25 1.4.4. Calcium Channel Blockers 43
1.3.3. Diuretics 26 1.4.4.1. Mechanism of Action 43
1.3.3.1. Mechanism of Action 26 1.4.4.2. Therapeutic Uses 43
1.3.3.3. Adverse Effects 27 1.4.4.4. Individual Drugs 43
1.3.3.4. Individual Drugs 27 1.4.5. Potassium Channel Openers 44
1.4.5.1. Mechanism of Action 44
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1.4.5.2. Therapeutic Uses 44 1.6.4.4. Individual Drug - 58

1.4.5.3. Adverse Effects 45 Cholestyramine
1.4.5.4. Individual Drug - 45 1.6.5. Fibric Acid Derivatives 59
Nicorandil (Fibrates)
1.4.6. β-Adrenoceptor 45 1.6.5.1. Mechanism of Action 59
Antagonists 1.6.5.2. Therapeutic Uses 59
1.4.6.1. Mechanism of Action 45 1.6.5.3. Adverse Effects 59
1.4.6.2. Therapeutic Uses 45 1.6.5.4. Individual Drug - 60
1.4.6.3. Adverse Effects 45 Clofibrate
1.4.6.4. Individual Drug - Atenolol 45 1.6.6. Triglyceride Synthesis and 60
1.4.7. Metabolic Modifiers 46 Lipolysis Inhibitors
1.5. Anti-Arrhythmic Drugs 47 1.6.7. Other Drugs 61
1.5.1. Introduction 47 1.7. Summary 62
1.5.2. Classification 47 1.8. Exercise 63
1.5.3. Sodium Channel Blockers 48
(Class I) Module 2
1.5.3.1. Mechanism of Action 48 Chapter 2: Pharmacology of Drugs
1.5.3.2. Therapeutic Uses 48 Acting on CVS and Haemopoietic
1.5.3.3. Adverse Effects 48
System
1.5.3.4. Individual Drugs 48
2.1. Drugs Used In The 66
1.5.4. -Blockers (Class II) 51
Therapy of Shock
1.5.4.1. Mechanism of Action 51 2.1.1. Introduction 66
1.5.4.2. Therapeutic Uses 51
2.1.2. Treatment for 66
Cardiovascular Shock
2.1.2.1. Sympathomimetic Amines 66
1.5.5. Potassium Channel 52
2.1.2.2. α-Adrenoceptor Blocking 68
Blockers (Class III) Agents
1.5.5.1. Mechanism of Action 53 2.1.2.3. Corticosteroids 69
2.1.2.4. Oxygen 69
2.1.2.5. Cardiac Glycosides 70
2.1.2.6. Glucagon 70
1.5.6. Calcium Channel Blockers 54 2.1.2.7. Dextrans 70
(Class IV)
2.2. Drugs Acting on 71
Haemopoietic System
2.2.1. Introduction 71
2.2.2. Hematinics 71
1.5.6.4. Individual Drug - 54
2.2.2.1. Iron 71
Verapamil 2.2.2.2. Folic Acid 74
1.6. Anti-Hyperlipidemic Drugs 55 2.2.2.3. Vitamin B 12 76
(Cyanocobalamin)
1.6.2. Classification 55
2.2.3. Coagulants 78
1.6.3. HMG-CoA Reductase 55
2.2.3.1. Classification 78
Inhibitors (Statins)
2.2.3.2. Vitamin K 78
1.6.3.1. Mechanism of Action 56 2.2.3.3. Other Drugs 79
1.6.3.2. Therapeutic Uses 56 2.2.4. Anticoagulants 80
2.2.4.1. Classification 80
2.2.4.2. Injectable Anticoagulants - 80
1.6.4. Bile Acid Sequ estrants 57
Heparin
(Resins)
2.2.4.3. Oral Anticoagulants 82
1.6.4.1. Mechanism of Action 58 2.2.4.4. Coumarin Derivatives 82
1.6.4.2. Therapeutic Uses 58 2.2.4.5. Indandione Derivative - 84
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Phenindione *
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2.2.5. Fibrinolytics 84 3.1.4.6. Contraindications 99

2.2.5.1. Mechanism of Action 84 3.1.5. Weak or Adjunctiv e 100
2.2.5.2. Therapeutic Uses 85 Diuretics
2.2.5.3. Adverse Effects 85 3.1.5.1. Mechanism of Action 100
2.2.5.4. Individual Drugs 86 3.1.5.2. Pharmacokinetics 102
2.2.6. Anti-Platelet Drugs 87 3.1.5.3. Therapeutic Uses 103
2.2.6.1. Classification 87 3.1.5.4. Adverse Effects 103
2.2.6.2. Prostaglandin Synthesis 87 3.1.5.5. Drug Interactions 104
(PG) Inhibitors 3.1.5.6. Contraindications 104
2.2.6.3. Phosphodiesterase 88 3.2. Anti-Diuretics 105
Inhibitors 3.2.1. Introduction 105
2.2.6.4. ADP-Induced Platelet 88 3.2.2. Classification 105
Aggregation Inhibitors 3.2.3. Antidiuretic Hormone 105
2.2.6.5. Glycoprotein II b/IIIa 88 3.2.3.1. ADH (Vasopressin) 106
Receptor Inhibitors Receptor
2.2.6.6. Mechanism of Action 89 3.2.3.2. Vasopressin Analogues 106
2.2.6.8. Adverse Effects 90 3.2.3.4. Pharmacokinetics 108
2.2.7. Plasma Volume Expanders 90 3.2.3.5. Pharmacological Actions 108
2.2.7.1. Classification 90 3.2.3.6. Therapeutic Uses 109
2.2.7.2. Human Albumin 90 3.2.3.7. Adverse Effects 109
2.2.7.3. Dextran-40 91 3.2.3.8. Drug Interactions 109
2.2.7.4. Dextran-70 91 3.2.3.9. Contraindications 110
2.2.7.5. Polyvinylpyrrolidone 91 3.2.4. Thiazide Diuretics 110
2.2.7.6. Hetastarch (Hydroxyethyl 91 3.2.4.1. Mechanism of Action 110
Starch) 3.2.4.2. Therapeutic Uses 110
2.2.7.7. Degraded Gelatin Polymer 91 3.2.4.3. Adverse Effects 110
2.3. Summary 92 3.2.4.4. Contraindications 111
2.4. Exercise 92 3.3. Summary 111
3.4. Exercise 111
Chapter 3: Pharmacology of Drugs
Acting on Urinary System Module 3
3.1. Diuretics 94 Chapter 4: Autocoids
3.1.1. Introduction 94 4.1. Autocoids 113
3.1.2. Classification 94 4.1.1. Introduction 113
3.1.3. High Efficacy D iuretics 94 4.1.2. Classification 113
(High Ceiling or Loop 4.1.3. Histamine 113
Diuretics) 4.1.3.1. Biosynthesis 114
3.1.3.1. Mechanism of Action 95 4.1.3.2. Histamine Receptor 115
3.1.3.1. Pharmacokinetics 95 Subtypes
3.1.3.3. Adverse Effects 96 4.1.3.4. Pharmacological Actions 116
3.1.3.4. Drug Interactions 96 4.1.3.5. Pathophysiological Actions 118
3.1.3.5. Contraindications 97 4.1.3.6. Histamine Agonists 119
3.1.4. Medium Efficacy Diu retics 97 4.1.4. Histamine Antagonists 119
(Thiazides and Thiazide - (Antihistamines)
Like Drugs) 4.1.4.1. H1-Antagonists 120
3.1.4.1. Mechanism of Action 97 4.1.4.2. H2-Antagonists 122
3.1.4.2. Pharmacokinetics 98 4.1.4.3. H3 Antagonists 123
3.1.4.3. Therapeutic Uses 98 4.1.4.4. H4 Antagonists 123
3.1.4.4. Adverse Effects 99 4.1.5. 5-HT (Serotonin) 124
3.1.4.5. Drug Interactions 99 4.1.5.1. Biosynthesis & Metabolism 124
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4.1.5.2. 5-HT Receptor Subtypes 125 5.1.3. Classification 147

4.1.5.3. Mechanism of Action 127 5.1.4. Salicylates - Aspirin 147
4.1.5.4. Pharmacological Actions 127 5.1.4.1. Mechanism of Action 147
4.1.5.5. 5-HT Agonists 128 5.1.4.2. Pharmacokinetics 147
4.1.6. 5-HT Antagonists 129 5.1.4.3. Pharmacological Actions 148
4.1.7. Prostaglandins (PGs) 130 5.1.4.4. Therapeutic Uses 149
4.1.7.1. Synthesis 131 5.1.4.5. Adverse Effects 149
4.1.7.2. Pharmacological Actions 131 5.1.4.6. Drug Interactions 150
4.1.7.3. Therapeutic Uses 132 5.1.4.7. Contraindications 150
4.1.7.4. Adverse Effects 132 5.1.5. Pyrazolone Derivatives 151
4.1.7.5. Prostaglandin Agonists 132 5.1.6. Indole Derivatives - 151
4.1.7.6. Prostaglandin Antagonists 134 Indomethacin
4.1.8. Thromboxanes 134 5.1.6.1. Mechanism of Action 151
4.1.8.1. Synthesis 134 5.1.6.2. Pharmacokinetics 152
4.1.8.2. Mechanism of Action 135 5.1.6.3. Therapeutic Uses 152
4.1.9. Leukotrienes (LTs) 135 5.1.7. Propionic Acid Derivatives 152
4.1.9.1. Types 135 - Ibuprofen
4.1.9.2. Synthesis 135 5.1.7.1. Mechanism of Action 153
4.1.9.3. Pharmacological Actions 136 5.1.7.2. Pharmacokinetics 153
4.1.9.4. Pathophysiological Actions 137 5.1.7.3. Therapeutic Uses 153
4.1.10. Angiotensin (AT) 137 5.1.7.4. Adverse Effects 154
4.1.10.1. Angiotensin Receptors 137 5.1.8. Anthranilic Acid Derivatives 154
(ATRs) – Mefenamic Acid
4.1.10.2. Synthesis and Metabolism 138 5.1.8.1. Mechanism of Action 154
4.1.10.3. Pharmacological Actions of 138 5.1.8.2. Pharmacokinetics 154
Angiotensin-II 5.1.8.3. Therapeutic Uses 154
4.1.10.4. Inhibition of Renin - 139 5.1.8.4. Adverse Effects 154
Angiotensin System 5.1.9. Aryl Acetic Acid Derivatives154
4.1.10.5. Angiotensin Converting 139 - Diclofenac
Enzyme (ACE) Inhibitor 5.1.9.1. Mechanism of Action 155
4.1.10.6. Angiotensin Receptor 140 5.1.9.2. Pharmacokinetics 155
Antagonists 5.1.9.3. Therapeutic Uses 155
4.1.11. Bradykinin 140 5.1.9.4. Adverse Effects 155
4.1.11.1. Synthesis and Metabolism 140 5.1.10. Oxicam Derivatives - 155
4.1.11.2. Receptors 141 Piroxicam
4.1.11.3. Pharmacological Actions 141 5.1.10.1. Mechanism of Action 155
4.1.11.4. Therapeutic Uses 141 5.1.10.2. Pharmacokinetics 155
4.1.12. Substance P 142 5.1.10.3. Therapeutic Uses 156
4.1.12.1. Pharmacological Actions 142 5.1.10.4. Adverse Effects 156
4.1.12.2. Therapeutic Uses 142 5.1.11. Pyrrolo-Pyrrole Derivatives 156
4.1.12.3. Substance P Antagonist 142 - Ketorolac
4.2. Summary 143 5.1.12. Preferential COX -2 156
4.3. Exercise 143 Inhibitors - Nimesulide
Chapter 5: Non-Steroidal Anti- 5.1.12.2. Therapeutic Uses 156
Inflammatory Agents 5.1.12.3. Adverse Effects 156
5.1. Non-Steroidal Anti - 145 5.1.13. Selective COX -2 Inhibitors 157
Inflammatory Drugs - Celecoxib
(NSAIDs) 5.1.13.1. Mechanism of Action 157
5.1.1. Introduction 145 5.1.13.2. Therapeutic Uses 157
5.1.2. Mechanism of Action 145 5.1.13.3. Adverse Effects 157
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– 12 –
5.1.14. Para-Aminophenol 157 7.1.1. Introduction and Basic 172

Derivatives - Paracetamol Concepts in Endocrine
5.1.14.1. Mechanism of Action 157 Pharmacology
5.1.14.2. Pharmacokinetics 157 7.1.2. Hormones 173
5.1.14.3. Therapeutic Uses 157 7.1.3. Classification 173
5.1.14.4. Adverse Effects 158 7.2. Anterior Pituitary 173
5.1.15. Pyrazolone Derivatives - 158 Hormones
Metamizol (Dipyrone) 7.2.1. Introduction 173
5.1.16. Benzoxazocine Derivatives 158 7.2.2. Growth Hormone 175
- Nefopam (Somatotropin)
5.2. Summary 159 7.2.2.1. Regulation of Secretion 175
5.3. Exercise 159 7.2.2.2. Physiological Actions 176
7.2.2.3. Growth Hormone 176
Chapter 6: Anti-Gout and Analogues
Antirheumatic Drugs 7.2.2.4. Growth Hormone Inhibitors 176
6.1. Anti-Gout Drugs 161 7.2.2.5. Growth Hormone 177
6.1.1. Introduction 161 Abnormalities
6.1.2. Classification 161 7.2.3. Prolactin (Prl) 177
6.1.3. Mechanism of Action 161 7.2.3.1. Regulation of Secretion 177
6.1.4. Therapeutic Uses 162 7.2.3.2. Physiological Actions 178
6.1.5. Adverse Effects 162 7.2.3.3. Prolactin Inhibitors - 178
6.1.6. Individual Drugs 162 Bromocriptine
6.1.6.1. Probenecid 162 7.2.3.4. Prolactin Abnormalities 179
6.1.6.2. Colchicine 163 7.2.4. Thyroid Stimulating 180
6.1.6.3. NSAIDs 164 Hormone (TSH,
6.1.6.4. Allopurinol 164 Thyrotropin)
6.1.6.5. Sulfinpyrazone 165 7.2.4.1. Regulation of Secretion 180
6.2. Antirheumatic Drugs 165 7.2.4.2. Physiological Actions 180
6.2.1. Introduction 165 7.2.4.3. Use 181
6.2.2. Classification 166 7.2.4.4. TSH Abnormalities 181
6.2.3. Disease Modifying Anti - 166 7.2.5. Gonadotropins 181
Rheumatic Drugs 7.2.5.1. Regulation of Secretion 182
(DMARDs) 7.2.5.2. Physiological Actions 182
6.2.3.1. Methotrexate (MTX) 166 7.2.5.3. Uses 183
6.2.3.2. Azathioprine 167 7.2.5.4. Gonadotropin Analogues 183
6.2.3.3. Sulfasalazine 167 7.2.5.5. Gonadotropin Inhibitors 184
6.2.3.4. Chloroquine 167 7.2.5.6. Gonadotropin 184
6.2.3.5. Leflunomide 167 Abnormalities
6.2.3.6. Gold Salts 168 7.3. Posterior Pituitary 184
6.2.3.7. Penicillamine 168 Hormones
6.2.4. Biologic DMARDs 169 7.3.1. Introduction 184
6.2.5. Corticosteroids 169 7.3.2. Vasopressin (Anti -Diuretic 185
6.3. Summary 170 Hormone, ADH)
6.4. Exercise 170 7.3.2.1. Regulation of Secretion 185
7.3.2.2. Physiological Actions 185
Module 4 7.3.2.3. Uses 186
7.3.2.4. Vasopressin Abnormalities 186
Chapter 7: Pharmacology of Drugs
7.4. Thyroid Hormones 187
Acting on Endocrine System - I 7.4.1. Introduction 187
7.1. Pharmacology of Drugs 172 7.4.2. Synthesis, Storage, 187
Acting on Endocrine Release, and Metabolism
System 7.4.3. Regulation of Secretion 188
* *
– 13 –
7.4.4. Physiological Actions 189 7.6.2.8. Insulin Analogues 207

7.4.5. Uses 190 7.6.2.9. Insulin Abnormalities 208
7.4.6. Thyroid Hormone 191 7.6.3. Oral Hypoglycaemic 208
Abnormalities Agents
7.4.7. Thyroid Hormone 191 7.6.3.1. Classification 209
Inhibitors 7.6.3.2. Sulfonylureas 209
7.4.7.1. Anti-Thyroid Drugs - 192 7.6.3.3. Biguanides 210
Propylthiouracil 7.6.3.4. Meglitinide Analogues 211
7.4.7.2. Ionic Inhibitors 192 7.6.3.5. Thiazolidinediones 211
7.4.7.3. Iodine and Iodides 192 7.6.3.6. -Glucosidase Inhibitors 212
7.4.7.4. Radioactive Iodine (RAI) 193 7.6.4. Glucagon 213
7.5. Hormones Regulating 194 7.6.4.1. Synthesis 213
Plasma Calcium Level 7.6.4.2. Regulation of Secretion 213
7.5.1. Introduction 194 7.6.4.3. Mechanism of Action 213
7.5.2. Parathormone (Parathyroid 194 7.6.4.4. Physiological Actions 214
Hormone, PTH) 7.6.4.5. Uses 214
7.5.2.1. Synthesis 195 7.6.4.6. Glucagon Abnormalities 215
7.5.2.2. Regulation of Secretion 195 7.7. ACTH (Corticotropin or 215
7.5.2.3. Mechanism of Action 195 Adrenocorticotropic
7.5.2.4. Physiological Actions 195 Hormone)
7.5.2.5. Uses 196 7.7.1. Introduction 215
7.5.2.6. PTH Abnormalities 196 7.7.2. Regulation of Secretion 215
7.5.3. Calcitonin 197 7.7.3. Physiological Actions 216
(Thyrocalcitonin) 7.7.4. Uses 216
7.5.3.1. Synthesis 197 7.7.5. ACTH Abnormalities 216
7.5.3.2. Regulation of Secretion 197 7.8. Corticosteroids 217
7.5.3.3. Mechanism of Action 198 7.8.1. Introduction 217
7.5.3.4. Physiological Actions 199 7.8.2. Biosynthesis 217
7.5.3.5. Uses 199 7.8.3. Glucocorticoids (GCs) 219
7.5.3.6. Calcitonin Abnormalities 199 7.8.3.1. Regulation of Synthesis 219
7.5.4. Vitamin D (Calcitriol) 199 7.8.3.2. Mechanism of Action 219
7.5.4.1. Synthesis 200 7.8.3.3. Pharmacokinetics 220
7.5.4.2. Regulation of Synthesis 200 7.8.3.4. Physiological Actions 220
7.5.4.3. Mechanism of Action 201 7.8.3.5. Uses 221
7.5.4.4. Pharmacokinetics 201 7.8.3.6. Adverse Effects 222
7.5.4.5. Physiological Actions 201 7.8.3.7. Contraindications 222
7.5.4.6. Uses 202 7.8.4. Mineralocorticoids 223
7.5.4.7. Drug Interactions 202 7.8.4.1. Regulation of Synthesis 223
7.5.4.8. Vitamin D Abnormalities 202 7.8.4.2. Mechanism of Action 224
7.5.4.9. Vitamin D Toxicity 202 7.8.4.3. Pharmacokinetics 224
7.6. Insulin, Oral 202 7.8.4.4. Physiological Actions 224
Hypoglycaemic Agents 7.8.4.5. Uses 225
and Glucagon 7.8.4.6. Adverse Effects 225
7.6.1. Introduction 202 7.8.5. Corticosteroid Inhibitors 225
7.6.2. Insulin 203 7.9. Summary 226
7.6.2.1. Insulin Preparations 203 7.10. Exercise 227
7.6.2.2. Synthesis 203
7.6.2.3. Regulation of Secretion 204 Module 5
7.6.2.4. Mechanism of Action 205 Chapter 8: Pharmacology of Drugs
Acting on Endorcine System - II
7.6.2.6. Uses 206
8.1. Male Sex Hormones 229
7.6.2.7. Drug Interactions 207
* *
– 14 –
8.1.2. Androgens 229 8.2.4.6. Adverse Effects 243

8.1.2.1. Classification 230 8.2.4.7. Drug Interactions 244
8.1.2.2. Synthesis 230 8.2.4.8. Contraindications 244
8.1.2.3. Regulation of Secretion 230 8.3. Drugs Acting on the 244
8.1.2.4. Mechanism of Action 231 Uterus
8.1.2.5. Pharmacokinetics 231 8.3.1. Introduction 244
8.1.2.6. Physiological Actions 231 8.3.2. Classification 244
8.1.2.7. Uses 231 8.3.3. Uterine Stimulants 245
8.1.2.8. Androgen Abnormalities 232 (Oxytocics, Abortifacients)
8.1.3. Anabolic Steroids 232 8.3.3.1. Oxytocin 245
8.1.3.1. Physiological Actions 233 8.3.3.2. Ergometrine 248
8.1.3.2. Uses 233 8.3.3.3. Prostaglandins 250
8.1.3.3. Adverse Effects 233 8.3.4. Uterine Relaxants 252
8.2. Female Sex Hormones 234 (Tocolytics)
8.2.1. Introduction 234 8.3.4.1. Adrenergic Agonists 253
8.2.2. Estrogens 234 8.3.4.2. Calcium Channel Blockers 253
8.2.2.1. Classification 234 8.3.4.3. Magnesium Sulphate 254
8.2.2.2. Synthesis 234 8.3.4.4. Oxytocin Antagonist 254
8.2.2.3. Regulation of Secretion 235 8.3.4.5. Miscellaneous Drugs 254
8.2.2.4. Mechanism of Action 236 8.4. Summary 254
8.2.2.5. Pharmacokinetics 236 8.5. Exercises 255
8.2.2.7. Uses 237 Chapter 9: Bioassay
8.2.2.8. Drug Interactions 237 9.1. Bioassay 257
8.2.2.9. Contraindications 237 9.1.1. Introduction 257
8.2.2.10. Estrogen Abnormalities 237 9.1.2. Principles 257
8.2.3. Progesterone 237 9.1.3. Applications 258
8.2.3.1. Classification 238 9.1.4. Types of Bioassay 259
8.2.3.2. Synthesis 238 9.1.5. Bioassay of Individual 262
8.2.3.3. Regulation of Secretion 238 Drugs
8.2.3.4. Mechanism of Action 238 9.1.5.1. Insulin 262
8.2.3.5. Pharmacokinetics 239 9.1.5.2. Oxytocin 265
8.2.3.6. Physiological Actions 239 9.1.5.3. Vasopressin 267
8.2.3.7. Uses 239 9.1.5.4. ACTH 269
8.2.3.8. Progesterone Abnormalities 240 9.1.5.5. d-Tubocurarine 270
8.2.4. Oral Contraceptives 240 9.1.5.6. Digitalis 271
8.2.4.1. Classification 240 9.1.5.7. Histamine 272
8.2.4.2. Contraception Methods 241 9.1.5.8. 5-HT 273
8.2.4.3. Mechanism of Action 242 9.2. Summary 276
8.2.4.4. Physiological Actions 243 9.3. Exercises 277
8.2.4.5. Uses 243
* *
Pharmacology of Drugs Acting on CVS (Chapter 1) 15
CHAPTER Pharmacology of Drugs

1 Acting on CVS
1.1. CARDIOVASCULAR SYSTEM

1.1.1. Introduction
Cardiovascular system comprises of the heart and an extensively branched
structure of blood vessels that transports oxygen, nutrients , heat, and other
substances throughout the body.
Cardiac or heart muscles are involuntary striated muscles found in the heart and
its walls, especially in the myocardium (the muscle tissue forming a thick
middle layer amid the outer epicardium and the inner endocardium ). For
delivering oxygen and nutr ients, and removing waste products such as carbon
dioxide, the cardiac muscle cells depend on the available blood and e lectrical
supply.
The myocardial tissue is made up of contracting cells and conducting cells .
The pumping action of the heart involves the contracting cells. The
conducting tissues of the heart include SA node (acts as the pacemaker), AV
node, and His -Purkinje system. Various parts of the conducting tissue exhibit
automaticity. Cardiac muscles being specialised tissues have distinct
properties of:
1) Excitability: It is the ability of cardiac cells to depolarise in response to a
stimulus.
2) Contractility: It is the ability of myocardium to contract and pump blood out
of the heart.
3) Automaticity: It is the ability of cardiac cells to generate electrical impulses
spontaneously.
1.1.2. Hemodynamics
The study of the dynamic behaviour of blood is termed hemodynamics.
Pressures are generated in the various parts of heart (cardiovascular pressures)
when blood flows from one chamber to another, when valves open and close, and
when the myocardium contracts and relaxes. Catheters are used to measure and
monitor these pressures by placing their tips in the atria, pulmonary artery , or
systemic arteries; these are called the hemodynamic lines.
Hemodynamic lines have multiple uses:
1) They allow the sampling of venous and arterial blood without having to stick
a patient frequently.
2) They help in monitoring different waveforms, thus providing evidences to
patient’s status.
* *
16 Pharmacology-II
3) The cardiac output can be calculated with the combination of pulmonary,

arterial, and systemic arterial lines.
4) They allow direct monitoring of various cardiac pressures, and a nalysis of
these pressures helps in planning and assessing therapy in shock, cardiac
failure, fluid overload or deficit, and other conditions.
1.1.3. Electrophysiology of Heart

The cardiac cell is a polarised membrane . It has a resting membrane potential of
–80 to –90mV, and a high Na+ ion concentration outside the membrane and K +
ion concentration inside the membrane. Upon excitation, depolarisation occurs as
the cell membrane permeability to Na + ions increases, the negativity of resting
potential is lost, and a positive current is gen erated inside the cell. The
characteristics of action potential rely on the type of the cell -myocardial
contractile cell, or pacemaker, or potential pacemaker cell. There are five phases
of the action potential of cardiac cells (figure 1.1):
1) Phase 0: In t his phase, rapid
depolarisation of the cell membrane +20 1
+10 2
is observed as the sodium ions
0
rapidly enter the cell through sodium –10 ERP
channels. This phase is followed by –20
re-polarisation. –30
2) Phase 1: In this short and initial –40 0 3
phase, rapid re-polarisation is –50
observed as the potassium ions move –60
out of the cell. –70
–80 4
3) Phase 2: This prolonged plateau –90
phase is observed as the calcium –100
ions enter the cell slowly through the Figure 1.1: Phases of Cardiac Action Potential.
Phase 0 Indicates Rapid Depolarisation, Phases
calcium channels . This phase of 1-3 Indicate Repolarisation, Phase 4 Indicates
action potential is present only in the Gradual Depolarisation during Diastole.
cardiac cells.
4) Phase 3: This phase is th e second period of rapid re -polarisation as the
potassium ions move out of the cell.
5) Phase 4: This is the resting phase as the resting membrane potential is re -
established when the potassium ions return into the cell and sodium and
calcium ions move out of it.
The cell s do not depolarise in response to another impulse during the phases 1
and 2; and this is called the absolute refractory period. The cells depolarise in
response to a powerful impulse d uring the phases 3 and 4 ; and this is called the
relative refractory period.
The heart rate and stroke volume are used for determining the cardiac output. The
stroke volume depends on the preload (which itself depends on venous return) ,
afterload, and contractility. The load on the heart due to the blood volume
reaching the left ventricle is called preload; while the resistance to the left
ventricular ejection, i.e., the total peripheral resistance is called afterload.
* *
1.2. DRUGS USED IN CONGESTIVE HEART

FAILURE
1.2.1. Introduction
When a heart fails to pump blood in a quantity sufficient to fulfil the body
requirements, a condition of Congestive Heart Failure (CHF) occurs, which is
also known as a Heart Failure (HF).
CHF is caused due to:
1) Narrowing of the arteries supplying blood to the heart muscles,
2) Any congenital heart defects,
3) Endocarditis (infection in heart valves) or myocarditis (infection of heart
muscles),
4) Cardiomyopathy (disease of the heart muscles),
5) Any long -term heart valve disease (due to past rheumatic fever or other
causes) and high blood pressure, and
6) Past history of the patient who has suffered from myocardial infar ction or
heart attack and the injured tissue obstructs the normal functioning of heart.
Some common symptoms of CHF are:
1) Fatigue, 2) Swelling or oedema,
3) Shortness of breath, and 4) Increased urination.
1.2.2. Classification
The following drugs are employed in the treatment of CHF:
1) Drugs with Positive Inotropic Effects
i) Cardiac Glycosides: Digoxin, Digitoxin, and Ouabain.
ii) Bipyridines/Phosphodiesterase Inhibitors: Amrinone and Milrinone.
iii) β-Adrenergic Agonists: Dobutamine and Dopamine.
2) Drugs without Positive Inotropic Effects
i) Diuretics: Thiazides, Furosemide, and Spironolactone.
ii) Angiotensin Antagonists: ACE inhibitors and Losartan.
iii) β-Adrenergic Antagonists: Bisoprolol, Carvedilol, and Metoprolol.
iv) Vasodilators: Nitrates and Hydralazine.
1.2.3. Cardiac Glycosides

