INTRODUCTION

Anatomy means the study of the various structures in the body and Physiology means the study of the function of these structures. Thus anatomy and physiology deal with the structure and function of the human body. All organisms are made up of cells. A cell is the basic structural and functional unit of living matter. Every human being begins his/her life as a single cell (the fertilized ovum) and is capable of self-reproduction. The fertilized ovum (the first single cell) divides to form 2 cells that in turn divide to form 4 cells and so on. As the cells divide, they also become specialized to carry on a particular function. The process of transformation of an unspecialised cell into a specialised cell is called cell differentiation.

THE CELL
The human body is composed of trillions of cells. Cell means a small chamber.

Structure of cells
A cell is made up of the following:

A cell membrane (plasma membrane) that forms the boundary, enveloping the cell constituents A fluid substance called protoplasm comprises water, proteins, carbohydrates, fats, and

electrolytes Certain physical structures scattered in the protoplasm called cell organelles A central rounded body called nucleus

Plasma membrane All cells show the presence of plasma membrane that covers the cell surface. The plasma membrane is made of mainly phospholipids and proteins together with small The cell membrane regulates the passage of substances in and out of the cell.

amounts of cholesterol.

Interior of Cell CELL Nucleus Cytoplasm

An oval structure in the center of the cell

It is the liquid base of the cell, which contains cell organelles

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The cell organelles (specific structures in the cytoplasm) present within the cell perform specific functions that contribute to cell survival. The following figure shows the plasma membrane, cell organelles and the cytoplasm of the cell.

Figure 1. Cell & Cell Organelles Functions of Cell Organelles Nucleus: The nucleus is involved in storage, transmission and expression of genetic information. It contains DNA (Deoxyribonucleic acid). It also contains the nucleolus, which contains RNA (ribonucleic acid). The nucleus controls and regulates the activities of the cell. Ribosomes: These are sites where protein synthesis takes place from amino acids. Proteins are then released into the cytoplasm. Endoplasmic Reticulum: It is a folded structure seen in close contact with the nucleus. It is mainly of two types:

1. Granular: The granular appearance is due to presence of minute structures called ribosomes. It is
responsible for synthesis of proteins and for distribution to other cell organelles.

2. Agranular or smooth: The synthesis of lipid molecules takes place within agranular endoplasmic
reticulum. It also stores and releases Ca +2. Golgi Apparatus: It sorts different types of proteins received from granular endoplasmic reticulum into vesicles (packets) that are delivered to various parts of the cells.

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Lysosomes: These contain fluid, which is highly acidic, surrounded by a membrane called lysosomal membrane. They also contain variety of digestive enzymes. They are also responsible for breakdown of bacteria and debris from dead cells. They are known as suicide bags of the cell.

Mitochondria: They are concerned with chemical processes by which energy is made available to the cells (in the form of ATP or Adenosine Tri Phosphate) from nutrients. Most ATP is produced by mitochondria. They are therefore called the powerhouse of the cell.

Peroxisomes : These are tiny organelles containing enzymes (oxidases, catalase) for oxidation of hydrogen peroxide, alcohol, and other toxic substances as well as for certain biochemical oxidative reactions in the cell.

THE TISSUES
Cells can be differentiated into several types such as: Epithelial cells Connective tissue cells Nerve cells Muscle cells

These cells later associate to form tissues. The different types of tissues are: 1. Epithelial Tissues Epithelial tissues are located at surfaces that cover the body or individual organs e.g. the epithelial cells at surface of the skin. They also line the walls of various tubular and hollow structures within the body e.g. the epithelial cells lining the inner walls of the blood vessels. Epithelial cells rest on a non-cellular material called basement membrane. Their functions include protection, secretion, absorption etc 2. Connective Tissues Connective tissues, as the name suggests, connect and support the structures of the body e.g. blood, bone, adipose (fat) tissue etc. 3. Nerve Tissues Nerve tissues are specialised to initiate and conduct electric signals over long distances. They thus, control the activities of other cells e.g. Brain cells. The nerve tissue consists of:

Nerve cell or the neuron Supporting cell or the glial (neuroglia) cells

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A typical neuron is made up of (see following figure): A cell body containing plasma membrane, cytoplasm and nucleus Certain extensions (called processes) of the cytoplasm, which may be:

o o

Many short and highly branched processes dendrites receive the impulse or message A single, long, unbranched process axon carries the impulse away from the neuron; this

may have a protective covering called myelin sheath

Myelin sheath Figure 2. Structure of Neuron The junction between the axon of one neuron and the dendrites of another is called a synapse. Nerve impulses are transmitted from the axon to the next dendrite by the release of certain chemical substances called neurotransmitters from the axon terminal (see figure below).

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Figure 3. Synaptic Neurotransmission 4. Muscle Tissues Muscle tissues are specialised to generate mechanical force that help in applying force and in movement e.g. Smooth muscle layer in blood vessels contract and expand leading to decrease or increase in the size of the vessel. This muscle is involuntary (not under the control of the will) in nature. Skeletal muscle shows lines called striations. They are for voluntary control (under the control of the will). Cardiac muscle is the specialised muscle found only in the heart that appears striated (like skeletal muscle) but is involuntary in function.

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ORGAN AND ORGAN SYSTEMS

Several types of tissues make up an organ while many organs carrying out a particular function form an organ system. The activities of the organ system aim to create an environment in which all cells can survive and function.

Figure 4. Diagrammatic representation of Organ Systems A brief description of the various organ systems is given below.

1. Circulatory System
The circulatory system is made up of heart, blood vessels and blood. The primary function of the circulatory system is transportation of blood throughout the body tissues. 2. Respiratory System Respiratory system is made up of the nose, pharynx, larynx, trachea, bronchi and lungs. Primary Functions of these organs are Exchange of carbon dioxide and oxygen. Regulation of hydrogen-ion concentration.

3. Digestive System The major organs or tissues of digestive system are the mouth, pharynx, esophagus, stomach, intestines small and large intestine, and the various glands that aid in digestion - salivary glands, pancreas, liver and gallbladder.

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This system is involved in the processes of digestion and absorption of organic nutrients, salts and water. 4. Urinary System The urinary system includes the kidneys, ureters, bladder and urethra. The primary function of this system includes regulation of plasma composition through controlled excretion of salts, water and organic wastes. 5. Musculoskeletal System Major organs or tissues of musculoskeletal system are cartilage, bone, ligaments, tendons, joints and skeletal muscle. Their primary functions include support, protection and movement of the body; production of blood cells. 6. Immune System The immune system is composed of white blood cells, lymph vessels and nodes, spleen, thymus and other lymphoid tissues. This system defends the body against foreign invaders; returns extracellular fluid to blood and helps in the formation of white blood cells. 7. Nervous System The nervous system comprises: The brain and spinal cord (forming the central nervous system or CNS) Nerves (dendrites and axons) originating and ending in the CNS Special sense organs (eyes, ears. Tongue, nose and skin)

The nerves may be somatic (supplying the skeletal muscles) or autonomic (regulating the smooth muscles of internal organs and the glands). The primary functions of nervous system are: Regulation and coordination of many activities in the body Detection of changes in the internal and external environments States of consciousness Learning and cognition

