role free radical in pharmacology

1. PRESENTED BY
Prashant Suresh Ingle
First Year M. Pharmacy [Sem-II]
Roll No - MPL-07
Department of Pharmacology
R. C. Patel Institute of Pharmaceutical Education and Research, Shirpur1

2. CONTENTS
• Introduction
• Sources of free radical
• Formation of free radical
• Steps involving free radical generation
• Causes of free radicals
• Free radical targets
• Role of free radicals in pathogenesis
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3. INTRODUCTION
• A free radical is defined as any chemical species that contains unpaired electrons,
because of these free radicals are highly reactive and readily take part in chemical
reactions leading to tissue injury.
• They are produced either from normal cell metabolisms in situ or from external
sources (pollution, cigarette smoke, radiation, medication).
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4. Cont….
• When an overload of free radicals cannot gradually be destroyed, their
accumulation in the body generates a phenomenon called oxidative stress. This
process plays a major part in the development of chronic and degenerative illness
such as cancer etc.
• Endogenous and exogenous antioxidants act as "free radical scavengers" by
preventing and repairing damages caused by ROS and RNS and enhance immune
defense
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6. SOURCES OF FREE RADICAL
• The most important free radicals in biological system are radical derivatives of
oxygen.
• (reactive oxygen species) ROS includes free radical as well as other non-radical
derivatives of oxygen.
• e.g. H O & Singlet Oxygen. These ROS can produce oxidative damage to the
tissue and hence are known as oxidants in biological system.
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8. FORMATION OF FREE RADICAL
• Normally, bonds don't split to leave a molecule with an odd, unpaired electron.
But when weak bonds split, free radicals are formed.
• Free radicals are very unstable and react quickly with other compounds, trying to
capture the needed electron to gain stability. When the "attacked" molecule loses
its electron, it becomes a free radical itself, beginning a chain reaction, resulting in
the disruption of a living cell.
• Some free radicals may arise normally during metabolism and by immune
system's cells purposefully to neutralize viruses and bacteria. 8

9. Cont….
A. Covalent bond cleavage of normal molecule or atom: Atoms are blinded together
when they share or transfer electron to form molecule. A covalent bond is
formed when a pair of electron is shared.
The bond breakage occurs in two ways "hemolytic cleavage" in this type of
cleavage both atoms retain one electron each due to symmetrical rupture of bond.
H-H →→Hᵒ + Hº
Such type of cleavage requires high energy input either in the form of high
temperature, Unlight or ionizing radiation to cause hemolysis of covalent bond. 9

10. cont….
• B) Electron transfer: Electron transfer is a far more common an important source
of generation of free radicals in biological system.
i) Oxidation reaction: By loss of a single electron from a normal molecule.
ii) Reduction reaction: By addition of a single electron to normal molecule
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12. Steps involving free radical generation
• free radicals take part in radical addition and radical substitution as reactive
intermediates. Chain reactions involving free radicals can usually be divided into
three distinct processes: initiation, propagation, and termination.
• Initiation reactions are those, which result in a net increase in the number of
free radicals. They may involve the formation of free radicals from stable species
or they may involve reactions of free radicals with stable species to form more
free radicals. 12

