The 'Big Four Snakes of India Venom Composition,

Pharmacological Properties and Treatment of Envenomation

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Ashis K. Mukherjee

The 'Big Four’ Snakes

of India
Venom Composition, Pharmacological
Properties and Treatment of
Envenomation
Ashis K. Mukherjee
Life Sciences
Institute of Advanced Study in Science
and Technology
Guwahati, Assam, India

ISBN 978-981-16-2895-5 ISBN 978-981-16-2896-2 (eBook)

https://doi.org/10.1007/978-981-16-2896-2

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Preface

Snakes, forming an important component of biota, are intrinsically fascinating and

enchanting reptiles. The word “snake” probably evokes a wider range of feeling than
any other living creature, both in the sense of admiration and respect and being
despised as a symbol of evil. Snakebite itself is an intimidating disaster. A minute
amount of toxic material of venomous snakes produced in their specialized salivary
glands, known as venom, when injected into the prey or victims, causes intense pain
and may lead to death within a very short span of time. This leads to distress, agony,
and pathos in the mind of common people, as a result of which snakes and their
venoms become shrouded with myths, mysteries, and superstitions. Besides, snake-
bite is a serious problem for the rural tropics, most particularly in the Southeast
Asian countries. In India alone, more than 100,000 cases of envenomation occur per
year (unreported cases may be more than this), which ultimately results in substantial
deaths and/or morbidity. Unfortunately, less attention has been paid to provide
affordable and effective treatment against snakebite. Due to lack of our knowledge
on geographical and species-specific variation in snake venoms’ composition and
mode of action, lack of good understanding of clinical features of envenoming, and
poor efficacy of commercial antivenom produced by Indian manufacturers, snake-
bite management remains highly unsatisfactory in the Indian subcontinent. There-
fore, the World Health Organization (WHO) has declared snakebite as one of the
neglected tropical diseases.
From the last few decades, people have been gradually realizing that the facts
about snakes are much more interesting than many popular beliefs, embellishment,
and misconceptions. Apart from understanding the molecular mechanism of action
of snake venom components and improvement of treatment of snakebite patients, it
is equally essential for us to appreciate the scientific contributions of snakes in our
ecosystem as well as therapeutic and diagnostic applications of snake venom
proteins. Therefore, during the recent years, the subject of snake venom has been
of scientific research interest from the perspective of biochemistry, toxinology,
pathophysiology, pharmacology, immunology, and biomedical research.
Such a high rate of mortality of snakebite in India as well as the remarkable
medical and diagnostic applications of snake venom toxins have prompted me to
pursue research activity in this exigent field. The “Big Four” venomous
snakes—Indian cobra, Indian common krait, Indian Russell’s viper, and Indian

v
vi Preface

saw-scaled viper—have received enormous medical importance in the Indian sub-

continent because they are responsible for the majority of snakebite deaths in these
regions. This book presents a comprehensive study of venoms of the “Big Four”
venomous snakes of India, evolution and variation in venom composition, biochem-
ical and pharmacological properties of venom, biomedical application of snake
venoms, and treatment of snakebite patients. I am sure that the book will serve as
a standard reference for researchers and medical students as well as for those
interested in snake venom. This book will cater to the quest of the readers, and
they will be eager to learn more about the “Big Four” venomous snakes and
biomedical application in snakebite patients.
It is a great pleasure for me to convey my words of appreciations to pioneers in
the field of snake venom research for their useful suggestions, constructive criticism,
and kind cooperation in editing the book chapters. I thank my wife Abira and son
Anandan for their patience and encouragement and for understanding my
idiosyncrasies, and my father Prof. Subhas C. Mukherjee and mother Mrs. (Dr.)
Sandhya Mukherjee for their constant inspiration. I duly acknowledge the editing of
book chapters by my brother Dr. Soumen Mukherjee, India, and Dr. Glen Wheeler,
Canada.