8. Endocrine System

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There are many glands in our body, which secrete substances needed for the functioning of our body. These glands may be: Exocrine glands secrete the products (e.g. enzymes) into tubular (like pipes) structures called ducts; these substances produce their effects on a part close to the gland e.g. salivary gland. Gastric gland, sweat gland etc Endocrine glands secrete their products (hormones) directly in the blood as they have no ducts. Thus they are ductless glands. The endocrine system is made up of all glands secreting hormones i.e. Pancreas, testes, ovaries, hypothalamus, kidneys, pituitary, thyroid, parathyroid, adrenal, intestinal, thymus, heart and pineal. Since hormones are directly released in the blood they produce their actions at a site distant from the site of secretion. Thus it is responsible for regulation and coordination of many activities in the body. 9. Reproductive System The reproductive system is made up of the following organs. Male: Testes, penis and associated ducts and glands. Female: Ovaries, uterine (fallopian) tubes, uterus, vagina and mammary glands

The functions of these systems are: fetus Nutrition of the infant Production of sperm and transfer of sperm to the female Production of eggs and provision of nutritive environment for the developing embryo and

10. Integumentary System The integumentary system is composed of the skin. It protects against injury and dehydration; defends against foreign invaders and regulates body temperature.

ENERGY AND CELLULAR METABOLISM

Thousands of chemical reactions occur in the cell. This is called METABOLISM. Synthesis is called Anabolism e.g. glycogenesis, lipogenesis whereas breakdown is called Catabolism e.g. glycogenolysis, lipolysis. Most of the chemical reactions would proceed at a very slow rate (if carried out in a test tube). They therefore require catalysts to speed up the reaction. In the body, these catalysts are the enzymes. Energy Production

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1. Glycolysis is the process where glucose is broken down to give two pyruvate molecules and 2 ATP.
Glycolysis : Glucose Pyruvate + 2 ATP 2. The further reaction takes place in the mitochondria where pyruvate gets converted into acetyl coenzyme A and enters into the Krebs cycle. The products then enter the electron transport chain. 3. This process is called oxidative phosphorylation (OP) where 36 ATPs are totally produced. 4. Thus majority of ATP produced by OP occurs in mitochondria. Therefore, mitochondria is called the power house of the cell. 5. If oxygen is absent, only 2 ATPs are produced and the pyruvate produced by glycolysis gets converted into lactate. 6. Thus glucose is the Cheque, which is Cashed to give ATP which is used for the energy requirement of the cell. Energy can also be produced by breakdown of carbohydrates, fats and proteins that are converted into acetyl coenzyme A and undergo the above processes to produce ATP. Heart uses fatty acids as a major source of energy. Fatty acids undergo oxidation to form acetyl coenzyme A. oxidation is a cyclic process wherein each time the fatty acid molecule loses two carbon atoms in the form of acetyl coenzyme A which enters the Krebs cycle. (Fatty acid)16 Acetyl coenzyme A
oxidation

(Fatty acid)14 + Acetyl coenzyme A Krebs cycle Energy

When required, ATP is broken down to release energy as shown below. ATP + H2O ADP + Pi + Energy

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MOVEMENT OF MOLECULES ACROSS CELL MEMBRANE

Contents of the cell are separated from the surrounding extracellular fluid by plasma membrane. The membrane is selectively permeable i.e. allows only some molecules to pass through it. Plasma Membrane

Plasma membrane is made up of two layers of Phospholipids (lipid bilayer) and Proteins (see adjacent figure)

The proteins forms channels (hollow tunnels) through which ions can pass through e.g. Na+, K+, Cl-, Ca2+; hence called ion channels (see figure

Figure 5. Structure of Plasma Membrane Diffusion and Osmosis

below)

Diffusion: Movement of molecules from region of higher to lower concentration (as a result of their motion) e.g. O2, nutrients and other molecules enter and leave the blood by diffusion. Movement of many substances across plasma membrane and organelle membrane occurs by diffusion.

Osmosis: Diffusion of Water from a region of lower concentration of the solute to a region of higher concentration of the solute.

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Diffusion Of Ions Through Protein Channels

The prote ins form s channe ls throug which h ions can pas s throug h E.g . Na+ K+ CI-, , , Ca2+

Figure 6. Ion Channels Diffusion accounts for some of the transmembrane movements (but does not account for all) e.g. Molecules, which are too big or too water soluble to pass through lipid bilayer. These molecules are transported with the help of a transporter e.g. Glucose is transported through a transporter called GLUT (GLUcose Transporter). This is called carrier-mediated transport. Carrier mediated transport is of two types:

1. 2.

Passive (Channel Operated): Moves substance from High to Low concentration across a

membrane. Does not require energy. Active (Pump operated): Moves substance from Low to High concentration across a

membrane. Requires energy.

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THE CARDIOVASCULAR SYSTEM The cardiovascular system consists of Heart, Blood vessels and Blood.

Cardiovascular System

Heart Arteries carry the blood from the heart to the tissues Divide further into smaller blood vessels, Arterioles

Blood Vessels Veins carry the blood from the tissues to the heart Divide further into smaller blood vessels, Venules

Blood Capillaries

Figure 7. Composition of Cardiovascular System BLOOD Blood is a liquid connective tissue, which is the means of communication between the cells of different parts of the body. Functions of blood Blood has two general functions: -

Transportation Transports oxygen from lungs to tissues. Carries nutrients & hormones to cells. Removes waste products from cells. Regulates pH & heat of the body.

Protection Contains cells which protect against foreign invaders (bacteria, viruses, toxins) Clotting mechanism prevents loss of blood.

Every cell in the body needs oxygen for living and functioning. In the body, blood vessels carry the blood to different parts of the body.

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BLOOD VESSELS The tubes carrying blood throughout the body are called blood vessels. There are two major types of blood vessels in the body: Arteries and Veins. Arteries Arteries are the blood vessels carrying blood away from the heart. Veins Veins are blood vessels that carry blood towards the heart.

In the tissues, arteries give rise to smaller diameter blood vessels called arterioles and veins divide into venules. Arterioles and venules finally lead into extensive capillaries.

Capillaries Capillaries are the smallest blood vessels. Exchange of nutrients and gases between the cells and blood occurs across the capillary walls. Then blood enters into venules, which carry deoxygenated blood away from the tissues and merge to form larger veins. From veins, ultimately blood flows back towards the heart.

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Layers of the blood vessels The 3 layers of the blood vessles are : Tunica adventitia (externa) Outermost layer composed of elastin and collagen fibres (fibrous layer). Middle (thickest) layer consists of elastic fibers and smooth muscle cells. Innermost layer made up of a lining of epithelial cells, which is in direct contact with the blood. Tunica media Tunica intima (Endothelium)

Tunica Intima Tunica media Tunica adventitia

Figure 8. Layers of Blood vessels ENDOTHELIUM Endothelium is a single layer of epithelial cells resting on a basement membrane. Basement membrane is made up of collagen. Functions of endothelial cells

To preserve and maintain vascular health. To keep blood vessel dilated. To inhibit growth of cells in the vascular wall. To inhibit thrombosis and inflammation. To decrease platelet and leukocyte adhesion. To prevent smooth muscle cell migration and proliferation. To protect against lipid deposition.