Cardiac glycosides are derived from plant derivatives and are steroidal in nature .
A glycoside is a sugar-containing compound in which one of the hydroxyl groups
of the sugar molecule is replaced with another compound.
Digoxin, digitoxin, and ouabain are the commonly used cardiac glycosides.
Often, the term digitalis refers to the complete group of cardiac glycosides as all
the drugs in this group exert the same effects on the heart. They differ only in
lipid solubility, rapidity, degree of absorption, protein binding, metabolic
pathway, and excretion.
* *
18 Pharmacology-II
1.2.3.1. Mechanism of Action

The mechanism of action of digitalis can be explained as follows (figure 1.2):
1) Digitalis exerts a positive inotropic effect due to its ability to potentiate the
excitation-contraction coupling. This is possible since digitalis increases the
concentration of free intracellular Ca2+ ions.
a b c Ca2+
Na+ K+
Na+ exchange Myocardial cell
K+ Na+ * Na+ Ca2+

Na+- K+-
ATPase Ca2+ SR d
e
Ca + Troponin
Actin + Myosin
Actomyosin
Myocardial contraction
* Digitalis acts on the enzyme Na+/K+-ATPase
Figure 1.2: Cellular Mechanism of Digitalis Action.
a) Tendency of Na+ to flow in and K+ to flow out along the concentration
gradient; b) Na+/K+-ATPase pushing the Na+ out and drawing the K+ in;
c) Na+/Ca2+ exchange mechanism; d) Release of Ca2+ from Sarcoplasmic
Reticulum (SR); e) Ca2+ + troponin initiating myocardial contraction.
2) It inhibits the membrane bound Na +/K+-ATPase transport system (sodium
pump), resulting in increase of intracellular Na + ions and loss of intracellular
K+ ions.
3) As Na + ions accumulate inside the cell, it activates a Na +/Ca2+ carrier system
(a non -enzymatic protein carrier) within the membrane. The activation of
Na+/Ca2+carrier system results in an increase in the influx of Ca 2+ ions. Three
Na+ ions are exchanged for each Ca2+ ion, thereby generating an electrogenic
potential by this exchanger.
4) Normally, the concentration of Ca2+ ions around the myofilaments is lowered by
the Ca2+ ion pump in the Sarcoplasmic Reticulum (SR). The energy for driving
+
this pump is obtained by ATP hydrolysis carried out by Na /K+-ATPase.
However, digitalis inhibits this enzyme and hence less energy is available for
driving the Ca2+ ion pump. Thus, the supply of Ca 2+ ions from SR around the
myofilaments increases, which in turn activates the contractile machinery.
5) The binding of digitalis to sodiu m pump is inhibited by the K+ ions present in
the serum. Hence, conditions of hypokalaemia facilitate the action of
digitalis. On the other hand, conditions of hyperkalaemia can decrea se
cardiac toxicity. Arrhythmia induced by digitalis, is increased by co nditions
of hypercalcaemia or hypomagnesaemia.
1.2.3.2. Pharmacokinetics
Route of administration of digitalis is either oral or intravenous. It is not
suitable for administration by subcutaneous or intramuscular routes as its
absorption from these sites is not re liable and may bring about local irritation,
tenderness, swelling, and abscess.
* *
Digitalis does not bind selectively to the myocardium when administered through
these sites. Digitalis is a cumulative drug. It has a prolonged half -life and the
duration of its action ranges from days to weeks . The prolonged plasma half -
life of digitoxin is due to its enterohepatic circulation.
1.2.3.3. Pharmacological Actions

Cardiac glycosides have the capability of increasing the myocardial contraction force,
which is the most sig nificant property of these drugs. Other than this, they have
several extra-cardiac effects on vascular smooth muscle s, kidneys, gut and theCNS:
1) Actions on Heart
i) Administration in small doses causes an increase in the vagal tone by
sensitisation of baroreceptors and/or activity of the afferent nerves. As a
result, sinus activity decreases which le ads to decrease in conductivity,
prolongation of refractory period of the AV node, decre ase in atrial
refractory period, and bradycardia.
ii) Contractility of the myo cardium increases by a direct positive
inotropic action of digitalis on the heart. Thus, the failing heart contracts
even more forcefully, which results in increased cardiac output, complete
ventricular emptying, and decreased diastolic pressure and ventricular
size. Systole lasts for a shorter duration, giving more time for ventricular
filling and rest to the heart.
iii) With the increase in contractility of heart, the oxygen consumption in the
myocardium increases. On the other hand, decrease in the heart rate and
ventricular size decreases oxygen requirements of the heart. Hence, the
general effect of digitalis is an improved ventricular performance of
the failing heart without any significant increase in energy requirement.
iv) When administered in comparatively small therapeutic doses, digitalis
improves the ability of excitation of the myocardium and the
conduction velocity. However, its administration in high doses causes an
increased automaticity and decreases the refractory period of the atria
and the ventri cles, resulting in extra -systoles, pulsus bigeminus , and
ventricular fibrillation.
v) Digitalis slows the conduction velocity in the AV node and His-Purkinje
system, regardless of the dose administered. This is achieved by an
increase in the refractory period by both vagal as well as the extra -vagal
actions of digitalis. Low doses are characterised by a predominance of
vagal effects . As the dose is increased, direct depressant action on the
AV node is seen.
vi) Digitalis does not act directly to influence the coronary flow. The
enhanced coronary circulation is a secondary effect of the increased
cardiac output and extended diastole.
vii) Changes evident in an ECG after administration of digitalis includes
prolongation of the PR interval (due to delayed conduction) and
shortening of QT interval (shorter ventricular systole). Other changes
are that the ST segment sags below the isoelectric line , and the T-wave
appear smaller, inverted or disappears.
* *
20 Pharmacology-II
2) Extra-Cardiac Effects of Digitalis

i) On Blood Vessels: Digitalis exerts a minor direct constrictor action on
the smooth muscles of arteries and veins.
ii) On Kidneys: Digitalis improves circulation and decreases sympathetic
activity, thereby increasing the blood flow to kidneys. This increases the
urinary output and relieves oedema ni patients with cardiac oedema.
iii) On Gastrointestinal Tract: Digitalis stimulates the Chemoreceptor
Trigger Zone(CTZ) in the medulla, thus resulting in nausea and vomiting.
iv) On CNS: Digitalis may produce symptoms of visual disturbances such
as blurring of vi sion, photophobia, a dark spot in centre of vision , and
disturbances of coloured vision with yellow and green. In some patients,
psychic symptoms and confusion may also be seen.
1.2.3.4. Therapeutic Uses

Cardiac glycosides have the following therapeutic benefits:
1) Patients with congestive heart failure characterised by a dilated, failing heart
with low cardiac output (impaired systolic function) are benefited by
administration of digitalis.
2) Treatment of low output cardiac failure with digitalis, in patients where t he
myocardium is not principally damaged, shows the best results. Examples of
such conditions include atrial fibrillation, valvular defects, and hypertension.
3) The management of cardiac arrhythmias (supraventricular tachyarrhythmias),
like atrial flutter and atrial fibrillation, occurring either with or without CCF,
employs the use of digitalis.
1.2.3.5. Adverse Effects

Digitalis is highly toxic. It has a low margin of safety with a therapeutic index
ranging from 1.5 -3. Patients with stead y-state plasma digoxin le vels report a
higher cardiac mortality during maintenance therapy. Nearly 25% of the patients
show either of the toxic symptoms, which include:
1) Extra-Cardiac Effects: These adverse effects are seen initially and include
anorexia, nausea, vomiting, and abdo minal pain. These effects appear due to
gastric irritation, mesenteric vasoconstriction, and CTZ stimulation. The
other adverse effects include fatigue, absence of a desire to walk or lift an
arm, malaise, headache, mental confusion, restlessness, hyperpno ea,
disorientation, psychosis, and visual disturbances . Rare adverse effects
include diarrhoea, skin rashes, and gynaecomastia.
2) Cardiac Effects: Digitalis produces almost every type of arrhythmia,
including pulsus bigeminus, nodal and ventricular extrasyst oles, ventricular
tachycardia, and terminally fibrillation.
1.2.3.6. Drug Interactions

Cardiac glycosides undergo the following drug interactions:
1) Administration of digitalis with a diuretic results in hypokalaemia, which
can precipitate digitalis arrhythmias.
* *
2) Administration of digitalis with calcium synergises the actions of digitalis,

thereby precipitating toxicity.
3) Quinidine decreases the binding of digoxin to tissue proteins.
4) Administration of digitalis with adrenergic drugs induces arrhythmias and
increases ectopic automaticity.
5) Metoclopramide (gastrointestinal hurrying), sucralfate, neomycin,
sulphasalazine, and antacids decrease the absorption of digoxin by adsorbing it.
6) Atropinic drugs including tricyclic antidepressants increase the absorption
of digoxin by delaying its gastric emptying.
7) Erythromycin, omeprazole, and tetracycline increase the bioavailability of
digoxin.
8) Propranolol, verapamil, diltiazem, and disopyramide oppose the positive
inotropic action of digitalis and may add to the depression of A
-V conduction.
9) Phenobarbitone accelerates the m etabolism of digitoxin , thus , reducing its
plasma half-life.
10) Administration of succinylcholine by the patients on digitalis therapy causes
arrhythmias.
1.2.3.7. Contraindications
Cardiac glycosides are contraindicated in the following conditions:
1) Digitalis is contraindicated in hypokalaemia as its binding to Na+K+-ATPase
is increased, thus increasing digitalis toxicity.
2) It is contraindicated in elderly and in patients having severe renal or hepatic
disease.
3) It is con traindicated in myocardial infarction as s evere arrhythmias may
develop.
4) It is contraindicated in thyrotoxicosis as the patient’s responsiveness
decreases, and arrhythmias may also develop.
5) It is contraindicated in ventricular tachycardia as it may precip itate
6) It is contraindicated in Wolff-Parkinson-White Syndrome as it may result
in ventricular failure.
7) Administration of digitalis in patients with a partial A-V block may convert
it into a complete A-V block.
8) Digoxin is contrain dicated in myxoedema as its elimination rate decreases,
thus, cumulative toxicity of digitalis may be seen.
1.2.3.8. Treatment of Digitalis Toxicity
The cases of digitalis toxicity can be treated in the following ways:
1) Withdrawal: Administration of digitalis should either be stopped or the dose
should be reduced based on the severity of toxicity. Use of potassium
depleting diuretics should be discontinued.
2) Potassium Repletion: KCl is administered by oral route (or by slow IV drip)
in a dosage of 2gm in every 4 hour s. During this time, ECG of the patient
should be continuously monitored. However, in case of a severe AV block,
*
KCl should not be given. *
22 Pharmacology-II
3) Antiarrhythmic Drugs: Ventricular tachyarrhythmias can be suppressed by

phenytoin and lignocaine since they have eith er little or no effect on
conduction. Phenytoin is administered in a dose of 100mg via IV infusion in
every 5 minutes till arrhythmia is treated.
Supraventricular and ventricular tachycardia, without AV block, can be
treated by administering propranolol in dosages of 20-80mg/day.
Sinus bradycardia and various degrees of AV block can be controlled with
atropine.
4) Advanced Cases of Life Threatening Digitalis Intoxication:Such conditions
can be reversed by inserting a temporary cardiac pacemaker catheter,long
a with
purified digoxin-specific antibody (digitalis immune fab) fragments.
1.2.4. Bipyridines
Bipyridine derivatives ( e.g., amrinone and milrinone) show phosphodieste rase
(PDE) inhibiting activity. These drugs are selective inhibitors of PDE-isoenzyme
III, found in the cardiac and smooth muscles.

Bipyridines increase the production of cAMP in the heart and blood vessels , and
thus exert a positive inotropic action along with vas odilator activities. Increased
2+
levels of intracellular cAMP enable the availability of more intracellular Ca
ions, thus, a more positive inotropism may result.

Cardiac output is increased. The peripheral vascular resistance and the after-load
are decreased with no significant change in heart rate and blood pressure.
Bipyridines are used only for the treatment of heart failure or exacerbation of CCF.

Given below are the adverse effects of bipyridine derivatives:
1) Amrinone causes nausea, vomiting, liver enzyme changes, and occasionally
thrombocytopenia.
2) Milrinone may cause cardiac arrhythmia, bone marrow depression, and liver
toxicity.
Due to these adverse effects, these agents are used for short-term therapy only.
1.2.5. β-Adrenergic Agonists

The discovery of 1-agonists has sufficed the search for a positive inotropic -
agonist with minimal positive chronotropic and arrhythmogenic potential, with
dobutamine being the most potential one amongst these agents.

The β-adrenergic agonists increase the cardiac output, and decrease the
ventricular filling pressure and pre -load. Some degree of tachycardia is also seen
with the use of these drugs. They increase the consumption of oxygen.
* *

The β-adrenergic agonists have been limited to the management of acute heart
failure. They may occasionally be employed in the treatment of refractory
CCF.

The β-adrenergic agonists may cause tachyphylaxis.
1.2.6. Diuretics
Diuretics are commonly used in the management of CHF. Since the last 50 years,
these agents are favoured for CHF treatment.

Diuretics increase the excretion of salt and water. This in turn decreases the
ventricular pre -load and the cardiac size, improves pump function , and helps
relieve oedema. In CHF patients, aldosterone promotes fibrosis in the heart and
blood vessels. This effect of aldosterone is antagonised by spironolactone (an
aldosterone antagonist).

Diuretics are used in the management of all stages of CHF. Furosemide is a very
efficient diuretic in treating acute left ventricular failure (cardiac asthma).

The adverse effects of various classes of diuretics are:
1) Loop Diuretics : Hypokalae mia is a common adverse effect. Patients on
long-term diuretics require potassium supplements and regular
monitoring. At high doses, hyponatraemia may occur, whi ch needs
careful supervision in heart failure patients. Ototoxicity characterised
with tinnitus, vertigo and deafness also occurs at high doses of loop
diuretics. Therefore, intravenous administration of furosemide should not
be faster than 4mg/min.
2) Thiazide Diuretics: Due to potassium and sodium loss, the adverse effects
of thiazide diuretics are similar to those of loop diuretics. However, the
potassium loss is reduced when ACE inhibitors are simultaneously
prescribed. Diabetic patients need monitoring as diabetes may occur with
thiazide diuretics. Impotence as well as sensitivity may also develop due to
the presence of sulphonamide in the drugs.
3) Aldosterone Antagonists : Adverse effects include fibrosis, hypertrophy ,
arrhythmogenesis, and hyperkalaemia, wh ich require regular monitoring
because of its potentially lethal effects in CHF patients due to renal
failure.
Hyponatraemia and feminisation such as gynaecomastia are other adverse

effects. In patients having severe symptomatic systolic heart failure,
spironolactone is recommended along with ACE inhibitors.
* *
24 Pharmacology-II
1.2.7. Angiotensin Antagonists

The ACE inhibitors and angiotensin receptor blockers are included in this group.
Drugs which inhibit the activity of RAS either interfere with the biosynthesis of
angiotensin II [Angiotensin Converting Enzyme (ACE) inhibitors], or act as
antagonists of angiotensin receptors [Angiotensin Receptor Blockers (ARBs)].
The production of an giotensin II from angiotensin I is inhibited by ACE
inhibitors. These agents neutralise the raised peripheral vascular resistance and
retention of sodium and water that resulted from angiotensin II and aldosterone.
1.2.7.2. Pharmacological Actions

The pharmacological actions of angiotensin antagonists are:
1) Reduction in peripheral arterial resistance and after-load.
2) Reduction in aldosterone secretion, thus decreasing the retention of salt and
water. This causes venodilatation and reduces pre-load.
3) Reduction in angiotensin concentration in the tissues, thus reducing
angiotensin-induced tissue norepinephrine release.
4) Reduction in the long-term remodelling of heart and blood vessels.
Angiotensin antagonists are indicated in all symptomatic and asympto matic
patients with Left Ventricular (LV) dysfunction . ACE inhibitors ( e.g., enalapril,
lisinopril, or ramipril) have a wide diversity of actions and are considered to be
better drugs for the treatment of CHF.
Angiotensin antagonists give rise to occasional adverse effects that include
hypotension, hyperkalemia, angioedema, cough, and syncope. Several studies
have suggested that the beneficial effects of ACE inhibitors are reduced when
they are given along with aspirin. Actually, ACE inhibitors did not produced any
different effects when were administered with or without aspirin.
1.2.8. β-Adrenoceptor Antagonists

The -blockers (most commonly propranolol and other agents having membrane-
stabilising activity) were contraindicated in patients with CHF as they were found
to precipitate acute decompensation. Yet, it has been found that some of these
drugs may be useful in the treatment of diastolic dysfunction or cardiomyopathies
in patients requiring bradycardia and in decreasing the contraction velocity. It has
been found in the current stud ies that bisoprolol, carvedilol, and metoprolol may
decrease mortality in patients with class II and III heart failure.
1.2.9. Vasodilators
Vasodilators have an indirect benef icial effect on the heart. Arteriolar dilatation
(caused by hydralazine and nitrates) decreases the afterload. Venodilatation
(caused by nitrates) decreases pre-load. These agents are useful adjunctive for the
primary treatment. Use of hydralazine or isoso rbide on a long -term has been
shown to decrease damage to the remodelling heart.
* *
1.3. ANTI-HYPERTENSIVE DRUGS
1.3.1. Introduction
A condition in which the blood pressure of systemic artery increases beyond the
normal pressure is known as hypertension. Therefore to deliver blood to tissues,
the heart works harder to overcome the increased systemic pressure. This
increased systemic arterial pressure puts strain on the heart and other arteries,
thus resulting in high blood pressure.
Based on the degree of severity, hypertension can be graded as:
1) Mild: Diastole up to 104mmHg,
2) Moderate: Diastole105-114mmHg, and
3) Severe: Diastole more than 115mmHg.
Symptoms of hypertension are:
1) Chest pain, 2) Confusion,
3) Ear noise or buzzing (tinnitus), 4) Irregular heartbeat (arrhythmia),
5) Nosebleed (epistaxis), 6) Exhaustion (lethargy), and
7) Vision changes.
Therapy for hypertensive patients aims at reducing the increased blood pressure.
This is accomplished by administration of drugs from different classes; t reatment
is often given in the form of a combination of several agents. If left untreated, it
would result in organ damage, thus an increased risk for MI and stroke.
The antihypertensive agents are classified into the following classes:
1) Diuretics
i) Thiazides: Hydrochlorothiazide, Chlorthalidone, and Indapamide.
ii) Loop Diuretics: Furosemide, Bumetanide, and Torsemide.
+
iii) K Sparing Diuretics: Spironolactone, Amiloride, and Triamterene.
2) Angiotensin Converting Enzyme Inhibitors:Captopril, Enalapril, Lisinopril,
Ramipril, Perindopril, Fosinopril, Trandolapril, Quinapril, and Benazepril.
3) Angiotensin II Receptor Antagonists: Losartan, Candesartan, Valsartan,
Eprosartan, and Irbesartan.
4) Ganglion Blockers: Trimethaphan.
5) Adrenergic Drugs
i) Centrally Acting D rugs: Clonidine, Methyldopa, Guanabenz, and
Guanfacine.
ii) Adrenergic Neuron Blockers: Guanethidine and Reserpine.
iii) Sympatholytics (Adrenergic Receptor Blockers)
a)  Blockers: Prazosin, Terazosin, Doxazosin, Phenoxybenzamine,
and Phentolamine.
b)  Blockers: Propranolol, Atenolol, Esmolol, and Metoprolol.
c) + Blockers: Labetalol and Carvedilol.
* *
26 Pharmacology-II
6) Calcium Channel Blockers: Verapamil, Nifedipine, Nicardipine,

Nimodipine, Amlodipine, and Felodipine.
7) Vasodilators
i) Arteriolar Dilators: Hydralazine, Minoxidil, and Diazoxide.
ii) Arteriolar and Venular Dilators: Sodium nitroprusside.
1.3.3. Diuretics
Drugs promoting urine output are known as diuretic s. They act directly on the
kidneys and primarily increase the excretion of water and ions [so dium (Na +),
chloride (Cl−) or bicarbonates ( HCO3 )] from the body.
The antihypertensive action of diuretics is that they promote the excretion of
sodium and water resulting in:
1) Decreased plasma volume   cardiac output   BP
2) Decreased body sodium  relaxation of vascular smooth m uscles (due to
Na+ ion depletion in the vascular smooth muscle)   PVR   BP.
The amount of diuretic required will be reduced if the intake of dietary salt is
restricted. Some common drugs used as diuretics are:
1) Thiazides: These diuretics (e.g., hydrochlorothiazide and chlorthalidone) are
the inexpensive first -line antihypertensive agents. They are commonly used
in hypertension treatment.
2) Loop Diuretics: These diuretics ( e.g., furosemide, bumetanide, and
torsemide) are powerful diuretics but have low an tihypertensive efficacy.
They are used only in hyper tensive patients having chronic renal failure or
congestive heart failure. They are included in the treatment of malignant
hypertension and hypertension with hypervolemia ( e.g., renal
insufficiency).
3) Potassium-Sparing Diuretics: These diuretics ( e.g., spironolactone,
amiloride, and triamterene) have comparatively low efficacy; however, they
correct the po tassium loss caused by thiazide and loop diuretics. They are
used in combination with hydrochlorothiazide.

The three commonly used diuretics act as follows:
1) Thiazides and Thiazide-like Diuretics: Thiazide (e.g., hydrochlorothiazide)
and thiazide-like diuretics (e.g., chlorthalidone, indapamide, and metolazone)
increase the excretion of Na+ ions t hrough urine by inhibiting the sodium -
chloride pump in the early segment of the distal convoluted tubule. This
initially reduces the plasma volume, which increases the plasma renin
activity and aldosterone. Ultimately, vascular resistance decrea ses by some
uncertain mechanisms because plasma volume approaches the pre -treatment
levels.
2) Loop Diuretics: These diuretics act at the thick ascending loop of Henle to
prevent the reabsorption of Cl− and Na+ ions from the urine. Their onset of
action in comparison to thiazide diuretics is rapid.
* *
3) Potassium-Sparing Diuretics: These diuretics decrease the excretion of

Mg2+ and K+ ions. Amiloride and triamterene inhibit the Na/proton exchanger
in the distal and collecting tubules. They block the epithelial sod ium
transport channel. Spironolactone inhibits the Na/K exchanger affected by
aldosterone, as it is a potent non -selective aldosterone blocker which
interacts with androgen and progesterone receptors.

Diuretics are used in the treatment of the following conditions:
1) Thiazide or thiazide-like diuretics are effective in reducing the incidences of
strokes, heart failure, or total cardiovascular mortality.
2) Combination of a thiazide diuretic and potassium -sparing diuretic in a fixed
dose reduces the potassium and magnesium wasting.
3) Diuretics can be effectively used in obese, elderly, and diabetic patients. They
are used in patients with systolic heart failure and excess sodium intake.
4) Thiazide diuretics increase calcium level and decrease osteoporosis.
5) Spironolactone reduces mortality and morbidity in cases of advanced heart
failure.
6) Eplerenone decreases cardiovascular mortality in patients who sustained a
myocardial infarction with left ventricular dysfunction. This drug is useful in
the treatment of resistant hypertension and diabetes mellitus.
Loop diuretics are ineffective in hypertensive patients having normal renal
function. Loop diuretics are used in patients with serum cre atinine level more
than 2.5mg/dl. Intravenous doses of furosemide in cases of heart failure produce
an acute vasodilator effect.

Thiazide diuretics give rise to many metabolic effects such as hypercalcaemia,
hypokalaemia, hypernatremia, hypomagnesaemia, hypercalcaemia,
hyperglycaemia, hyperlipidaemia, and hyperuricemia; however, in low doses,
their side effects are minimised. They may also cause go ut, sexual dysfunction,
and sulphonamide-related skin eruptions (occasionally).
Loop diuretics produce quite intense metabolic imbalances like hypokalaemia
and hypocalcaemia, thus are not prescribed as initial monotherapy for
hypertension.
1.3.3.4. Individual Drugs

Some commonly used diuretics are discussed below:
1) Hydrochlorothiazide: This prototype agent of thiazide diuretic reduces the
electrolyte reabsorption from the renal tubules , thus increases the excretion
of water and electrolytes (sodium, potassium, chloride, and magnesium). It is
used in several disorders like oedema, hypertension, diabetes insipidus, and
hypoparathyroidism.
2) Furosemide: Chemically, it is a benzoic-sulfonamide-furan compound. It has a
*
fast onset of action and short duration of action. It is used in oedemaassociated
*
28 Pharmacology-II
with CHF, liver cirrhosis, renal disease (including nephrotic syndrome) , and
chronic renal insufficiency. Furosemide either alone or in combination with
other antihypertensive drugs is used for treating hypertension.
3) Spironolactone: This potassium sparing diuretic antagonises the aldosterone
in the distal renal tubules. It is used in the treatment of refractory oedema in
patients with CHF, nephrotic syndrome, or hepatic cirrhosis.
1.3.4. Angiotensin Converting Enzyme (ACE) Inhibitors

ACE inhibitors act by inhibiting the action of ACE enzyme. The y competitively
inhibit the conversion of angiotensin I to angiotensin II occurring in the presence
of angiotensin-converting enzyme. This results in lower levels of angiotensin II,
which is a potent vasoconstrictor. Lower levels of angiotensin II increase plasma
renin activity and reduce aldosterone secretion.

ACE inhibitors slow down the formation of angiotensin II and as a result,
vascular resistance, blood volume, and blood pressure are reduced. Renin is an
enzyme which the kidneys release in res ponse to reduced renal blood circulation
or hyponatremia. This enzyme acts in the plasma angiotens inogen to produce
angiotensin I, which is further converted into angiotensin II (mainly in the lungs).
Angiotensin II causes vasoconstriction and also helps in sodium retention by

releasing aldosterone. Angiotensin II is converted to angiotensin III in adrenal
gland. Aldosterone release is stimulated by both angiotensin II and angiotensin
III. Angiotensin I is inactive in the cardiovascular system, while angio tensin II
has some cardiovascular -renal actions. The angiotensin -converting enzyme is
mostly found in the lungs; however they are also found in kidneys, central
nervous system, and some other body tissues also.

The ACE inhibitors have the following therapeutic uses:
1) Hypertension: They are the first line drugs for the treatment of all grades of
hypertension. Around 50% of patients respond to monotherapy with ACE
inhibitors, and majority of the remaining respond to the combination of ACE
inhibitors with diuretics or β-blockers. The hypotensive effect of lower doses
develops over 2-3 weeks.
2) Congestive Heart Failure (CHF): They cause arteriolar as well as
vasodilatation in CHF patients, and also reduce both after -load and pre-load.
They do not produce any direct myocardial action, thus increasing stroke
volume and cardiac output while reducing the heart rate. Accumulated salt
and water are lost due to improved renal perfusion and abolition of
mineralocorticoid mediated Na+ ion retention occurs.
3) Myocardial Infarction (MI): Oral administration of ACE inhibitors is
continued for 6 weeks . It results in reduction of the early and long -term
mortality, regardless of the presence or absence of systolic dysfunction,
provided hypotension is avoided. In p atients with high risk and those with
* *
latent or overt ventricular dysfunction (CHF), the therapy is continued to

afford survival benefit over years.
4) Prophylaxis in High Cardiovascular Risk Subjects: They reduce the risk
of heart failure or diabetes; thus, act as protective in subjects with a high
cardiovascular risk even when there is no associated hypertension or left
ventricular dysfunction.
5) Diabetic Nephropathy: Prolonged therapy of ACE inhibitors prevents or
delays the end stage renal disease in type s I and II diabetic patients.
Albuminuria remains stable in patients on ACE inhibitor, but worsens in
untreated diabetic patients.
6) Scleroderma Crisis: Angiotensin II mediates the marked rise in BP and
deterioration of renal function in scleroderma crisis. AC E inhibitors improve
this condition and are lifesaving.