Guwahati, India Ashis K. Mukherjee

Contents

1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1.1 A Glimpse of the Venomous Snakes of India . . . . . . . . . . . . . . . . 2
1.2 The Concept of the “Big Four” and Non-“Big Four” Medically
Important Venomous Snakes of India . . . . . . . . . . . . . . . . . . . . . . 4
1.3 Medical Aspects of Snakebite: The Snakebite Problem . . . . . . . . . 6
1.3.1 Snakebite in Developed Countries . . . . . . . . . . . . . . . . . . . 8
1.3.2 Epidemiology of Snakebite in Asia . . . . . . . . . . . . . . . . . . 9
1.3.3 Epidemiology of Snakebite in India . . . . . . . . . . . . . . . . . 10
1.4 Key Issues Pertaining to Snakebite in India . . . . . . . . . . . . . . . . . 15
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2 Evolution of Snakes and Systematics of the “Big Four” Venomous
Snakes of India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
2.1 Evolution of Snakes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.2 Studies of the Genomics, Phenomics, and Fossil Record Show
the Origin and Evolution of Snakes . . . . . . . . . . . . . . . . . . . . . . . 24
2.3 Studies on the Genomic Regression of Claw Keratin, Taste
Receptors, and Light-Associated Genes and the Evolutionary
Origin of Snakes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
2.4 Skull Evolution and the Ecological Origin of Snakes . . . . . . . . . . . 26
2.5 Systematics of the “Big Four” Venomous Snakes of India . . . . . . . 26
2.6 The “Big Four” Venomous Snakes of India Represent the
Advanced Group of Snakes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
2.6.1 Family Elapidae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
2.6.2 Family Viperidae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
3 Snake Venom: Composition, Function, and Biomedical
Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.1 The Venom Gland and Venom Delivery Apparatus in the
Viperidae and Elapidae Families of Snakes . . . . . . . . . . . . . . . . . . 36
3.2 Comprehensive Review of the Venom Composition of the
“Big Four” Venomous Snakes of India . . . . . . . . . . . . . . . . . . . . . 39
3.2.1 Enzymatic Toxins of the “Big Four” Snake Venoms . . . . . 40

vii
viii Contents

3.2.2 Nonenzymatic Toxins in the “Big Four” Snake

Venoms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41
3.2.3 Nonprotein Components of Snake Venom . . . . . . . . . . . . . 45
3.3 Variation in Snake Venom Composition and Its Impact on the
Pathogenesis of Snakebite and Antivenom Treatment . . . . . . . . . . 49
3.4 Evolution of Genes for the Toxins in Snake Venom . . . . . . . . . . . 50
3.4.1 Toxicofera Hypothesis . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3.4.2 Independent Origin Hypothesis . . . . . . . . . . . . . . . . . . . . . 50
3.5 Mechanism of the Evolution and Diversification of Venom
Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
3.5.1 Accelerated Evolution of Venom Protein Genes . . . . . . . . . 51
3.5.2 Selection Pressure for Rapid Adaptive Evolution . . . . . . . . 52
3.5.3 Diet and Snake Venom Evolution . . . . . . . . . . . . . . . . . . . 52
3.6 Biological Functions of Venom . . . . . . . . . . . . . . . . . . . . . . . . . . 52
3.6.1 Prey-Specific Venom Toxicity . . . . . . . . . . . . . . . . . . . . . 53
3.6.2 Immobilization and Predigestion of Prey . . . . . . . . . . . . . . 53
3.6.3 Prey Re-localization . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
3.7 Indian Snake Venom Proteins: A Treasure House of Drug
Prototypes and Diagnostic Tool . . . . . . . . . . . . . . . . . . . . . . . . . . 54
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 58
4 Indian Spectacled Cobra (Naja naja) . . . . . . . . . . . . . . . . . . . . . . . . . 69
4.1 Taxonomic Classification of the Indian Spectacled Cobra
(Naja naja) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
4.2 Characteristic Features of the Indian Spectacled Cobra . . . . . . . . . 70
4.3 Geographical Distribution and Reproduction of the Indian
Spectacled Cobra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73
4.4 Biochemical Composition of the Indian Spectacled Cobra
Venom . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 74
4.5 Biochemical and Proteomic Analyses to Demonstrate the
Geographical Differences in Venom Composition of Indian
Spectacled Cobra (N. naja) Venom . . . . . . . . . . . . . . . . . . . . . . . 82
4.6 Genomic and Transcriptomic Analyses of Indian Spectacled
Cobra Venom Toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 84
4.7 Species-Specific Differences in the Venom Composition Between
N. naja and N. kaouthia from the Same Geographical Location of
the Country . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 86
4.8 Pharmacology, Pathophysiology, and Clinical Features of Indian
Spectacled Cobra Envenomation . . . . . . . . . . . . . . . . . . . . . . . . . 88
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
5 Indian Common Krait (Bungarus caeruleus) . . . . . . . . . . . . . . . . . . . 95
5.1 Taxonomic Classification of the Indian Common Krait
(Bungarus caeruleus) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 96
5.2 Characteristic Features of the Indian Common Krait . . . . . . . . . . . 96
Contents ix