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To perform all these functions, there should be a balance between endothelium derived relaxing factors and endothelium derived contracting factors. Endothelium Derived Relaxing Factors

Nitric oxide (NO) Prostaglandin E2 (PGE2) Prostacyclin (PGI2)

Endothelium-Derived Contracting Factors

Endothelin-1 (ET-1) Thromboxane A2 (TXA2) Angiotensin II

HEART

Heart is a hollow, cone-shaped organ. It is about the same size as the persons closed fist. Heart is situated in the middle of the thoracic cavity made up by bony framework, which is made up of
the bones, viz. sternum, ribs and thoracic vertebrae.

Heart rests on the diaphragm, in the mediastinum, which is a mass of tissues between the lungs that
extends from the sternum to the vertebral column.

About 2/3rd of the mass of the heart lies to the left of the bodys midline.
Structure of Heart

Figure 9. Structure of Heart

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Layers of Heart

Pericardium
It is the outermost layer that surrounds and protects the heart. Fibrous pericardium: It is tough, inelastic and dense. Prevents overstretching of the heart and provides protection. Serous pericardium: It is thinner, more delicate membrane that forms a double layer around the heart.

Myocardium
It is made up of cardiac muscle tissue and is responsible for pumping action. Cardiac muscle cells (fibres) are involuntary, striated and branched.

Endocardium
It is the innermost thin layer of endothelial cells. It provides a smooth lining for the interior of the heart. Endocardium is continuous throughout for all the arteries and veins of the circulatory system. Chambers of the Heart The interior of the heart is divided into four chambers: The two upper chambers are called the right atrium and left atrium. (plural: atria) The two lower chambers are called the right ventricle and left ventricle.

Atria and ventricles are separated by a wall made up of connective tissue. The right and the left side of the heart are separated by a wall called septum.
The septum between the two atria is called intra-atrial septum The septum between the two ventricles is called intra-ventricular septum

Valves of the Heart As each chamber of the heart contracts, it pushes the blood into the next chamber or out of the heart. To prevent the back flow of the blood, the heart is provided with the valves. Valves are composed of connective tissue. Atrioventricular valves (AV valves)

These are the valves present between the atria and ventricles. The valves open and close according to the changes in the pressure in the chambers. They open when the pressure in the atria is greater than in the ventricles. During ventricular systole (contraction) the pressure in the ventricles rises above that in atria. Now the valves close preventing backward flow of blood. These valves are prevented from opening upwards into the atria by cords called chordae tendineae, which extend from the inferior surface of the flaps to little projections of the myocardium called papillary muscles.

1. Right atrioventricular valve (RAV) The valve between the right atrium and right ventricle Also called as tricuspid valve because it consists of three flaps.

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2. Left atrioventricular valve (LAV) The valve between the left atrium and left ventricle Also called as bicuspid valve because it consists of two flaps. The valve that is situated at the opening between the pulmonary trunk and the right ventricle. The valve that lies at the opening of the aorta.

3. Pulmonary valve 4. Aortic valve -

Blood vessels associated with Heart

Superior venacava
It is one of the largest veins of the body. It brings the deoxygenated blood from upper parts of the body and empty it into the right atrium.

Inferior venacava
It is the second largest vein in the body. It brings deoxygenated blood from lower parts of the body and empty into the right atrium.

Pulmonary artery
This is the only artery in the body, which carries deoxygenated blood. It carries blood from right ventricle to the lungs (pulmonary) where it is oxygenated (purified). Pulmonary artery bifurcates into right pulmonary artery and left pulmonary artery.

Pulmonary veins
Two pairs of pulmonary veins, right pulmonary veins and left pulmonary veins from each lung carry oxygenated blood to the left atrium. Blood then passes into the left ventricle.

Aorta
It is the biggest artery in the body. It carries oxygenated blood from left ventricle to supply to the different parts of the body.

Coronary arteries
These are the arteries supplying blood to the heart (myocardium).

Coronary sinus
It is a vein that collects deoxygenated blood from the heart and drains it in the right atrium.

CONDUCTING SYSTEM OF HEART The heart has an intrinsic system whereby the cardiac muscle is automatically stimulated to contract without the need for a nerve supply from the brain. However, the intrinsic system can be stimulated or depressed by nerve impulses initiated in the brain. CARDIAC MUSCLES

Cardiac muscles form the bulk of the heart. 30

 They include the conducting system of the heart that causes the heart to beat.
For the continuous beating of the heart, an inherent and rhythmical electrical activity is required. Certain cardiac muscle cells repeatedly produce impulses, which produce heart contractions. There are small groups of specialized neuromuscular cells in the myocardium, which initiate and conduct impulses causing co-ordinated and synchronised contraction of the heart muscle. COMPONENTS OF THE CONDUCTING SYSTEM OF THE HEART

Sinuatrial node (SA node)

It is a small mass of specialised cells in the wall of right atrium near the opening of the superior vena cava. SA node is often described as the pace-maker of the heart.

Atrioventricular node (AV node)

It is a small mass of neuromuscular tissue situated in the wall of the atrial septum near the atrioventricular valves. AV node is stimulated by impulses that sweep over the atrial myocardium.

Atrioventricular bundle (AV bundle or bundle of His)

This consists of a mass of specialised fibres that originate from the AV node. The AV bundle divides into right and left bundle branches. Within the ventricular myocardium the branches break up into fine fibres, called Purkinje fibres. AV bundle, bundle branches and Purkinje fibres convey impulses of contraction from the AV node to the apex of the myocardium. Impulse begins then sweeps upwards and outwards, pumping blood into the pulmonary artery and the aorta.

Figure 10. Components of Conducting System

UNIQUE PROPERTIES OF CARDIAC MUSCLES

Automaticity
Impulse begins on its own in sinuatrial node (SA node) located in the right atrium. This property of heart to initiate its own impulse is called Automaticity.

Rhythmicity
The heart beats at a constant interval i.e. in rhythm. Time period between two beats is always constant.

Conductivity
Impulse once generated travels throughout atria. The cardiac impulse also spreads from the SA node down to the atrioventricular node (AV node) located in the septum between the two atria. From AV node, impulse enters the atrioventricular bundle. After conducting along the AV bundle, then it enters

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both the right and left bundle branches that course through the inter-ventricular septum towards the apex of the heart. Finally, Purkinje fibers rapidly conduct the impulse first to the apex of the ventricular myocardium and then upward to the remainder of the ventricular myocardium.

All or None response

Whenever there is an impulse either all the cells of the heart contract or not a single cell contracts. TERMINOLOGIES

Heart rate: No. of heart beats per minute (72 beats/min) Tachycardia: Increase in heart rate (> 100 beats/min) Bradycardia: Decrease in heart rate (< 60 beats/min). Inotropic: Related to the force of contraction. Chronotropic: Related to the rate of contraction.

