This document provides information on antiviral and antiretroviral drugs. It begins by describing viruses and their replication processes. It then discusses several important viruses and the diseases they cause. The document outlines the mechanisms of replication for DNA, RNA, and retroviruses. It proceeds to classify antiviral drugs according to their therapeutic uses and mechanisms of action. Several specific antiviral and antiretroviral drugs are described in detail, including their mechanisms of action, pharmacokinetics, and side effects. The human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) are also discussed.
Hello friends. In this PPT I am talking about Anti-viral drugs drugs. If you like it, please do let me know in the comments section. A single word of appreciation from you will encourage me to make more of such videos. Thanks. Enjoy and welcome to the beautiful world of pharmacology where pharmacology comes to life. This video is intended for MBBS, BDS, paramedical and any person who wishes to have a basic understanding of the subject in the simplest way.
Antiviral drugs are a class of medication used specifically for treating viral infections.Like antibiotics for bacteria, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic (also termed antibacterial), antifungal and antiparasitic drugs,or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Antivirals also can be found in essential oils of some herbs, such as eucalyptus oil and its constituents.
synthetic antimicrobials having a quinolone structure that are active primarily against gram-negative bacteria, though newer fluorinated compounds also inhibit gram-positive ones.
Hello friends. In this PPT I am talking about Anti-viral drugs drugs. If you like it, please do let me know in the comments section. A single word of appreciation from you will encourage me to make more of such videos. Thanks. Enjoy and welcome to the beautiful world of pharmacology where pharmacology comes to life. This video is intended for MBBS, BDS, paramedical and any person who wishes to have a basic understanding of the subject in the simplest way.
Antiviral drugs are a class of medication used specifically for treating viral infections.Like antibiotics for bacteria, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.
Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic (also termed antibacterial), antifungal and antiparasitic drugs,or antiviral drugs based on monoclonal antibodies. Most antivirals are considered relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from viricides, which are not medication but deactivate or destroy virus particles, either inside or outside the body. Antivirals also can be found in essential oils of some herbs, such as eucalyptus oil and its constituents.
synthetic antimicrobials having a quinolone structure that are active primarily against gram-negative bacteria, though newer fluorinated compounds also inhibit gram-positive ones.
classification of antiviral agents,replication of HIV virus and replication of virus.targets of virus,classification of antiviral agents with structure and mechanism action of antiviral agents
Hello friends. In this PPT I am talking about anti-fungal drugs. If you like it, please do let me know in the comments section. A single word of appreciation from you will encourage me to make more of such videos. Thanks. Enjoy and welcome to the beautiful world of pharmacology where pharmacology comes to life. This video is intended for MBBS, BDS, paramedical and any person who wishes to have a basic understanding of the subject in the simplest way.
This PPT covers Drug therapy for Viral Infection or disease. It includes Viral replication cycle, classification of antiviral drugs, Anti-Herpes drug, Anti Influenza drugs, Anti hepatitis drugs and anti retroviral drugs
Tetracyclines slide contains full information about uses, adverse effect, marketed preparation, precaution, route of drug administration, antimicrobial spectrum, mechanism of action, pharmacokineticks and pharmacodynamics of tetracyclines. This slide is very helpful for pharmacy and pharmacology student for the study about tetracyclines.
Antiviral Drugs – A Brief (Classification & Mechanism of Actions)Parth Thosani
This presentation gives you an overview of antiviral agents (both retro and non-retro viruses), focusing on the sites of actions, classification and class-wise mechanism of actions.
classification of antiviral agents,replication of HIV virus and replication of virus.targets of virus,classification of antiviral agents with structure and mechanism action of antiviral agents
Hello friends. In this PPT I am talking about anti-fungal drugs. If you like it, please do let me know in the comments section. A single word of appreciation from you will encourage me to make more of such videos. Thanks. Enjoy and welcome to the beautiful world of pharmacology where pharmacology comes to life. This video is intended for MBBS, BDS, paramedical and any person who wishes to have a basic understanding of the subject in the simplest way.