5.3 Geographical Distribution, Habitat, Behavior, and Reproduction

of the Indian Common Krait . . . . . . . . . . . . . . . . . . . . . . . . . . . . 97
5.4 Venom Composition of the Indian Common Krait . . . . . . . . . . . . 98
5.5 Pharmacology, Pathophysiology, and Clinical Features of the
Indian Common Krait Envenomation . . . . . . . . . . . . . . . . . . . . . . 101
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 102
6 Indian Russell’s Viper (Daboia russelii) . . . . . . . . . . . . . . . . . . . . . . . 105
6.1 Taxonomic Classification of Indian Russell’s Viper
(Daboia russelii) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106
6.2 Characteristic Features of the Indian Russell’s Viper . . . . . . . . . . . 106
6.3 Geographical Distribution, Habitat, and Reproduction of Indian
Russell’s Viper . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 108
6.4 Composition of Indian Russell’s Viper Venom . . . . . . . . . . . . . . . 109
6.5 Pharmacology, Pathophysiology, and Clinical Features of
Envenomation by Indian Russell’s Viper . . . . . . . . . . . . . . . . . . . 123
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128
7 Indian Saw-Scaled Viper (Echis carinatus carinatus) . . . . . . . . . . . . . 135
7.1 Taxonomic Classification of the Indian Saw-Scaled Viper
(Echis carinatus carinatus) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136
7.2 Characteristic Features of the Indian Saw-Scaled Viper . . . . . . . . . 136
7.3 Geographic Distribution, Habitat, Behavior, and Reproduction
of the Indian Saw-Scaled Viper . . . . . . . . . . . . . . . . . . . . . . . . . . 137
7.4 Composition of the Indian Saw-Scaled Viper Venom . . . . . . . . . . 138
7.5 Pharmacology, Pathophysiology, and Clinical Features of
Envenomation by the Indian Saw-Scaled Viper . . . . . . . . . . . . . . . 141
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 143
8 Prevention and Treatment of the “Big Four” Snakebite in
India . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 145
8.1 Prevention of Snakebite: Some Useful Strategies . . . . . . . . . . . . . 146
8.2 First Aid for Snakebite . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
8.2.1 First Aid for Snakebite: World Health Organization-
Recommended Guidelines . . . . . . . . . . . . . . . . . . . . . . . . 147
8.3 Antivenom Production in India . . . . . . . . . . . . . . . . . . . . . . . . . . 148
8.3.1 Monovalent vs. Polyvalent Antivenom . . . . . . . . . . . . . . . 148
8.3.2 Production of F(ab0 )2 PAV in India . . . . . . . . . . . . . . . . . 149
8.3.3 Quality Control of Commercial Antivenom: World
Health Organization Guidelines . . . . . . . . . . . . . . . . . . . . 150
8.4 Diagnosis and Clinical Treatment of Snakebite . . . . . . . . . . . . . . . 152
8.5 Management of Adverse Effects of Antivenom . . . . . . . . . . . . . . . 155
8.5.1 Early Adverse Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 155
8.5.2 Endotoxin-Mediated Pyrogenic Reactions . . . . . . . . . . . . . 155
8.5.3 Late Serum Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . 155
x Contents