Circulation of Blood through Heart

The blood flow through heart is unidirectional i.e. from atria to ventricles and then into the aorta. Aorta divides into different arteries. Arteries supply blood to the different parts of the body. Then, veins (superior vena cava, inferior vena cava and coronary sinus) collect the blood from different parts and empty it back into the right atrium. This blood then passes into the right ventricle. The blood now is pumped into the pulmonary artery. After leaving the heart, pulmonary artery divides into right and left pulmonary artery, which carry blood to the lungs In the lungs, blood gets oxygenated via interchange of gases. Two pulmonary veins from each lung carry oxygenated blood to the left atrium. Blood then passes into the left ventricle through left atrioventricular valve From left ventricle, blood is pumped into the aorta. Thus blood flow through the heart is in the circular motion.

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Begin Superior and inferior vena cava empty the blood in the right atrium Right AV valve Right ventricle Pulmonary valve Pulmonary arteries (Blood is purified in lungs) Through pulmonary veins in left atrium Left AV valve Left ventricle Aortic valve Aorta Figure 11. Summary of the Circulation of Blood through Heart The heart pumps blood into three closed circuits - the systemic circulation, the pulmonary circulation and the coronary circulation.

Pulmonary Circulation

Veins Venules Capillaries Arterioles Arteries

Systemic Circulation

Systemic Circulation
The left side of the heart pumps freshly oxygenated blood into the systemic circulation to all tissues of the body except the alveoli of the lungs (air sacs). In systemic capillaries, blood unloads oxygen and picks up carbon dioxide.

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 Pulmonary Circulation
At the same time, the right side of the heart pumps deoxygenetated blood into the pulmonary circulation to the alveoli of the lungs (air sacs). In pulmonary capillaries, blood picks up oxygen and unloads carbon dioxide, which is exhaled.

Coronary Circulation
Since the heart is the most important organ in the body, it also requires adequate supply of blood. Coronary circulation supplies blood to the heart. The flow of blood through coronary vessels to provide the blood to the heart [myocardium] is known as coronary circulation.

The arteries of the heart encircle it like a crown (corona means crown) so known as coronary circulation. Coronary arteries originate from the ascending arch of aorta. Coronary artery is divided into: - Right Coronary Arteries - Left Coronary Arteries

Both the arteries branch from the aorta immediately distal to the aortic valve.

Collateral Circulation
This is a process in which small (normally closed) arteries open up and connect two larger arteries or different parts of the same artery serve as alternate routes of blood supply. Everyone has collateral vessels, at least in microscopic form. These vessels are closed normally but open under conditions of ischemia resulting out of a blockade in the artery. When a collateral vessel on the heart opens, it forms a kind of alternate route around a blockage. This collateral circulation provides routes of blood flow to the heart in cases when the heart is not getting the blood supply it needs (myocardial ischemia). This collateral circulation restores blood flow to the affected part.

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BLOOD PRESSURE Blood pressure is the lateral pressure exerted by the flowing blood on the vessel walls.

Systolic BP
When the left ventricle contracts and pushes blood into the aorta, the pressure produced is called the systolic blood pressure. In adults, it is about 120 mm Hg. (systole: contraction)

Diastolic BP
When heart completely relaxes, the pressure within the arteries is called diastolic blood pressure. In adults, it is about 80 mm of Hg. (diastole: relaxation) Normal blood pressure is written as 120/80 mm of Hg. BP is measured by an instrument called sphygmomanometer.

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THE RESPIRATORY SYSTEM The cells in our body are in constant activity. They use oxygen and nutrients (glucose and fats) to derive energy for this activity. In the process, carbon dioxide is generated in the cells. The continued activity of the cells needs constant supply of oxygen and removal of carbon dioxide. The respiratory system is concerned with the function of exchange of gases. THE RESPIRATORY TRACT

Figure 12. Respiratory System The respiratory system essentially consists of :

Nose Pharynx (throat) Larynx (voice box) Trachea (windpipe) Two bronchi (one to each lungs) Bronchioles and smaller air passages Two lungs

Structurally, the respiratory tract consists of:

The upper respiratory tract made up of the nose, and the pharynx and the associated structures, adenoids and tonsils The lower respiratory tract made up of the larynx, trachea, bronchi and lungs The accessory muscles comprising the intercostal muscles (located between the ribs) and the diaphragm

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Figure 13. Upper Respiratory System THE NOSE Structure of Nose

The air enters the respiratory tract through the nostrils (anterior or external nares). They open into a cavity called the vestibule of the nose. The vestibule is lined by stratified epithelial cells and contains number of sebaceous glands and coarse hairs. This filters out the large dust particles. The vestibule opens into the nasal cavities, a large, irregularly shaped cavity. The nasal cavity is divided into light and left sides by a vertical partition called the nasal septum . The nasal cavities open into the pharynx, through two openings called the internal nares. Three turbinate (shaped like a top) bones called conchae project from the lateral (side) walls of the nose into the nasal cavity. These greatly increase the surface area of the nasal activity.

Lining of the Nose

The entire nasal cavity is lined with mucous membrane, which is highly vascular (rich in blood supply). This mucous membrane is the thickest over the nasal septum and the conchae. The mucous membrane consists of columnar and ciliated epithelium containing the mucus secreting goblet cells. The mucus secretion keeps the surface moist and sticky and helps to maintain and warm the air, and filter out dust particles.

Openings into the nasal cavity

Into the nasal cavity, open the paranasal sinuses the frontal, sphenoidal, ethmoidal and maxillary sinuses . Sinuses are hollow air-filled cavities within the skull, lined with mucus membrane. They lighten the weight of the skull and act as resonant chambers for the production of speech.

The mucous membrane of the nasal cavity is continuous with the lining of the pharynx and the sinuses. The nasolacrimal duct, which drains tears from the eyes, also opens into the nasal cavity.

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Functions of the Nose The internal structures of the nose are specialized for three functions:

To warm, moisten and filter the incoming air. To receive the olfactory (sense of smell) stimuli (the special olfactory receptors are located on the superior conchae and the adjacent septum. To serve as hollow resonating chambers thus modifying speech sounds.

The cilia of the epithelial cells move the mucus and dust particles towards the pharynx so that they can be eliminated by swallowing or spitting (expectoration). THE PHARYNX (THROAT)

It is a roughly funnel-shaped muscular tube, about 13cm long, extending from the internal nares to the cricoid cartilage of the larynx.

Structure of Pharynx

The pharynx is divided into three parts:

o The Nasopharynx lying just behind the nasal cavity. o The Oropharynx lying behind the oral cavity or mouth o The Laryngopharynx lying above the larynx

The Pharynx is made up of skeletal muscles and is lined with mucous membrane. There are five openings in the wall of the nasopharynx: o Two internal nares

o Two openings leading to the auditory (Eustachian) tubes

o

One opening to the oropharynx

A pad of lymphoid tissue called adenoids or pharyngeal tonsils is present on the posterior wall of the nasopharynx The oropharynx is the common pathway for both, the digestive and respiratory tracts, serving as a common passageway for air, food and drink. Two collections of lymphoid tissue called tonsils or palatine tonsils are located in the oropharynx. The oropharynx has only one opening that of the oral cavity, called fauces. The laryngopharynx (or hypopharynx) also is a digestive and respiratory pathway.

