Mechanism of inactivation of free radicals

Free radicals produced within the body can be inactivated by the following ways

• Antioxidants: Antioxidants either block the initiation of free radical formation or inactivate free radicals and terminate radical damage. Example: Vit-A, Vit-E, Vit-C, Glutathion.
• Iron copper can catalyze the formation of reactive oxygen species. The levels of these reactive forms are minimized by binding of the ions to storage and transport proteins (Transferrin, Ferritin, Lactoferrin and ceruloplasmin) thereby minimizing OH formation.
• A series of enzymes acts as free radical scavenging systems and breakdown hydrogen peroxide and superoxide anion. Example:
• Catalase
• Superoxide dismutases
• Glutathion peroxidase 

Classification of free radicals.

Free radicals can be classified as:

• Reactive oxygen species
• Superoxide anion
• Hydrogen Peroxide (H2O2)
• Hydroxyl radical (OH)
• Hypochlorous acid (HOCl)
•  Reactive nitrogen Species:
• Nitric oxide (NO)
• Peroxynitrite anion (ONOO)

Role of free radicals in cell injury OR mechanism of cell injury by free radicals.

The effects of reactive oxygen species are wide ranging, but three reactions are particularly relevant to cell injury:

1. Lipid peroxidation of membrane: Free radicals in the presence of oxygen may cause peroxidation of lipids within plasma and organellar membrane
2. Oxidative Modification of protein: Oxidative modification enhances degradation of critical proteins by the multicatalytic proteosome complex, raising havoc throughout cell.
3. Lesions in DNA: Reactions with thymine in nuclear and mitochondrial DNA produce single stranded breaks in DNA.   

Mechanism of production of free radicals.

The following mechanisms are involved in production of free radicals.

1. Absorption of radiant energy
2. Enzymatic metabolism of exogenous chemicals or drugs
3. The reduction-oxidation reactions that occur during normal metabolic process
4. Re-perfusion injury
5. Oxygen Toxicity  

What are free radicals?

Free radicals are chemical species that have a single unpaired electron in an outer orbit.

Reduced reactive oxygen forms are produced as an unavoidable byproduct of mitochondrial respiration. Some of these forms are free radicals

Describe the effects of cellmembrane damage.

Plasma membrane damage results in loss of osmotic balance and influx of fluids and ions as well as loss of proteins, enzymes, co-enzymes and ribonucleic acids. The cells may also leak metabolites, which are vital for the reconstitution of ATP thus further depleting net intracellular high energy phosphates. Injury to lysosomal membranes results in leakage of their enzymes into the cytoplasm and activation of these enzymes. Activation of these enzyme leads to enzymatic digestion of cell components resulting in loss of ribonucleoprotein, deoxyribonucleoprotein and glycogen and the cells die by necrosis.

What are the common causes of cell injury?

The common causes of cell injury are as follows:

• Oxygen deprivation

• Hypoxia

• Physical agents
• Mechanical Trauma
• Extremes of temperature
• Sudden changes in atmospheric pressure
• Radiation
• Electric shock

• Chemical agents and drugs:
• Oxygen in high concentration
• Arsenic
• Cyanide
• Mercuric salt
• Insecticides
• Carbon-mono-oxide
• Asbestos

• Infectious agents:
• Virus, Bacteria, Fungi, Helminths, Rickettsiae

• Immunological reactions
• Genetic derangements
• Nutritional imbalance

Describe The Biochemical Mechanism Leading To Cell Membrane Damage

The following biochemical mechanism contribute to cell membrane damage:
A. Mitochondrial dysfunction- Defective mitochondrial function results in decreased phospholipid synthesis, which affects all cellular membrane. At the same time increase cytosolic Ca++ activate phospholipases and leading to breakdown of phospholipids. The net result is a depletion of phospholipids from the mitochondria and other dellular membranes and accumulation of free fatty acids. In the mitochondria this changes causes permeability defects.

B. Loss of membrane phospholipids: This is because activation of endogenous phospholipases by increased levels of cytosolic calcium, phospholipid loss can also occur secondary to decreased ATP-dependant reacylation or diminished de novo synthesis of phospholipids.

C. Cytoskeletal abnormalities: Activation of proteases by increased cytosolic Calcium may cause damage to elements of the cytoskeleton.

D. Reactive oxygen species: Partially reduced oxygen free radicals cause injury to cell membranes and to other cell constituents.

E. Lipid breakdown products: These includes unestirified free acids, acyl carnitine and lysophospholipids catabolic products that are known to accumulate in injured cells as a result of phospholipid degradation. They have detergent effect on membrane.