In most of the patients , ACE inhibitors do not produce any side effects or
toxicities but some of the rarely occurring or d ose related adverse effects are
dizziness, angioedema, loss of taste, photosensitivity, severe hypotension, dry
cough, hyperkalaemia, blood dyscrasias, and renal impairment.

The commonly used ACE inhibitors are discussed below:
1) Captopril: It is a sulfhydryl -containing dipeptide substitute of proli ne. It
abolishes the pressor action of only a ngiotensin I, i.e., it does not block the
angiotensin II receptors. It is a potent and competitive ACE inhibitor, which
is responsible for the conversion of angiotensin I to angiotensin II (an agent
which regulates blood pressure and is a key component of the RAAS).
Captopril administered with thiazide diuretics is used for treating essential or
renovascular hypertension. In combination with other drugs ( e.g., cardiac
glycosides, diuretics, and β-adrenergic blockers), it is used to treat congestive
heart failure. It improves the survival in patients having left ventricular
dysfunction following myocardial infarction.
Studies show that if daily dose is kept below 150mg, captopril is well -
tolerated in most of the patients, but some mild adverse reactions like
hypotension, hyperkalaemia, cough, rashes, urticaria, angioedema, dysgeusia,
fetopathic, headache, dizziness, nausea, bowel upset, granulocytopenia,
proteinuria, and acute renal failure, may occur.
2) Enalapril: It is the second drug of this class which is a prodrug, converted
into enalaprilat (a tripeptide analogue). This converted form is not effective
orally due to poor absorption, thus is available as injectable preparation.
Enalaprilat is a potent and competitive ACE blocker, which is responsible for
the conversion of angiotensin I to angiotensin II.
Enalaprilat is used in essential or renovascular hypertension and symptomatic

congestive heart failure, either alone or in combination with thiazide diuretics.
* *
30 Pharmacology-II
The same adverse effects are produced by all the ACE inhibitors. Some
additional adverse effects of enalapril are b lurred vision, confusion, dizziness,
faintness, or light-headedness (when getting up suddenly from a lying or sitting
position), unusual tiredness or weakness, chest pain, cough producing mucus,
diarrhoea, laboured breathing,fainting, fever or chills,nausea, and sore throat.
1.3.5. Angiotensin II Receptor Antagonists

Angiotensin II receptor antagonists [or Angiotensin Receptor Blocker
(ARBs)/AT1-receptor antagonists/ Sartans] act by modulating the renin -
angiotensin-aldosterone system. They are mainly used in th e treatment of
hypertension, diabetic nephropathy, and congestive heart failure.

The ARBs inhibit the final step of Renin -Angiotensin System (RAS). These
agents block the interaction between angiotensin II and its type 1 receptor (AT 1),
which mediates all the pressor effects of this hormone and some of its effects that
promote atherosclerosis. In comparison to ACE inhibitors, ARBs cause more
complete antagonism of angiotensin II, as angiotensin II can also be produced by
non-ACE pathways (figure 1.3).
ARBs are preferred over ACE inhibitors because they do not increase bradykinin
which causes dry cough.

Angiotensin II receptor antagonists have the following uses:
1) These agents are mainly used in the prevention of hyperte nsion where the
patient is intolerant to ACE inhibitor therapy.
2) They are used in the treatment of heart failure in patients intolerant to ACE
inhibitor therapy, particularly candesartan. The on -going studies show that
irbesartan and losartan benefit the hypertensive patients with type II diabetes,
and also delay the progression of diabetic nephropathy.
Angiotensinogen
Non-renin Other substrates
Renin
blockade
RENIN
Angiotensin I BK and substrates
ACE
Non-ACE ACE
inhibitors
Angiotensin II
A II Receptor
Antagonist
AT II AT I
Actions Physiological
Actions
Figure 1.3: ACE inhibitors block the conversion of angiotensin I and
angiotensin II via angiotensin converting enzyme, but do not prevent
the formation of angiotensin II via alternate pathways.
* *

Generally ARBs are well -tolerated in most of the patients and they also do not
produce dry and persistent cough (like ACE i nhibitors). However, some rarely
occurring side effects of ACE inhibitors are:
1) They are associated with angioedema, but less commonly than ACE inhibitors.
2) Hyperkalaemia (in patients taking potassium -sparing diuretics, having
significant renal insufficienc y, renovascular hypertension, diabetes mellitus,
or hypoaldosteronism), oliguria (hypouresis), and progressive azotemia (in
patients with severe heart failure whose renal function depends on the renin -
angiotensin-aldosterone system) are other adverse effects.
1.3.5.4. Individual Drug - Losartan
Losartan is a competitive antagonist of a ngiotensin II. It does not have partial
agonistic activity and is 10,000 times more selective for AT 1 than AT 2 receptor.
It does not block any other receptor or ion channel.
Losartan and other angiotensin I antagonists are used as the first line
antihypertensive drugs (as alternative to ACE inhibitors). It produces maximum
hypotensive effect within 3 -6 weeks. Losartan is also effective in portal
hypertension due to liver cirrhosis.
The adverse effects caused by losartan are similar to ACE inhibitors such as
hypotension and hyperkalaemia, but first dose hypotension is uncommon.
Angioedema occurs rarely. Mild and occasional headache, dizziness, weakness, and
upper gastrointestinalside effects are observed.Losartan has a uricosuric effect.
1.3.6. Ganglion Blockers

Ganglionic blockers block the sympathetic as well as parasympathetic ganglia,
thus decreasing sympathetic tone and blood pressure. Due to this effect, they give
rise to many side effects and thus are not used now.
Trimethaphan is the only ganglionic blocker used nowadays. It is given via
intravenous route to produce controlled hypotension during certain surgeries for
its rapid and short action (15 minutes).

Trimethaphan acts by preventing the stimulation of postsynaptic receptors by
competing for these receptor sites with acetylcholine. Its other effects are direct
peripheral vasodilation and histamine relea se. The hypotensive effect of
trimethaphan results by reduction in sympathetic tone and vasodilation.

Trimethaphan is used for controlled reduction of blood pressure during surgery
and in the treatment of hypertensive emergencies.
The adverse effects of ganglionic blockers are a norexia, nausea, vomiting,
constipation, dryness of mouth, itching, urticaria, impotence, tachycardia, and
urinary retention.
* *
32 Pharmacology-II
1.3.7. Adrenergic Drugs

Sympatholytic agents act as antihypertensive by depressing the sympathetic
nervous system by different mechanisms. This class of antihypertensive agents is
further divided into five sub-classes on the basis of their mode of action:
1) Centrally acting sympatholytic drugs,
2) Adrenergic neuron blockers,
3) α-Adrenergic receptor antagonists,
4) β-Adrenergic receptor antagonists, and
5) Mixed (α+β) adrenergic receptor antagonists.
1.3.7.1. Centrally Acting Sympatholytic Drugs

The pharmacological profile of centrally acting symp atholytic drugs is similar to
that of prazosin; however the pharmacokinetic profile differs. Clonidine, -
methyldopa, guanabenz, and guanfacine are the examples of centrally acting
sympatholytic drugs. Some of the common members of this class are:
1) Methyldopa: It is an α2-adrenergic agonist having central and peripheral
nervous system effects. It is mainly used as an antihypertensive agent.
Mechanism of Action
In the CNS, methyldopa gets decarboxylated to α-methyl noradrenaline which
stimulates the central α-adrenergic receptors. As a result, the sympathetic
outflow from the CNS is reduced, resultingin decreased blood pressure.
Therapeutic Uses
Methyldopa is used in hypertension. It was one of the earliest
antihypertensive agents available and is still used widely.
Adverse Effects
Nasal stuffiness, headache, sedation, mental depression, dryness of mouth,
bradycardia, impotence, extrapyramidal symptoms (due to false transmitter),
gynaecomastia, and haemolytic anaemia (rarely) are some common adverse
effects of methyldopa.
2) Clonidine: It is an imidazoline -derivative and is a centrally -acting α2-
adrenergic agonist. It crosses the blood -brain barrier and acts on the
hypothalamus to decrease the blood pressure.
Mechanism of Action
Clonidine stimulates α2-adrenergic recepto rs in the CNS and reduces the
sympathetic tone, which further decreases the systolic and diastolic blood
pressure and heart rate.
Therapeutic Uses
i) In hypertension,
ii) To treat withdrawal symptoms in opioid and alcohol addicts,
iii) As a pre-anaesthetic agent,
iv) As an anti-diarrhoeal in diabetic neuropathy, and
v) For prophylaxis of migraine.
* *
Adverse Effects
Clonidine causes dry mouth and eyes, sedation, depression, bradycardia,
impotence, nausea, dizziness, parotid gland swelling, and pain.
On suddenly stopping the use of clonidine after prolonged use, withdrawal
syndrome occurs characterised by headache, nervousness, tachycardia,
sweating, tremors, palpitation, and rebound hypertension.
1.3.7.2. Adrenergic Neuron Blockers

Adrenergic neuron blockers act directly on α- or β-receptors, and produce similar
effects as those produced by the stimulation of sympathetic nerves or by the
release of epinephrine from the medulla of adrenal gland. Adrenergic neuron
blockers are primarily used in hypertension and hypertensive emergencies.
The adverse effects produced by these agents include postural hypotension,
weakness, worsening of CHF, diarrhoea, delayed ejaculation, and nasal congestion.
Individual Drugs
1) Reserpine: It is an alkaloid obtained from the roots of the plant Rauwolfia
serpentina. It is a slow acting drug which shows its complete effect within 2 -
3 weeks. Its hypotensive action is due to depletion of NA from peripheral
adrenergic nerve endings. It has both central and peripheral actions.
Mechanism of Action
Reserpine acts by inhibiting the uptake and storage of DA and NA (vesicular
catecholamines), as it can enter the adrenergic neuron to bind with the
storage vesicle (figure 1.4). The catecholamines leak into the cytoplasm and
are destroyed there by MAO enzyme. Reserpi ne produces antihypertensive
effect due to depletion of biogenic amines.
Tyrosine
DOPA
DA – Reserpine
–
Storage DA
vesicle
NA MAO
NA
NA
Effector cell
Figure 1.4: Mechanism of Action of Reserpine. DA: Dopamine;
NA: Nor-adrenaline; MAO: Monoamine Oxidase
* *
34 Pharmacology-II
Therapeutic Uses
Reserpine is not used clinically due to its serious adverse effects.
Adverse Effects
Reserpine produces n asal congestion, lethargy, drowsiness, nightmares,
depression, diarrhoea, and impotence.
2) Guanethidine: It is an antihypertensive drug that acts by selectively
inhibiting the transmission in post -ganglionic adrenergic nerves. It prevents
the norepinephrine (NE) release at nerve endings and ca uses NE depletion in
peripheral sympathetic nerve terminals and tissues.
Mechanism of Action
Guanethidine acts at the sympathetic neuroeffector junction and inhibits or
interferes with NE release and/or distribution. It is taken up by the NE
transporters, and becomes concentrated in NE transmitter vesicles, where it
replaces the NE.
This gradually depletes the NE stores in the nerve endings. Within the
terminal, guanethidine inhibits NA release in response to an action
potential.
Therapeutic Uses
Guanethidine is used either alone or as an adjunct in moderate and severe
hypertension. It is also used in renal hypertension.
Adverse Effects
The side effects of guanethidine are orthostatic and exercise hypotension,
sexual dysfunction, and diarrhoea.
1.3.7.3. Sympatholytics (Adrenergic Receptor Blockers)

Adrenergic receptor blockers interrupt with the functioning of sympathetic
nervous system. They block the impulse transmission and sympathetic nervous
system stimulation at adrenergic neurons or adrenergic receptor sites. The action
of these agents is exerted by:
1) Interrupting the action of sympathomimetics (adrenergics),
2) Reducing the available nor-epinephrine, and
3) Preventing the cholinergic action.
α-Blockers
The peripheral vascular α-receptors are of two types:
1) Postsynaptic 1-Receptors: These are stimulatory in nature and located on
vascular smooth muscle cells.
2) Presynaptic 2-Receptors (Autoreceptors): These are inhibitory in nature.
Mechanism of Action: NE causes vasoconstriction by interacting with the 1-

receptors. The 1-blockers reverse the vasoconstriction effects of NE and
epinephrine; thus due to selective 1-blockade, a decrease in blood pressure is
observed. -receptor blockers cause both venous and arterial dilatation.
* *
Therapeutic Uses
1) High blood pressure,
2) Enlarged prostate,
3) Raynaud’s disease,
4) Scleroderma (hardening and thickening of skin), and
5) Adrenal gland tumours (pheochromocytoma).
Adverse Effects: The -blockers cause dizzi ness, drowsiness, headache,

lethargy, palpitations, and nausea.
Individual Drugs
1) Phentolamine: It is α-adrenergic blocking agent with a short duration of
action. It is used to diagnose the pheochromocytoma ( tumours of adrenal
gland which secretes adrenal ine and NA). Phentolamine mesylate when
given to an individual with pheo chromocytoma in the dose of 5mg via
intravenous route, it reduces the blood pressur e (35mmHg systolic and
25mmHg diastolic ) within 2 minutes. The similar reduction is observed in
patients with essential hypertension (taking a sedative or an antihypertensive
drug) or having concomitant renal failure. Phentolamine in 2.5-10mg dose is
given through intravenous route for the treatment of severe hypertension (due
to catecholamine release during management of pheochromocytoma).
2) Phenoxybenzamine: It is a long acting α-adrenergic blocking drug, used in
the pre -operative preparation for the treatment of pheochromocytoma. It
controls hypertension, expands the plasma volume, and prevents
intraoperative hypertensive episodes. In combination with a β-adrenergic
blocker, it is used for long -term management of pheochromocy toma (which
cannot be operated).
3) Prazosin: It is a selective α1-receptor blocker, which reduces the preload and
afterload. It produces a lower degree of reflex tachycardia , and has been
proved to be valuable for monotherapy of hypertension and also in
combination therapy with other drugs. Its continuous use results in salt and
water retention and this accentuates postural hypotension.
β-Blockers
These agents act by inhibiting adrenergic response mediated by β-receptors. All
the β-blockers are competitive agonist. They are the drugs of choice for the
treatment of essential hypertension.
Mechanism of Action: The -blockers reduce cardia c output by blocking -

adrenergic receptors present in the heart, thus resulting in negative chronotropic
(heart rate) and inotropic (contractility) effects. They also decrease renin release
from kidneys and decrease the peripheral sympathetic outflow via central effect.
Therapeutic Uses: The -blockers are effective in post -MI patients and those
with systolic heart failure; but they are less effective against stroke. Young
patients are more responsive to monotherapy with a -blocker.
* *
36 Pharmacology-II
Adverse Effects: More frequent adverse effects are:

1) Fatigue,
2) Bradycardia,
3) Decreased exercise tolerance,
4) Worsening claudication in patients with peripheral arterial disease,
5) Bronchospasm,
6) Masking of symptoms and delayed recovery from hypoglycaemia,
7) Increase in serum triglycerides, and
8) Lowering of HDL cholesterol.
Less common adverse effects are:
1) Insomnia,
2) Vivid dreams or hallucinations, and
3) Impotence.
Sudden withdrawal of these agents can lead to exacerbation of angina and
myocardial infarction.
Individual Drug - Propranolol
Propranolol is used in mild to moderate hypertension. It prevents reflex
tachycardia when given in combination with vasodilators. It prevents tolerance
development even on long-term use in combination with a diuretic.
The adverse effects caused by pr opranolol are the results of β-blocking actions,
viz., lowered myocardial reserve, peripheral vascular insufficiency, asthma, and
diabetes mellitus. Its withdrawal after prolonged use causes nervousness,
tachycardia, precipitation of hypertension, angina, or myocardial inf arction (due
to up -regulation of β-receptors). It may also increase plasma triglycerides and
lower HDL cholesterol.
Propranolol is a non-selective β-blocker and should be avoided in patients having
bronchial asthma and diabetes mellitus.
α+ Blockers
Compounds which block both - and -adrenergic receptors show structural
resemblance with both- and -adrenergic receptor antagonists in a single molecule.
Adverse effects of - and -adrenergic receptor antagonists occurs due to excessive
pharmacologicalactivity or due to blockade of receptors of an undesired site.
Mechanism of Action: The -blockers compete with sympathomimetic
neurotransmitters (catecholamines) for binding at 1-adrenergic receptors in the
heart and vascular smooth muscles; thus they i nhibit sympathetic stimulation.
This causes a reduction in resting heart rate, cardiac output, systolic and diastolic
blood pressure, and reflex orthostatic hypotension.
Therapeutic Uses
1) Angina pectoris,
2) Atrial fibrillation,
3) Cardiac arrhythmia,
4) Congestive heart failure,
* *
5) Glaucoma,
6) Hypertension,
7) Migraine prophylaxis,
8) Mitral valve prolapse,
9) Myocardial infarction,
10) Symptomatic control t(achycardia, tremor) in anxiety and hyperthyroidism, and
11) Theophylline overdose.
Adverse Effects : The common adverse effects of α+ blockers are n ausea,
diarrhoea, bronchospasm, dyspnoea, heart f ailure, fatigue, dizziness,
hallucinations, insomnia, nightmares, and erectile dysfunction
Individual Drugs
1) Labetalol: It is a mixed blocker which acts on b oth - and -receptors. It is
used in hypertension and pheochromocyto ma. Its usual dose is 200 -
600mg/day in divided doses.
2) Carvedilol: It effectively antagonises the actions of catecholamines at -
receptors. Its half -life is 6 -8 hours. It undergoes hepatic metabolism. It also
has a free radical scavenger action (antioxidant effect) which is inde pendent
of adrenoceptor blockade. It is clinically beneficial in congestive heart
failure. Its oral dose is 6.25-25mg/day in divided doses.
1.3.8. Calcium Channel Blockers

Calcium channel blockers (CCBs) are commonly used in the treatment of
hypertension. These can be used safely in patients having hypertension along with
asthma, hyperlipidaemia, diabetes mellitus, or renal dysfunction. A calcium channel
2+
blocker acts by inhibiting the movement of Ca ions through calcium channels.
1.3.8.1. Classification
Calcium channel blockers are further classified into three classes:
1) Phenyl Alkylamine: Verapamil
2) Benzothiazepine: Diltiazem
3) Dihydropyridines: Nifedipine, Felodipine, and Amlodipine

CCBs act by blocking or altering the cell membrane calcium flux. Calcium
channel blockers of class dihydropyridine lower the blood pressure via arteriolar
and venous vaso dilation, while non -dihydropyridine calcium channel blockers
(e.g., verapamil, diltiazem) have less potent vasodilation properties, and reduce
the blood pressure through peripheral vasodilation and negative inotropic effect.

CCBs can be u sed in patients to whom β-blockers are contraindicated, and those
who are suffering from obstructive lung disease and peripheral vascular disease.
CCBs are used to treat the following conditions:
1) Angina Pectoris: All CCBs effectively reduce the fre quency and severity of
classic and variant angina. In classic angina, CCBs reduce the cardiac work
* *
38 Pharmacology-II
as a result of reduced after -load. They can increase coronary flow in normal
individuals, but not in patients having fixed arterial obstruction. CCBs
prevent arterial spasm, and therefore are useful in variant angina.
2) Hypertension: Diltiazem and verapamil are used in this condition.
3) Arrhythmias: PSVT (Paroxysmal Supraventricular Tachycardia) and
ventricular rate in supraventricular arrhythmias are controlled by vera pamil
and diltiazem.
4) Hypertrophic Cardiomyopathy: Verapamil’s negative inotropic action is
useful in this condition.
5) Other Uses: Nifedipine can be used in premature labour. Verapamil can be
used to reduce nocturnal leg cramps.

The common adverse effects of calcium channel blockers are d izziness,
headache, peripheral oedema (more than with verapamil and diltiazem; more
common in women), flushing, tachycardia, rash, and gingival hyperplasia.

Some of the commonly used calcium channel blockers are discussed below:
1) Verapamil: It is categorised under phenyl alkylamine class of organic
compounds. It contains a pheny lbutylamine moiety consisting of a phenyl
group substituted at C4 by butan-1-amine.
2) Nifedipine: It is categorised under dihydropyridine carboxylic acid class of
organic compounds. It contains a dihydropyridine moiety with a carboxylic
acid group.
1.3.9. Vasodilators
Vasodilators cause vasodilation by directly relaxing the vascular smooth muscles.
This effect is dire ct because it does not depend on the innervation of vascular
smooth muscles and is not controlled by various receptors, like adrenoceptors,
cholinoreceptors, or histaminic receptors, on which classical transmitters and
mediators act.
Vasodilators reduce the total peripheral resistance, thus correct the hemodynamic
abnormality which elevates the blood pressure in primary hypertension. These
agents directly act on vascular smooth muscle s, therefore are effective in
lowering blood pressure, regardless of the cause of hypertension. Vasodilators do
not cause orthostatic hypotension and impotence as they do not inhibit the
activity of sympathetic nervous system like other antihypertensive drugs.
The vasodilators relax the ar terial smooth muscles more than the venous smooth
muscles; thus they reduce postural hypotension.

Various studies suggest that each vasodilator has a different mechanism and act
differently in a step -by-step process which couple excita tion of vascular smooth
* *
muscle cells with contraction. For example, the CCBs either inhibit or limit the
influx of Ca2+ ions through the vascular smooth muscle cell membrane via voltage -
dependent channels. This is how the CCBs restrict the amount of intracellular Ca2+
ions available in free form to interact with smooth muscle contractile proteins.
Other vasodilators ( e.g., diazoxide and minoxidil) dilate the blood vessels by
activating the potassium channels in vascular smooth muscles. Relaxation of
vascular smooth muscles occurs due to increase in potassium conductance which
causes hyperpolarisation in cell membrane.
Another class of drugs known as nitrovasodilators(e.g., nitroprusside) activate the
soluble guanylate cyclase in vascular smooth musclesand increase the intracellular
levels of cyclic Guanosine Monophosphate (cGMP), thereby causing relaxation in
vascular smooth muscles. It has been seen that nitrovasodilators act like endogenous
vasodilator released by a variety of endothelial cells of blo od vessels. This
endogenous vasodilator (formerly named as Endothelial -Derived Relaxing Factor or
EDRF) is nitric oxide or a closely related nitrosothiol compound.

Vasodilators have the following therapeutic uses:
1) Nitroprusside is the drug of choice in hypertensive emergencies.
2) It is used when myocardial work is to be reduced for a shorter time period (as
in myocardial infarction).

The common adverse effects of vasodilators are t achycardia, angina, headache,
dizziness, fluid retention, nasal congestion, and hepatitis.

Some commonly used vasodilators are:
1) Arteriolar Vasodilator - Minoxidil: Chemically, it belongs to
dialkylarylamines ( aliphatic aromatic amines in which the amino group is
linked to two aliphatic chains and one aromatic group).
Mechanism of Action
Minoxidil is a powerful arteriolar dilator which is effective when given via
oral route. It causes reflex tachycardia, sodium and water retention with
oedema; therefore, should be used with a -blocker and a loop diuretic.
Therapeutic Uses
Minoxidil is used to treat severe hypertension. It is used topically in
androgenic alopecia to stimulate regrowth and stabilise hair loss both in
males and females.
Adverse Effects
Normally minoxidil is well t olerated, b ut some common side effects are
burning or irritation of the eye, itching, redness or irritation at the treated
area, unwanted hair growth, alopec ia, c hest pain, dizziness, tachycardia,
sudden weight gain, and swelling of hands and feet.
* *
40 Pharmacology-II
2) Arteriolar and Venular Dilator - Sodium Nitroprusside: It is a rapidly

acting vasodilator which relaxes arterioles and venules. Myocardial oxygen
consumption is lowered by this drug as it
reduces peripheral resistance and cardiac Sodium nitroprusside
output.
Mechanism of Action Nitric oxide
Sodium nitroprusside allows release of
nitric oxide which activates g uanylyl
Guanylyl cyclase
cyclase and forms cGMP (Cyclic
Guanosine 3',5' -Monophosphate), which
further relaxes the vascular smooth GTP cGMP
muscles (figure 1.5).
Vasodilation
Therapeutic Uses
Sodium nitroprusside is used f or
immediate reduction of blood pressure BP
during hypertensive crisis, for reducing
Figure 1.5: Mechanism of Action
bleeding during surgical procedures, and
for treating acute congestive heart failure.
Adverse Effects
The common adverse effects occurring with s odium nitroprusside are
palpitation, sweating, weakness, nausea, and hypotension. If given in higher
doses, it converts into cyanide and thiocy anate which causes toxicity
characterised by nausea, anorexia, weakness, disorientation and psychosis.
Therefore, nitroprusside is given along wi th sodium thiosulphate for
preventing cyanide accumulation.
1.4. ANTI-ANGINAL DRUGS
1.4.1. Introduction
Angina pectoris (or chest pain) is a symptom experien ced due to myocardial
ischemia, wherein the blood supply to the heart decreases . As a result, the
heart muscles do not get sufficient oxygen and nutrient s, and fails to work
properly.
The following two types of angina are mainly seen:
1) Classic Angina (Angina of Exercise): This angina pain occurs w hen the
demand of oxygen exceeds the s upply of oxygen, most commonly due to
diminished coronary flow.
2) Vasospastic (Prinzmetal’s or Variant) Angina: This angina pain occurs at
rest and is characterised by reversible coronary vasospasm , which in tu rn
reduces the supply of oxygen.
Some individuals however show mixed angina, characterised by both exercise -

induced and resting attacks of angina.
* *
Patients may also suffer from symptoms like:

1) Weakness, 2) Heartburn,
3) Cramping, 4) Indigestion,
5) Sweating, 6) Nausea, and
7) Shortness of breath.
Anti-anginal drug therapy aims at restoring the balance between the supply and
demand of oxygen in the ischemic area of the myocardium.
The anti-anginals are divided into the following groups:
1) Vasodilator Drugs
i) Organic Nitrites and Nitrates : Amyl ni trite, Isosorbide dinitrate,
Isosorbide mononitrate, and Nitroglycerine.
ii) Calcium Channel Blockers : Amlodipine, Nifedipine, Diltiazem, and
Verapamil.
iii) Potassium Channel Opener: Nicorandil.
2) -Adrenoceptor Antagonists (-Blockers): Atenolol, Metoprolol, Nadolol,
and Propranolol.
3) Metabolic Modifiers: Ranolazine and Trimetazidine.
1.4.3. Organic Nitrites and Nitrates

Organic nitrites and nitrates are simple nitric and
Nitrates
nitrous acid esters of glycerol having dif ferent
volatilities (e.g., isosorbide dinitrate and isosorbide
mononitrate are so lids at room temperature, Nitrites
nitroglycerine is moderately volatile, and amyl
nitrite is highly volatile). These compounds are Nitric oxide
used in angina pectoris. They rapidly reduce the
myocardial oxygen demand, followed by rapid
relief of symptoms. They are effective in classic as cGMP
well as in variant angina pectoris.
Dephosphorylation of
1.4.3.1. Mechanism of Action myosin light chain
Nitrates inhibit coronary vasoconstriction or spasm
as a result of which perfusion of the myocardium Vascular smooth muscle
increases, thus, relieving vasospastic angina. relaxation
Nitrates also cause venodilation, resulting in Figure 1.6: Mechanism of
decreased preload and myocardial oxygen Action of Nitrates and
consumption. Due to this action, nitrates are Nitrites
effectively used in classic angina.
It is believed that organic nitrates ( e.g., nitroglycerine) act on vascular smooth
muscles and relax them by their intracellular conversion to nitrite ions and then
to nitric oxide. It results in activation of guanylate cyclase and elevates the levels
of cGMP. This leads to dephosphorylation of the myosin light chain, causing
vascular smooth muscle relaxation (figure 1.6).
* *
42 Pharmacology-II

Drugs categorised under class organic nitrates are used for treating the ischemic
symptoms of angina and for congestive heart failure.

The most common adverse effects of organic nitrates caused by excessive
vasodilatation include headache, hypotension, dizziness, and reflex tachycardia.