Functions of the Pharynx

It serves as a passage way for both, air and food. The air is warmed and moistened as it passes through the pharynx. The lymphoid tissue (adenoids and tonsils) produces antibodies and thus helps in protecting the body from microbial infections Contributes to satisfactory hearing as well as in taste perception.

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THE LARYNX (VOICE BOX)

The larynx is a short pathway connecting the laryngopharynx with the trachea.

Structure of the larynx

The larynx is composed of pieces of cartilage connected together by ligaments and membrane. The mucous membrane of the larynx consists of two pairs of folds :

o The superior (upper) folds called ventricular folds (or false vocal cords). o The inferior (lower) folds called true vocal cords or vocal folds. The vibration of the vocal
cords due to the passage of air is responsible for voice production.

The glottis consists of the vocal folds and the space between them (called the rima glottidis). During the act of swallowing, one of the laryngeal cartilage, called the epiglottis, closes off the larynx, directing the food or drink straight into the oesophagus. If dust particles, food, liquids or smoke pass into the larynx, cough reflex is triggered so as to expel the material.

Functions of the Larynx

To produce sound and help in producing speech. To serve as a passage for air between the pharynx and the trachea. To warm, filter and moisten the air. To protect the lower respiratory tract from the entry of food.

THE TRACHEA

Also called the windpipe, the trachea is a tubular passage for air. It is about 12cm long and 2 cm in diameter.

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Structure of the Trachea

The trachea is made up of 16 to 20 incomplete rings of cartilage, connected together by fibrous tissue and smooth muscle (called the trachealis muscle) at the back. The trachea is lined by a mucous membrane comprising ciliated epithelium and goblet cells. The cilia move upwards, towards the larynx; this helps to expel any inhaled particles of dust, pollen etc. The trachea in the thoracic (chest) cavity, divides into two bronchi the right and the left bronchi.

Functions of the Trachea

To maintain patent passageway for the air To warm, moisten, and filter the air To protect the lungs and smaller air passages from dust particles or pollen and other inhaled substances To initiate the cough reflex

THE BRONCHI AND SMALLER AIR PASSAGES (The Bronchial Tree) The two bronchi formed when the trache divides enter the lungs and branch and rebranch to form the bronchial tree. Each of the division makes the air passage progressively smaller. Structure of Bronchial Tree

The right bronchus enters the right lung while the left bronchus enters the left lung. The bronchi also are made up of incomplete rings of cartilages, just like the trachea and are lined by ciliated epithelium. The bronchioles do not have any cartilage but are entirely made of smooth muscles and are lined with cuboidal epithelium. The alveolar duct and alveoli (tiny air sacs) do not have a muscle layer but are only made of a single layer of epithelial cells. These are supported by a loose network of elastic connective tissue in which macrophages, fibroblasts, nerves, blood and lymph vessels are embedded. The alveoli are surrounded by a network of capillaries. The exchange of gases during respiration takes place across the membranes of the alveolus and the capillary.

Function of the bronchi and bronchioles

The bronchi and the terminal bronchioles serve to o o o o Support an unobstructed air flow Warm and moisten the air Remove any particulate matter Initiate cough reflex Exchange of gases

The functions of the respiratory bronchioles and alveoli include : o

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Protection / defense against microbes due to the presence of macrophages and neutrophils in the surroundings connective tissue as well as protection against inhaled foreign particles not trapped by the mucus.

o THE LUNGS

Warming and moistening of the air.

Figure 14. The Lungs

The lungs (lungs lightweight) are paired, cone-shaped organs lying the thoracic (chest) cavity. The area between the two lungs is called mediastinum, which is occupied by the heart, great blood vessels, trachea, the right and the left bronchi, lymph nodes, lymph vessels, oesophagus and nerves. The lung is covered with a two-layered membrane called pleura and the space between these two layers called the pleural cavity, contains a fluid that helps prevent friction between the layers during breathing. This fluid (serous fluid) is secreted by the epithelial cells of the membrane.

The lung tissue is elastic, spongy and porous.

Internal Structure of Lung

Each lung is divided by fissures into lobes the right lung has three lobes and the left lung has two lobes. Each lobe of the lung received its own branch of the bronchus (lobar bronchi or secondary bronchi). The secondary bronchi branch further to form tertiary bronchi. There are about ten tertiary bronchi in each lung. The segment of the lung tissue that each of the tertiary bronchi supplies is called the bronchopulmonary segment.

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The bronchopulmonary segment is made up of many small compartments called lobules. Each of these lobules receives a branch of the bronchiole called the terminal bronchiole. The terminal bronchioles subdivide into microscopic branches called respiratory bronchioles, which in turn subdivide to form alveolar ducts. Around the alveolar duct are alveoli (air sacs) and alveolar sacs (two or more alveoli sharing a common opening). The alveoli are surrounded by a network of capillaries and exchange of gases takes place between the alveolar and capillary membranes as has been explained earlier. Thus, the main function of the lungs is exchange of gases.

Physiology of Respiration Respiratory Rate The act of respiration (breathing) consists of:

Inspiration or inhalation of the air containing oxygen (breathing in) Expiration or exhaling the air containing carbon dioxide (breathing out).

The act of respiration occurs 12-15 times per minute; thus the normal respiratory rate if 12-15 per minute. Respiratory Muscles The process of respiration is aided by some skeletal muscles, which include

Intercostals (between the ribs) muscles The diaphragm

Variables affecting respiration

Loss of elasticity of the connective tissue in the lungs necessitates greater effort for breathing. Bronchoconstriction (constriction of bronchial smooth muscle) increases the resistance to air flow, needing more effort to inflate the lungs.

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BLOOD
Blood is the liquid connective tissue, which is one of the means of communication between the cells of different parts of the body and the external environment.

Plasma Plasma is mainly made up of water with suspended solutes like proteins (albumin, globulin, fibrinogen etc), vitamins, electrolytes, nutrients, gases, waste products etc.

Blood Cells The cells of the blood are mainly of three types: Erythrocytes (RBCs): Erythrocytes or Red Blood Cells are the oxygen carriers of blood. They amount to approximately 4.5 to 5 million / mm3 of blood. Leukocytes (WBCs): Leukocytes or White Blood Cells are the first line defense system of the body and are about 7 to 11 thousand / mm3 of blood. Thrombocytes (Platelets): Thrombocytes or Platelets are present to the extent of 1.5 to 4.5 lacs / mm3 of blood and are responsible for thrombus formation.