This PPT covers Drug therapy for Viral Infection or disease. It includes Viral replication cycle, classification of antiviral drugs, Anti-Herpes drug, Anti Influenza drugs, Anti hepatitis drugs and anti retroviral drugs
Tetracyclines slide contains full information about uses, adverse effect, marketed preparation, precaution, route of drug administration, antimicrobial spectrum, mechanism of action, pharmacokineticks and pharmacodynamics of tetracyclines. This slide is very helpful for pharmacy and pharmacology student for the study about tetracyclines.
Antiviral Drugs – A Brief (Classification & Mechanism of Actions)Parth Thosani
This presentation gives you an overview of antiviral agents (both retro and non-retro viruses), focusing on the sites of actions, classification and class-wise mechanism of actions.
Antiviral drugs are a class of medications used to treat viral infections by inhibiting the replication or growth of viruses in the body. These drugs work by targeting specific components of a virus, such as the viral enzymes, proteins, or nucleic acids, and disrupting their ability to infect or replicate inside host cells. This can help reduce the severity of symptoms, prevent complications, and speed up recovery.
There are many types of antiviral drugs available, including:
1. Nucleoside or nucleotide analogues: These drugs mimic the structure of the nucleosides or nucleotides needed for viral replication, thereby interfering with virus replication.
2. Protease inhibitors: These drugs block the activity of viral proteases, which are enzymes that are required for the replication and assembly of some viruses.
3. Interferons: These drugs are naturally occurring proteins that help the immune system fight viral infections by boosting the body's antiviral response.
4. Neuraminidase inhibitors: These drugs block the activity of viral neuraminidase, an enzyme that is required for the release of virus particles from infected cells.
5. Fusion inhibitors: These drugs block the fusion of viral and host cell membranes, which is an essential step in viral entry and replication.
Antiviral drugs can be used to treat a variety of viral infections, including influenza, HIV/AIDS, hepatitis B and C, herpes, and Ebola. However, the effectiveness of these drugs can vary depending on the specific virus and the stage of infection. Antiviral drugs may also have side effects, and it is important to consult with a healthcare provider before taking them.
medicinal chemistry of Antiviral drugsFatenAlsadek
medicinal chemistry of antiviral drugs with its chemical structures and how they chemically work
Done by: Faten Al-Sadek , Pharmacy student at Mohammed Al-Mana college for Health Sciences -MACHS
I have tried to provide an outline regarding the general antivirals available in our country..and discussed regarding MOA,indications and Therapeutic uses.
antiviral drugs medicinal chemistry by padala varaprasadVaraprasad Padala
medicinal chemistry of antiviral drugs by padala varaprasad
mainly includes structures, SAR , mechanism of action, uses and toxicity of antiviral drugs
The Art of the Pitch: WordPress Relationships and SalesLaura Byrne
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Keynote at DIGIT West Expo, Glasgow on 29 May 2024.
Cheryl Hung, ochery.com
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https://alandix.com/academic/papers/synergy2024-epistemic/
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All of this illustrated with link prediction over knowledge graphs, but the argument is general.
2. Viruses
• Viruses are the smallest infective agents, consisting essentially of
nucleic acid (either RNA or DNA) enclosed in a protein coat or
capsid.
• A virus cannot replicate on its own. It must attach to and enter a
host cell. It then uses the host cell’s energy to synthesize protein,
DNA, and RNA. Viruses are difficult to kill because they live inside
the cells. Any drug that kills a virus may also kill cells
3. Some important examples of viruses and the diseases they
cause are as follows:
DNA viruses
• Pox viruses (smallpox)
• Herpes viruses (chickenpox,
herpes etc.)
• Adenoviruses (sore throat,
conjunctivitis)
• Hepadnaviruses (serum
hepatitis)
• Papillomaviruses (warts)
RNA viruses
•Orthomyxoviruses (influenza)
•Paramyxoviruses (measles, mumps)
•Rubella virus (German measles)
•Rhabdoviruses (rabies)
•Picornaviruses
(colds, meningitis, poliomyelitis)
•Retroviruses (AIDS, T-cell
leukaemia)
•Arenaviruses (meningitis, Lassa
fever)
•Arboviruses (arthropod-borne
encephalitis, yellow fever)
4.