Some commonly used organic nitrates and nitrites are described below:
1) Nitroglycerine: It is t he drug of choice for angina pectoris since it is
effective, fast acting, and economic. If taken via sub -lingual route , it acts
rapidly and its action lasts for an hour.
Mechanism of Action
Nitroglycerine acts by dilating the blood vessels , thus affecting the vascular
smooth muscles. It decreases the cardiac oxygen demand in case of stable
angina, and increases the oxygen supply in variant angina.
Nitroglycreine is also available in the form of patches and topical ointment. Its
transdermal patches are used once daily due to their slower but longer effect.
Therapeutic Uses
Nitroglycerine is administered sublingually for the treatment of acute anginal
pain or for prevention of angina; w hile it’s intravenous administration helps
to reduce hypertension.
Adverse Effects
Nitroglycerine causes headache (due to vascular dilation), syncope (due to
postural hypotension and reflex tachycardia), apprehension, blurred vision,
weakness, vertigo, and dizziness. Some serious adverse effects are
circulatory collapse and anaphylactic reactions.
2) Isosorbide Mononitrate and Isosorbide Dinitrate: These drugs provide
longer duration of action than nitroglycerine. Isosorbide mononitrate is
available as chewable tablets; while isosorbide dinitrate is formulated as
sublingual tablets.
Both isosorbide mononitrate and isosorbide dinitrate are long -acting nitrates.
The former does not undergo the first-pass metabolism. It decreases pre-load,
left ventricular end volume, diastolic pressure, and thus the m yocardial
oxygen consumption. The latter relaxes the vascular smooth muscles to dilate
the peripheral blood vessels.
Both the drugs effectively treat all types of angina pectoris. Isosorbide
dinitrate relieves acute anginal attack and manages long -term a ngina
pectoris. Isosorbide mononitrate is not used to treat acute attacks of angina.
The most common adverse effects of these drugs are headache, hypotension,
facial flushing, dizziness, nausea, vomiting, fatigue, and weakness. The
adhesives used in transdermal patches can produce allergic reactions, and the
*
sublingual dosage forms can cause burning or stinging under the tongue. *
1.4.4. Calcium Channel Blockers

The following f our chemically distinct classes of calcium channel blockers are
currently used to treat angina:
1) Phenylalkylamines: Verapamil.
2) Benzothiazepines: Diltiazem.
3) Dihydropyridines: Nifedipine, Nimodipine, and Nicardipine.
4) Diarylaminopropylamine Ethers: Bepridil.

CCBs act by blocking the voltage -sensitive calcium channels. They act on the
inner side of the membrane and bind to the channels in depolarised membrane .
As a result of drug binding , the channels open rarely after depolarisation. A
marked decrease in transmembrane Ca2+ ion current relaxes the smooth muscles.

CCbs are used for the treatment of stable as well as variant angina. In variant
angina, they cause relaxation of coronary artery spasm , thus increasing the
cardiac oxygen supply; while in stable angina, they cause relaxation of peripheral
arterioles, resulting in decreased afterload and cardiac oxygen demand.
Verapamil and diltiazem moderately reduce oxygen demand by suppressing the
heart rate and contractility.

CCBs give rise to c ardiovascular adverse effects. Blood pressure reduces due to
dilation of peripheral arterioles , resulting in induced reflex tachycardia. This
reaction mainly occurs with nifedipine and rarely with verapamil and diltiazem.
Due to their suppressant effects o n the heart, verapamil and diltiazem should be
used carefully in patients taking β-blockers and suffering from bradycardia, heart
failure, or AV block.

Some commonly used CCBs are described below:
1) Verapamil: It is a calcium channel blocker of class IV anti -arrhythmic
agent. It acts by inhibiting the voltage-dependent calcium channels. Due to
its effect on L-type calcium channels in the heart, ionotropy and chronotropy
is reduced, which further reduces heart rate and blood pressure.
Verapamil is used for the treatment of hypertension and angina.
The common adverse eff ects of v erapamil are myocardial depression, heart
failure, and oedema. Peripheral vasodilating effects may also occur which
reduces the afterload and blood pressure. The peripheral effects of verapamil
include headache, reflex tachycardia, and fluid retention.
2) Nifedipine: This drug is a long - as well as short -acting 1,4-dihydropyridine
calcium channel blocker. It acts by decreasing the contractility of arterial
smooth muscles and also vasoconstriction by inhibiting the influx of Ca2+
ions through L-type calcium channels.
* *
44 Pharmacology-II
This inhibition in turn blocks the contractility of smooth muscle cells, and
causes dilation of the coronary and systemic arteries, increased oxygen
supply to myocardial tissues, decreased total peripheral resistance, decreased
systemic blood pressure, and decreased afterload. These vasodilatory effects
overall decreases the blood pressure.
Nifedipine is used in the treatment of vasospastic angina, chronic stable
angina, hypertension, and Raynaud’s phenomenon. It can also be used as a
first line agent for left ventricular hypertrophy and for isolated systolic
hypertension (long-acting agents).
Common adverse effects of nifedipine include palpitation, flushing, ankle
oedema, hypotension, headache, drowsiness, and nausea.
3) Bepridil: It is a long-acting, non-elective, calcium channel blocker showing
significant anti -anginal activity. It shows significant coronary vasodilation
and moderate peripheral effects.
It gives inhibitory effects on the slow calcium (L-type) as well as fast sodium
inward currents in myocardial and vascular smooth muscles. Bepridil acts by
inhibiting the binding of calcium with calmodulin protein , and further
blocking the voltage and receptor operated calcium channels. It also blocks
the transmembrane influx of Ca2+ ions into the cardiac and vascular smooth
muscles.
Bepridil is used for the treatment of hypertension and chronic stable angina
(classic effort-associated angina).
Adverse effects of bepridil are abnormally fast or slow heartbeat, severe

dizziness, chest pain, psychosis, jaundice, and swelling of legs or ankles.
1.4.5. Potassium Channel Openers

The potassium channel openers which were used earlier for the treatment of
severe hypertension and hypertensive eme rgencies are minoxidil and diazoxide;
but use of these agents has been reduced after synthesis of some novel potassium
channel openers, like nicorandil, pinacidil, and cromakalim.

Potassium channel openers activate (open) the ATP -sensitive K +-channels in
vascular smooth muscles. These opened channels hyperpolarise the smooth
muscles, which further closes the voltage -gated calcium channels and decreases
intracellular calcium. Since less calcium is available to bind with calmodulin,
less activation of myosin light chain kinase and less phosphorylation of myosin
light chains occur. This results in relaxation and vasodilation.

Potassium channel openers are used in patients who have undergone optimal
management wit h other d rugs, but still remain symptomatic, often while they
await surgery or angioplasty.
* *

Common adverse effects o f potassium channel openers are f lushing, palpitation,
weakness, headache, mouth ulcers, nausea, and vomiting.
1.4.5.4. Individual Drug - Nicorandil

Nicorandil is a derivative of niacinamide. It activates the potassium channels and
causes vasodilation of arterioles and large coronary arteries.
Nicorandil acts as a nitrate and activates ATP -sensitive potassium channels in

vascular smooth muscl es, thus leading to vasodilation in coronary, arterial, and
venous system. This in turn reduces preload, afterload, and myocardial oxygen
consumption.
Nicorandil is used for preventing and treating chronic stable angina pectoris, and
for reducing the risk of acute coronary syndromes.
Common adverse effects of nicorandil include nausea, vomiting, dizziness, and

facial flushing. Angina, palpitations, mouth ulcers, myalgia, angioedema,
bronchitis, and dyspnoea occur rarely.
1.4.6. β-Adrenoceptor Antagonists

The β-adrenergic blockers commonly used in angina are atenolol, metoprolol,
nadolol, and propranolol.

The β-adrenergic antagonists decrease the oxygen demand by reducing the heart
rate. They oppose sympathetic stimulation , which increases heart rate,
contraction force, and oxygen rate.

The β-adrenergic antagonists in combination with nitrates are used for the
treatment of angina pectoris. Persistent angina can be trea ted using drugs from
two or more classes, i.e., β-adrenergic blockers combined with long -acting
nitrates or calcium channel blockers.
The β-adrenergic antagonists due to their antihypertensive action are ideal for
patients having hypertension and coronary artery disease. They are the drugs of
choice for the prophylaxis of chronic angina.

The adverse effects of β-adrenergic antagonists are h ypotension, bradycardia,
insomnia (inability to sleep), bizarre dreams, diminished sex drive, impotence,
and depression.
1.4.6.4. Individual Drug - Atenolol

Atenolol is a selective β1-receptor antagonist, and belongs to the group of β-
blockers.
* *
46 Pharmacology-II
Atenolol competes with sympathomimetic neurotransmitters like

catecholamines for binding at β1-adrenergic receptors in the heart and
vascular smooth muscles, thus inhibits sympathetic stimulation. This re duces
the resting heart rate, cardiac output, systolic and diastolic blood pressure,
and reflex orthostatic hypotension.
Atenolol is used to treat h ypertension, angina, long QT syndrome, acute

myocardial infarction, supraventricular tachycardia, ventricular tachycardia, and
the symptoms of alcohol withdrawal.
The adverse effects of a tenolol are slow or uneven heartbeats, light-headedness,

fainting, breathlessness (even on mild exertion ), swelling of ankles or feet,
nausea, stomach pain, low fever, loss o f appetite, dark urine, clay -coloured
stools, jaundice, depression, and cold sensation in hands and feet.
1.4.7. Metabolic Modifiers

The drugs which are commonly used as metabolic modifiers are discussed below:
1) Ranolazine: This drug reduces the number of angina episodes per week and
increases exercise tolerance. These benefits were however moderate and
smaller in women than in men.
Mechanism of Action
Ranolazine acts on the sodium -dependent calcium channels durin g
myocardial ischemia by altering the intracellular sodium level. Thus,
this drug indirectly prevents the calcium overload causing cardiac
ischemia.
Therapeutic Use
Ranolazine is used to treat chronic angina.
Adverse Effects
Ranolazine produces the following adverse effects:
i) QT Prolongation: It causes a dose -related increase in the QT interval,
and thus increases the risk of torsades de pointes (a serious ventricular
dysrhythmia).
ii) Elevation of Blood Pressure: It raises the blood pressure by 15mmHg
in patients having severe renal impairment.
iii) Other Adverse Effects: Constipation, dizziness, nausea, and headache.
2) Trimetazidine: It is an anti -ischemic (anti -anginal) metabolic agent. It
improves myocardial glucose utilisation by inhibiting fatty acid
metabo lism.
Mechanism of Action
Trimetazidine improves myocardial glucose utilisation by inhibiting long -
chain 3 -ketoacyl CoA thiolase activity, which in turn reduces fatty acid
oxidation and stimulates glucose oxidation.
* *
Therapeutic Uses
Trimetazidine improves left ventricular function in diabetic patients having
coronary heart disease. It limits intracellular acidosis, corrects the disturbed
transmembrane ion exchanges, and prevents excessive free radical production.
Adverse Effects
Some of the adverse effects of trimetazidine are allergy, anaphylactic shock,
and heart failure. Side effects of the drug over an extended amount of time
include interactions with other medications, overdoses, and liver problems.
1.5. ANTI-ARRHYTHMIC DRUGS

1.5.1. Introduction
Arrhythmia is a common disorder of cardiac excitation, which may be benign but
may also be fatal ( e.g., ventricular fibrillation following a heart attack).
Antiarrhythmic drugs are used to control or correct cardiac rhythm.
Four types of arrhythmias are:
1) Atrial fibrillation,
2) Bradycardia,
3) Tachycardia, and
4) Ventricular arrhythmias.
The symptoms of arrhythmias are:
1) Shortness of breath,
2) Feeling tired or light-headed,
3) Rapid thumping in chest or palpitations,
4) Chest pain, and
5) Losing consciousness.
The classification of antiarrhythmic drugs is as follows:
Table 1.1: Classes of Antiarrhythmic Drugs
Classes Basic Mechanism Examples
I Sodium Channel Reduce phase 0 slope and peak of action
Blockers potential.
IA Moderate Moderate reduction in phase 0 slope; Quinidine and
increase APD; increase ERP. Procainamide.
IB Weak Small reduction in phase 0 slope; reduce Lidocaine and
APD; decrease ERP. Phenytoin.
IC Strong Pronounced reduction in phase 0 slope; no Flecainide and
effect on APD or ERP. Propafenone.
II β-Blockers Block sympathetic activity; reduce rate and Propranolol and
conduction. Metoprolol.
III Potassium Delay re -polarisation (phase 3) and thereby Amiodaron and
Channel Blockers increase action potential duration and Bretylium.
effective refractory period.
IV Calcium Channel Block L -type calcium -channels; most Verapamil,
Blockers effective at SA and AV nodes; reduce rate Diltiazem, and
and conduction. Nifedipine.
* *
48 Pharmacology-II
1.5.3. Sodium Channel Blockers (Class I)

Sodium channel blockers are the most wi dely used antiarrhythmic agents. They
act by blocking myocardial Na + ion channels. They are mainly used for the
treatment of supraventricular, nodal and ventricular arrhythmias , especially after
MI and DC shock.

Antiarrhythmic activity of sodium channel blockers is due to:
1) Decrease in inflow of sodium during phase 0 which slo ws the maximum rate
of depolarisation,
2) Decrease in excitability and conduction velocity,
3) Prolongation of effective refractory period, and
4) Decrease in slope of phase 4 spontaneous depolarisation (automaticity).

The sodium channel blockers have the following therapeutic uses:
1) Treatment of supraventricular, nodal and ventr icular arrhythmias, especially
after MI and DC shock.
2) After treatment of atrial flutter and fibrillation to maintain sinus rhythm.

The adverse effects of sodium channel blockers are marked depression of AV
conduction, hypotension, bradycardia, anorexia, nausea, and vomiting.

Class I antiarrhythmic agents are further classified into:
1) Moderate (Class IA): These drugs slow the rate of rise of action potential
and prolong the duration of action potential. They block Na+ ion channels and
prolong the repolarisation time.
Examples
i) Quinidine: It is the prototype of Class IA drug. Because of its
concomitant Class III activity, it can precipitate arrhythmias such as
polymorphic ventricular tachycardia ( torsades de pointes ), which ca n
degenerate into ventricular fibrillation. Due to the toxic effects, the
clinical uses of quinidine are replaced with calcium antagonists (like
amiodarone and verapamil).
Mechanism of Action: Quinidine binds to open and inactivated Na+ ion
channels to pr event the influx of Na+ ions; thus slowing down the rapid
upstroke during phase 0. It also reduces the slope of phase 4 spontaneous
depolarisation and inhibits potassium channels. These actions result in
slow conduction velocity and increased refractoriness.
Therapeutic Uses: Quinidine is used in the treatment of a wide variety
of arrhythmias including atrial, AV -junctional, and ventricular
tachyarrhythmia. It is used to maintain sinus rhythm after direct -current
cardioversion of atrial flutter or fibrilla tion and to prevent frequent
*
ventricular tachycardia. *
Adverse Effects
a) A potential adverse effect of quinidine is development of arrhythmia
(torsades de pointes).
b) It may cause SA and AV blockage or asystole.
c) At toxic levels, it may induce ventricular tachycardia.
d) Nausea, vomiting, and diarrhoea are commonly observed.
e) In l arge doses , it may induce the symptoms of cinchonism ( e.g.,
blurred vision, tinnitus, headache, disorientation, and psychosis).
f) It has a mild α-adrenergic blocking action as w ell as an atropine-like
effect.
g) It can increase the steady -state concentration of digoxin by
displacement of digoxin from tissue -binding sites (minor effect) and
by decreasing digoxin renal clearance (major effect).
ii) Procainamide: It is a derivative of the local anaesthetic procaine and
shows actions similar to those of quinidine.
Mechanism of Action: Procainamide stabilises the neuronal membrane
by inhibiting the ionic fluxes required for the initiation and conduction of
impulses, thereby affecting local anaesthetic action.
Therapeutic Uses:Procainamide can be given in place of quinidine as it is
better tolerated in the treatment of atrial fibrillation and flutter. It is an
alternative to lidocaine in preventi on and treatment of frequent VPBs
(Ventricular Premature Beats) and sustained tachycardia after MI. Its use is
also declining because of frequent dosing and unacceptable adverse effects.
Adverse Effects: With chronic use, procainamide causes a high
incidence of side effects, including a reversible lupus erythematous -like
syndrome. Toxic concentrations of procainamide may cause asystole or
induction of ventricular arrhythmias. CNS side effects include
depression, hallucination, and psychosis.
2) Weak (Class IB): The characteristic effects of these drugs are reduced rate
of rise of action potential and reduced or unchanged APD ( Action Potential
Duration). The drugs of Class IB rapidly associate and dissociate from the
sodium channels. Thus , their actions are m anifested when the cardiac cells
are depolarised or firing rapidly.
Examples
i) Lidocaine: It is a local anaesthetic which shortens phase 3 repolarisation
and decreases the duration of action potential . Lidocaine is useful in
treating ventricular arrhythmias. It was the drug of choice for emergency
treatment of cardiac arrhythmias. It does not slow down conduction, thus
has a little effect on the AV junction arrhythmia.
Lidocaine in higher doses causes cardiac and CNS manifestations. SA
nodal arrest and hypotension may also occur. Paraesthesia, tremor (facial
twitching), vomiting, light headedness, slurred speech, and convulsions
also occur commonly.
* *
50 Pharmacology-II
ii) Phenytoin: It is an antiepileptic drug used in tonic -clonic seizures. It

produces unique cardiac electrophys iological effects, thus is used in
digoxin-induced arrhythmia.
Phenytoin blocks the inactivated sodium channels , thus recovery occurs
rapidly and depresses automaticity in ventricular tissues and PF, thus
suppresses DAPs (Delayed After -Polarisations). It facilitates AV nodal
conduction, therefore can be suitably used in supraventricuar arrhythmia
associated with AV blocks such as digitalis -induced atrial tachycardia
and digoxin-induced ventricular tachycardia.
Phenytoin is mainly used in children with con genital heart disease and
congenital prolonged QT syndrome to treat ventricular tachycardia.
Some common adverse effects of phenytoin include decreased
coordination, mental confusion, nervousness, slurred speech, trouble
with breathing, speaking, or swal lowing, unsteadiness, trembling, and
other problems with muscle control or coordination.
3) Strong (Class IC): Drugs of this class are powerful blockers of fast Na + ion
channels, and thus reduce upstroke of AP in normal and diseased
myocardium. There is dela yed inactivation of slow Na + ion channels during
down slope of AP , and this result in prolongation of APD. In addition, there
is inhibition of delayed rectifier K + current (less K + efflux), so the APD is
prolonged in His Bundle and Purkinje fibre system.
These changes create heterogeneity of impulse conduction, non -uniform

slowing and unidirectional block predisposing to development of re -entry
(proarrhythmic potential). Arrhythmias are more likely to occur in structural
heart disease, sympathetic over activity and at faster heart rates.
Examples
i) Flecainide: It blocks Na + and K + ion channels in normal and ischemic
+
myocardium, t hus slow ing down the recovery of blocked Na ion
channels. It further slows down the conduction of electrical impulse in
the heart, i.e., reduces excitability.
Flecainide is useful in terminating PSVT, and treating atrial fibrillation
and atrial flutter occurring in normal heart. It stabilises the heart rhythm
when the heart beats too fast or beats irregularly.
Common adverse effects of flecainide are:

a) During Cardiac Arrhythmia Suppression Trial (CAST), it causes
serious ventricular arrhythmias and even sudden death.
b) During the treatment of atrial fibrillation, it should be administered
with a rate -reducing drug (digoxin) otherwise paradoxical
tachycardia may occur.
c) It is contraindicated in sick sinus syndrome, bundle branch block and
should be avoided in acute MI.
* *
ii) Propafenone: It blocks fast Na + ion channels and gives a mild β-

blocking action (1/10 of propranolol) and class -IV action (Ca ++ ion
channel block age). QT interval does not change but QRS and PR
intervals are prolonged. It is effective orally and is metabolised by CYP
2D6 (in persons with CYP 2D6 deficiency, it is slowly metabolised).
Propafenone acts by slowing down the influx of Na+ ions into the cardiac
muscle cells, thus decreasing the excitability of the cells.
Propafenone is used in life -threatening ventricular tachyarrhythmias, for
suppressing supraventricular tachycardia in Wolff -Parkinson-White
(WPW) syndrome, i n recurrent atrial fibrillation, and in suppression of
paroxysms of atrial fibrillation.
The main adverse effects of propafenone are constipation, and sometimes
it worsens CHF. Serious ventricular arrhythmias, sudden death, and
increased mortality have also been reported.
1.5.4. -Blockers (Class II)

The -blockers or β-adrenergic receptor blockers produce some important
electrophysiological effects. They are highly effective in arrhythmias in which
excess of catecholamine plays a role after MI, CHF, pheochromocytoma, anxiety,
anaesthesia and postoperative period, exercise and mitr al valve prolapse. Excess
of cAMP is considered to be responsible for causing ischemia induced

Reduction in intracellular Ca ++ ions leads to reduced phase 2 of AP. There is
reduction in SA nodal automaticity, slowing of conduction, and prolongation of
ERP ( Effective Refractive Period ) in AV node. They counteract catecholamine
++
induced after depolarisations (arrhythmias) by reducing cAMP and Ca ion
accumulation.
-blockers are also effective prophylactically in suppressing supraventricular

tachycardia because they suppress automaticity of ectopic foci and slow AV
nodal conduction , thereby reducing ventricular response in atrial fibrillation.
They reduce cardiac contractility and blood pressure.

At present -blockers are considered to be better antiarrhythmic agent s because
they improve survival, have broader spectrum of antiarrhythmic action, and are
comparatively safer. In addition , they act synergistically with many other
antiarrhythmic agents reducing their arrhythmogenic potential.

Some common adverse effects of β-blockers are:
1) Worsening of CHF,
2) Bronchospasm,
* *
52 Pharmacology-II
3) Cardiac conduction blocks,

4) Bradycardia,
5) Peripheral vasospasm,
6) Insomnia, and
7) Hypotension.

Some commonly used β-blockers are described below:
1) Propranolol: It reduces sudden arrhythmic death after myocardial infarction.
It reduces the mortality rate after a heart attack by preventing ventricular
arrhythmia.
Propranolol acts by binding at β1-adrenergic receptors in the heart by
competing with the sympathomimetic neurotransmitters (catecholamine s),
thus inhibiting sympathetic stimulation. This reduces the resting heart rate,
cardiac output, systolic and diastolic blood pressure, and reflex orthostatic
hypotension.
Propranolol is used therapeutically for the management of hypertension,
angina pec toris (with the exception of variant angina ), tachyarrhythmia,
myocardial infarction, tachycardia or tremor associated with anxiety, panic,
hyperthyroidism, or lithium therapy , migraine, cluster headache , and
hyperhidrosis.
The adverse effects caused by p ropranolol include insomnia, vivid dre ams
and nightmares as it can cross the BBB much easily as compared to the less
lipophilic β-blockers due to high lipophilic nature.
2) Metoprolol: It is a -adrenergic antagonist used for the treatment of cardiac
arrhythmia. Like propranolol, it can also b e metabolised easily and can
penetrate CNS. It reduces the risk of bronchospasm.
Metoprolol is a β1-selective adrenergic receptor blocker, but at higher plasma
concentrations it also inhibits β2-adrenoreceptors located in the bronchial and
vascular musculature.
Metoprolol is used in the treatment of acute myocardial infarction, angina
pectoris, heart failure, and mild to moderate hypertension. It is also used for
the treatment of supraventricular and tachyarrhythmia, and as prophylaxis for
migraine.
Common adverse effects of metoprolol include d izziness or lightheadedness,
tiredness, depression, nausea, dry mouth, stomach pain, and vomiting.
1.5.5. Potassium Channel Blockers (Class III)

Class III agents block K+ ion channels, thus the outward potassium current during
re-polarisation of cardiac cells diminishes. These agents prolong the duration of
action potential without altering p hase 0 of depolarisation or the resting
membrane potential. They prolong the effective refractory period and increase
refractoriness. All class III drugs have the potential to induce arrhythmias.
* *

Blocking of K+ ion channels in phase 3 of the action potential reduces the efflux
of K+ ions from the myocyte; t hus slowing down the repolarisation rate of the
cell and increasing the length of plateau phase of the action potential. These
actions result in increase of the refractory period of atrial, ventricular and
Purkinje cells as well as increase of the QT interval.

Potassium channel blockers are used to treat:
1) Recurrent ventricular fibrillation,
2) Unstable ventricular tachycardia, and
3) Atrial fibrillation.

Common adverse effects of potassium channel blockers are p ulmonary fibrosis,
photosensitivity, corneal micro deposits, hypothyroi dism, and peripheral
neuropathy, AV block, bradycardia, ventricular arrhythmia s, bronchospasm, and
severe hypotension.

Some commonly used potassium channel blockers are discussed below:
1) Amiodarone: It is a potent and broad spectrum antiarrhythmic agent, having
cardiac and extracardiac actions.
Amiodarone prolongs the APD of atrial and ventricular tissues by blocking
delayed rectifier K + ion current. The blocking of K + ion channel prevents K +
ion efflux, thus the down slope of phase 3 of action potential is delayed. It
also blocks the Na + ion channels increasing their inactivation time in phase 3
thus prolonging APD. The Na + ion channels get recovered very quickly from
this blockage. Amiodarone also blocks Ca ++ ion channels resulting an altered
phase 4 of AP. It actively inhibits abnormal automaticity and slows
conduction by prolonging ERP in all tissues.
Following are the common therapeutic uses of amiodarone:
i) Suppressing of chronic at rial fibrillation and for maintaining NSR after
cardioversion.
ii) Preventing recurrent ventricular extra systoles and VT alone or as an
adjunct to Implanted Cardioverter Defibrillator (ICD).
iii) It is also used for suppressing atrial fibrillation in WPW syndrome.
The adverse effects caused by amiodarone may be cardiac and extra-cardiac:
i) Cardiac adverse effects include hypotension (due to direct myoca rdial
depression), vasodilation, bradycardia, and QT prolongation.
ii) If used for a long-term, amiodarone give some extra-cardiac adverse
effects like pulmonary fibrosis, corneal micro deposits and halos in
visual fields, optic neuritis, hepatic dysfunction, peripheral neuropathy,
proximal muscle weakness, photodermatitis, slate blue discoloration of
skin, testicular failure, and thyroid malfunction.
* *
54 Pharmacology-II
2) Sotalol: It is a non -selective -blocker with no intrinsic sympathomimetic

activity. The L-isomer of sotalol has class II antiarrhythmic action, while D and
+
L-isomers show class III antiarrhythmic action. It blocks the K ion channels and
inhibits delayed rectifier K+ ion current. It prolongs APD in atrial and ventricular
tissues. It reduces automaticity and slows down the AV nodal conduction.
Sotalol is therapeutically used as an alternative to quinidine for treating
recurrent or sustained VT and can be given in structural heart disease (where
flecainide is not effective). It is also used in tachyarrhythmia in WPW
(Wolff-Parkinson-White) syndrome.
The common adv erse effects of sotalol include b radycardia, depression of
cardiac contractility, CHF, dose-dependent TDP, fatigue, and bronchospasm.
1.5.6. Calcium Channel Blockers (Class IV)

+
The drugs included in CCBs are verapamil, diltiazem, and bepridil (blocks Na
ion channels also).

CCBs block the slow in ward calcium channels, and slow down the conduction
through the AV node.

CCBs are used to treat atrial fibrillation and flutter, prinzmetal and variant angina
and unstable or chronic stable angina pectoris, and hypertension.