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FUNCTIONS OF BLOOD Blood has three general functions: -

Transportation

Transports oxygen from lungs to tissues Carries nutrients and hormones to cells Removes waste products from cells

Regulation

Regulates pH and heat of the body Protection

Contains cells which protect against foreign invaders (bacteria, viruses, toxins) Clotting mechanism to prevent loss of blood

ERYTHROCYTES (RBCs)
The main function of blood is to supply oxygen to different cells of the body. Cells cannot survive without oxygen. 99% of the total cell content of blood is made up of erythrocytes, which perform this important function. The physical characteristics of erythrocytes are as follows:

Shape: Biconcave disc Size: 7 microns in diameter Life Span: 120 days

An Erythrocyte has no nucleus or cell organelles and cannot reproduce itself. It shows an outer membrane enclosing 200-300 million molecules of hemoglobin, which are responsible for carrying oxygen. Since RBCs have no nucleus, all the space within is devoted to hemoglobin. Life span of RBCs is approximately 120 days. HEMOGLOBIN (Heme + Globin) The specialized component within the RBC responsible for carrying oxygen is called hemoglobin. Each RBC contains 200-300 million molecules of hemoglobin.

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Hemoglobin is made up of 4 hemes (iron part) and one globin (protein part). Each heme contains Fe+2 in the centre, which can reversibly bind with one molecule of oxygen. Globin is made up of 4 polypeptide chains (long chain of amino acids). Hence, one hemoglobin molecule shows 4 polypeptide chains (globin) and 4 hemes with a capacity to bind four molecules of oxygen. Hemoglobin binds to oxygen to form oxyhemoglobin in lungs and transports this oxygen to all the tissues. Hemoglobin also transports about 23% of CO2 (released as waste product by cells) to the lungs from where it is exhaled out. Thus hemoglobin, an important component of RBCs is responsible for exchange of O2 and CO2 in our body.

Normal Values of Hemoglobin

Male: 14 to 16.5 g / dL Female: 12 to 14.5 g / dL

FORMATION OF BLOOD CELLS

The process of formation of all blood cells is called haemopoiesis. It takes place in the red bone marrow present in the ends of long bones (epiphyses), flat bones (e.g. skull) and irregular bones (e.g. vertebra). The originator cell is called the Hemopoietic Stem Cell. ERYTHROPOIESIS The hemopoietic stem cell gives rise to the precursors of all blood cells. The formation of RBCs is called erythropoiesis. Out of these, the proerythroblasts give rise to erythrocytes or RBCs. The entire process requires the presence of folic acid and Vit.B12 for maturation of the RBC. Iron is also required to form hemoglobin during the maturation of RBC. The hemopoietic stem cell divides to form proerythroblast. The proerythroblast divides to form basophilic, then polychromatophilic and lastly acidophilic erythroblast. This acidophilic erythroblast now ejects its nucleus to form reticulocyte which then matures to form erythrocyte or RBC. So the final product i.e. the mature erythrocyte has no nucleus.

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47

If erythropoiesis takes place continuously, the number of RBCs will increase, causing an increase in blood viscosity and accompanying problems. On the other hand, decrease in erythropoiesis will cause tissue hypoxia (lack of oxygen). Hence, RBC production is always equal to RBC destruction. A hormone called erythropoietin produced by the kidney regulates erythropoiesis. Whenever there is tissue hypoxia due to decrease of RBCs in blood, extremely sensitive receptors in the kidney are stimulated. These receptors release the hormone erythropoietin which increases erythropoiesis to bring back the balance in oxygen supply. Once the oxygen carrying capacity of blood is restored, a negative feedback is sent and erythropoietin production is stopped. RBC DESTRUCTION At the end of their life span, the worn out RBCs are swallowed by macrophages present in spleen, liver or red bone marrow. The hemoglobin is split into heme and globin (protein). The globin is broken down into amino acids which are recycled. The heme is again split into the surrounding ring portion and the iron (Fe+2). The iron is stored in the form of ferritin and hemosiderin and reused for RBC formation when required. The outer ring portion of heme is broken down further and excreted in urine and faeces. THE WHITE BLOOD CELLS OR LEUKOCYTES

Leukocytes (leucocytes) are concerned with defending our body against invasion by foreign substances and pathogens. The largest of all the blood cells, the leukocytes account for about 1% of the blood volume.

Types of Leukocytes

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Leukocytes are of two main types:

1. Granulocytes: They contain granules in the cytoplasm. They are also called polymorphonuclear
leukocytes as their nucleus is multilobed. Depending on the stain taken up by the granules in the cytoplasm, the granulocytes can be further classified into :

Eosinophils -take up red, acid dye (eosin) Basophils - take up blue, alkaline dye (methylene blue) Neutrophils - take up both the dyes and appear purple.

2. Agranulocytes : They have no granules in the cytoplasm and have a large nucleus. They are further
classified into :

Monocytes Lymphocytes : of two types T and B lymphocytes

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The functions of the different types of leukocytes are presented in Table 1 TYPE OF WBC GRANULOCYTES 1. Neutrophils 40-75

% Total WBC

FUNCTIONS

2.

Basophils

<1

3.

Eosinophils

1-6

To protect against any foreign substances that gains entry into the body by phagocytosis. To remove the cell debris (waste materials) To stimulate interferon production Contain heparin (anticoagulant) and histamine (a substance involved in allergic reactions) in the cytoplasmic granules Involved in allergic reactions Contain lysosomes in the granules and thus protect the body against foreign substances, especially parasites Neutralise histamine and transport plasminogen (which is involved in fibrinolysis and in later stages of wound healing) The number of eosinophils increase during an allergic reaction Monocytes in the blood are involved in phagocytosis In the tissues, monocytes develop into macrophages, which are also phagocytic Monocytes and macrophages produce interleukin1(IL1) (endogenous pyrogen, which o Causes elevation of body temperature (fever) at the hypothalamus. o Stimulate production of globulin by the liver. o Enhances production of activated Tlymphocytes Production of antibodies against specific foreign substances (antigens) (B-lymphocytes). Cell-mediated immunity (T-lymphocytes) against specific antigens

AGRANULOCYTES 1. Monocytes 2-10

2.

Lymphocytes

20-50

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THE PLATELETS OR THROMBOCYTES

Platelets are the cells (cell fragments) circulating in the blood. Platelets in mammals are anuclear (no cell nucleus) and discoid (disc shaped); they measure 1.53.0 m in diameter. They contain RNA, mitochondria, and several different types of granules; lysosomes (containing acid hydrolases), dense bodies (containing ADP, ATP, serotonin, histamine, and calcium) and alpha granules (containing fibrinogen & factor V), the contents of which are released upon activation of the platelet.

Function: Platelets are involved in the cellular mechanisms of primary hemostasis leading to the formation of blood clots.

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AN OVERVIEW OF THE IMMUNE SYSTEM

Our body is constantly under attack by disease-causing microorganisms (called pathogens), smoke, dust and other environmental pollutants, ultra-violet (UV) light and many toxic chemicals. Our body has an inherent capacity to ward off or resist diseases and carry out repair and regeneration of the tissues damaged by such offending agents. This section outlines the specific defenses present in our body.