5. Replication in viruses
• Replication in DNA viruses
Viral DNA enters the host cell nucleus, where transcription into mRNA
by the host cell RNA polymerase occurs. Translation of the mRNA into
virus-specific proteins takes place. These proteins are enzymes that
then synthesise more viral DNA, as well as proteins for the viral coat
and envelope. After assembly of coat proteins around the viral DNA,
complete virions are released by budding or after host cell lysis.
• Replication in RNA viruses
Enzymes within the virion synthesise its mRNA from the viral RNA
template, or sometimes the viral RNA serves as its own mRNA. This is
translated by the host cell into various enzymes, including RNA
polymerase and also into structural proteins of the virion. Assembly and
release of virions occurs as explained above. With these viruses, the
host cell nucleus is usually not involved in viral replication, although
some RNA viruses (e.g. orthomyxoviruses) replicate exclusively within
the host nuclear compartment.
6. • Replication in retroviruses
The virion in retroviruses contains a reverse transcriptase enzyme
(virus RNA-dependent DNA polymerase), which makes a DNA copy of
the viral RNA. This DNA copy is integrated into the genome of the host
cell, and it is then termed a provirus. The provirus DNA is transcribed
into both new viral genome RNA as well as mRNA for translation in the
host into viral proteins, and the completed viruses are released by
budding. Many retroviruses can replicate without killing the host cell.
8. CLASSIFICATION OF ANTIVIRAL DRUGS ACCORDING TO THE MECHANISM OF ACTION
The viral growth cycle Selective inhibitors
1) Attachment
2) Penetration
- Antiviral antibodies
(gamma globulin)
3) Uncoating - Amantadine, Rimantadine - Interferon
4) Early translation
(early mRNA and protein synthesis)
- fomivirsen
5) Transcription
(viral genome replication)
Inhibitors of DNA-polymerase
-Acyclovir, Gancyclovir, Famcyclovir, Cidofovir
- Vidarabine, Idoxuridine -Foscarnet
Inhibitors of RNA-dependant DNA-polymerase
(reverse transcriptase inhibitors)
-Zidovudine, Stavudine, Lamivudine
- Didanosine, Zelcitabine
6) Late translation
(late mRNA an protein synthesis)
- Ribavirin -Interferons
7) Posttranslational modifications
(proteolytic cleavage)
Protease inhibitors
- Saquinavir, Indinavir, Ritonavir
8) Assembly
(packaging of viral nucleic acids)
-Interferons -Rifampin
9) Release
(virion is releasing from cell) (budding)
-Antiviral antibodies
- Cytotoxic T lymphocytes
Neuraminidase Inhibitors
-Zanamivir, Oseltamivir
9.
10. Mechanism of action of antiviral drugs
Inhibition of penetration of host cell
• Amantadine and also Rimantadine
inhibit uncoating and are effective
against influenza A virus.
• Amantadine
CNS effects: insomnia, nervousness,
lightheadedness.
GI effects: anorexia, nausea, others.
• Rimantadine
Same spectrum of activity,
mechanism of action, and
indications as amantadine. Fewer
CNS adverse effects. Causes GI
upset.
• Gammaglobulins neutralize
viruses.
11. Antiviral mechanism of action: Inhibition
of nucleic acid synthesis I
• Acyclovir a guanosine derivative selectively inhibits viral DNA
polymerase; minimal unwanted effects. Used to suppress replication of:
– HSV-1(oral herpes), HSV-2(genital herpes), VZV (chickenpox or
shingles), To some extend EBV and CMV.
• Gancyclovir, also a guanosine derivative is phosphorylated and then
incorporated into viral DNA, suppressing its replication; used in
cytomegalovirus infections; especially
CMV retinitis in AIDS patients.
CMV retinitis
– Ophthalmic form surgically
implanted.
– Ocular injection (fomivirsen).
Dose-Limiting Toxicities
• Gancyclovir and zidovudine
– Bone marrow toxicity.
• Foscarnet and cidofovir
– Renal toxicity.
12. Antiviral mechanism of action: Inhibition
of nucleic acid synthesis II
• Vidarabine, an adenosine
derivative, is a relatively selective
inhibitor of viral DNA polymerase;
effective against Herpes simplex
and Varicella zoster; can have
serious unwanted effects.