CCBs give rise to dizziness, hypotension, bradycardia, oedema, constipation, AV
block, ventricular systole, ventricular fibrillation, and nausea.
1.5.6.4. Individual Drug - Verapamil

Verapamil blocks L -type voltage operated Ca +2 ion channels in activated and
inactivated state. Since Ca +2 ions are the main ion participating in the generation
of AP in slow automatic tissues of SA and AV nodes, verapamil has predominant
depressant effects on these pacemakers. I t slows automaticity and increases
refractoriness. It also blocks the re-entry in AV node.
Verapamil also suppresses EADs (Early After Depolarisations ) and DADs
(Delayed After Depolarisations), which are calcium dependent. These effects cause
bradycardia, prolongation of PR interval , and reduction in anterograde impulses
from atria to ventricles, thus slowing ventricular rate in atrial fibrillation/flutter. It
also has negative inotropic and peripheral vasodilatory effects.
Verapamil is used in the treatment of hypertension, angina, and cluster headache
prophylaxis.
The adverse effec ts caused by verapamil include c onstipation, heartburn,
dizziness or light headedness, headache, slow heartbeat, blurred vision, nausea,
loss of appetite, rash, and fever.
* *
1.6. ANTI-HYPERLIPIDEMIC DRUGS

1.6.1. Introduction
Lipids or fats, which are usually transported in various combinations with
proteins (lipoproteins), play a key role in cardiovascular disorders. Lipids,
including cholesterol and trigl ycerides, are essential elements in the body. They
are synthesised in the liver; therefore, they can never be eliminated from the
body. Dietary or drug therapy of elevated plasma cholesterol levels can reduce
the risk of atherosclerosis, and subsequent cardiovascular disease.
A patient with high serum cholesterol and increased Low -Density Lipoprotein
(LDL) is at risk of atherosclerotic coron ary disease and myocardial infar ction.
Atherosclerosis is a disorder in which lipid sub -groups [total cholesterol,
triglycerides, Low -Density Lipoproteins (LDL), and High -Density Lipoproteins
(HDL)] in various proportions indicate risk factors for the individual.
Antihyperlipidemics are the group of drugs prescribed in adjuvant therapy to

reduce elevated cholesterol lev els in patients with high cholesterol and LDL
levels in the blood. These medications are used to decrease the risk of
arteriosclerosis.
The major drugs for reduction of LDL cholesterol levels are bile acid
sequestrants and nicotinic acid. The fibric acid derivatives and clofibrate
(Atromid-S) are less effective in reducing LDL cholesterol. The most effective
agents for reducing plasma LDL levels are the statins.
The anti- hyperlipidemic drugs are classified into:
1) HMG-CoA Reductase Inhibit ors (Statins): Lovastatin, Simvastatin,
Pravastatin, and Atorvastatin.
2) Bile Acid Sequestrants (Resins): Cholestyramine and Colestipol.
3) Fibric Acid Derivatives (Fibrates): Clofibrate, Gemfibrozil, Bezafibrate,
and Fenofibrate.
4) Triglyceride Synthesis and Lipolysis Inhibitors: Nicotinic acid.
5) Others: Probucol and Omega-3 fatty acids.
1.6.3. HMG-CoA Reductase Inhibitors (Statins)

Statins are the most effective and best tolerated agents used to treat
hyperlipidemia. Statins are competitive inhibitors of 3 -hydroxy-3-methylglutaryl
coenzyme reductase and also the most effective and best tolerated agents for
treating hyperlipidemia.
They catalyse an early, rate limiting step in cholesterol biosynthesis. Hi gher

doses are more potent and can even reduce the triglyceride levels caused by high
VLDL levels.
* *
56 Pharmacology-II

Statins inhibit the enzyme 3 -hydroxy-3-methylglutaryl-coenzyme A reductase
(HMG-CoA reductase) which catalyses the conversion of HMG -CoA to
mevalonate. Mevalonate is required to initiate cholesterol biosynthesis and its
production is inhibited by statins. Statins act as a competitive inhibitor for HMG -
CoA which binds to the HMG -CoA reductase. Statins are inactive in its native
form, so the form in which they are administered is hydrolysed to the β-hydroxy
acid form and becomes active.

The therapeutic uses of statins are:
1) They are used for secondary prevention of myocardial infarction and stroke
in patients having symptomatic atherosclerotic disease (e.g., angina, transient
ischemic attacks, following acute myocardial infarction or stroke).
2) They are used for primary prevention of arterial disease in patients having
high risk due to increased serum cholesterol concentration, specifically when
there are other risk factors for atherosclerosis.
3) Serum cholesterol level can be lowered by atorvastatin in patients with
homozygous familial hypercholesterolemia.
4) A bile acid binding resin is added to treatment with a statin in cases of severe
drug-resistant dyslipidaemia(e.g., heterozygous familial hypercholesterolemia).

Statins are generally well -tolerated and adverse effects are very rare. However,
some patients may experience some mild and transient reactions like h eadache,
rashes, and GI disturbances (dyspepsia, cramps, flatulence, constipation, and
abdominal pain).
Some serious side effects that may occur rarely are hepatotoxicity and myopathy.
However, some statins give more hazardous reactions than others:
1) Myopathy/Rhabdomyolysis: Sometimes statins can cause muscle injury.
Mild injury characterised by muscles ache, tenderness or weakness localised
to certain muscle group occurs in 5-10% patients.
2) Hepatotoxicity: It may develop in 0.5-2% of patients treated for one or more
year with statins. But jaundice and other clinical signs are very rare. Use of
statin in patients with active liver disease depends on the disease;
for example, statins should not be given to patients suffering from viral or
alcoholic hepatitis, while statins use is acceptable in patients of non-alcoholic
fatty liver disease.

Some commonly used statins are discussed below:
1) Atorvastatin: It is an aromatic heterocyclic compound belonging to the class
diphenylpyrroles, having a structure based on a pyrrole ring linked to two
phenyl groups.
* *
Atorvastatin acts by decreasing hepatic cholesterol levels. It is a selective and

competitive inhibitor of HMG -CoA reductase enzyme which catalyses
conversion of HMG -CoA to mevalonate in t he cholesterol biosynthesis
pathway.
Atorvastatin has the following therapeutic uses:
i) It may be used as a primary prevention in patients of multiple risk factors
for Coronary Heart Disease (CHD) and as secondary prevention in
individuals with CHD to redu ce the risk of myocardial infarction (MI),
stroke, angina, and revascularisation procedures.
ii) It reduces the risk of cardiovascular events in patients with Acute
Coronary Syndrome (ACS).
iii) It may be used in the treatment of primary hypercholesterolemia and
mixed dyslipidaemia, homozygous familial hypercholesterolemia,
primary dysbetalipoproteinemia, and/or hypertrigly ceridemia as an
adjunct to dietary therapy to decrease serum total and Low-Density
Lipoprotein-Cholesterol (LDL-C), apolipoprotein B (apoB), an d
triglyceride concentrations, while increasing High-Density Lipoprotein
Cholesterol (HDL-C) levels.
The common adverse effects occurring with the use of atorvastatin include
muscle pain, confusion, memory problems, fever, unusual tiredness, dark
coloured urine, weight gain, and urinating less than usual or not at all.
2) Lovastatin: It is used as a cholesterol-lowering agent. It is a prodrug,
showing structural similarity with HMG, a substituent of the endogenous
substrate of HMG -CoA reductase. It gets activated in vivo by the hydr olysis
of lactone ring to form β-hydroxy acid. The hydrolysed lactone ring mimics
the tetrahedral intermediate produced by the reductase. The resultant
hydrolysed lactone ring binds to HMG -CoA reductase with 20,000 times
greater affinity than its natural s ubstrate. Thus , the bicyclic portion of
lovastatin binds to the coenzyme A portion of the active site.
Lovastatin is used as an adjunct to diet to reduce elevated total -C, LDL -C,
apo B, and TG levels in patients with primary hypercholesterolemia and
mixed dyslipidaemia. It is also used for primary prevention of CHD and for
slow progression of coronary atherosclerosis in patients with CHD.
The more common adverse effects of lovastatin include gastric disturbance s
like (pain in abdominal area, nausea, heart burn, and constipation), headache,
weakness, muscle pain, memory loss, confusion, and inability to fall asleep.
1.6.4. Bile Acid Sequestrants (Resins)

Bile acid sequestrants bind with certain components of bile in the gastrointestinal
tract. They prevent the re -absorption of bile acids from the gut by disrupting the
enterohepatic circulation of bile acids by sequestering them. They may be used
for purposes other than lowering cholesterol, but they are cla ssified as
hypolipidemic agents.
* *
58 Pharmacology-II

Bile acid sequestrants are polymeric compounds which act as ion exchange
resins. They exchange anions (like Cl− ions) for bile acids by binding with
bile acid and sequestering them from enterohepatic circulation. They are not
well-absorbed from the gut into the bloodstream because they have large
polymeric structures. Therefore, the bile acid sequestrants along with the bile
acid bound to the drug , are excreted via faeces after passing through the
gastrointestinal tract.

Bile acid sequestrants are used for the treatment of hypercholesterolemia and
dyslipidemia as they help in decreasing the cholesterol levels, mainly low density
lipoprotein (commonly known as “bad cholesterol”). They act by inhibiting the
re-absorption of bile acid, which is biosynthesised from cholesterol.
They may cause pruritus during chronic liver diseases (such as cirrhosis )
because the bile acids may deposit in the skin. Therefore, in patients with
chronic live r diseases, bile acid sequestrants may be used for the prevention
of pruritus.
They are also used in the treatment of diarrhoea caused by excess bile salts
entering the colon rather than being absorbed at the end of the small intestine.
Diarrhoea caused by excessive bile is a possible side effect occurring after
surgical removal of gallbladder.

Bile acid sequestrants do not have any systemic side effects because they are
designed to stay in the gut. However, they may cause problems like constipation,
diarrhoea, and flatulence in the gastrointestinal tract.
1.6.4.4. Individual Drug - Cholestyramine

Cholestyramine is a bile acid sequestrant which serves as ion exchange resins. It
is a quite hydrophilic compound, but insoluble in water.
Cholestyramine acts by preventing the reabsorption of bile in the gastrointestinal

tract. It binds to bile as it is a strong anion exchange resin which can exchange
its chloride anions with anionic bile acids in the GIT and bind them in the resin
matrix strongly.
It is used as an adjunctive therapy to diet for reducing the increased serum

cholesterol in the patients who have primary hypercholesterolemia (elevated
LDL cholesterol) and do not respond adequately to diet. It can also be used for
pruritus associated with partial biliary obstruction.
Cholestyramine gives rise to many adverse effects which include mild

constipation, diarrhoea, stomach pain, nausea, loss of appetite, weight changes,
bloating, hiccups, a sour taste in mouth, skin rashes, itching, irritation of tongue
and around the rectal area, and muscle or joint pain.
* *
1.6.5. Fibric Acid Derivatives (Fibrates)

Fibrates are the drugs reducing the triglyceride levels more than LDL cholesterol
levels. The m ost common examples of fibrates are gemfibrozil, bezafibrate,
ciprofibrate, and fenofibrate. They are the most heterogeneous lipid modifying
drugs.

The mechanism of action of fibrates is not completely understood but it is
believed tha t they increase peripheral clearance and reduce hepatic
triglyceride synthesis. The effects given by fibrates on blood lipids depend on
their binding to Peroxisome Proliferators Activator Receptors (PPARs) ,
which regulate gene transcription. , , and  are the three PPAR isotopes
that have been identified.
Fibrates act as agonists for the nuclear transcription factor Peroxisome

Proliferators-Activated Receptor-alpha (PPAR-alpha), at the molecular level.
This mechanism is used by fibrates for the down reg ulation of the apolipoprotein
C-III (apo C-III) gene and up regulation of the genes for apolipoprotein A -I (apo
A-I), fatty acid transport protein, fatty acid oxidation, and LPL. Thus, VLDL
triglycerides get reduced due to the enhanced catabolism of trigly cerides by LPL
along with enhanced fatty acid oxidation.

The fibrates are used in the following cases:
1) Fibrates (gemfibrozil) are the first -line of drugs f or patients with type III
hyperlipidaemia or familial dysbetalipoproteinemia.
2) They are used to treat mixed hyperlipidaemia, where in the predominant
abnormality is hypertriglyceridemia (in combination with resins) and to treat
moderate to severe hypertriglyceridemia.
3) They are used with statins in patients with high risk of CHD and mixed
hyperlipidaemia. But because of the increased risk of myopathy, careful
safety monitoring is required.

Generally, fibrates do not give an y adverse reaction and are well -tolerated in
most of the patients. But in some patients minor side -effects like GI disturbance
symptoms like abdominal pain, diarrhoea, and nausea may be seen that are
corrected by the discontinuation of the treatment.
An important but rare adverse effect of fibrates is myositis with muscle pain and
tenderness and elevated creatinine kinase levels.
fibrates Are contraindicated in patients of renal dysfunction , as they get

accumulated in the kidney leading to enhanced frequency of adverse effects
specially myositis.
* *
60 Pharmacology-II
1.6.5.4. Individual Drug - Clofibrate

Clofibrate is an anti -lipidemic drug that lowers the elevated serum lipids by
reducing the very low -density lipoprotein fraction (S f 20-400) rich in
triglycerides. Serum cholesterol may be decreased in those patients whose
cholesterol elevation is due to the presence of IDL as a result of Type III
hyperlipoproteinemia.
Clofibrate enhances lipoprotein triglyceride lipolysis by increasing the activity

of extrahepatic Lipoprotein Lipase (LL). Degradation of chylomicrons converts
VLDLs to LDLs , which are further converted into HD Ls. These changes occur
by a minor increase in the secretion of lipids into bile and finally in the
intestine.
Clofibrate also helps to inhibit the synthesis , and thus increases the clearance of
apolipoprotein B (a carrier molecule for VLDL).
Clofibrate is used to treat primary dysbetalipoproteinemia (Type III

hyperlipidaemia) which does not respond adequately to diet. Thus , it helps to
control high cholesterol and high triglyceride levels.
Clofibrate may cause diarrhoea, nausea, headache, dec reased sexual ability,
increased appetite, slight weight gain, muscle aches or cramps, sores in mouth
and on lips, stomach pain, gas, heartburn, unusual tiredness or weakness, and
vomiting.
1.6.6. Triglyceride Synthesis and Lipolysis Inhibitors

Triglyceride synthesis and lipolysis inhibitors act either by inhibiting the
synthesis of triglyceride or by inhibiting the process of lipolysis. These agents
reduce the level of LDLs and VLDLs in blood, and thus prevent the deposition of
lipid in blood vessels. Nicotinic acid is the most common example of this class.
Higher doses of nicotinic acid help in the reduction of plasma lipid concentration.
Individual Drug
1) Nicotinic Acid (Niacin): Nicotinic acid is an organic compound that belongs
to the pyridine carboxylic acids group of compounds. At high concentrations,
this drug gives cholesterol and triglyceride lowering effects, resulting in a
decrease of LDLs and VLDLs and an increase in HDLs.
Mechanism of Action
Nicotinic acid helps in the inhibition of release of free fatty acids from
adipose tissue and enhances the lipoprotein activity. It results in increased
rate of triglyceride removal from plasma. These actions decrease the total
LDL (bad cholesterol) and triglyceride levels, causing increased HDLs (good
cholesterol).
Therapeutic Uses
Nicotinic acid is not used therapeutically due to its side effects but
sometimes can be prescribed as an adjunct to diet for treatment of high serum
* *
triglyceride levels in adult patients who have a risk of pancreatitis, and who
do not respond properly to dietary control.
Adverse Effects
The major adverse effects of nicotinic acid are headache, anxiety,
hypotension, dry skin, flushing or burning of skin, peptic ulcer, and abnormal
liver function tests.
Other mild ad verse effects are hyperuricemia, glucose intolerance, nausea,
vomiting, diarrhoea, hyperglycaemia, and elevated plasma uric acid.
2) Probucol: It helps in the reduction of LDL and HDL levels, but shows
minute effects on serum-triglyceride or VLDL cholesterol levels.
Mechanism of Action
Probucol acts by increasing the fractional rate of LDL catabolism in the
final metabolic pathway for cholesterol elimination from the body. This
results in t he reduction of serum cholesterol level s. It can also inhibit
early stages of cholesterol biosynthesis and slightly inhibit dietary
cholesterol absorpti on. According to recent studies, probucol can also
control atherogenesis as it may inhibit the oxidation and tissue deposition
of LDL cholesterol.
Therapeutic Uses
Probucol is used to lower LDL and HDL cholesterol levels.
Adverse Effects
The common adverse effects of probucol are d izziness or fainting and fast or
irregular heartbeat.
Some rarely occurrin g adver se effects are s wellings on face, hands, or
feet, or in mouth, unusual bleeding or bruising, and unusual tiredness or
weakness
1.6.7. Other Drugs

Some rarely used anti-hyperlipidemic drugs are omega-3 fatty ac ids (fish oils).
Eicosapentaenoic acid (EPA) a nd docosahexaenoic acid (DHA) are the omega-3
fatty acids richly found in fish oil ; while linoleic acid is the omega -3 fatty acid
obtained from p lant sources , such as mustard oil, canola oil, linseed oil, black
gram dal, fenugreek seeds, walnuts, and green leafy vegetables. EPA and DHA
are formed by linoleic acid conversion in the body. Clinical studies have shown
that they reduce serious coronary events.
Mechanism of Action
Hepatic VLDL triglyceride synthesis is reduced by omega -3 fatty acids , thus,
reducing the plasma triglyceride levels. Secretion of VLDL apo B is reduced at
high doses of omega -3 fatty acids . The triglyceride levels ar e reduced at low
doses of omega -3 fatty acids, but LDL cholesterol levels may rise due to
conversion of VLDL to LDL -HDL cholesterol. Because of the decrease in
thromboxane synthesis, fish oils also have antiplatelet aggregatory activity.
Plasma fibrinogen levels are also reduced.
* *
62 Pharmacology-II
Therapeutic Uses
1) Fish oils, available as gela tin capsules are used in severe
hypertriglyceridemia along with fibrates.
2) Fish oils along with statins (LDL-C may increase during monotherapy, thus
they should not be used alone) are helpful in patients having mixed
hyperlipidaemia with slight increase in triglycerides.
Adverse Effects
The most common side effect of fish oils is nausea. However, their long-term use
has no obvious side effect.
1.7. SUMMARY
The details given in the chapter can be summarised as follows:
1) Cardiovascular system comprises of the heart and an extensive ly branched
structure of blood vessels that transports oxygen, nutrients, heat, and other
substances throughout the body.
2) The myocardial tissue is made up of contracting cells and conducting cells.
3) The study of the dynamic behaviour of blood is termed hemodynamics.
4) There are five phases of the action potential of cardiac cells.
5) When a heart fails to pump blood in a quantity sufficient to fulfil the body
requirements, a condition of Congestive Heart Failure (CHF) occurs,
which is also known as a Heart Failure (HF).
6) Cardiac glycosides are derived from plant derivatives and are steroidal in
nature.
7) Digoxin, digitoxin, and ouabain are the commonly used cardiac glycosides.
8) Route of administration of digitalis is either oral or intravenous.
9) When administered in co mparatively small therapeutic doses, digitalis
improves the ability of excitation of the myocardium and the conduction
velocity.
10) Digitalis improves circulation and decreases sympathetic activity, thereby
increasing the blood flow to kidneys.
11) Digitalis is highly toxic . It has a low margin of safety with a therapeutic
index ranging from 1.5-3.
12) Bipyridine derivatives (e.g., amrinone and milrinone) show
phosphodiesterase (PDE) inhibiting activity.
13) Bipyridines increase the production of cAMP in the heart and blo od vessels,
and thus exert a positive inotropic action along with vasodilator activities.
14) The β-adrenergic agonists increase the cardiac output, and decrease the
ventricular filling pressure and pre-load.
15) The β-adrenergic agonists may cause tachyphylaxis.
16) Diuretics increase the excretion of salt and water.
17) The production of angiotensin II from angiotensin I is inhibited by ACE
*
inhibitors. *
18) A condition in which the blood pressure of systemic artery increases beyond
the normal pressure is known as hypertension.
19) Drugs promoting urine output are known as diuretics.
20) Losartan is a competitive antagonist of angiotensin II.
21) Trimethaphan is the only ganglionic blocker used nowadays.
22) Reserpine is an alkaloid obtained from the roots of the plant Rauwolfia
serpentina.
23) Propranolol is used in mild to moderate hypertension.
24) Calcium channel blockersare commonly used in the treatment of hypertension.
25) Vasodilators cause vasodilation by directly relaxing the vascular smooth
muscles.
26) Angina pectoris (or chest pain) is a symptom experienced due to myocardial
ischemia, wherein the blood supply to the heart decreases.
27) Organic nitrates and nitrates are used in angina pectoris.
28) Ranolazine reduces the number of angina episodes per week and increases
exercise tolerance.
29) Arrhythmia is a common disorder of cardiac excitation, which may be
benign but may also be fatal ( e.g., ventricular fibrillation following a heart
attack).
30) Sodium channel blockers are the most widely used antiarrhythmic agents.
31) Antihyperlipidemics are the group of drugs p rescribed in adjuvant therapy
to reduce elevated cholesterol levels in patients with high cholesterol and
LDL levels in the blood.
32) Statins are the most effective and best tolerated agents used to treat
hyperlipidemia.
33) Cholestyramine is a bile acid sequestrant which serves as ion exchange resins.
34) Fibrates are the drugs reducing the triglyceride levels more than LDL
cholesterol levels.
35) Fibrates act as agonists for the nuclear transcription factor Peroxisome
Proliferators-Activated Receptor -alpha (PPAR-alpha), at the molecular
level.
36) Triglyceride synthesis and lipolysis inhibitors act either by inhibiting the
synthesis of triglyceride or by inhibiting the process of lipolysis.
1.8. EXERCISE
1.8.1. True or False

1) The study of the dynamic behaviour of blood is termed hemokinetics.
2) Digitalis is highly toxic.
3) Route of administration of digitalis is either oral or intravenous.
4) There are four phases of the action potential of cardiac cells.
5) The β-adrenergic antagonists may cause tachyphylaxis.
6) Trimethaphan is the only ganglionic blocker used nowadays.
* *
64 Pharmacology-II
7) Propranolol is used in high hypertension.

8) Ranolazine reduces the number of angina episodes per week and increases
exercise tolerance.
9) Statins are the most effective and best tolerated agents used to treat
hypolipidaemia.
1.8.2. Fill in the Blanks

10) The myocardial tissue is made up of________ and ___________.
11) Cardiac glycosides are derived from plant derivatives and are ________ in
nature.
12) Digoxin, digitoxin, and ouabain are the commonly used__________.
13) ________ improves circulation and decreases sympathetic activity.
14) The β-adrenergic agonists may cause___________.
15) A condition in which the blood pressure of systemic artery increases beyond
the normal pressure is known as____________.
16) ___________ is a competitive antagonist of angiotensin II.
17) Reserpine is an alkaloid obtained from the roots of the plant_____________.
18) ___________ reduces the number of angina episodes per week and increases
exercise tolerance.
19) _________ are the most effective and best tolerated agents used to treat
hyperlipidaemia.
20) The most common side effect of fish oils is________.
Answers
1) False 2) True 3) True 4) False 5) False
6) True 7) False 8) True 9) False
10) contracting cells, conducting cells 11) steroidal
12) Cardiac glycosides 13) Digitalis 14) tachyphylaxis
15) hypertension 16) Losartan 17) Rauwolfia serpentina
18) Ranolazine 19) Statins 20) nausea
1.8.3. Very Short Answer Type Questions

1) What is hemodynamics?
2) What are the uses of hemodynamic lines?
3) Define cardiac glycosides.
4) Give therapeutic uses of cardiac glycosides.
5) Define bipyridines.
6) What are -adrenergic agonists?
7) Define diuretics.
8) What are vasodilators?
9) Define ganglion blockers.
10) What is angina pectoris?
11) What is arrhythmia?
12) Explain fibrates.
* *
1.8.4. Short Answer Type Questions

1) Explain the electrophysiology of heart.
2) Classify the drugs employed in treatment of CHF.
3) Give mechanism of cardiac glycosides.
4) Give mechanism of action, uses and adverse effect of β-adrenergic Agonists
5) Classify anti-hypertensive drugs.
6) Explain the mechanism of action of diuretics.
7) Write about captopril and enalapril.
8) Classify and give mechanism of action of calcium channel blocker.
9) What are organic nitrites and nitrates and give its mechanism of action.
10) Classify anti-arrhythmic drugs.
1.8.5. Long Answer Type Questions

1) Explain cardiovascular system and its drugs in detail.
2) Classify and explain drugs of anti-hypertensive drugs in detail.
3) Explain adrenergic drugs in detail.
4) Write about anti-arrhythmic drugs in detail.
5) Write about potassium channel blockers.
6) Discuss in detail about anti-hyperlipidimic drugs.
* *
66 Pharmacology-II
CHAPTER Pharmacology of Drugs Acting on

2 CVS and Haemopoietic System
2.1. DRUGS USED IN THE THERAPY OF SHOCK
2.1.1. Introduction
Shock is a medical condition in which the blood perfusion to the tissues
decreases, resulting in cellular injury and inadequate tissue function. It is a life -
threatening condition signified by rapid heart rate, hypotension (low blood
pressure), weak pulse, and sign of poor end -organ perfusion (i.e., low urine
output, confusion, or loss of consciousness).
Shock alters the mental state of the patient and is a state of medical emergency. A
state of sho ck increases lactate metabolism as it leads to anaerobic metabolism.
Mortality rate in a patient with shock is quite high, even though optimal
treatment is provided in an ICU.
2.1.2. Treatment for Cardiovascular Shock

The treatment of cardiovascular shock involves:
1) Primary Therapy: This therapy aims at correcting the cause (i.e.,
haemorrhage, infection, myocardial infarction, and anaphylaxis), and
2) Secondary Therapy: This therapy aims at correcting the associated
hemodynamic disturbance. The following drugs are employed for their
hemodynamic effects:
1) Sympathomimetic amines, 2) α-adrenoceptor blocking agents,
3) Corticosteroids, 4) Oxygen,
5) Cardiac glycosides, 6) Glucagon, and
7) Dextrans.
2.1.2.1. Sympathomimetic Amines

Sympathomimetic amines act via β1-adrenoceptors in the heart, - and β2-
adrenoceptors in the blood vessels, and dopamine receptors in the cerebral,
coronary, mesenteric, and renal vascular beds. Patients with shock resulting from
decreased circulating volume of blood should be given either blood or plasma
volume expanders. They may later be given sympathomimetic agents for the
improvement of tissue perfusion.
Mechanism of Action
Either one or more mechan ism of action of sympathomimetic amines helps to
maintain the perfusion of vital organs (brain, heart, and kidney), and other
visceral organs:
1) Increased Myocardial Contractility: Sympathomimetic amines increase
*
the cardiac output in case of adequate venous return. *
Pharmacology of Drugs Acting on CVS and Haemopoietic System (Chapter 2) 67
2) Constriction of the Capacitance: Sympathomimetic amines contract the

vessels or venules to prevent venous pooling.
3) Dilation of Resistance: Sympathomimetic amines dilate the a rterioles either
by affecting or constructing the resistance vessels in non-vital organs.
Adverse Reactions
Restlessness, headache, pallor, dizziness, precordial pain, and palpitation are the
adverse effects of therapeutic doses of sympathomime tic amines. As a result of
overdosage, convulsions, cerebral haemorrhage, and tachyarrhythmia resulting in
fatal ventricular arrhythmias are induced.
Prolonged Administration of Vasoconstricting Sympathomimetic Amines:

When these agents (especially, nor-adrenaline) are administered for a long time,
a strong constriction of the post -capillary sphincter occurs due to decreased
plasma volume. As a result, the capillary pressure is increased , leading to loss of
fluids through the capillary walls. Also, a decrease in renal blood flow and
glomerular filtration rate is seen. Thus, a conditio n of marked tissue
hypoperfusion and irreversible shock usually results.
Prolonged Administration of Large Doses of Nor -Adrenaline: When large

doses of nor -adrenaline are administered for a long time, necrosis of the
intestines, liver and kidneys, haemorr hage, focal myocarditis, intravascular
platelet aggregation, and subepicardial haemorrhage occur.
If the sympathomimetic amines are suddenly withdrawn after a prolonged

therapy, recurrent and profound hypotension occurs; thus, the therapy should be
discontinued gradually with appropriate fluid replacement.
Examples of Drugs
Nor-adrenaline, adrenaline, dopamine, and the synthetic compounds like
isoprenaline, metaraminol , and dobutamine , are some of the sympathomimetic
amines employed in the treatment of sh ock. Mephentermine, methoxamine, and
phenylephrine are the s ympathomimetic amines preferred as pressor agents
during anaesthesia. Some of these drugs are discussed below:
1) Nor-Adrenaline: It increases the perfusion pressure and cardiac output in
patients with shock who have very low peripheral vascular resistance. Hence,
it is employed in patients suffering from low peripheral resistance shock.
However, it should not be administered in patients with shock syndrome,
characterised by high peripheral resistance and low or normal blood pressure.
This is because in such patients, nor -adrenaline further induces
vasoconstriction, resulting in loss of plasma volume via capillaries and a
further worsening of kidney function.
2) Adrenaline: Administration of this drug increases the cardiac output ,
decreases the renal blood flow , and increases t he Total Peripheral
Resistance (TPR). Adrenaline is employed in the management of
anaphylactic shock.
* *
68 Pharmacology-II
3) Dopamine: Renal and mesenteric blood flow is increased by this drug due to
its action on dopamine receptors. Dopamine causes stimulation of the heart
via activation of β-receptors. It increases the cardiac output and renal blood
flow. It does not affect the TPR. It successfully treats oliguric patients having
either low or normal peripheral vascular resistance. Dopamine can also be
combined with α-blocking agent in a vasoconstricted patient. It is used in the
treatment of cardiogenic, septic and traumatic shock.
4) Isoprenaline: It exerts its action by a β-adrenergic activity. It acts on the
heart and the periphery. It does not cause vasoconstriction in the kidneys
(unlike adrenaline). It is helpful in patients with shock who have a high
peripheral vascular resistance.
5) Metaraminol: Its haemodynamic actions are similar to those of nor -
adrenaline. However, its duration of action is longer than that of nor -
adrenaline.
6) Dobutamine: It is a newly synthesised synthetic catecholamine that exerts
its actions by acting primarily on β1-receptors. It targets the cardiac β1-
receptors, and thus its action on β2- and -receptors are less pronounced. Its
action on - and β2-receptors of blood vessels are not much efficient, and
thus have comparatively fewer vascular effects.
Dobutamine is employed in patients with severe CHF, and in those who have
undergone cardiac surgery as a short-term therapy. It increases the cardiac
output as efficiently as is oprenaline. Its adverse effects in the form of
tachycardia and arrhythmias are fewer as compared to those associated with
the use of isoprenaline.
2.1.2.2. α-Adrenoceptor Blocking Agents

The α-adrenoceptor blocking agents are used to reduce the intense vasoconstriction
caused by the reflex release of nor -adrenaline (from the adrenergi c nerves) and
catecholamines (from the adrenal medulla) as a result of shock.
Advantages of α-adrenoceptor blocking agents are:

1) The harmful effect of vasoconstriction on microcirculation in tissues is avoided.
2) Rapid administration of intravenous fluid is enabled such that the central
venous pressure is not increased.
3) The occult plasma volume deficit is unmasked.
However, hypotension may be seen as an adverse effect of these agents,

particularly in patients with myocardial insufficiency. Therefore, therap y
constituting -blockers should be followed by adequate replacement of fluids.
Thus, tissue perfusion is markedly improved.
The most commonly employed α-adrenoceptor blocking agent is

phenoxybenzamine. It is a life -saving drug in patients with surgical shock or
trauma. It causes an intense re-distribution of blood flow and plasma volume. For
this effect, it needs to be administered intravenously in a dose of 1mg/kg of body
* *
weight diluted well in 500ml of glucose (5%). In 30 minutes , the complete effect
of the drug is seen. It has duration of action of several hours. It exerts its action in
the form of a non-competitive inhibitor at the -receptor.
Phentolamine is another -blocking agent having a shorter duration of action.