RESISTANCE AND IMMUNITY

The ability of our body to ward off diseases through the various defensive mechanisms is called resistance. The lack of resistance or vulnerability is called susceptibility. The resistance to a disease may be classified into:

1. Nonspecific resistance: These include all those mechanisms that provide a general protection
to a variety of invading/offending agents such as: The mechanical barriers offered by the intact skin and the various mucous The acidity of the stomach, that kills many pathogens ingested in the food. Antimicrobial substances produced in the body e.g. lysozyme in tear, membranes.

immunoglobulins in nasal secretion and saliva, interferon produced by a type of white blood cells (called T-lymphocytes) etc. which can inactivate/kill bacteria or viruses. Inflammatory reaction and fever Phagocytosis (ingestion of the offending agent by the neutrophil and

macrophages) These mechanisms operate right from the birth and are referred to as innate immunity

2. Resistance to a specific pathogen on foreign substance: Also known as acquired

immunity, it develops only when the body is first attacked by a specific pathogen or agent. The immunological response is specifically directed at the offending agent and is produced by a particular type of whole blood cells called lymphocytes. To understand the immune responses, refer to the section on the white blood cells (above), which are closely concerned with the defense of the body and the lymphatic system, which is responsible for the generation and differentiation of lymphocytes. THE LYMPHATIC SYSTEM The lymphatic system consists of

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Lymph : It is a fluid that flows within the lymph vessels; its composition is identical to the interstitial

fluid. Lymph vessels (lymphatics): They begin as closed-ended vessels called lymph capillaries in

spaces between the cells. These capillaries converge to form larger tubes called lymph vessels. Lymph nodes: At intervals along the lymphatic vessels, the lymph flows through lymphatic tissue

structures called lymph node. The lymphatic tissue: It is a specialized form of reticular connective tissue containing a large o o The primary lymphatic tissue is the red bone marrow (in flat bones and epiphyses of long bones) and the thymus gland. The secondary lymphatic tissue is the spleen and the lymph nodes.

number of lymphocytes.

Lymphatic nodules are clusters of lymphocytes that stand guard in all mucous membranes from

where foreign substances may invade (e.g. respiratory tract, gastrointestinal tract, urinary tract, reproductive tract etc.) The lymph ultimately drains into the veins (subclavian veins).

Functions of the Lymphatic System Draining excess interstitial fluid from the tissue spaces. Transporting dietary lipids and the fat-soluble vitamins (Vitamins A, D, E and K) absorbed from the gastrointestinal tract into the blood. Protecting the body against invasion by foreign substances and microorganisms i.e. immune responses. The lymphatic system and immune responses The ability of the body to defend itself against specific invading agents such as bacteria, toxins, viruses and foreign tissues is called immunity or acquired immunity. Substances that are recognized as foreign by the immune system and provoke immune responses are called antigens. Immunity differs from non-specific defenses in terms of two factors : o o Specificity for a particular foreign invader (antigen). Memory for a previously encountered antigen, so that a second attack by the same antigen results in a more vigorous and rapid immune response.

The lymphocytes, which are located in the lymphoid tissue and lymph nodes are responsible for the immune responses. The lymphocytes are mainly produced in the red bone marrow from haemopoietic stem cells, as shown below :-

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Haemopoietic stem cells (Red Bone Marrow)

Pre-T-Cells Processing in the Thymus Gland Acquire antigen receptors Undergo maturation Mature T-lymphocytes Migrate to lymphoid tissue throughout the body ready for use Types of Acquired Immunity There are two types of acquired immunity:

B-Lymphocytes Processing in the Bone Marrow Acquire antigen receptors Undergo maturation Mature B-lymphocytes Migrate to lymphoid tissue throughout the body, ready to use

Humoral or -cell immunity i.e. through production of antibodies to the specific antigen by lymphocytes. Cell-mediated immunity activation of T-lymphocytes to directly attack the invading agent.

Antibodies The antibodies are specific proteins gamma globulins called immunoglobulins that circulate in the blood and are secreted by the B-lymphocytes. When the B-lymphocytes recognize the antigens, they are activated to plasma cells in the lymphoid tissue and secrete specific antibodies into the blood. These antibodies bind to the specific antigen and inactivate it. The antibody-mediated responses are mainly directed against the extracellular pathogens e.g. bacteria. The antibodies or immunoglobulins (Ig) are of five types IgG, IgA, IgM, IgD & IgE T-Cells Types

When an antigen binds to the T-lymphocytes in the lymphoid tissue, many activated T-cells are released into the lymph, which then circulate throughout the body. The T-cells proliferate and differentiate into many types of T-cells as shown below:-

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T-cell Helper T-cells (CD4

Characteristics Comprise >75% of T-cells

Functions

cells or T4 or Th cells)

Cytotoxic or killer Tcells (CD8 or T8 cells)

Kill the foreign substance without itself getting destroyed

Suppressor (T5cells)

T-cells

Helps regulate immune responses

Helps in function of immune system by secreting cytokines (lymphokines) Also, activate Blymphocyes to secrete antibodies Direct attack on invading agent or even bodys own cells. Destroy cancer cells, transplant tissue, viruses etc. Prevents attack against bodys own tissue

THE IMMUNE RESPONSE The antigen-antibody reaction results in:

Neutralization of the antigens Immobilization of the bacteria Clumping and precipitation of the antigen Enhanced phagocytosis of the antigen

Activation of T-lymphocytes leads to:

Formation of helper T-cells that secrete lymphokines, resulting in damage to cell membranes and cell rupture. Secretion of interferons from helper T-cells, which protect the cells from virus infections. Activation of B-lymphocytes by helper T-cells, which increases antibody production. Differentiation of T-cells to killer T-cells that directly attack the invading agent. Thus, ultimately the body succeeds in getting rid of the invading agent.

FAULTY IMMUNE RESPONSES

When this immune response is misdirected i.e. when the immune response is against bodys own cells (e.g. type 1 diabetes), it leads to destruction of tissues. This is known as auto-immunity (immunity against own or self cells).

An important undesirable feature of immunity is development of allergy or hypersensitivity reactions. In these reactions, a person, who is excessively sensitive to certain foreign substances (e.g. dust, pollen grains, which may not cause harm in other people, reacts to the antigen severely, resulting in tissue damage.

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THE DIGESTIVE SYSTEM

The organs of digestive tract are divided into two main groups:

Gastrointestinal (GI) tract / Alimentary canal A continuous tube about 15 feet long, running through mouth anus. It includes organs like mouth, pharynx, esophagus, stomach, small intestine, large intestine, rectum and anus. to

Accessory structures These include teeth, tongue, salivary gland, liver, gall bladder and pancreas.

Figure 15. GI Tract & Accessory Structures FUNCTIONS OF DIGESTIVE SYSTEM

Ingestion :- Taking food into the mouth (eating). Secretion :- Cell within the walls of the GI tract and accessory organs secrete a total of about 9 L/day of water, acid, buffers and enzymes into the lumen of the tract. Mixing and propulsion :- Alternating contraction and relaxation of smooth muscle in the wall. Digestion :- Process of breaking down of food molecules in smaller fragments. Absorption :- Products of digestion enter the epithelial cell lining the lumen of the GI tract and pass into the lymph. Defecation :- Elimination of indigestible substances and bacteria through anus.