• Ribavirin is similar to guanosine
and is thought to interfere with
synthesis of viral DNA; can inhibit
many DNA and RNA viruses.
Given orally, or oral or nasal
inhalation.
Inhalation form (Virazole) used for
hospitalized infants with RSV
(respiratory syncytial virus)
infections.
13. Antiviral mechanism of action: Inhibition
of nucleic acid synthesis III
• Foscarnet inhibits viral DNA polymerase by attaching to the
pyrophosphate binding site; approved for CMV infections.
• Zidovudine, an analogue of thymidine, inhibits reverse
transcriptase and is relatively effective in HIV infection.
• Zalcitabine and didanosine are reverse transcriptase
inhibitors used in HIV infection.
14. Neuraminidase
inhibitors
• Zanamivir and oseltamivir
inhibits neuraminidase
which is essential for virus
replication. They are used
against influenza A and B.
They are for avian and swine
influenza (H5N1 and H1N1
respectively) which are
influenza A subtypes.
Zanamivir is used by
inhalation; oseltamivir
orally.
• oseltamivir: causes nausea
& vomiting
• Zanamivir: causes diarrhea,
nausea, sinusitis
15. Immunomodulators
• Interferons induce, in the host cells’ ribosomes, enzymes which
inhibit viral mRNA; Interferon has broad spectrum anti-viral activity
HSV 1 & 2, HZV, HPV (DNA viruses), influenza, chronic hepatitis,
common cold, breast cancer, lung cancer, Karposi’s sarcoma (cancer
associated with AIDS) (RNA viruses).
• ADRs: Flue like symptoms, neurotoxicity, myelosuppression etc.
• Pavilizumab is a monoclonal
antibody against fusion proteins
of respiratory syncytial virus.
• Imiquimod is an immune response
modulator used topically against
genital and perianal warts.
16. The human immunodeficiency virus (HIV)
and AIDS
• Infection with HIV results in the acquired immune deficiency
syndrome (AIDS). In 1997 it was estimated that nearly 30 million
adults world-wide were infected with HIV, with the number of
HIV infections increasing by five every minute. The epidemic is
overwhelmingly centred on sub-Saharan Africa, where about
7% of the population is infected.
17. The interaction of HIV with the host's
immune system
• The interaction of HIV with the host's immune system is
complex. Cells of the immune system have the equivalent of
“name badges” that identify them. The surface glycoprotein
CD4 is the name badge of a particular group of helper T
lymphocytes; it also occurs on macrophages and dendritic
cells.
18. Highly active antiretroviral therapy
• The advent of highly active antiretroviral therapy (HAART) has
changed the prognosis, in countries that can afford it. HAART
is a combination of three antiviral drugs including at least
one protease inhibitor. There are 20anti-HIV drugs available;
six nucleoside reverse transcriptase inhibitors, four non-
nucleoside reverse transcriptase inhibitors, one nucleotide
reverse transcriptase inhibitor, eight protease inhibitors,
and one fusion inhibitor. Most are discussed below.
• With a HAART regime, HIV replication is inhibited -its
presence in the plasma being reduced to undetectable levels-
and patient survival is prolonged; but the regime is complex,
difficult to adhere to and may well have to be lifelong. It is
also extremely expensive-which effectively prevents its use in
developing countries. In any case, with the high mutation rate
of the virus, resistance is an important problem. HIV has
certainly not yet been outsmarted.
21. Zidovudine (Azidothymidine, AZT)
• Zidovudine is an analogue of
thymidine. In retroviruses-such as the
HIV virus-it is an active inhibitor of
reverse transcriptase. It is
phosphorylated by cellular enzymes to
the triphosphate form, in which it
competes with equivalent cellular
triphosphates which are essential
substrates for the formation of proviral
DNA by viral reverse transcriptase
(viral RNA-dependent DNA
polymerase); its incorporation into the
growing viral DNA strand results in
chain termination.
• Mammalian alpha DNA polymerase is
relatively resistant to the effect.
However, gamma DNA polymerase in
the host cell mitochondria is fairly
sensitive to the compound and this
may be the basis of unwanted effects.