Pressor drugs reverse the effect of this drug because the y competitively inhibit
the action of phentolamine at the α-receptor. Either dopamine or nor-adrenaline
is simultaneously administered along with the -blockers to counteract the
vasoconstriction produced. Any of these drugs do not affect the cardiac stimulant
action of the -blockers.
2.1.2.3. Corticosteroids
The useful effects of corticosteroids in states of shock are not completely
understood. Their efficacy is also controversial. The sensitivity to endotoxin may
be decreased when corticosteroids are administered in cases of septic shock.
However, this increases the chances of infection, while increasing the probability
of bacteraemia. A high dose of corticosteroids are administered in a patient with
shock as they bring the following responses:
1) A positive inotropic effect,
2) Decreased peripheral resistance,
3) Stabilisation of lysosomes,
4) Preservation of integrity of small vessels, preventing leakage from
microcirculation, and
5) Decreased adhesiveness of the platelets.
It is suggested that microcirculation is improv ed by all these effects that account

for a combination of increase in cardiac output, vasodilatation and protection of
cells from the damaging effects of proteases (by lysosomal membrane
stabilisation). Although no suggestion relating to their advantageous effects in
patients with shock has been reported. Yet, administration of corticosteroids in
large doses has been established to decrease the formation and liberation of
cardio-depressant elements from tissues due to their property of lysosomal
membrane stabilisation. This property of corticosteroids also accounts for other
cellular effects that protect the cells from damage against hypoxia.
2.1.2.4. Oxygen
Maintenance of adequate oxygen exchange requires positive pressure ventilation.
Also, the concentration of gases in blood should be monitored frequently to avoid
toxicity of oxygen.
Advantages of supplemental oxygen in shock patients are:

1) Cardiac output is increased by the supplementation of oxygen, and
2) Oxygenation of the tissues can be improved significantly.
Supplementation of oxygen in patients with shock is of immense importance in:
1) Conditions of arterial hypoxaemia (usually seen in cardiogenic shock),
2) Conditions of dyspnoea or cyanosis, and
3) When arterial PO2 falls below 60mm Hg.
* *
70 Pharmacology-II
2.1.2.5. Cardiac Glycosides

In patients with Congestive Cardiac Failure (CCF) accompanied with shock,
cardiac glycosides should be administered slowly in low doses to avoid th eir
peripheral vasoconstrictive action. Cardiac glycosides improve myocardial
contractility, raise the cardiac output , and improve tissue perfusion in CCF
patients. In oliguric patients, the doses of cardiac glycosides should be more
reduced to avoid cumulative toxicity resulting from their accumulation.
2.1.2.6. Glucagon
Mechanism of action of glucagon resembles to that of sympathomimetic amines,
yet it is slightly different. It differs from the sympathomimetic amines as its
actions are not blocked by β-blockers.
Advantages of administering glucagon are:

1) Increase in myocardial contractility and cardiac output, and
2) Intravenous administration of 1-2mg glucagon causes a definite improvement
in the hemodynamic status of patients with acute heart failure af ter a cardiac
surgery and in patients of shock after myocardial infarction.
Adverse effects of using glucagon in patients with shock:

1) Extreme nausea and vomiting (major effects), and
2) Cardiac arrhythmias (rarely seen).
2.1.2.7. Dextrans
Dextrans are efficient plasma volume expanders. They are employed in the
emergency treatment of hypovolemic shock. However, they are not effective in
the treatment of haemorrhagic shock as they do not replace blood (or its
derivatives). High molecular weight dextran (mol. w t. 1 ,10,000) is employed
for this purpose. It stays in the blood for a long time, thereby, maintaining the
osmotic pressure of blood.
Characteristic features of low-molecular-weight dextran:

1) Available in mol. wt. of 40,000, also referred to as Dextran 40.
2) Available in the form of a 10% solution in either isotonic saline or 5%
dextrose in water.
3) Intravenous use is usually recommended.
4) Has a powerful yet temporary oncotic effect on blood.
5) Withdraws fluid into the vascular space, thus helps improve blood flow,
6) Possesses a property of decreasing the viscosity of blood by inducing a
negative charge on the erythrocytes; thus the erythrocytes repel each other
and hence the microcirculation is improved.
7) Improves tissue perfusion and can thus be employed in patients with shock.
8) Prolongs bleeding time.
9) May show anaphylactoid reactions.
Hence, dextran 40 has been established to have only a limited use in the
management of patients with shock.
* *
2.2. DRUGS ACTING ON HAEMOPOIETIC

SYSTEM
2.2.1. Introduction
The word haemopoietic relates to the blood making processes . Hematologic
system includes the blood and blood -forming organs. The main function of the
blood is transportation of oxygen and nutrients required by the cells and
elimination of wastes from the body. It also transports hormones released by
the endocrine system. White blood cells are also required in prevention of
infection.
The blood is made up of two types of components, viz., plasma which is a straw-
coloured liquid (around 55%) and the formed elements (other 45%) which
include erythrocytes (red blood cells or RBCs), leukocytes (white blood cells or
WBCs), and platelets (clotting fragments).
2.2.2. Hematinics
Hematinics are involved in the formation of blood and are used in the treatment
of anaemia (a condition in which blood lacks healthy RBCs or haemoglobin ).
Haemoglobin is a major part of the red blood cells to which oxygen molecules
get bound.
Body cells do not get sufficient amount of oxygen, if a n individual has a few or
abnormal red blood cells, or the haemoglobin level is low or abnormal. The main
symptom of anaemia is fatigue which occurs if organs do not get sufficient
amount of oxygen that is required for different body functions.
Anaemia generally results from the deficiency of the following factors:

1) Iron,
2) Folic acid, and
3) Vitamin B12.
2.2.2.1. Iron
A healthy adult human body contains around 3.5g m of iron, of which about 2/3 rd
is found in the blood, whereas the remaining portion is preserved as ferritin and
hemosiderin in the bone marrow, spleen and muscles. The iron released by the
destruction of red blood cells (around 3 × 10 6 RBCs are destroyed every second)
is re -utilised for the production of haemoglobin. The healthy human adul t
requires a diet containing around 10-15mg iron per day.
Sources
Meat, chicken, egg yolk, liver, fish, oyster s, wheat germ, dry fruits, dry beans,
spinach, yeast, banana s, and apple s are the rich sources of iron; h owever, milk
and root vegetables have p oor amounts of iron. The iron in meat protein is
helpful in efficient absorption. Haemoglobin consists of haem iron and
* *
72 Pharmacology-II
myoglobin which can be absorbed completely as haemin (ferric form of haem)

without being broken down into elemental iron. In other foods , iron is less
available for absorption because it is bound to phytates or other complexing
agents. Non-haem iron and inorganic iron salts can be absorbed by intestinal
mucosal cells only after getting converted into ferrous iron.
Ferrokinetics
Depending on the physiological needs of the body, iron is absorbed in the
duodenum and proximal jejunum via active transport mechanism. Large doses of
iron absorb by diffusion across the mucosal barrier. In foodstuffs, iron is mostly
present in ferric form , which is reduced by the gastric acid to readily absorbable
ferrous form. Due to this, achlorhydria reduces iron absorption , whereas ascorbic
acid (in high doses of 200mg in every 8 hour) being a reducing agent increases
iron absorption.
The ferrous iron reaches the bloodstream directly by passing through the mucosal
cell. It is bound to transferrin in the blood and is carried to the storage sites. The
excess ferrous iron in the mucosal cell is re-oxidised into the insoluble ferric state
(ferric hydroxide phosphate complex), which forms ferritin (a complex ) by
combining with apoferritin (a protein).
Ferritin is a storage form of iron. A mucosal barrier is formed when the

mucosal cell cannot take up iron due to the saturation of apoferritin with iron.
Most of these mucosal cells are desquamated and lost in the lumen of the gut.
Therefore, this mucosal barrier, called as ferritin curtain , controls iron
absorption in the body . However, this mucosal barrier theory is still in question
by some workers.
Iron (Fe3+) is re leased by ferritin into the blood stream, where iron binds to
transferrin (glycoprotein β1-globulin). The resultant complex is carried to the
storage depots (liver, spleen, and bone marrow) and stored as ferritin to be
utilised for erythropoiesis. This iron is exchangeable, while the iron used in the
cytochrome system is non -exchangeable. Trace amounts of iron are excreted in
bile, urine, hair, nails , and sweat; however, its excessive quantities are excreted
in the skin and gut through desquamation of ferritin-containing cells.
Iron Therapy
In case of iron -deficiency anaemia, approximately 25 mg of iron is needed every
day for increasing haemoglobin by 1% per day. It is assumed that in oral therapy,
about 30% of iron is absorbed , and therefore it is necessary to administer around
180mg of elemental iron every day.
The following iron preparations are given to treat anaemic conditions:
1) Oral Iron Preparations: It is the most common and preferred route for iron
therapy. Dissociable ferrous salts have high iron content and can be absorbed
more easily than ferric salts. Iron salts are mainly used i n tablet form as their
solution forms stain the teeth. The following preparations and dosages are
*
given for the treatment of anaemia: *
Salt Taken Dose

Ferrous sulphate, hydrated* 0.3g tid
Ferrous sulphate, exsiccated 0.2g tid
Ferric ammonium citrate 1.0g tid
Reduced iron 0.5g tid
Ferrous gluconate* 0.6g tid
Ferrous fumarate* 0.2g tid
Ferrocholinate 0.5g tid
(*most commonly used)
The available slow release and chelated iron formulations cause less
gastrointestinal upsets and are better tolerated by children. High dose therapy
for a long time leads to haemosiderosis.
2) Parenteral Iron Preparations: Generally oral iron therapy is enough to cure
anaemia and parenteral therapy is needed only in critical cases, such as:
i) Intolerance to oral therapy,
ii) Improper iron absorption from the intestines,
iii) Malabsorption syndromes,
iv) Inadequate response, or
v) Severe iron-deficiency anaemia.
Before the beginning of therapy , the total dose to be administered
parenterally should be calculated (based on the haemoglobin level ) by the
given formula:
Total dose (mg) = 4.4 × Bodywt. in kg × Haemoglobin deficit in g/100ml blood
The following parenteral preparations of iron are commonly used:
i) Intramuscular Preparations: Iron dextran injection (Imferon) is the
commonly used intra muscular preparation which contains 50mg/ml of
elemental iron. Daily 1 -4ml of this injection is administered through
deep intramuscular route using Z -track technique (a way of applying
intramuscular injection that prevents tracking or leakage of the
medication into the subcutaneous tissue).
ii) Intravenous Preparations: Intravenous injections of iron are free of
preservatives. The f irst dose should be limited to 25mg, and should be
gradually increased to 100mg/day.
Therapeutic Uses
Iron therapy is mainly usedin the treatment of iron-deficiency anaemia which results
due to severe or chronic haemorrhage, malabsorption syndromes, simple
achlorhydria, malignancy, infection, nutritional deficiency, pregnancy, lactation, and
parasitic infestations (mainly ankylosto miasis). The iron -deficiency anaemia
responds to iron therapy quickly; however the given cause should also be treated
concurrently. Evenif the haemoglobin level become s normal, the iron therapy should
be continued for replenishing the exhausted stores of iron. As per the medical
examinations, the haemoglobin reaches normal levels within 10 weeks of oral
therapy and 3-6 months of treatment is requiredfor replenishment of the iron stores.
* *
74 Pharmacology-II
Iron Toxicity
1) Acute Toxicity: Excessive intake of iron salts lead t o acute toxicity. Adults
can tolerate large doses without any fatality; however, doses of 1-2gm of iron
can be fatal to young children. Therefore , these preparations should be kept
out of the reach of children. The symptoms of acute poisoning include
abdominal pain, vomiting, and diarrhoea followed by shock, lethargy, pallor,
and cyanosis. These signs and symptoms of acute toxicity appear within 30
minutes or sometimes later. In case the patient survives for 6 hours, then it
can be a passing period of recovery followed by death within 12-24 hours.
Emergency therapy is needed that includes gastric lavage with phosphate or

carbonate solution to produce insoluble iron complexes. The i ron chelating
agent, deferoxamine should be infuse d parenterally in the st omach so that it
binds the iron in blood and improve the excretion. Supportive therapy is
given in case of shock, dehydration, and acid-base abnormalities.
2) Chronic Toxicity: The condition, in which excessive iron is deposited in the
heart, liver, pancreas, and other organs , is known as haemochromatosis and
haemosiderosis. This ultimately leads to organ failure and death.
Haemochromatosis is an inherited disorder in which absorption of iron increases
abnormally. For treating iron toxicity , deferoxamine is u sed but it is less
satisfactory and costly; however, it may be used in conjunction with phlebotomy.
2.2.2.2. Folic Acid

Folic acid (or pteroylglutamic acid) belongs to the B complex group of vitamins
and its deficiency causes mega loblastic anaemia. Around 50 -100µg/day folic is
required by a healthy adult and about 200-400g/day is required in pregnancy
and lactation. It is used in the treatment of macrocytic hyperchromic anaemia.
Sources
Yeast, green vegetables, and liver are the rich sources of folic acid. The body
stores of folic acid are low; thus on stopping the intake of folic acid, the stores
deplete and anaemia develops within 1-6 months.
Mechanism of Action
Folic acid is an inactive biochemical compound that changes to te trahydrofolic
acid and methyltetrahydrofolate in the presence of dihydrofolate reductase
enzyme. These folic acid congeners are transported across the cells through
receptor-mediated endocytosis for regulation of erythropoiesis, synthesis of
purine and thymidylate nucleic acids, inter -conversion of amino acids, methylate
tRNA, and generation of formate. Folic acid can regulate the high homocysteine
levels by re -methylation of homocysteine to methionine in the presence of
methionine synthetase enzyme and using vitamin B12 as a cofactor.
Pharmacokinetics
The polyglutamate form of 5CH 3-H4-folate, i.e., dietary folate, is hydrolysed by
-glutamyl transferase enzyme in the brush border of the intestinal mucosa. The
oxidation of active H 4-folate is prevented by a scorbic acid. The monoglutamate
* *
form of 5CH 3-H4-folate is absorbed and transported while being bound to folate -
binding plasma protein. It is stored in the liver (5 -20mg) and in some tissues (as
polyglutamates). Folic acid experiences enterohepatic circulat ion and is excreted
through urine and stool in trace amounts.
Therapeutic Uses
Folic acid is mainly used in the treatment of megaloblastic anaemia occurring
due to folate deficiency. Other than this it is also used to cure:
1) Nutritional megaloblastic anaemia,
2) Megaloblastic anaemia of pregnancy,
3) Megaloblastic anaemia in infancy and childhood,
4) Megaloblastic anaemia associated with alcoholism and liver disease,
5) Chronic haemolytic states,
6) Megaloblastic anaemia of malignant disease, and
7) Some cases of agranulocytosis.
Adverse Effects
Adverse effects are very rare in injectable and oral preparations. Large doses of
folic acid may counteract the antiepileptic effect of phenytoin and phenobarbital ,
so fits may occur in a controlled patient.
Folate Deficiency
Normal plasma folate levels in a healthy adult human lie between 4-20ng/ml; and
its deficiency results due to nutritional deficiency, small intestine diseases,
alcoholism, haemolytic anaemia, and some drugs.
Folic acid is required in the following intracellular reactions:

1) Conversion of homocysteine to methionine,
2) Conversion of serine to glycine,
3) Synthesis of thymidylate,
4) Synthesis of purines, and
5) Metabolism of histidine.
These reactions are affected in cases of folic acid deficiency characterised by the
development of megaloblastic anaemia. Folate deficiency does not result in
neurological irregularities. The effects of folate deficiency are observed early as
the total body stores of folic acid are low.
The symptoms of folate deficiency develop within 1 -4 weeks depending on the
individual’s dietary habits and vitamin stores. Through measuring plasma folate
levels and examining the peripheral blood smear , the deficiency of folate can be
easily diagnosed.
Preparations and Dosage

Folic acid is formulated in the form of tablets, either alone or with other vitamins.
Tablets have 0.1, 0.4, 0.8, or 1mg of pteroylglutamic acid. Folic acid injections
are formulated in aqueous solution of sodium salt of pteroylglutamic acid. The
intramuscular injections of Leucovorin calcium are also commercially available.
* *
76 Pharmacology-II
2.2.2.3. Vitamin B12 (Cyanocobalamin)

A wide range of both natural and semi -synthetic compounds are grouped in the
cobalamines family which include cyanocobalamin (vitamin B 12) and
hydroxycobalamin (vitamin B12a). Various other cobalamins are present, but they
are not as beneficial as vitamin B 12 and are also less stable . Vitamin B 12 is
primarily used in the treatment of pernicious anaemia.
Sources
Vitamin B12 is one of the most important vitamins. In humans, it is formed by the
colonic bacteria (but is not absorbed) and is excreted through faeces. Hence, the
dietary intake of vitamin B 12 is essential. In food, the cobalamins are found
bounded with protein and before absorption this bond is broken by proteolysis.
Around 0.6 -1.2µg/day of vitamin B 12 is required and it is mainly stored in the
liver. Total vitamin B12 stored in the adults is around 5mg. It is naturally found in
animal products, including fish, meat, poultry, eggs, milk, and milk products.
Mechanism of Action
In the body vitamin B12 is used in the following two forms:
1) Methylcobalamin: This form of vitamin B 12 is used as a cofactor by
methionine synthase enzyme, which is involved in the conversion of
homocysteine into methionine (required in DNA methylation ). In tissues ,
vitamin B 12 changes to coenzyme B 12 (methylcobalamin), which i s needed
for the conversion of methylmalonate to succinate and for the synthesis of
methionine from homocysteine (a reaction in which folate is also r equired).
Vitamin B 12 also regulates sulfhydryl (S H) groups in the reduced form
required by various SH-activated enzyme systems.
2) 5-Deoxyadenosylcobalamin: It acts as a cofactor for L -methylmalonyl-CoA
mutase enzyme, which changes L -methylmalonyl-CoA to suc cinyl-CoA.
This conversion is essential for the extraction of energy from proteins and
fats. Succinyl CoA is also required for the production of haemoglobin.
Pharmacokinetics
Food contains vitamin B 12 as protein conjugates. Free vitamin B 12 is released in
the stomach and duodenum by gastric acid and proteolytic enzymes. It is also
released by cooking food. Intrinsic factor (a specific glycoprotein) is secreted by
the parietal cells of stomach. This glycoprotein complexes with vitamin B 12
(extrinsic factor) and gets absorbed in the distal ileum through a highly specific
receptor-mediated transport mechanism. But if high doses (1mg) of vitamin B 12
are given orally, a little amount is absorbed by diffusion even if the intrinsic
factor is absent.
Vitamin B 12 is combined with transcobalamin (a specified plasma globulin) and

transported into the blood. The liver (hepatic store 3 -5mg) stores the surplus
vitamin B 12; and this hepatic store lasts for 5 years if due to any reason the
absorption of intestinal vitamin B12 is stopped. Deficiency anaemia occurs only
when the hepatic store of vitamin B 12 also gets exhausted. 3-7g of vitamin B 12 is
excreted in bile every day; however, most of it gets reabsorbed in enterohepatic
* *
circulation. The excess amount of administered vitamin B12 remains free and does
not bound to transcobalamin, thus gets excreted in urine. Sincehydroxycobalaminis
more protein-bound, it is better retained than cyanocobalamin.
Therapeutic Uses
1) Pernicious (Addisonian) Anaemia : The treatment may continue through
whole life.
2) Malabsorption Syndromes: Deficiency of vitamin B 12 and folic acid occurs
with coeliac diseases, like sprue and idiopathic steatorrhoea; these conditions
in later stages result to megaloblastic anaemia.
3) Neurological Conditions: High doses (1mg or more) of vitamin B 12 are
given to the patients of trigeminal neuralgia, toxic/diabetic/alcoholic neuritis,
and other nutritional neuropathies. High doses of vitamin B 12 are used in
neuroblastoma in children.
4) Psychiatric Disorders: This is an old age disorder which may favourably
respond to vitamin B12 therapy.
Deficiency Diseases
Vitamin B12 deficiency arises either due to its malabsorption from distal ileum or
due to absence of the intrinsic factor (in cases o f pernicious anaemia and
gastrectomy). The cause of vitamin B 12 deficiency is not the lack of its dietary
supply because the daily requirement is only 2 g and the daily diet contains 5 -
40g of vitamin B 12.Vitamin B 12 deficiency results in the following disorders of
haematopoietic and nervous system:
1) Megaloblastic Anaemia and Pernicious Anaemia: In megaloblastic
anaemia, very large-sized RBCs are formed. It causes hypercellular marrow
due to abnormal maturation and defective DNA synthesis. Pernicious
anaemia is a type of megaloblastic anaemia which occurs due to vitamin B12
deficiency in the absence o f castle intrinsic factor (secreted by the normal
gastric mucosa). This intrinsic factor is required for the intestinal absorption
of the extrinsic factor, i.e., dietary vitamin B12.
Vitamin B 12 deficiency mainly occurs due to ineffective haemopoiesis

(maturation arrest at the megaloblastic stage) , inadequate epithelial cells of
the gut (histamine-fast achlorhydria and achylia gastric a), inadequate myelin
synthesis (sub -acute combined degeneration of the dorsal columns of the
spinal cord) and general debility.
2) Neurological Disorders: Neurological symptoms of vitamin B 12 deficiency
are paraesthesias of hand and feet, reduction on the sensation of vibration and
position, reduced deep tendon reflexes, memory l oss, confusion, delusion,
loss of central vision, hallucination, and psychosis.
Preparations and Dosage

Vitamin B 12 is available as tablet s, syrup s, and injectable s along with other
vitamins. Cyanocobalamin injections are available as red coloured aqueous
solutions of various concentrations. They are given through IM or SC route.
* *
78 Pharmacology-II
However, some patients show reduction in plasma concentration of B12 within 30

days of injection and the development of antibodies against transcobalamin
vitamin B12 complex is also seen; therefore, hydroxycobalamin is not suggested.
2.2.3. Coagulants
Coagulants are agents that help in the coagulation of blood and are given in
haemorrhagic conditions. The elements oractors
f required for coagulation are found
in the fresh whole blood or plasma, and are therefore indicated in case of deficiency
of any clotting factor. Blood coagulation is an important biochemical reaction which
ensures the cessation of blood loss from the damaged blood vessels. Coagulation is
an important part of the haemostatic mechanism. Disorders of blood coagulation
result in excessive haemorrhage and/or thrombosis and embolism.
Following are the other drugs used to restore haemostasis:
1) Vitamin K
i) K1 (from plants, fat-soluble) – Phytonadione (Phylloquinone).
ii) K3 (synthetic)
a) Fat-soluble – Menadione and Acetomenaphthone.
b) Water-soluble – Menadione sodium bisulfite and Menadione sodium
diphosphate.
2) Miscellaneous: Fibrinogen (human), Antihaemophilic factor, Desmopressin,
Adrenochrome monosemicarbazone, Rutin, and Ethamsylate.
2.2.3.2. Vitamin K
Vitamin K takes part in blood coagulation reaction , and therefore is indicated in
the treatment of haemorrhages. Whole blood o r plasma is best for the immediate
effects as it provides all the endogenous coagulation factors along with plasma
volume replenishment. Vitamin K is fat -soluble vitamin which takes part in the
synthesis of clotting factors.
Sources
Green leafy vegetables , liver, cheese, butter, and egg yolk are good sources of
vitamin K.
Mechanism of Action
Vitamin K is required for the synthesis of various factors II, VII, IX, and X that
take part in blood coagulation reaction. Chemically, these factors are
glycoproteins with a number (10 or 11) or -carboxyglutamic acid at the ─NH2
terminal of the peptide chains. Vitamin K -regulated synthesis of -
carboxyglutamic acid residues occurs after the peptide chain synthesis. In the
carboxylation reaction, vitamin K acts as a co-factor.
II, VII, IX, and X
(-carboxylated form)
Factor II, VII, IX, and X
(Decarboxylated form)
Vit K (hydroquinone Vit K (epoxide form or
form or reduced form) oxidised form)
* *
Therapeutic Uses
1) Prolonged Antimicrobial Therapy: Antimicrobial therapy for a long period
causes destruction of GIT bacteria , thus formation of vitamin K is either
reduced or stopped. For the treatment of this condition , vitamin K
preparations are given through oral route.
2) Obstructive Jaundice: It is caused by malabsorption of dietary or intestinal
vitamin K. Vitamin K 3 can be administered orally, while K1 or K 2 can be
given through parenteral route.
3) Overdosage of Oral Anticoagulants: In this case, vitamin K is given as
specific antidote. Vitamin K 1 is the preparation of choice due to its rapid
onset of action. Menadiol sodium diphosphate (K 3) should not be used due to
its late onset of action (24 hours).
4) Malabsorption Syndrome: In this condition, parenteral vitamin K or oral
vitamin K3 may be used.
Adverse Effects
Adverse effects are very rare in oral administration. However, in some patients
serious an aphylactoid reactions may occur after IV administration. Large doses
of synthetic menadione may cause haemolytic anaemia , hyperbilirubinemia and
kernicterus in new-borns, mainly in premature infants.
Preparations
1) Phytomenadione (Phytonadione, Vitamin K 1): It is a naturally found
vitamin and works within 12 hours. It can be given through IV, IM, SC , and
oral routes. It should be given slowly in case of intravenous administration as
flushing, sweating, chest tightness, and peripheral vascu lar collapse may
occur due to the presence of castor oil in the preparation.
2) Menadione Sodium Diphosphate (Vitamin K 3): It is a water-soluble,
synthetic analogue of vitamin K given daily in 5 -40mg dose by IV, IM, and
oral route. The major drawback of this preparation is that it takes 24 hours to
work, whereas its action lasts for days.
2.2.3.3. Other Drugs