13. Cont….
• Propagation reactions involve free radicals in which the total number of free
radicals remains the same.
• Termination reactions are those reactions resulting in a net decrease in the
number of free radicals. Radicals may also be formed by single electron oxidation
or reduction of an atom or molecule. An example is the production of superoxide
by the electron transport chain.
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15. CAUSES OF FREE RADICALS
• Production of free radicals in the body is continuous and inescapable. The basic
causes include the following:
• The immune system: The body tries to harness the destructive power of the
most dangerous free radicals - the oxy radicals and ROS- for use in the immune
system and in inflammatory reactions.
• Certain cells in these systems engulf bacteria or viruses, take up oxygen molecules
from the bloodstream, remove an electron to create a flood of oxy radicals and
ROS, and bombard the invader with the resulting toxic shower.
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16. Cont….
• This aggressive use of toxic oxygen species is remarkably effective in protecting
the body against infectious organisms.
• Energy production: The energy-producing process in every cell generates oxy
radicals and ROS as toxic waste, continuously and abundantly Oxygen is used to
burn glucose molecules that act as the body's fuel.
• The cell includes a number of metabolic processes with the constant creation of
oxy radicals and ROS..
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17. FREE RADICAL TARGETS
• Free radicals attack three main cellular components. Peroxidation of lipids in cell
membranes can damage cell membranes by disrupting fluidity and permeability.
• Lipid peroxidation can also adversely affect the function of membrane bound
proteins such as enzymes and receptors. Direct damage to proteins can be caused
by free radicals.
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19. Role of free radicals in pathogenesis
• When produced in excess, free radicals and oxidants generate a phenomenon
called oxidative stress, a deleterious process that can seriously alter the cell
membranes and other structures such as proteins, lipids, lipoproteins, and
deoxyribonucleic acid (DNA).
• Oxidative stress results from an imbalance between formation and neutralization
of ROS/RNS
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21. Cancer and oxidative stress:
• Oxidative DNA damage is responsible for cancer development.
• This adduct formation interferes with normal cell growth by causing genetic
mutations and altering normal gene transcription.
• Cancer initiation and promotion are associated with chromosomal defects and
oncogene activation induced by free radicals.
• Oxidative DNA damage also produces a multiplicity of modifications in the DNA
structure including base and sugar lesions, strand breaks DNA-protein cross-links
and base-free sites.
• Example, tobacco smoking and chronic inflammation resulting to the development
of lung cancer and other tumors from noninfectious diseases like asbestos.
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23. Cardiovascular disease and oxidative stress
• the role of oxidative stress in a number of CVDs such as atherosclerosis, ischemia,
hypertension, cardiomyopathy, cardiac hypertrophy and congestive heart failure.
• Cardiovascular disease (CVD) is of multifactorial etiology associated with a
variety of risk factors for its development including hyper cholesterolaemia,
hypertension, smoking, diabetes, poor diet, stress and physical inactivity.
• Potential sources of free radicals during ischemia and reperfusion have been
identified in myocytes, vascular endothelium, and leukocytes.
• Injury to processes involved in regulation of the intracellular Ca2+ concentration
may be a common mechanism underlying both free radical-induced and
reperfusion abnormalities.
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24. Neurological disease and oxidative stress
• Oxidative stress has been investigated in neurological diseases including
Alzheimer's disease, Parkinson's disease, multiple sclerosis, memory loss,
depression.
• In Alzheimer's, numerous experimental and clinical studies have demonstrated that
oxidative damage plays a key role in the loss of neurons and the progression to
dementia.
• The production of B-amyloid, a toxic peptide often found present in Alzheimer's
patients' brain, is due to oxidative stress and plays an important role in the
neurodegenerative processes. 24

25. Rheumatoid arthritis and oxidative stress
• Rheumatoid arthritis is an autoimmune disease characterized by chronic
inflammation of the joints and tissue around the joints with in filtration of
macrophages and activated T cells.
• The pathogenesis of this disease is due to the generation of ROS and RNS at the
site of inflammation.
• Oxidative damage and inflammation in various rheumatic diseases were proved by
increased levels of isoprostanes and prostaglandins in serum and synovial fluid
compared to controls. 25

26. Nephropathy and oxidative stress
• Oxidative stress plays a role in a variety of renal diseases such as
glomerulonephritis and tubulointerstitial nephritis, chronic renal failure,
proteinuria, uremia.
• The nephrotoxicity of certain drugs such as cyclosporine, gentamycin, bleomycin,
vinblastine, is mainly due to oxidative stress via lipid peroxidation. Heavy metals
and transition metals act as free radical inducers causing different forms of
nephropathy and carcinogenicity.
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27. Ocular disease and oxidative stress
• Oxidative stress is implicated in age-related muscular degeneration and cataracts
by altering various cell types in the eye either photochemically or non-
photochemically.
• Under the action of free radicals, the crystalline proteins in the lens can cross-link
and aggregate, leading to the formation of cataracts. In the retina, long-term
exposure to radiation can inhibit mitosis in the retinal pigment epithelium and
choroids, damage the photoreceptor outer segments, and has been associated with
lipid peroxidation.
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28. Free radicals in beneficial role
• Free radicals perform many critical functions in our bodies in controlling the flow
of a blood through our arteries, to fight infection, to keep our brain alert and in
focus.
• Phagocytic cells involved in body defense produce and mobilize oxygen free
radicals to destroy the bacteria and other cells of foreign matter which they ingest.
• Similar to antioxidants, some free radicals at low levels are signaling molecules,
i.e. they are responsible for turning on and off of genes.
• Some free radicals such as nitric oxide and superoxide are produced in very high
amount by immune cells to poison viruses and bacteria.
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30. REFERENCES
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31. THANK YOU
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