8.5.4 Prevention and Treatment of Adverse Serum

Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 156
8.6 Geographical and Species-Specific Variation in Snake Venom
Composition and Its Impact on Antivenom Treatment . . . . . . . . . . 157
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159
About the Author

Ashis K. Mukherjee is the Director of the Institute of Advanced Study in Science

and Technology, Guwahati, Assam, India, and also a Professor of Molecular Biol-
ogy and Biotechnology at Tezpur University, Assam, India. He did M.Sc. (Bio-
chemistry) from Banaras Hindu University, Ph.D. in Biochemistry and
Pharmacology of Indian Cobra and Russell’s Viper Venom from Burdwan Medical
College under Burdwan University, and D.Sc. (Biotechnology) from Calcutta Uni-
versity on characterization and biotechnological application of phospholipase A2
and proteases from Indian cobra and Russell’s viper venom. Prof. Mukherjee has
more than 25 years of research experience on Indian snake venoms and treatment of
venomous snakebites. His current research interest includes biochemical, pharmaco-
logical, and proteomic analyses of Indian snake venoms; quality assessment of
commercial antivenom; and novel diagnostics and drug discovery from natural
resources including snake venom. He has published numerous research papers in
peer-reviewed national and international journals and book chapters, guided Ph.D.
students, and received several awards and medals for his academic competence and
research achievements, the most notable being Visitor’s Award for Research in
Basic and Applied Sciences from the Honorable President of India in 2018. Prof.
Mukherjee is also the task force member of the Department of Biotechnology,
Ministry of Science and Technology, Government of India; Indian Council of
Medical Research, Government of India; and the World Health Organization
(WHO) on prevention and control of snakebite envenoming.

xi
Introduction
1

Abstract

Snakes are legless, elongated, carnivorous reptiles of the suborder Serpentes’

group. More than 3400 living species of snakes are distributed in most parts of the
world in a wide variety of habitats. India has a very rich diversity of snake fauna
where approximately 60 species of snakes are venomous and among them, the
famous “Big Four” venomous snakes, namely Indian spectacled cobra (Naja
naja), Indian common krait (Bungarus caeruleus), Indian Russell’s viper
(Daboia russelii), and Indian saw-scaled viper (Echis carinatus), are found
almost all over the country, except in few regions. These “Big Four” venomous
snakes are accountable for majority of envenoming in the Indian subcontinent and
they are considered as class I medically important venomous snakes of the
country, the bite of which requires immediate medical treatment. In addition to
the “Big Four” several other species of venomous snakes, for example, Indian
monocellate cobra, Wall’s krait, Sind krait, king cobra, and several species of pit
vipers, are also inhabitants of different regions of India but because of less
frequency of bite by these snakes they have received poor medical attention.
The epidemiological study on the global incidence of snakebite shows that the
incidence of snakebite as well as bite deaths in developed countries are much less
compared to those in developing countries. South Asia, followed by Southeast
Asia, and East sub-Saharan Africa have recorded the highest incidence of snake-
bite. Notably, India has the highest incidence of snakebite in the world. Poor
attention, inappropriate healthcare system, and scarcity of antivenom are the
major reasons for high rate of morbidity and/or mortality post-snake envenom-
ation in the developing nations; therefore, snakebite is declared as a neglected
tropical disease by the World Health Organization. Because of the lack of a
proper coordinated survey on snakebite, poor maintenance of hospital records,
and dearth of awareness among people, it is very difficult to envisage the type(s)
of snakebite in a particular region of the country. In conclusion, it may be

# The Author(s), under exclusive license to Springer Nature Singapore Pte 1

Ltd. 2021
A. K. Mukherjee, The 'Big Four’ Snakes of India,
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2 1 Introduction

suggested that a combined effort from clinicians, toxinologists, antivenom

manufacturing companies, and health authorities, along with awareness among
mass, can certainly eradicate the snakebite problem.