Following are the examples of drugs used as coagulants:
1) Fibrinogen: It is the soluble component of human plasma. On addition of
thrombin, it transforms to fibrin. It regulates the haemorrhage related to low
blood fibrinogen concentration in afibrino genaemia or hypofibrinogenaemia;
however, the plasma or cryoprecipitate is used. It is also used in disseminated
intravascular coagulation (the defibrination syndrome).
2) Antihaemophilic Factor: It is a sterile freeze -dried powder having factor
VIII fraction obtained from human plasma from whole blood don ors. It is
used in patients of haemophilia (a genetic disorder of factor VIII deficiency),
who are susceptible to bleeding.
3) Epsilon Aminocaproic Acid (EACA): It is an anti -fibrinolytic that acts by
preventing activation of plasminogen and plasmin ( to a sm aller degree ).
* *
80 Pharmacology-II
EACA prevents the lysis of existing clot and results in thrombosis. It is used
in haemorrhage with extreme fibrinolysis, such as overdose of streptokinase,
urokinase (UK), and alteplase. It is clinically used in the treatment of
haemorrhagic conditions occurring due to some surgery or obstetric
complications, especially in patients of menorrhagia or haematuria in
neoplasms like metastatic carcinoma of the prostate and leukaemia. Initially,
5gm of oral dose is given followed by 1gm hourly to a maximum of 25-30gm
in 24 hours until bleeding stops.
4) Thrombin: It is an enz ymatic preparation. It changes fibrinogen to fibrin. A
solution of human or bovine thrombin is used locally as a haemostatic.
Topically, it controls the haemorrhage from puncture sites or capillary oozing
during surgery.
5) Fibrin Foam: It is extracted, dried, and artificial foam, f ormulated in the
form of strips, cut in any size and used for local haemostasis. It is used in
surgery along with thrombin. Fibrin foam dipped in thrombin is kept at the
bleeding site and can be left in place as the clotting material of human origin.
6) Snake Venoms: Venom of the Russell’s viper and copper head snake is used
as coagulant s. The venom increases coagulation by activating
thrombokinase. It can be used systemically or locally.
7) Oxidised Cellulose (Oxycel): It is a dry absorbable surgical gauze. It is used
in haemostasis and helps in clotting by reaction between haemo globin and
cellulosic acid. If used on bleeding surface , it swells to form a gelatino us
mass which get s absorbed in 2 -7 days. When haemostasis occurs, it should
be removed. It should be used in moderate bleeding where suturing or
ligation is impractical.
2.2.4. Anticoagulants
Anticoagulants are a gents decreasing the coagul ation ability of blood. They do
not dissolve the already formed clots, but are used to inhibit the formation of new
clots. Examples of these agents are heparin and warfarin. Heparin is given
intravenously to patients at risk of thrombus formation and warfa rin is
administered orally.
Anticoagulantsare used to decreaseblood coagulability. Theyare classified as follow
s:
1) Injectable Anticoagulants: Heparin, Ancrod, and Lepirudin.
2) Oral Anticoagulants
i) Coumarin Derivatives: Bishydroxycoumarin ( Dicumarol), Warfarin
sodium, Acenocoumarin, and Ethylbiscoumacetate.
ii) Indandione Derivative: Phenindione.
2.2.4.2. Injectable Anticoagulants - Heparin

Heparin is a strong anticoagulant agent which is naturally found in human
blood cells (mainly in basophils or mast cells). It is synthesised in the liver and
lungs of domestic animals. It is synthetically available as heparin sodium and
* *
the low - and high -molecular weight heparins (fractionated heparins). It is a

potent organic acid and commercially obtained from bovine lung and porcine
intestinal mucosa.
Mechanism of Action (Figure 2.1)

Heparin binds and potentiates the activity of plasma antithrombin -III, which
forms stable complexes with the activated clotting facto rs (Xa, IIa, IXa, Xia,
XIIa, and XIIIa) to prevent them. In low concentrations, heparin selectively
prevents the conversion of prothrombin to thrombin. Hence, heparin inhibits
thrombus formation; however it does not have thrombolytic action. It has
antiplatelet action in high doses , and hence increase the bleeding time. It
decreases the blood lipid level by releasing lipop rotein lipase from vessel wall
and tissues.
Intrinsic system Extrinsic system
XIIa
XI XIa VIIa
IX IXa + VIII
X Xa + V
LMWHs –
Prothrombin Thrombin (IIa)
Fibrinogen Fibrin (soluble)

XIIIa
Fibrin (stable)
Figure 2.1: Coagulation Cascade. Heparin Inactivates Factor XIIa, XIa, IXa, Xa, IIa,
and XIIIa through Antithrombin. LMWHs inhibit Xa through Antithrombin
Pharmacokinetics
Heparin is given parenterally through intravenous or subcut aneous route because
it is absorbed orally. It does not cross the placenta. It is metabolised in the liver
and follows first-order kinetics. The IV injection of less than 100 units per kg has
the half-life of average one hour; however beyond this dose, it becomes dose -
dependent and half -life increases to 5 hours. The half -life also increases in
patients with hepatic cirrhosis, and decreases in patients with pulmonary
embolism.
Therapeutic Uses
Heparin is an anticoagulant and is used in the treatment of var ious pathological
conditions like unstable angina, dialysis, pulmonary embolism, arterial or venous
thrombosis, and angioplasty.
Adverse Effects
1) Heparin shows allergic reactions with fever, urticaria, and anaphylactic shock
.
2) Transient and mild thrombocytopenia may occur in 2-5% patients because of
heparin-induced platelet aggregation.After 7-14 days, severe thrombocytopenia
is seen because of formation of heparin -dependent platelet antibodies . This
condition is recovered by replacing heparin with oral anticoagulants.
* *
82 Pharmacology-II
3) Haemorrhage may occur which can be inhibited through administration of

minimum effective dose by monitoring a PTT.
4) If heparin is used for 6 months or more , it can cause hair loss, transient
alopecia, and osteoporosis.
Other Formulation: Low Molecular Weight Heparin

Low Molecular Weight Heparin (LMWH) is used as an anticoagulant in
thrombosis and prophylaxis conditions which cause the high danger of
thrombosis. LMWHs have an average molecular weight of less than 8000Da.
They contain short chai ns of polysaccharide and 60% of all chains are having
molecular weight less than 8000Da. LMWHs are known as heparin salts. They
are formed by using various methods such as fractionation or depolymerisation
of polymeric heparin. They possess a potency of greater than 70 units/mg of anti-
factor Xa and a ratio of anti-factor Xa activity to anti-thrombin activity of > 1.5.
LMWHs have following characteristic features over the heparin:
1) They have a higher bioavailability on subcutaneous administration.
2) They have a longer half-life.
3) They are less bound to plasma proteins.
4) They do not require frequent monitoring of partial thromboplastin time.
5) They undergo weaker interactions with platelets.
6) They rarely cause heparin-induced thrombocytopenia.
Due to their high molecular weight, the high molecular weight heparins do not
cross the placenta of human easily, thus are not used anymore.
2.2.4.3. Oral Anticoagulants

Oral anticoagulants are the antagonists of vitamin K that prevent th e γ-
carboxylation of glutamic acid resi dues at many locations at the amino terminal
and of coagulation factors. The fir st used oral anticoagulant was
bishydroxycoumarin, and later several other congeners were synthesised that are
termed as coumarin derivatives.
2.2.4.4. Coumarin Derivatives

Coumarin derivatives show anticoagulant activity only in vivo (and not in vitro)
as they indirectly inhibit the synthesis of vitamin K -dependent clotting factors in
the liver. They decrease the availability of vitamin K and results in its deficiency.
Some examples of coumarin derivatives are:
1) Bishydroxycoumarin: It has a half-life of 24-100 hours.
2) Warfarin Sodium: It has a half-life of 36-44 hours and its duration of action
is 4 -7 days with a loading dose of 10 -15mg followed by 1 -10mg/day
maintenance dose. The clinically used warfarin is a racemic mixture of equal
amounts of the R - and S -enantiomers. The levorotatory S -warfarin is four
times more effective than dextrorotatory R-warfarin.
3) Acenocoumarin: It is used in a loading dose of 10 -20mg followed by a
maintenance dose of 2 -10mg. It can cause oral ulceration, GIT disturbances,
*
and dermatitis. *
Mechanism of Action (Figure 2.2)

Coumarin derivatives act as the competitive antagonist of vitamin K. They inhibit
the synthesis of factors II (prothrombin), VII, IX, X, and protein C and S. For
these coagulation factors, γ-carboxylation is essential. Coumarin derivatives
prevent the regeneration of vitamin K from its epoxide derivatives in vitro, thus
causes vitamin K deficiency.
Descarboxyprothrombin Prothrombin
(and factor VII, IX, and X) (and factor VII, IX, and X)
O2 CO2
Vit K-hydroquinone Vit K-epoxide

(Reduced and active form) (Oxidised and inactive form)
NAD+ NADH
Epoxide reductase (oral anticoagulants
inhibit epoxide reductase)
Figure 2.2: Mechanism of Action of Oral Anticoagulants
They inhibit the regeneration of active vitamin K-hydroquinone (reduced form of

vitamin K). This reduced vitamin K is oxidised to vitamin K epoxide (inactive
form). This reaction is coupled with protein carboxylation by which Des Carboxy
Prothrombin (DCP) is converted to prothrombin by carboxylation of glutamate
residue. By the reactions of enzyme, vitamin K hydroquinone is regenerated from
vitamin K -epoxide, using NADH as a co -factor. Synthesis of clotting factors
reduces in 2 -4 hours and the effect of anticoagulant lasts for 1 -3 days, if the
synthesis of clotting factors decreases by 40-50%.
Pharmacokinetics
Coumarin derivatives are well -absorbed when given through oral, intramuscular,
and rectal route. Peak plasma level is obtained within 2 -8 hours after oral
administration. They are 90 -99% bound to plasma protein, mainly albumin.
Sensitivity towards anticoagulants differs from patient to patient, therefore
individual dose adjustment is required. Adjustments of dose are done to retain the
prothrombin time between 1.5 -2 times and an international normalised ratio
(INR) of 2 to 3 times of control.
Therapeutic Uses
Warfarin is used as an anticoagulant in patients of pulmonary embolism, deep
vein thrombosis, atrial fibrillation, to inhibit thromboembolism, prosthetic valves,
primary pulmonary hypertension, and sometime in cerebrovascular disease.
Adverse Effects
The most severe risk factor with oral anticoagulant therapy is haemorrhage in any
organ which further results in haematomas and anaemia. Alopecia, fever, nausea,
vomiting, diarrhoea, hypersensitivity reaction, priapism, and skin reactions are
some other side effects.
* *
84 Pharmacology-II
During pregnancy warfarin causes teratogenicity. When given in the first

trimester, it can cause foetal warfarin syndrome with bone stippling, and
abnormalities of face and CNS. It causes neonatal hypoprothrombinaemia in the
second and third trimester. Patients with bleeding should not be given warfarin.
In patients with haemorrhagic blood disorders, peptic ulcers, severe wounds, and
bacterial endocarditis, warfarin should be used very carefully.
2.2.4.5. Indandione Derivative - Phenindione

Phenindione acts as an anticoagulant and shows actions similar to warfarin. It is
now used rarely due to higher cases of severe adverse effects.
Mechanism of Action
Phenindione acts by inhibiting vitamin K reductase enzyme, which causes
depletion of the reduced form of vitamin K (vitamin KH 2). Vitamin K ac ts as a
cofactor for the carboxylation of glutamate remains on the N -terminal regions of
vitamin K-dependent proteins, therefore reduced level of vitamin K limits the γ-
carboxylation and subsequent activation of vitamin K -dependent coagulant
proteins. Phenindione prevents the formation of vitamin K -dependent
coagulation factors (II, VII, IX, and X ) and anticoagulant proteins (C and S ).
Depression of the three vitamin K-dependent coagulation factors (II, VII, and X)
causes reduction in the prothrombin levels and in the amount of thrombin
generated and bound to fibrin.
Therapeutic Uses
Phenindione is used for the treatment of pulmonary embolism, cardiomyopathy,
atrial fibrillation and flutter, cerebral embolism, mural thrombosis, and
thrombophilia. It is also used for anticoagulant prophylaxis.
Adverse Effects
Phenindione gives rise to r eddish purple swollen patches on skin, feeling of
sickness, red or brown coloured urine, severe stomach pain or back pain,
difficulty in b reathing, chest pain, numbness, black or red stools, consciousness,
slurred speech, and bleeding cuts or wounds.
2.2.5. Fibrinolytics
Fibrinolytics are used for dissolving the blood clots ( or thrombi). Blood clotting
can occur in any vascular bed ; but they can be life threate ning, if they occur in
coronary, cerebral or pulmonary vessels. Myocardial infarctions are caused by
coronary thrombi, strokes are produced by cerebrovascular thrombi , and
pulmonary thromboemboli can cause respiratory and cardiac failure. Therefore,
blood clots should be diagnosed and treated as early as possible.

Blood coagulation and thrombus formation are significant for haemostasis; but,
to check bleeding it should be restricted to a smallest area. Two endogenous
mechanisms, i.e.,fibrin inhibition and fibrinolysis, restrict the extension of thrombus
formation. Some endogenous clotting factor protease inhibitors  ( 1-antitrypsin, 2-
macroglobulin,2-antiplasmin, and antithrombin III) affect the inhibition of fibrin
*
.*
Activation Plasminogen Inhibition
Factor XIIIa*
tissue Plasminogen Activators* (tPA) Epsilon aminocaproic
acid (EACA)
Kidney Urokinase Tranexamic acid
Streptokinase
Proactivator *
proactive
plasminogen
complex
Streptokinase Deacylation
Streptococci -Antiplasmin*
Apsac
Plasmin
Degradation Fibrin Fibrin
Fibrinogen
products fragments
* :Intrinsic factors
Figure 2.3: Mechanism of Action of Drugs Affecting Fibrinolytic System
The main process of fibrinolysis involves the conversion of inactive plasminogen

(bound to the fibrin of thrombus) to the active proteolytic enzyme plasmin.
Factor XIIIa activates the plasminogen at the beginning of coagulation. The
formation of tissue Plasminogen Activator (tPA) from the kidneys is initiated by
thrombus formation. The active plasmin formed from the fibrin -bound
plasminogen re -modifies the thrombus, and restricts its extension by breaking
down fibrin into fragments (figure 2.3). Fibrinolytic mechanism is not affected
by heparin and oral anticoagulants.

Thrombolytic drugs were initially used for treating deep vein thrombosis and
serious pulmonary embolism; but now, they are used less frequently. Their use in
the treatment of acute myocardial infarction or peripheral arterial thrombosis is
also restricted because they have a tendency to cause bleeding. However,
thrombolytic agents dissolve clots by causing occlusions, thus help in restoring
catheter and shunt function. They are also used for dissolving the clots resulting
in strokes.

The fibrin of an unwanted thrombus and the fibrin of a beneficial haemostatic
plug are not discriminat ed by the thrombolytic agents, t hus, resulting in
haemorrhage; this is t he m ajor side effect. For example, a previously
unsuspected peptic ulcer may haemorrhage after a thrombolytic agent is
injected.
Thrombolytic agents are contraindicated in pregnancy, head trauma, brain

tumour, metastatic cancer, intracranial bleeding, and in patients with healing
wounds or hist ory of cerebrovascular accident . After lysis of the initial clot ,
continued presence of thrombogenic stimuli may cause re-thrombosis.
* *
86 Pharmacology-II

Some commonly used fibrinolytics are discussed below:
1) Alteplase: Previously known as tissue plasminogen activator , alteplase is a
serine protease obtained from cultured human melanoma cells. However,
currently it is derived as a product of recombinant DNA technology. It is
administered in 0.9mg/kg of dose as it has a v ery short half -life (5 -30
minutes). 10% of this dose is injected intravenously as a bolus and the
remaining is administered over 60 minutes.
Even with a low affinity for free plasminogen in the plasma, alteplase rapidly
activates plasminogen bound to fibrin in a thrombus or haemostatic plug.
Therefore, alteplase is fibrin selective. In low doses , it lyses fibrin without
degrading other proteins ( especially, fibrinogen). Alteplase is used for
treating myocardial infarction, massive pulmonary embolism, a nd acute
ischemic stroke. Bleeding complications like GI and cerebral haemorrhages
are the adverse effects of alteplase.
2) Streptokinase: It is an extracellular protein purified from culture broths of
group C -haemolytic Streptococci. The half-life of streptokinase is less than
30 minutes. Therapy with this drug is started within 4 hours of myocardial
infarction and is infused for an hour. Thromboplastin time is monitored and
maintained at 2 -5 times the control value. Either heparin or oral
anticoagulants may be administered on discontinuation of streptokinase.
Streptokinase has no enzymatic activity , but it forms an active complex with
plasminogen. This complex converts the uncomplexed plasminogen to the
active enzyme plasmin. Streptokinase hydrolyses fibrin, plugs this complex,
and also catalyses degradation of fibrinogen and clotting factors V and VII.
Streptokinase is used in acute pulmonary embolism, acute myocardial
infarction, occluded access shunts, deep vein thrombosis, and arterial
thrombosis. The adverse effects of streptokinase are:
i) Bleeding Disorders: Since streptokinase activates the circulating
plasminogen, the p lasmin levels are raised. This may dissolve the
haemostatic plugs and precipitate bleedin g. Aminocaproic acid may be
administered in rare cases of life threatening haemorrhage.
ii) Hypersensitivity: Streptokinase is a foreign protein that gives rise to
rashes, fever, and anaphylaxis. This is because as most individuals have
already suffered from streptococcal infection, antibodies against
streptokinase are present in their blood . These antibodies neutralise the
fibrinolytic properties of streptokinase by combining with it. To
overcome the antibodies and provide a therapeutic plasmin
concentration, streptokinase should be administered in adequ ate doses.
The presence of anti -streptococcal antibodies may cause fever, allergic
reactions, and therapeutic failure of streptokinase.
3) Urokinase: It is a low molecular weight human urokinase which has an A
chain (of 2,000 Daltons ) joined to a B chain (of 30,400 Daltons ) by a
sulphydryl bond. It is a recombinant urokinase plasminogen activator.
Urokinase acts on the endogenous fibrinolytic system by producing active
* *
plasmin through cleaving the Arg -Val bond in plasminogen. The formed
plasmin degrades the fi brin clots, fibrinogen, and other plasma proteins.
Urokinase is a non-antigenic enzyme which was earlier isolated from human
urine, but now is obtained from cultured human kidney cells. It directly
activates plasminogen and has a plasma half-life of 10 -15 minutes. It is
prescribed to patients who have used streptokinase in an earlier episode.
Hypotension and allergic reactions occur rarely but fever occurs commonly
during the treatment with urokinase.
2.2.6. Anti-Platelet Drugs

Anti-platelet or anti -thrombotic drugs affect platelet plug formation and are
mainly used for preventing arterial thromboembolism.
Combination of anti-platelet drugs produces additive or synergistic effect. These
properties are used for preventing restenosis af ter coronary angioplasty and
coronary stenting.
Anti-platelet drugs based on their mechanism of action are classified as follows:
1) Prostaglandin Synthesis (PG) Inhibitors: Aspirin and Dazoxiben.
2) Phosphodiesterase Inhibitors: Dipyridamole.
3) ADP-Induced Platelet Aggregation Inhibitors: Ticlopidine and
Clopidogrel.
4) Glycoprotein IIb/IIIa Receptor Inhibitors: Tirofiban and Eptifibatide.
2.2.6.2. Prostaglandin Synthesis (PG) Inhibitors

Some common PG inhibitors are discussed below:
1) Aspirin: In low doses (75 -300mg/day), it is used as a prophylaxis of
myocardial infarction and also as a prophylaxis against secondary myocardial
infarction. Aspirin acts through irreversible acetylation of plat elet
cyclooxygenase. In low doses, it produces a nominal and transient effect on
vascular cyclooxygenase. It has been proved that aspirin in low doses
reduces the occurrence of non -fatal myocardial infarction and re -infarction;
however, t he overall mortali ty rate is left unaffected. Scientifically, low
doses of aspirin can be used for long -term prevention of myocardial
infarction. Its effects can be improved by using it along with dipyridamole.
2) Dazoxiben: It is a thromboxane synthetase inhibitor, thus sele ctively
decreases TxA 2. It does not inhibit platelet aggregation when given alone;
however, with aspirin it produces considerable effects.
3) Epoprostenol (PGI 2): It is a potent inh ibitor of platelet aggregation; but its
use has been prohibited due to its ve ry short half-life. It may be used during
renal dialysis or cardiac bypass surgery.
4) Sulphinpyrazone: It is a uricosuric drug and a cyclooxygenase inhibitor. It
is not selective for platelets. Earlier it was used in low doses to prevent
myocardial re -infarction (like aspirin) , but after multi-centric long -term
*
trials, it has been withdrawn. *
88 Pharmacology-II
5) Diet: Dietary therapy can be adjunctive in the prophylaxis of thrombosis.

The Eskimos intake high amounts of dietary eicosapentaenoic acid (an
unsaturated fatty acid) , thus they generate PGI3 that is an anti -aggregating
substance like PGI2.
2.2.6.3. Phosphodiesterase Inhibitors

Phosphodiesterase inhibitors inhibit platelet function by inhibiting cGMP
phosphodiesterase activity and/or adenosine uptake. It is never used alone due to
its minimal antiplatelet action, thus is used along with aspirin to enhance the
antiplatelet action. In secondary prophylaxis of cerebrovascular diseases,
dipyridamole is used along with aspirin. Dipyridamole with warfarin is used after
prosthetic heart valve surgery for primary prophylaxis of thromboembolism.
2.2.6.4. ADP-Induced Platelet Aggregation Inhibitors

The commonly used drugs that inhibit platelet aggregation are discussed below:
1) Dipyridamole: It inhibits phosphodiesterase for increasing platelet cAMP. It
can also release PG precursors from vascular endothelium. It is a vasodilator
and can inhibit platelet adhesion to thr ombogenic surfaces. It can be used
along with low-dose aspirin.
2) Timolol: It is a β-adrenoceptor blocker, and its concurrent use synergises the
action of low -dose aspirin. It is used for long -term prevention of secondary
myocardial infarction.
3) Clopidogrel and Ticlopidine: These drugs inhibit the ADP pathway of
thrombocytes, and thus reduce platelet aggregation. The binding of ADP to
its receptors is inhibited irreversibly by these drugs. They do not inhibit
prostaglandin synthesis. Clinically, they are used for treating unstable angina
pectoris, acute coronary syndrome, acute neurovascul ar disease, peripheral
vascular disease, and for preventing thrombosis coronary surgery. The dose
of ticlopidine is 250mg twice daily via oral route , and that of clopidogrel is
75mg/day, with a subsequent loading dose of 300mg via oral route . Nearly
80% pl atelet activity is inhibited by these doses. Gastrointestinal adverse
effects, leucopenia, and haemorrhage are the adverse effects of ticlopidine ,
whereas clopidogrel may cause haemorrhage. Because of less adverse effects
and the dosage factor, clopidogrel is preferred over ticlopidine.
4) Clofibrate: It is a hypolipidaemic drug which may be used for reducing
platelet adhesiveness. It does not prevent secondary myocardial infarction.
5) Dextran-70 and Dextran-75: These are plasma volume expanders given as
IV infusions. They have no effect on platelet function in vitro, but damages
platelet function and fibrin polymerisation in vivo. Postoperatively, they are
used for preventing venous thrombosis.
2.2.6.5. Glycoprotein IIb/IIIa Receptor Inhibitors

Glycoprotein II b/IIIa receptor inhibitors are integrin or platelet surface adhesive
receptors. The receptor complex binds fibronectin and Von Willebrand factor,
and also functions as a receptor for fibrinogen and vitronectin. The receptor
* *
complex on activation mediates platelet aggregation by helping the platelets to

bind to the exposed collagen and also to the adjacent platelet. The effect of other
platelet agonist s (e.g., collagen, thrombin, TXA 2, ADP, etc. ) is inhibited by
GPIIb/IIIa receptor inhibitors. They also inhibit the final common pathway for
platelet aggregation.
GPIIb/IIIa receptors including vitronectin receptor are blocked by abciximab (a

humanised monoclonal antibody ). Eptifibatide and Tirofiban (chemical
analogues of fibrinogen) block fibrinogen binding. These drugs are parenterally
administered as a short course therapy in percutaneous coronary intervention and
acute coronary syndrome.

Antiplatelet agents affect various pla telet functions, such as aggregation, release
of granule contents, and platelet-mediated vascular constriction. The mechanisms
of action of different classes of anti-platelets are given below:
1) Class I: Irreversible cyclooxygenase ( or prostaglandin H syntha se) is the
enzyme mediating the first step in prostaglandin and thromboxane
biosynthesis from arachidonic acid. This enzyme is blocked by as pirin and
related compounds (NSAIDs and sulfinpyrazone).
2) Class II: Dipyridamole inhibits cAMP breakdown mediated by
phosphodiesterase, thus prevents platelet activation by multiple mechanisms.
3) Class III: Ticlopidine and clopidogrel block the binding of ADP to a low -
affinity, type -2 purinergic receptor and prevent the activation of GPII b/IIIa
receptor complex, thus subsequent aggregation.
4) Class IV: The final common pathway of platelet aggregation is inhibited by
anti-IIb/IIIa antibodies (abciximab) and receptor antagonists (tirofiban and
eptifibatide). They may also prevent the initial adhesion to the vessel wall.

Anti-platelet drugs prevent arterial thromboembolism in the following situations:
1) Coronary Artery Diseases
i) Unstable Angina: The risk of death and myocardial infarction is reduced
by aspirin in 75-325mg/day dose . However, aspirin along with
clopidogrel (75mg/day) is preferred. Abciximab via intravenous route
due to its rapid action is used as a short -term therapy for the same
purpose. Maintenance therapy is given for an indefinite period by oral
aspirin or clopidogrel in 75mg/day dose.
ii) Acute Myoc ardial Infarction: Survival (30% reduction in mortality)
and thrombolytic therapy is improved by oral aspirin in 325mg dose (1
tablet) followed by a maintenance dose of 75mg/day.
iii) Post MI Patients: Aspirin in 75mg/day dose is administered for an
undefined period as a secondary prophylactic agent for reducing the risk
of infarction by 25%. A suitable alternative can be Clopidogrel
administered in the same dose orally.
* *
90 Pharmacology-II
2) Cerebrovascular Diseases: Aspirin in 75-325mg/day dose is used as a

secondary prophylactic agent for preventing transient ischemic attacks and
strokes.
3) Prosthetic Heart Valves and Arteriovenous Shunts: Dipyridamole and
oral anticoagulants prevent microthrombi formation on artificial heart valves.
They also reduce embolism. Aspirin is not a drug of choice in combination
with warfarin due to the adverse drug reactions that may occur.
4) Venous Thromboembolism: Anticoagulants are used to prevent venous
thromboembolism, while anti-platelet drugs are unimportant.