22. Pharmacokinetic aspects of zidovudine
• Given orally, the bioavailability
of zidovudine is 60-80% and the
peak plasma concentration occurs
at 30 minutes. It can also be given
intravenously. Its half-life is 1 hour,
and the intracellular half-life of the
active triphosphate is 3 hours.
• Zidovudine enters mammalian cells by passive diffusion and in
this is unlike most other nucleosides which require active
uptake. The drug passes into the CSF and brain. Most of the
drug is metabolized to inactive glucuronide in the liver, only
20% of the active form being excreted in the urine.
23. Unwanted effects of zidovudine
• Anaemia and neutropenia are common, particularly
with long-term administration. Administration of
erythropoietin and GM-CSF may alleviate these
problems.
• Other unwanted effects include gastrointestinal
disturbances, paraesthesia, skin rash, insomnia,
fever, headaches, abnormalities of liver function and,
more particularly, myopathy. Confusion, anxiety,
depression and a flu-like syndrome are also reported.
The prophylactic use of the drug, short-term, in fit
individuals, after specific exposure to the virus, is
associated with only minor, reversible unwanted
effects.
24. Resistance to the antiviral action of
zidovudine
• Because of rapid mutation the virus is a constantly
moving target, thus the therapeutic response wanes
with long-term use, particularly in late-stage disease.
Furthermore, resistant strains can be transferred
between individuals. Other factors which underlie
the loss of efficacy of the drug are decreased
activation of zidovudine to the triphosphate and
increased virus load due to reduction in immune
mechanisms.
25. Didanosine(dideoxyinosine, ddl)
• Didanosine is a synthetic purine dideoxynucleoside
analogue. It is phosphorylated in the host cell to the
triphosphate, dideoxyadenosine, in which form it acts as
a chain terminator and inhibitor of the viral reverse
transcriptase. It is used to treat AIDS.
• Pharmacokinetic aspects of didanosine
Didanosine is given orally, rapidly absorbed and is
actively secreted by the kidney tubules. The plasma half-
life is 30 minutes but the intracellular half-life is more
than 12 hours. The cerebrospinal fluid/plasma ratio is
0.2.
26. Unwanted effects of didanosine
• The main unwanted effect -
occurring in >30% of patients-is
dose-related pain and sensory
loss in the feet. Dose-related
pancreatitis occurs in 5-10% of
patients and has been fatal in a
few cases. Headache and
gastrointestinal disturbance are
also common and insomnia, skin
rashes, bone marrow depression
(less marked than with AZT) and
alterations of liver function have
been reported.
27. Zalcitabine(dideoxycytidine, ddC)
• Zalcitabine, a synthetic nucleoside analogue, is used in
combination with zidovudine for the therapy of AIDS. It is a
reverse transcriptase inhibitor and it is activated in the T cell
by a different phosphorylation pathway from zidovudine. It is
given orally, its plasma half-life is 20 minutes, its intracellular
half-life is nearly 3 hours and its cerebrospinal fluid/plasma
ratio is ~0.2.
• Unwanted effects of zalcitabine
The most important unwanted effect is a dose-related
neuropathy (which can increase for several weeks after the
drug has been stopped). Other unwanted effects include
gastrointestinal disturbances, headache, mouth ulcers, nail
changes, edema of the lower limbs and general malaise. Skin
rashes occur but may resolve spontaneously. Pancreatitis has
been reported.
28. Nevirapine
• Mechanism Of Action:
– Direct inhibitor of reverse transcriptase without intracellular
phosphorylation.
– NNRTIs bind to the Reverse transcriptase near the catalytic site
and cause its denaturation.
– More potent on HIV-1 than Zidovudine but not HIV-2.
– Cross resistance among themselves but not with others.
• Kinetics:
– Administered Orally. Plasma half-life – 20 min. Conc. in CSF –
45% of that in plasma. Metabolism – Metabolized in the liver
and metabolite is excreted in the urine (CYP3A4).
– Nevirapine can prevent mother-to-baby transmission of HIV if
given to the parturient mother and the neonate
• Unwanted effects:
– Skin rash(17%), Fever, Headaches, Lethargy.
– If not monitored carefully: Stevens-Johnson syndrome or Toxic
epidermal necrosis.