Keywords

Big Four venomous snakes · Bungarus · Daboia · Echis · Epidemiology of

snakebite · Indian cobra · Indian krait · Indian Russell’s viper · Indian saw-scaled
viper · Medically important snakes of India · Naja · Non-Big Four venomous
snakes · Snakebite

1.1 A Glimpse of the Venomous Snakes of India

The snake is undoubtedly one of the most mysterious, enchanting but misunderstood
creatures of the world! The word “snake” invokes in the mind of the people a curious
mixture of scare and admiration. Fear is evoked because the snake venom is deadly;
the venom, when injected, causes a variety of pathophysiological dysfunctions in the
body of the victim, which most often leads to death or morbidity. Ophidiophobia
(fear of snakes) is a response that we have possibly inherited from our ancestors.
Simultaneously, however, snakes have been worshipped as a deity and have been
shown great veneration by many communities in different parts of the world,
including India (Fig. 1.1).
The Sanskrit name of snake is “Bhujanga” or “Sarpa.” From ancient times, snakes
have been envisaged to be an integral part of Indian cultural heritage. The cobras are
garlands of Lord Shiva (the Hindu deity of creative power) (Fig. 1.2a) whereas Lord
Vishnu (the Hindu deity of restoration) sleeps on a thousand-headed snake known as
“Shesha (means one which remains) Nag” (Fig. 1.2b). The mythological text of
India describes that “Shesha Nag” holds the universe. Again, “Devi Manasa” (the
Hindu goddess of snakes) is worshiped mostly in West Bengal, Tripura, and
Andaman and Nicobar Islands and some other parts of Northeast India, mainly to

Fig. 1.1 Snake as a symbol of deity in temples of India (photography by the author)
1.1 A Glimpse of the Venomous Snakes of India 3

Fig. 1.2 Indian mythological pictures showing (a) snake as the garland of Lord Shiva and (b) Lord
Vishnu sleeping on a thousand-headed snake (sketch by Mr. Anandan Mukherjee)

get rid of snakes and for curing of snakebite. The “Nag Panchami” is celebrated on
the fifth day of bright half of lunar month of “Shravana” (generally in the month of
August) to worship and pay homage to the snakes throughout the country; neverthe-
less, it is more popular in northern India. Nonetheless, Indian culture does not allow
indiscriminate killing of snakes and it is often considered as a debauchery.
As a subject, perhaps snakes and snake venom has been far more fascinating than
many other subjects for the scientific community. At the same time, however, many
of us are not yet entirely free from prejudice about snakes. Consequently, we seem to
have failed to sufficiently highlight the bright sides of this innocent creature, mainly
due to our ignorance over knowledge about snakes. It is important that we under-
stand the molecular mechanism of snake venom components in inducing toxicity,
but it is equally important that we should recognize the role played by snake venom
proteins in therapeutics. The countless contribution that snakes make to our echo
system, and the great help they render to our farmers by being an integral part of the
pest management system in feeding rodents, is noteworthy.
Snakes are legless, elongated, carnivorous reptiles of the suborder Serpentes’
group. The lack of eyelids and external ears can very well distinguish snakes from
legless lizards. Today, there are more than 3400 living species of snakes (serpents)
on earth, distributed in most parts of the world and inhabiting fossorial (primarily
lives in underground), arboreal (living in trees), terrestrial (on earth), and aquatic
(water bodies) environments (Hsiang et al., 2015). Snakes inhabit desserts, tropical
rain forests, as well as oceans. India has a very rich diversity of snake fauna, of which
only 250 species have so far been identified (Sharma, 1998). Among them, 60 of
these species are either venomous or harmful (Sharma, 1998).
The evolution of snakes is disputed and is an enduring mystery. Every venomous
organism, such as snakes, is armed with venom gland—the primary function of
which is to synthesize and store a myriad of toxins, for performing some important
4 1 Introduction