What is agonist, antagonist, Partial agonist?

Agonist:
A drug that binds with receptor and activate them to produce a pharmacological response is called agonist.

Antagonist:
Drugs that bind with receptor but no activating effect are termed antagonist.

Partial antagonist:
Drugs that bind with receptor and are capable of exert low degree of activity are termed partial agonist.

What are the difference between alkaloid and glycoside?

Alkaloid	Glycoside
1. Alkaloids are basic nitrogenous compound of plant origin.	1. Glycosides are condensation products of a sugar and non sugar part.
2. Soluble in alcohol not in water	2. Solubility depends on sugar part present in that particular glycoside
3. It give salt with acid	3. Does not form salt with acid
4. Name of alkaloids usually ends in –ine	4. Name of glycosides usually ends in –in.

What is plasma half life? What are the importance of plasma half life?

Plasma half life:
It is the time by which plasma concentration of a drug reduced to it's half.

Importance:

• Plasma half life gives idea about
• Duration of action of drug
• Amount of drug to be administered
• Frequency of administration
• Useful in estimating the time to steady state.
• Useful in estimating time required for drug removal from the body.
• Useful in estimation for appropriate dosing interval.

What is bioavailability? Significance of bioavailability. Factors modifying bioavailability.

Bioavailability: The rate at which and the extent to which the unchanged drugs become available for systemic action at the site of action, following administration is called bioavailabilty.

Significance of Bioavailability: 

• For comparing different formulation of same drug.
• For comparing different formulation of same drug produced by different companies.

Factors modifying bioavailability:

• Pharmaceutical factors
• Physical state of drug and particles size.
• Formulation properties.
• Manufacturing variability.
• Presystemic elimination.
• Enterohepatic circulation of drug.
• Biological factors.

What is prodrug? Advantages of prodrug.

Prodrug: Drugs which do not produce any pharmacological effect until they are chemically altered within the body are called prodrug.

Advantages of prodrug:

• Improve absorption from the site of administration.
• Avoid first pass metabolism.
• Reduce local adverse effects of drugs.
• Improve bio-availability of the drug.
• To overcome pharmaceutical formulation.  

What is partition co-efficient.

Partition co-efficient is defined as the ratio of the concentration of the agent in two phases. The movement of drug through biological membrane depends on the partition co-efficient.
e.g. Lipid water partition co-efficient.

What is ionizing constant or PKa of a drug

Ionizing constant or PKa:

The Pka of a drug is that P^H , at which the concentration of ionized and non-ionized form are equal.

Ionization of the drug depends on the Pka of the drug and p^H of the media.

What are the types of glycosides

Types of glycosides:

1. Cardiac glycosides; e.g. Digitalis
2. Aminoglycosides: e.g. Streptomycin
3. Sennoside: e.g. Selicin

Difference between Alkaloid and Glycoside

Alkaloid	Glycoside
1. Alkaloids are basic nitrogenous compound of plant origin	1. Glycosides are condensation products of a sugar and a non-sugar part.
2. Soluble in alcohol, not in water	2. Solubility depends on sugar part
3. It gives salt with acid	3. Does not form salt with acid
4. Name of alkaloids usually ends with –ine	4. Name of glycosides usually ends with -in

Define Drugs. Discuss different sources of drug with example.

Drug: Any substance or product that is used or intended to be used to modify or explore physiological system or pathological states for the benefit of the recipient is called drug. The benefit of the recipient includes:
1. The diagnosis of disease. e.g. Barium salt, Lopamodol
2. The prevention of disease. e.g. Vaccines
3. The control of disease. e.g. Insulin to control diabetes, Anti-hypertensive to control hypertension.
4. The treatment of disease. e.g. Antibiotics to treat infection.

Sources of drugs:

1. Natural
1. Animal source. e.g. Insulin, Heparin, Gonadotropin
2. Plant source. 
• Alkaloids. e.g. Atropine, Morphine, Ergotamine
• Glycosides. e.g. Digoxin, Digitoxin.
• Oil. e.g. Olive oil, Castor oil
• Tannin. e.g. Tincture of catechu
3. Minerals. e.g. Ferous Fumerate, Liquid paraffin
4. Micro-organism. e.g. Penicillin, Chloramphenicol, Tetracycline
2. Synthetic. e.g. Aspirin, Sulfonamides, Paracetamol
3. Semi synthetic. e.g. Pethidine, Ampicillin
4. Recombinant DNA technology. e.g. Human Insulin