Free Radicals & Antioxidants - Current status

• Introduction
• What are Free radicals & Antioxidants
• Invivo origin of free radicals
• Sources of oxidative stress in human pathophysiology
• Major targets of oxidative activity
• Antioxidants
• General principles of Antioxidant therapy
• indications for Antioxidant therapy 
• Current status of Antioxidants

Antioxidants

Antioxidants are substances whose presence in relatively low concentration significantly inhibit the rate of OXIDATION of the major targets of oxidative activity viz., cell membranes & components, proteins and other cellular constitutes.

The antioxidants that are therapeutically available are conveniently divided as;

1. Natural antioxidants (Physiological)-normally present in
        the body
2. Pharmacological antioxidants (Synthetic)

Within each group three categories of antioxidants have been recognized viz.,

• Antioxidant enzymes catalyzing the breakdown of Free radicals
• Preventative antioxidants (sequestration of metal ions)- those which prevent the participation of transition metal ions in free radical generation.
• Those which are Free radical SCAVENGERS (Chain breaking) Antioxidants.

Natural Antioxidants:

a) Enzyme Antioxidants-

• Super oxide Dismutase (SOD) – intracellular removes superoxide radical by speeding their dismutation.
• Catalase – intracellular removes H₂O₂
• Glutathione Peroxidase – Selenium containing enzyme removes H₂O₂ and other peroxides, regenerates ascorbate from dehydroascorbate and detoxification of xenobiotics.

b) Natural Preventive Antioxidants:

• Transferrin & lactoferrin
• Caeruloplasmin – Cu containing has ferroxidase activity, prevents Fe⁺⁺ from reacting with H₂O₂.
• Albumin =SH- groups contribute to chain breaking antioxidants

c) Natural Chain Breaking antioxidants:

• Ascorbic acid – potent inhibitor of lipid peroxidation (25-100 umol/L) regenerates tocopherol.
• Uric acid, bilirubin, thiols etc.
• Tocopherol (20-30 micro mol/L) – Major chain breaking antioxidant and oxides to un-reactive tocopherol radicals.
• Beta carotene – Lipid soluble – Retinol (Vitamin A) precursor synergises with tocopherol in Lipid peroxidase.
• Ubiquinol-10 – Reduced from Coenzyme Q₁₀
• Flavonoids – fruit, vegetables & wing plays a contributory role.
• Estrogens- some activity has been detected in vitro but not in vivo.

Pharmacological Antioxidants:

a) Augmenting antioxidant enzymes

• S O D – Generated by recombinant synthesis in pharmacological doses, SOD may reduce adherence neutrophils to endothelium
• Catalase – Liposome encapsulated or PEG conjugated

b) Preventive Antioxidant

• Desferoxamine – Iron chelator – useful in Thalassemia

c) Scavenging (Chain breaking antioxidants)

• Probucol – Retards atherosclerosis, regression of Lipid deposits (Xanthlasma)
• Salicylates – NSAIDs have antioxidant and radical scavenging effects.
• Lazaroids – (21 aminosteroids) – Inhibits iron dependent Lipid peroxidation.
• Mannitol, Dimethyl sulfoxide, Dimethyl thiourea – Hydroxy radical scavengers.
• Drugs : Captoril, Beta Blockers, Calcium antagonists, cinnarizine, amiodarone, NSAIDs, Methylprednisolone etc.,

d) Xanthine Oxidase Inhibitors

• Allopurinol and Oxypurinol

Neutrophil & Macrophage inhibitors (NADPH oxidase inhibitors) Ex; adenosine, NSAIDs, Ca antagonists

Antineutrophil serum – depletes circulating neutrophils

• Antiadhesion agents – Monoclonal antibodies – CD11/CD18.

General principles of Antioxidant therapy

Before contemplating antioxidant therapy, the below mentioned questions need to be answered. The most important aspect is to consider whether the patient really needs antioxidant therapy and if so the rationale behind the decision.

1. Whether the oxidative damage has been implicated in the disease pathophysiology.
2. Whether the oxidative activity is central to the pathophysiology of the disease or an epiphenomenon.
3. Whether there is a known antioxidant defect.
4. Whether the oxidative damage is occurring.
5. Whether the antioxidant reaches sufficient concentration at the site of action.
6. Whether the antioxidant will have an impact on oxidation process in vivo
7. Whether the antioxidant can be given and if so can it be tolerated at the necessary doses.
8. If prolonged therapy is needed whether it will be safe
9. Whether antioxidant can be given safely.