functions for the snake. The detailed description on the composition and evolution of
snake venom is given in the next chapters. Snakes use their venom primarily as an
offensive weapon to kill, incapacitate, and paralyze their prey, for example, agile
rodent and flying bird, before swallowing it. They use their venom as a defensive
strategy against predators and rarely against humans. This is the secondary use of
snake venom, which includes its use as an aid to the digestion of the food (Weinstein
et al., 2010); however, we know very little about the role of natural selection in the
evolution of venoms.
In recent years, the subject of snake venom has been ever increasingly important
in biochemistry, toxicology, pathophysiology, pharmacology, immunology, and
biomedical research. It is noteworthy to mention that the use of snake venom is
not limited only to the production of antivenom for saving the lives of snakebite
patients albeit snake venom toxins have a huge potential use in the treatment of
diseases, some of which has been realized in the invention of novel drugs. The
therapeutic applications of components of the “Big Four” snake venoms have been
described elsewhere in this book.

1.2 The Concept of the “Big Four” and Non-“Big Four”

Medically Important Venomous Snakes of India

The planet is home to more than 3000 species of snakes inhabited across every parts
of the world, except Antarctica (Gold et al., 2002; Kasturiratne et al., 2008).
However, only about 600 species of snakes of the world are venomous and therefore
most of them are nonvenomous (Gold et al., 2002). More than 250 species of snakes
are endemic to India; nonetheless only 60 species are venomous (Sharma, 1998;
Whitaker et al., 2004; Mohapatra et al., 2011) and among them, the famous “Big
Four” venomous snakes (Fig. 1.3), namely Indian spectacled cobra (Naja naja),
Indian common krait (Bungarus caeruleus), Indian Russell’s viper (Daboia russelii),
and Indian saw-scaled viper (Echis carinatus), are found all over the country, except
in few localities.

Fig. 1.3 Photographs of Big Four venomous snakes of India. (a) Indian spectacled cobra Naja naja
(PC Mr. Romulus Whitaker); (b) Indian common krait Bungarus caeruleus (PC Mr. Vivek
Sharma); (c) Indian Russell’s viper Daboia russelii (PC author); (d) Indian saw-scaled viper
Echis carinatus (PC Mr. Romulus Whitaker; this picture is reproduced from Patra et al., 2017)
1.2 The Concept of the “Big Four” and Non-“Big Four” Medically Important. . . 5

The Big Four snakes are accountable for the majority of envenoming that results
in morbidity and/or mortality in India and in its neighboring countries (McNamee,
2001; Whitaker, 2006). The Indian cobra (N. naja) is uncommon in Northeast India
and similarly E. carinatus is not found in eastern and north-eastern India. Therefore,
bite by these species of snakes is highly unlikely in these regions. However,
considering the all-India scenario, the “Big Four” snakes have received a consider-
able medical attention not only in our country but also in neighboring countries and
equine polyvalent antivenom, the only acceptable therapy against snakebite, is
available only against the venom of these species of snakes (Mukherjee et al., 2021).
However, the concept of the “Big Four” is highly controversial and criticized by
the scientific community and the reason behind is that apart from them, some other
species of venomous snakes, for example, Indian monocellate cobra (N. kaouthia),
Wall’s krait (B. walli), Sind krait (B. sindanus), king cobra (Ophiophagus hannah),
several species of pit vipers (Hypnale hypnale, Protobothrops spp.), and
E. sochureki, also dwell in different locales of the country and may cause fatalities
(Mukherjee & Maity, 2002; Kochar et al., 2007; Joseph et al., 2007; Sharma et al.,
2008; Pillai et al., 2012; Warrell et al., 2013; Senji Laxme et al., 2019; Kalita &
Mukherjee, 2019). Nevertheless, occurrence of snakebite by these species of snakes,
excluding N. kaouthia in eastern and north-eastern India, is not reported as compared
to bite and death by the “Big Four” venomous snakes (Warrell et al., 2013; Kalita &
Mukherjee, 2019). The sea snake (Hydrophiinae sp.) and king cobra can also cause
lethal envenomation albeit their frequency of contact with human is extremely low;
therefore, the number of fatalities from the bite of these snakes is relatively low and
negligible. On the contrary, the majority of snakebite patients attending a health
center of Himachal Pradesh for snakebite treatment displayed hemotoxic symptom
which was correlated with the prevalence of green pit vipers in this region (Gupt
et al., 2015). The polyvalent antivenom against the “Big Four” snake venoms did not
work well against green pit viper envenomation (Gupt et al., 2015). There was a
report showing life-threatening envenoming by the hump-nosed pit viper (Hypnale
hypnale) in Kerala, south-western India (Joseph et al., 2007). However, a major
problem has been encountered that due to lack of snakebite detection kit the hump-
nosed pit viper-envenomed patients were also sometimes misidentified by treating
physicians as saw-scaled viper (Simpson & Norris, 2007). Similarly, systemic
envenoming due to E. sochureki is a severe problem in Rajasthan and antidote
against this species of snake is not included in Indian commercial polyvalent
antivenom (Kochar et al., 2007). Identically, Levantine viper (Macrovipera
lebetina)-envenomed patients in Jammu and Kashmir show clinical signs of necrosis
and hemostatic manifestations and antivenom against this species is also not avail-
able in the market (Sharma et al., 2008). Therefore, treatment with Levantine viper
antivenom against venomous heterologous species of snakes is debatable and may
not provide the best treatment against envenomation.
Therefore, although the decade-long concept of the “Big Four” venomous snakes
of medical importance still exists in India, from the aforementioned discussion it
seems that this perception may need to be reviewed for the treatment of all types of
venomous snakebites across the country. To achieve this much-needed objective, it
6 1 Introduction