– Fulminant hepatitis (occasionally)
• Dose: 200 mg/day
29. Other reverse transcriptase inhibitors
• New nucleoside reverse transcriptase
inhibitors now in use include Lamivudine and
Stavudine. Non-nucleoside reverse
transcriptase inhibitors now in use include
nevirapine and delavirdine. All are given
orally.
30. Protease inhibitors
• Host mRNAs code directly for functional proteins, but in HIV, the
RNA is translated into biochemically inert polyproteins. A virus-
specific protease then converts the polyprotein into various
structural and functional proteins by cleavage at the appropriate
positions. Since this protease does not occur in the host, it is a good
target for chemotherapeutic intervention.
• Several protease inhibitors have now been developed, and their
use, in combination with reverse transcriptase inhibitors, has
transformed the therapy of AIDS. Examples of current protease
inhibitors are: amprenavir, atazanavir, indinavir, fosemprenavir,
nelfinavir, ritonavir and saquinavir.
• They are all given orally and all can cause gastrointestinal disorders:
nausea, vomiting and diarrhoea. Raised concentrations of liver
enzymes in the blood are reported with ritonavir and indinavir.
Ritonavir can cause paraesthesia around the mouth, and in the
hands and feet, and patients on indinavir may develop kidney
stones.
31. Protease inhibitors(continued)
• All inhibit the cytochrome P450 enzymes (indinavir and saquinavir
to a lesser extent than ritonavir) and can interact with other drugs
handled by this system, and all can increase the plasma
concentration of benzodiazepines. Preliminary evidence suggests
that long-term use may lead to an unusual redistribution of
cutaneous fat.
• Class-Specific Toxicities:
NRTI Mitochondrial DNA toxicity
NtRTI Proximal renal tubular dysfunction
NNRTI Hypersensitivity, Rash
PI Metabolic disorders
32. Fusion inhibitors
• Enfuvirtide inhibits the entrance of HIV virus into
host cells. It is applied subcutaneously in
combination with other anti-AIDS drugs.
33. Principles of HIV/AIDS therapy
• Monitor plasma viral load and CD4 count.
• Start treatment before immunodeficiency
becomes evident.
• Aim to reduce plasma viral concentration as
much as possible for as long as possible.
• Use combinations of at least three drugs, e.g. two
reverse transcriptase inhibitors and one protease
inhibitor.
• Change to a new regime if plasma viral
concentration increases.
34. New Agents to Treat HIV Infection
Phase
Reverse
Transcriptase
Inhibitors
Protease
Inhibitors
Entry
Inhibitors
Integrase/
Maturation
Inhibitors;
Immunologics
2/3 Etravirine
(TMC 125)
Darunavir Maraviroc
Vicriviroc
MK-0518
2 BILR 355 BS TNX-355 GS-9137
1/2 Amdoxovir
Apricitabine
Rilpivirine
(TMC 278)
Brecanavir AMD 070
PRO 542
Bevirimat
CTLA4-mAb
1 Fosalvudine PPL-100 PRO 140
TAK 652
Pre-clinical 22 7 21 11
35. Bibliography
• Tripathi KD, “essentials of Medical Pharmacology”, 6th edition, Jaypee
Brothers Medical Publishers (P) Ltd., 2008, Pg no: 767-776.
• Rang H.P., Dale M.M., Ritter J.M., Moore P.K., “Pharmacology”, 5th
edition, Churchill Livingstone, 2003, Pg no: 679,680,684-689.
• Trevor Anthony J., Katzung Bertram G., Masters Susan B., “ Katzung &
Trevor's Pharmacology Examination and board review”, 9th edition, Mc
Graw Hill Publishers, 2009, Ch no: 49.
• Harvey Richard A., Champe Pamela C., “Pharmacology”, 4th edition,
Lippincott Williams & Wilkins, 2008, Pg no: 584-595.
• Goyal Dr. R.K., “ Elements of Pharmacology”, 19th edition, B S Shah
Prakashan, 2009, Pg no: 571,572,578,580.
• Satoshkar R.S., Bhandarkar S.D., Rege Nirmala N., “Pharmacology &
Pharmacotherapeutics”, 21st edition, Popular Prakashan, 2009, Pg no:
792,793.