The adverse effects of anti-platelet drugs include s tomach upset, heartburn,
nausea, constipation, flushing, dizziness, weakness, headache, bloody stools, GI
bleeding, rashes, liver impairment, and anaphylactic shock.
2.2.7. Plasma Volume Expanders

Plasma volume expand ers are the colloidal solutions used to control the blood
volume temporarily in critical conditions. Colloidal solutions with smaller size
particle and lower molecular weight apply a greater oncotic pressure (or colloid
osmotic pressure). Conditions of an ideal plasma volume expander are given
as follows:
1) The oncotic pressure, pH , and viscosity of the solution should be similar to
plasma.
2) It should be retained in the circulation for a sufficient duration.
3) It should be non-pyrogenic and non-antigenic.
4) It should be stable and inexpensive.
5) It should not inhibit blood grouping and cross matching of blood.
Following are the important plasma volume expanders:
1) Human albumin,
2) Dextran,
3) Polyvinylpyrrolidone,
4) Hetastarch,
5) Degraded gelatin polymer.
2.2.7.2. Human Albumin

Albumin and plasma protein fraction are obtained from pooled human plasma.
They are the commonly used plasma expanders and are rich protein molecules not
having any risk of hepatitis. Around 25gm of 5% albumin is osmotically equal to
about 500ml of fresh frozen plasma. Plasma protein fraction also has globulin with
albumin. Plasma substitutes like dextran, hetastarch, gelatin, etc., can be used in
case human albumin is not available. Albumin temporarily increases the blood
volume, which further decreases haemoglobin concentration and blood viscosity.
Human albumin is used for the treatment of severe blood loss, hypervolemia, and
hypoproteinemia. Some common side effects include allergic or pyrogenic
reactions, fever, chills, rash, nausea, vomiting, tachycardia, and hypotension.
* *
2.2.7.3. Dextran-40
Dextran-40 is a glucose polymer having molecular weight of 40,000. In the form
of 10% solution, it exerts high osmotic pressure than plasma proteins. Hence, it
forms a greater expansion of plasma volume than dextran of higher molecular
weight, while the expansion can have smaller period of action due to more fast
renal excretion. Dextran-40 is primarily used for the t reatment of shock,
cerebrovascular accidents, foetal distress syndrome, prevention of peritoneal
adhesions, and burns. Sometimes, dextran infusions may cause hypersensitivity
reactions like fever, nasal congestion, joint pains, urticaria, hypotension, and
bronchospasm. Severe anaphylactic reactions are very uncommon and can be
fatal. Nausea and vomiting can also occur. After discontinuing dextran, these
symptoms can be treated symptomatically.
2.2.7.4. Dextran-70
Dextran-70 is a glucose polymer having molecular weight of 70,000. It is formed
by sucrose fermentation, just like d extran-40. Dextran-70 as a 6% solution
applies a colloidal osmotic pressure same as plasma protein. Therefore, it is used
for short -term expansion of the plasma volume in situations like shock or
impending shock occurs due to burns, surgery, haemorrhage or trauma. It also
inhibits the post-operative thromboembolic disorders.
The adverse effects of dextran-70 are similar as dextran-40. Dextran-70 infusions

are contraindicated in patients with severe CHF, bleeding disorders (like
hypofibrinogenemia or thrombocytopenia), and renal failure. Heparin
anticoagulant effect can be improved by dextran. Its higher molecular weight
inhibits the blood group and cross matching of blood. The presence of dext ran
can affect the determination of glucose, bilirubin, or proteins in blood or urine.
2.2.7.5. Polyvinylpyrrolidone
Polyvinylpyrrolidone is a synthetic polymer that affects the blood grouping and
cross matching of blood. It binds with insulin and penicillin in ci rculation and
decreases their effect.
2.2.7.6. Hetastarch (Hydroxyethyl Starch)

Hetastarch contains more than 90% of amylopectin and has an average molecular
weight of 4,50,000. It has a different plasma retention and volume effect. Its 6%
iso-oncotic infusion sol ution permits blood volume regulation and an effective
stabilisation of blood volume. It applies same colloidal osmotic pressure as
human albumin and this effect lasts for 24-36 hours. Hetastarch is used for short -
term expansion of the plasma volume i n sho ck or impending shock that may
result from burns, surgery, haemorrhage, or trauma. Anaphylactic reactions,
shock, and bronchospasm are the major adverse effects of h etastarch. It does
not affect the blood groupi ng and cross matching of blood.
2.2.7.7. Degraded Gelatin Polymer

Degraded gelatin polymer is a polypeptide and exerts osmotic pressure simila r to
albumin. Polygeline is non -antigenic, therefore it does not affect the blood
grouping and cross matching. The plasma volume expansion of degraded gelatin
* *
92 Pharmacology-II
polymer lasts for 12 hours. It is used in hypovolemic shock, trauma, and burns. It
is also used as a vehicle for drugs and for priming the heart -lung machine. The
adverse effects of degraded gelatin polymer include urticaria, wheals,
hypotension tachycardia, nause a, vomiting, dyspnoea, fever, and anaphylaxis.
Synergistic effects of the calcium in polygeline should be considered during the
digoxin therapy of patients.
2.3. SUMMARY
The details given in the chapter can be summarised as follows:
1) Shock is a medical condition in which the blood perfusion to the tissues
decreases, resulting in cellular injury and inadequate tissue function
2) Patients with shock resulting from decreased circulating volume of blood
should be given either blood or plasma volume expanders.
3) Restlessness, headache, pallor, dizziness, precordial pain, and palpitation are
the adverse effects of therapeutic doses of sympathomimetic amines.
4) The most commonly employed α-adrenoceptor blocking agent is
phenoxybenzamine.
5) The useful effects of corticosteroids in states of shock are not completely
understood.
6) Dextrans are efficient plasma volume expanders. They are employed in the
emergency treatment of hypovolemic shock.
7) The word haemopoietic relates to the blood making processes.
8) Hematologic system includes the blood and blood-forming organs.
9) Hematinics are involved in the formation of blood and are used in the
treatment of anaemia (a condition in which blood lacks healthy RBCs or
haemoglobin).
10) Coagulants are agents that help in the coagulation of blood and are given in
haemorrhagic conditions.
11) Vitamin K takes part in blood coagulation reaction, and therefore is
indicated in the treatment of haemorrhages.
12) Anticoagulants are agents decreasing the coagulation ability of blood.
13) Fibrinolytics are used for dissolving the blood clots (or thrombi).
14) Anti-platelet or anti-thrombotic drugs affect platelet plug formation and
are mainly used for preventing arterial thromboembolism.
15) Plasma volume expanders are the colloidal solutions used to control the
blood volume temporarily in critical conditions.
2.4. EXERCISE
2.4.1. True or False

1) The most commonly employed α-adrenoceptor blocking agent is phenoxybenzamine.
2) The useful effects of corticosteroids in states of shock are completely understood.
3) The word haemopoietic relates to the blood removing processes.
* *
4) Vitamin K takes part in blood coagulation reaction, and therefore is indicated in the
treatment of haemorrhages.
5) Anticoagulants are agents decreasing the coagulation ability of blood.
6) Fibrinolytics are used for making the blood clots (or thrombi).
2.4.2. Fill in the blanks

7) _______ is a medical condition in which the blood perfusion to the tissues decreases,
resulting in cellular injury and inadequate tissue function
8) The most commonly employed α-adrenoceptor blocking agent is _________.
9) ___________ are efficient plasma volume expanders.
10) The word _________ relates to the blood making processes.
11) ____________ includes the blood and blood-forming organs.
12) Vitamin K takes part in __________, and there fore is indicated in the treatment of
haemorrhages.
13) __________ are used for dissolving the blood clots (or thrombi).
14) ___________ are the colloidal solutions used to control the blood volume
temporarily in critical conditions.
Answers
1) True 2) False 3) Flase 4) True
5) True 6) False 7) shock 8) Phenoxybenzamine
9) Dextrans 10) Haemopoietic 11) Hematologic system
12) Blood coagulation reaction 13) Fibrinolytics
14) Plasma volume expanders
2.4.3. Very Short Answer Type Questions

1) What treatments are involved in cardiovascular shocks?
2) Give mechanism of action of sympathomimetic amines.
3) Write advantages of administering glucagon.
4) Give source of folic acid.
5) What are the therapeutic uses of vitamin B 12?
6) What are coagulants?
7) Classify the drugs used to store haemostatis.
8) Classify anticoagulants.
9) What are plasma volume expanders?
2.4.4. Short Answer Type Questions

1) Give a summary about hematinics.
2) Give mechanism of action and therapeutic uses of coagulants.
3) Explain Fibrinolytics and give its mechanism.
4) Write about prostaglandin Synthesis inhibitors.
5) Give mechanism of action of Glycoprotein II b/IIIa Receptor Inhibitors.
6) Define and classify plasma Volume Expanders.
2.4.5. Long Answer Type Questions

1) Briefly describe drugs used in the therapy of shock.
2) Write about drugs acting on haemopoietic system in detail.
3) Explain in detail about plasma volume expanders.
* *
94 Pharmacology-II
CHAPTER Pharmacology of Drugs

3 Acting on Urinary System
3.1. DIURETICS
3.1.1. Introduction
Diuretic drugs promote urine output. They act directly on the kidneys and increase
the excretion of water and ions (Na+, Cl−, or HCO 3 ) from the body. Diuretics are
also used for the treatment of cardiac oedema (accumulation of fluid in extra
vascular tissues), especially the one associated with congestive heart failure. They
are also employed in the treatment of various disorders like nephrotic syndrome,
diabetes insipidus, hypertension, nutritional oedema, oed ema of pregnancy, and
liver cirrhosis. They also decrease the intracellular and cerebrospinal fluid pressure.
On the basis of their intensity, diuretics are categorised as follows:
1) High Efficacy Diuretics (Inhibitors of Na+/K+/2Cl– Co-transport)
i) Sulphamoyl Derivatives: Furosemide and Bumetanide.
ii) Phenoxyacetic Acid Derivatives: Ethacrynic acid.
iii) Organomercurials: Mersalyl.
2) Medium Efficacy Diuretics (Inhibitors of Na+/Cl– Symporter)
i) Benzothiadiazines (Thiazides): Chlorothiazide, Hydrochloroth iazide,
Benzthiazide, Hydroflumethiazide, and Clopamide.
ii) Thiazide-like Diuretics (Related Heterocyclics): Chlorthalidone,
Metolazone, Xipamide, and Indapamide.
3) Weak or Adjunctive Diuretics
i) Carbonic Anhydrase Inhibitors: Acetazolamide.
ii) Potassium Sparing Diuretics
a) Aldosterone Antagonists: Spironolactone.
+
b) Directly Acting Diuretics (Inhibitors of Renal Epithelial Na
Channel): Triamterene and Amiloride.
iii) Osmotic Diuretics: Mannitol, Isosorbide, and Glycerol.
iv) Xanthine Derivatives: Theophylline.
3.1.3. High Efficacy Diuretics (High Ceiling or Loop Diuretics)

High efficacy diuretics exhibit their effects by acting on the ascending limb of
the loop of Henle, therefore also known as loop diuretics . They are the most
effective amo ng all diuretic agents , since the reabsorptive capacity of the
ascending limb of the loop of Henle is very high . The loop diuretics are also
known as high ceiling diuretics or Na +/K+/2Cl– co-transporter inhibitors. The
most commonly used loop diuretic is furosemide.
* *
Pharmacology of Drugs Acting on Urinary System (Chapter 3) 95

Furosemide inhibits the reabsorption of NaCl and the Na+/K+/2Cl– symporter in
the thick ascending limb of Henle’s loop. It facilitates or increases urinary
excretion of Na + and Cl – ions ( figure 3.1). High efficacy diuretics prove to be
highly efficient and show dose -dependent response (increase in dose results in
greater action). However, administration of exceedingly large amounts of the
dose may cause dehydration (high ceiling effect, i.e., maximal effect).
High efficacy Lumen Thick ascending limb Interstitium

diuretics or loop
diuretics
Na+ Na+ Na+

– –
Co-transporter 2Cl 2Cl ATPase
K+ K+ K+
Figure 3.1: Na+/K+/2Cl– Co-transport System in Thick Ascending Limb

and the Mechanism of Action of Loop Diuretics
On oral administration, furosemide absorbs rapidly from the GIT. After
intravenous administration, its action furosemide is even more rapid, i.e., within
10 minutes and duration of action is 2 hours. About 95% of furosemide is bound
to t he plasma proteins. Furosemide undergoes metabolism in the liver and
excretion by the kidneys. It has the ability to cross the placental barrier and is
also excreted in the breast milk. The pharmacokinetic profile of some important
loop diuretics is enlisted in table 3.1:
Table 3.1: Important Pharmacokinetic Characteristics of Some Loop Diuretics
Drugs Relative Oral Half-Life Routes of
Potency Bioavailability (Hours) Elimination
Furosemide 1 60% 1.5 65% (renal)
35% (metabolised)
Bumetanide 40 80% 0.8 60% (renal)
40% (metabolised)
Torsemide 3 80% 3.5 20% (real)
80% ( metabolised)
Ethacrynic acid 0.8 100% 1 65% (renal)
35% (metabolised)

Therapeutic uses of loop diuretics include:
1) Acute Pulmonary Oedema: These agents are found to be highly effective in
acute pulmonary oedema. In this condition, the vascular effect precedes the
onset of diuretic effect. A decrease in the left ventricular pressure is
responsible for its therapeutic effect.
* *
96 Pharmacology-II
2) Refractory Oedema: Furosemide is used to treat refractory oedema related

to congestive cardiac failure and renal disease, in case other diuretics are not
effective.
3) Acute Renal Failure: The rate of urine flow and excretion of K + ions
increases during acute renal failure. Loop diuretics can effective ly convert
oliguric renal failure into non-oliguric renal failure. Yet, the duration of renal
failure cannot be decreased by these agents.
4) Hypercalcaemia: In patients with hypercalcaemia, intravenous
administration of loop diuretics along with normal salin e infusion stimulates
the excretion of Ca2+ ions. As a result, the serum calcium level decreases.
5) Hyperkalaemia: Intravenous administration of furosemide along with saline
infusion helps treating hyperkalaemia.
6) Poisoning by Barbiturates and Halides:Furosemide with copious intravenous
saline (forced diuresis) is used inarbiturate
b and halide poisoning.
7) Raised Intracranial Pressure: Loop diuretics decrease the blood volume ,
and hence reduce intracranial tension.
Though utilised for the treatment of several diseases, the high efficacy diuretics
are not employed as antihypertensive agents since they have a high diuretic
potential, short duration of action, and high dose requirement.

The adverse reactions of high efficacy diuretics include:
1) Effects Related to Renal Actions: Loop diuretics severely disrupt water and
electrolyte balance and may manifest as:
i) Hypokalaemia and metabolic hypochloremic alkalosis resulting from the
exchange of K+ and H+ ions with Na+ ions in the distal tubule.
ii) Depletion of calcium on chronic administration.
iii) Hypovolemia and hypotension.
iv) Hyperuricemia ( may precipitate attack of gout), except with the
uricosuric drugs (indacrinone and ticrynafen).
v) Hypomagnesaemia which is reversed by oral magnesium
supplementation. There may be wasting on chronic administration.
2) Effects Related to Extra-Renal Actions: These effects include:
i) Dose-related, reversible ototoxicity with loss of hearing. It is more with
ethacrynic acid.
ii) Pancreatitis.
iii) Hypersensitivity (e.g., skin rash, blood dyscrasias, and allergic interstitial
nephritis) in patients allergic to sulphonamides.
iv) Myalgia may occur with bumetanide and piretanide.
v) GIT upset may occur due to ethacrynic acid.
vi) Hepatic encephalopathy in hepatic cirrhosis.

Loop diuretics interact with the following drugs and cause toxicity:
1) They interact with aminoglycoside, antibiotics, and increase ototoxicity.
* *
2) They interact with cephalosporins and cause kidney damage.

3) Indomethacin decreases the efficiency of loop diuretics because t hey inhibit
the synthesis of vasodilator prostaglandins in the kidney.
4) They increase the toxicity caused by digitalis and result in cardiac
abnormalities due to hypokalaemia.
Contraindications to the use of furosemide include:
1) Presence of anuria.
2) Hypersensitivity to compounds.
3) Allergy to sulpha drugs.
3.1.4. Medium Efficacy Diuretics (Thiazides and Thiazide-

Like Drugs)
Thiazide diuretics are referred to as moderately efficacious diuretics as a
majority (nearly 90%) of the filtered sodium is already re-absorbed even before it
reaches the distal tubule. They comprise of two distinct groups of diuretics:
1) Thiazide: These d iuretics, e.g., chlorothiazide, hydrochlorothiazide,
polythiazide, etc., contain a benzothiadiazine ring.
2) Thiazide-Like: These diuretics, e.g., chlorthalidone, indapamide,
metolazone, etc., do not contain benzothiadiazine ring, but an un -substituted
sulphonamide group.
The most commonly used thiazide is chlorothiazide.

Thiazide diuretics act by blocking the Na+/Cl– co-transport system and exert their
actions on the distal convoluted tubules (figure 3.2). Carbonic anhydrase activity
is also inhibited by these drugs and they increase the excretion of bicarbonate
ions, Mg + and K +. These agents also inhibit the excretion of Ca ++ ions and uric
acid in the urine which leads to hypercalcaemia and hyperuricaemia ,
respectively.
Lumen Early distal tubule Interstitium
Na+
Thiazides
Symport Na + Na+
ATPase
Cl– Cl– K+ K+
Cl–
Figure 3.2: NaCl Reabsorption in DCT and Mechanism of Action

of Thiazides
* *
98 Pharmacology-II
Absorption of thiazides is fast, when they are administered orally. The organic
acid secretory system excretes these agents in the proximal tubule of kidneys.
They inhibit the excretion of uric acid resulting in hyperuricaemia. Onset of
action generally occurs in 1-2 hours, with the maximal effect occurring in 4 -6
hours. The action lasts for 8-12 hours.
Actions of bendroflumethiazide last for 24 hours. The duration of action of

chlorthalidone is 48-72 hours as it undergoes slow absorption. The medium
efficacy diuretics differ from each other only in the onset and duration of action.
The mechanism of action of all the drugs in this group is similar , thus resistance
to any one compound in this group makes the other drugs of this group also
resistant for that pati ent. Moreover, beyond an acceptable limit, the actions of
this group of drugs do not depend on the dosage administered.

Medium efficacy diuretics have the following therapeutic uses:
1) Oedema: Cardiac, hepatic and renal oedema associated with chronic heart
failure, cirrhosis, nephrotic syndrome, chronic renal failure , and
glomerulonephritis can be successfully treated using thiazides. However,
when the GFR falls below 30ml/min, thiazides are not effective. These
agents cannot be employed in the treatment of acute pulmonary oedema.
2) Hypertension: It can be effectively treated using thiazides. In the elderly and
obese patients, thiazides alone (as monotherapy) are useful in the treatment
of mild hypertension. For the treatment of moderate and severe hypertension,
they are employed as a combinational therapy along with other anti -
hypertensives.
Advantages of thiazides as anti-hypertensives include:
i) Low-cost, good efficiency and tolerability, decreased cardiovascular
morbidity and mortality,
ii) Effective even when administered once a day,
iii) Shows better patient compliance, and
iv) Additive or synergistic effect with other anti-hypertensive agents.
3) Calcium Nephrolithiasis: Calcium re-absorption is increased by the use of
thiazides by the following two mechanisms:
i) Increased re-absorption in the proximal tubule due to volume depletion.
ii) Direct increase in Ca2+ ion re-absorption in the distal convoluted tubule.
Thus, the excretion of Ca 2+ ions i n urine is increased by the action of
thiazides, and hence these agents effectively treat calcium nephrolithiasis.
4) Diabetes Insipidu s: Nephrogenic diabetes insipidus is primarily treated
using thiazides. Upto 50% of urine volume is decreased by the action of
thiazides. They act possibly by the following mechanisms:
i) They promote complete re-absorption of water in the proximal tubule by
volume depletion.
ii) They increase the sensitivity of the collecting tubules to ADH.
* *
5) Bromide Intoxication: Bromine (a halogen) is excreted by renal processes

–
in a manner similar to those for excretion of Cl ions. Thus, bromine
intoxication may be treated using thiazides.

Though the safety margin of thiazides is wide and the toxic effects are very rare,
yet, in some conditions the following adverse effects may be seen:
1) Electrolyte disturbances may be seen in the form of hyponatremic,
hypochloremic metabolic alkalosis together with hypokalaemia and may
manifest as weakness, fatigability, and paraesthesia.
2) In patients susceptible to diabetes mellitus, the suppression of insulin release
from the pancreas may exacerbate glycosuria and hyperglycaemia.
3) Inhibition of uric acid secretion in proximal renal tubules causes decreased
urinary excretion of uric acid, which may cause hyperuricemia. This
condition may act as a precipitating factor for an acute attack of gout in
patients susceptible to it.
4) Administration of high doses of thiazides may result in reversible
hyperlipidaemia (increase in serum cholesterol and LDL).
5) In some patients, hypersensitivity reactions may occur.
6) Thiazides decrease the renal excretion of ammonia , and thus can precipitate
hepatic encephalopathy in patients with hepatic insufficiency.

Drug interactions of thiazide diuretics include:
1) They increase the potency of other anti -hypertensive agents, and this
property of thiazides is used therapeutically.
2) They induce hypokalaemia, which in turn brings about the following effects:
i) Increases digitalis toxicity,
ii) Increases the chances of polymorphic ventricular tachycardia resulting
from quinidine and other anti-arrhythmic agents used, and
iii) Increases the potency of neurom uscular blockers and decreases the
action of sulphonylureas.
3) The use of cotrimoxazole along with diuretics increases the prevalence of
thrombocytopenia.
4) NSAIDs reduce anti-hypertensive activity of thiazides and furosemide.
5) The tubular secretion of thiazid es is compet itively inhibited by probenecid,
which decreases the action of thiazide by reducing the concentration in the
tubular fluid. On the other hand, the uricosuric action of probenecid is
diminished by probenecid.
6) Patients undergoing diuretic therapy show an increase in the serum level of
+
lithium due to increased reabsorption of Li ions (and Na + ions) in the
proximal tubule.
In patients sensitive to sulpha drugs, thiazide diuretics should be used cautiously.
If possible, these drugs should be avoided in such patients.
* *
100 Pharmacology-II
3.1.5. Weak or Adjunctive Diuretics

The third category of diuretics based on their intensity is the weak diuretics. They
are named so because they exert a very weak action of their own , and hence are
usually employed as an adjunctive agent to potentiate the effects of other agents.
Thus, they are also termed as adjunctive diuretics.

The mechanism of action of each class of weak diuretics is given below:
1) Carbonic Anhydrase Inhibitors: Acetazolamide inhibit s carbonic
anhydrase enzyme, thus prevent the formation of H + ions. As a result, the
exchange of Na+/H+ ions does not take place. The Na + ions are excreted in the
urine along with HCO3 ions ( figure 3.3). In the distal convoluted tubule,
increased Na+/K+ exchange leads to loss of K+ ions. Thus, the overall effect is
the loss of Na+, K+ and HCO3 ions in the urine or alkaline urine.
Lumen PCT Interstitium
Na+ K+
Antiport
ATPase
H+ H+ Na+
+
HCO3 HCO HCO
H2CO3
CA inhibitors
H2CO3
Carbonic Carbonic
CA inhibitors
anhydrase anhydrase
CO2 + H2O CO2 + H2O
Figure 3.3: Mechanism of Action of Carbonic Anhydrase (CA) Inhibitors
2) Potassium Sparing Diuretics: The late distal tubule and the collecting duct
have two types of cells, i.e., the principal cell and intercalated cells. The
Na+ ion channel present in the luminal membrane of the principal cells
+
provides pathway for the entry of Na ions into the ce lls, down the
electrochemical gradient. This electrochemical gradient is created by the
basolateral Na + pump. The luminal membrane is highly permeable to Na +
ions, thereby creating a lumen negative trans -epithelial potential difference.
This potential diff erence provides an important driving force enabling the
secretion of K+ ions into the lumen (figure 3.4).
The H + is secreted into the tubular lumen by the intercalated cells. This
secretion occurs by the H+-ATPase pump or proton pump (figure 3.4) and the
lumen negative trans-epithelial voltage difference that acts as the driving force.
The potassium sparing diuretics (amiloride and triamterene) block the Na+ ion
channels in the luminal membrane of the principal cells in the late distal tubule
*
and collecting duct. This inhibits the transport of Na + ions through the cells, *
thereby reducing the luminal secretion of H + ions from the intercalated cells
and K+ ions from the principal cells. The net effect is increased in the excretion
of Na+ ions in the urine and retention of K+ and H+ ions.
Lumen Blood
+ – Principal + –
Cell
60m 75m
v v
K+ K+ K+
ATPase
Na+ Na+ Na+
Na+ channel inhibitors
Intercalated
Cell HCO
H++
H+ 3 HCO3
ATPase Cl– Cl–
H2C
O3
CO2 + H2O
Figure 3.4: Mechanism of Action of Potassium Sparing Diuretics

3) Osmotic Diuretics: These diuretics are named so as they utilise their
osmotic action to draw water from the tissues. As a result, excretion of water
and electrolytes increases. Osmotic diuretics mainly act on the loop of Henle.
20% mannitol on iv administration
Increases osmolality of plasma
Shift of fluid (osmotic effect) from the Intracellular Compartment

(ICC) to Extracellular Fluid (ECF)
ECF ICC
Expansion of ECF volume
Increases glomerular filtration rate, mannitol is freely filtered at the glomerulus
Increases osmolality of tubular fluid
Inhibits re-absorption of water and NaCl
The net effect is the increased urinary excretion of Na+, K+,

Ca2+, Mg2+, Cl–, HCO3– and PO4– ions
Figure 3.5: Mechanism of Action of Osmotic Diuretics
* *

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* *

Dr. Pankaj Mishra

Dr. Pragnesh Patani

Books are Available for Online Purchase at: tppl.org.in

THAKUR PUBLICATION PVT. LTD., LUCKNOW

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Shri P. C. Mishra and Mrs. Geeta Mishra”

-Dr. Pragnesh Patani

-Dr. Kishor Vasant Otari

Please e-mail us at, thakurpublication@gmail.com

I am also thankful to all staff members of Thakur Publication Pvt. Ltd.

Finally my greatest debt of gratitude is to my family members for being supportive

I express my special thanks to Honorable Shri Narendrasinh Zala Sir

At the outset, I take this opportunity to e xpress my sincere gratitude to

I am honored to express my profound and deep sense of gratitude towards whole

Finally I wish to acknowledge the assistance given by the editorial and

The way to accomplish my ambitions was shown by Dr. C. D. Upasani ,

-Dr. K.V. Otari

1.4.5.2. Therapeutic Uses 44 1.6.4.4. Individual Drug - 58

2.2.5. Fibrinolytics 84 3.1.4.6. Contraindications 99

4.1.5.2. 5-HT Receptor Subtypes 125 5.1.3. Classification 147

5.1.14. Para-Aminophenol 157 7.1.1. Introduction and Basic 172

7.4.4. Physiological Actions 189 7.6.2.8. Insulin Analogues 207

8.1.2. Androgens 229 8.2.4.6. Adverse Effects 243

CHAPTER Pharmacology of Drugs

1.1. CARDIOVASCULAR SYSTEM

3) The cardiac output can be calculated with the combination of pulmonary,

1.1.3. Electrophysiology of Heart

1.2. DRUGS USED IN CONGESTIVE HEART

1.2.3. Cardiac Glycosides

1.2.3.1. Mechanism of Action

K+ Na+ * Na+ Ca2+

1.2.3.3. Pharmacological Actions

2) Extra-Cardiac Effects of Digitalis

1.2.3.4. Therapeutic Uses

1.2.3.5. Adverse Effects

1.2.3.6. Drug Interactions

2) Administration of digitalis with calcium synergises the actions of digitalis,

3) Antiarrhythmic Drugs: Ventricular tachyarrhythmias can be suppressed by

1.2.4.1. Mechanism of Action

1.2.4.2. Therapeutic Uses

1.2.4.3. Adverse Effects

1.2.5. β-Adrenergic Agonists

1.2.5.1. Mechanism of Action

1.2.5.2. Therapeutic Uses

1.2.5.3. Adverse Effects

1.2.6.1. Mechanism of Action

1.2.6.2. Therapeutic Uses

1.2.6.3. Adverse Effects

Hyponatraemia and feminisation such as gynaecomastia are other adverse

1.2.7. Angiotensin Antagonists

1.2.7.2. Pharmacological Actions

1.2.8. β-Adrenoceptor Antagonists

1.3. ANTI-HYPERTENSIVE DRUGS

6) Calcium Channel Blockers: Verapamil, Nifedipine, Nicardipine,

1.3.3.1. Mechanism of Action

3) Potassium-Sparing Diuretics: These diuretics decrease the excretion of

1.3.3.2. Therapeutic Uses

1.3.3.3. Adverse Effects

1.3.3.4. Individual Drugs

1.3.4. Angiotensin Converting Enzyme (ACE) Inhibitors