is extremely essential to have a well-coordinated, national level hospital-based as

well as door-to-door snakebite survey initiative to explore all the venomous snakes
of India, epidemiology, and frequency of snakebite in each and every remote corner
of the country. The results of such survey will assist the health authorities and policy
makers of India to make a sound policy which proclaims that besides the “Big Four”
venomous snakes of India, the other species of snakes should also be incorporated in
the list of medically important snakes to eradicate the snakebite problem forever.
As an alternative concept to the “Big Four,” the World Health Organization in
1981 proposed the following for the identification of snakes of medical importance
in India (WHO, 1981):
Class I: Snakes commonly cause death or serious disability. Examples include
Indian cobra, Indian Russell’s viper, and Indian saw-scaled viper.
Class II: Frequency of bites is rare but envenomation by this class of snakes
causes serious pharmacological effects leading to local necrosis and/or death.
Examples are Indian krait, king cobra, and Levantine viper.
Class III: Bites by this class of snakes may be common; however, they produce
least toxic effect in humans and are therefore nonlethal. Example is white-lipped pit
viper.

1.3 Medical Aspects of Snakebite: The Snakebite Problem

Estimates show that about five million people around the world are bitten by
venomous snakes annually, thus resulting in about 100,000 fatalities (Chippaux,
1998). The latest global epidemiological study on snake envenoming conducted in
227 countries demonstrates that worldwide approximately 421,000 people are bitten
by snakes that results in almost 20,000 snakebite deaths annually (Kasturiratne et al.,
2008). In many countries of the world, snakebite cases are not systematically
reported; therefore, the actual snakebite death may be as high as 94,000 annually
(Kasturiratne et al., 2008). Notably, only few countries of the world possess a
reliable epidemiological reporting system that can provide precise data on
snakebites. Therefore, the magnitude of the snakebite problems has to be assessed
through only available scientific reports and literatures which may be more reliable
(Chippaux, 1998; Kasturiratne et al., 2008; Gutiérrez et al., 2010). Consequently,
due to lack of data, the true global incidences of snake envenoming, death rate, and
associated complications such as morbidity are difficult to estimate which is aston-
ishing and alarming (Kasturiratne et al., 2008; Gutiérrez et al., 2010). Recently, by
literature analysis on snake envenoming and modeling based on regional estimates
of snakebite and deaths, a new method has been developed for an up-to-date estimate
of the global burden of snakebite (Kasturiratne et al., 2008; Gutiérrez et al., 2010).
On the basis of their findings, the authors have concluded that morbidity and
mortality due to snakebite are a serious concern worldwide; however, the highest
burden is experienced in South Asia, Southeast Asia, and sub-Saharan Africa
(Fig. 1.4).