WALL OF THE GI TRACT The wall of the GI tract, from the stomach to the anal canal has the same basic four layers of tissues. These four layers are :

Mucosa :- It consists of o o o A layer of epithelial cells in direct contact with contents of GI tract. A layer of connective tissue A layer of smooth muscle cells The epithelial cell has function of secretion and absorption in stomach and intestine. There are two types of epithelial cells -

Exocrine cells : Secrete mucus and fluid into the lumen. Endocrine cells : Secretes hormone into the blood stream. Hormones are required to control the release of gastric fluid from exocrine cells.

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Submucosa- It is a connective layer between mucosa and muscularis. Muscularis- This layer is made up of either

o Skeletal muscle: It is found in mouth, pharynx, esophagus and anal canal. It is

responsible for voluntary contraction and relaxation of the organ (eg. Swallowing)

o Smooth muscle: The rest of the GI tract contains this kind of muscle. It is involuntary in
nature. Involuntary contraction helps breakdown food physically, mix it with digestive secretions and propel it.

Serosa- It is the outermost superficial covering of the GI tract.

STOMACH
Stomach is a J shaped organ of GI tract. It connects oesophagus to duodenum, the first part of small intestine. Stomach is divided into 3 major parts

Fundus: - Rounded and initial portion of the stomach. Body: - Inferior to fundus, large central portion. Antrum: - Also known as pyloric antrum. It connects stomach with duodenum.

Also stomach is provided with sphincters on both the ends. Sphincters regulate entry or release of the food from the stomach.

Figure 16. Stomach: Structure & Layers of Stomach wall (inset) The sphincter present on the upper end of the stomach i.e. at the junction of esophagus and stomach is known as lower esophageal sphincter (LES). It controls entry of the food from esophagus and also prevents reflux of the gastric contents back into the esophagus. The sphincter present on the lower end of the stomach i.e. at the junction of stomach and duodenum, is known as pyloric sphincter. It allows slow release of partially digested food from stomach to intestine. FUNCTIONS OF STOMACH

Secretion of gastric juice from exocrine cells of the stomach, which is required for digestion of the food. Peristaltic movement to mix saliva, food and gastric juice to form chyme. Reservoir for holding food before release into small intestine

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WALL OF THE STOMACH The stomach wall is composed of the same four basic layers as the rest of the GI tract. These are,

Mucosa, Submucosa, Muscularis & Serosa

Mucosa of the stomach has structural similarity to the rest of the GI tract. Mucosa of the stomach is made up of a layer of columnar epithelial cell. Mucosa of the stomach also contains exocrine and endocrine cells. CELLS OF STOMACH Exocrine cells of the stomach are also known as GASTRIC GLAND CELLS. They are the mucous cells, the parietal (oxyntic) cells and the chief (zymogenic) cells. The secretions of these cells are collectively called GASTRIC JUICE, which totals to about 2000-3000 mL/day.

Mucous cells:- Secrete mucus Parietal (Oxyntic) cells:- Produce gastric acid (hydrochloric acid-HCl) and intrinsic factor The Chief (Zymogenic) cells:- Secrete pepsinogen and gastric lipase.

Endocrine cells of the stomach are G cells and mast cells or enterochromaffin-like (ECL) cells.

G cells :- These are located in pyloric antrum and secrete hormone gastrin into the bloodstream. Gastrin stimulates parietal cells to secrete HCl and chief cells to secrete pepsinogen. It also contracts LES, increases motility of the stomach and relaxes pyloric sphincter.

Mast cells :- Mucosa of body and fundus part of the stomach also contains mast cells. These cells are responsible for release of histamine in blood stream. Histamine is one of the factors responsible for the release of the gastric juice.
Mucus cell

Gastric pit

Parietal cell

Chief cell

G cell

Figure 17. Cells of the Stomach Thus out of all the secretory cells of stomach only parietal cells are responsible for the secretion of acid in the stomach. FUNCTIONS OF GASTRIC JUICE

Mucus :- Forms a protective barrier that prevents digestion of stomach wall. HCl :- Kills microbes in food, converts pepsinogen into pepsin, dissolves iron from the food. Intrinsic factor :- Absorption of Vit. B12. Pepsinogen :- Converted into pepsin in presence of HCI. Pepsin breaks down proteins. Gastric Lipase :- Initiates fat digestion.

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59

THE BONE - STRUCTURE AND FUNCTION

The bone is a highly vascular, specialized type of connective tissue. It is the hardest tissue in the body. There are about 206 bones in an adult. FUNCTIONS OF BONE

Support: Provides structural framework and points of attachment for tissues/organs (e.g. muscles via tendons). Protection: Protects internal organs such as the heart and the lungs (rib cage), the brain (skull) and the spinal cord (vertebral column). Movement: Skeletal muscles attach to the bones. Contraction of the skeletal muscles pulls the bone, thus producing movement. Mineral storage: The bone acts as the reservoir of calcium and phosphorus, thus helping in maintaining calcium balance in the body. Blood cell production: Hemopoiesis (blood cell production) occurs in the red bone marrow. Storage of energy: The Yellow bone marrow which is a type of adipose tissue, stores fat.

CLASSIFICATION OF BONES Bones may be classified depending on their shape into: Long bone: long bone acts as a lever for movements. E.g. Bones of upper and lower limbs Short bone: e.g. Wrist, finger and ankle bones Flat bone: flat bones have broad, dense surface for muscle attachment or protection of underlying organs. E.g. Bones of the skull, ribs Irregular bone: these bones are used for muscle attachment and protection. E.g. Vertebrae; bones of the vertebral column protect the spinal cord.

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Figure 18. : Bones forming the skeleton

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GROSS STRUCTURE OF THE BONE A typical long bone consists of the following parts

Figure 19. Parts of a long bone

Epiphysis (epi = above, physis = growth) - The ends of the bones Diaphysis (dia = through, physis = growth) - The centre or shaft of the bone Metaphysis - The region in the mature bone where the diaphysis joins the epiphysis. Articular Cartilage - A thin layer of hyaline cartilage covering the epiphysis where the bone forms a joint with another bone. Medullary cavity The central hollow cavity containing yellow bone marrow, which is filled with fat.

BONE MEMBRANES There are three membranes of the bone:

Periosteum (peri = around, osteum = bone) - A dense white fibrous, highly vascular double layered outer covering of the bone. The outer layer of periosteum has blood vessels, lymph vessels and nerve fibres that pass into the bone. The inner layer of periosteum, the osteogenic (bone-forming) layer has connective tissue fibres, blood vessels and bone cells.

Endosteum - This is the membrane that surrounds the medullary cavity and contains the osteoprogenitor (bone forming) cells and osteoclasts (bone resorbing cells; see below).

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Haversian Membrane - This is the membrane that lines the Haversian canal.

BONE TISSUES

Figure 20.Bone tissues Bone consists of two kinds of tissues 1. Compact (cortical) Bone Tissue It forms the outer shell of all the bones. It is hard and dense tissue. It is made of dense deposits of minerals, chiefly calcium phosphate (in the form of hydroxyapatite crystals) and collagen. These are arranged in concentric circles around a central Haversian canal through which blood and lymph vessels as well as nerves pass (see below). 2. Spongy (trabecular or cancellous) Bone Tissue It is found beneath the compact bone and also at the ends (epiphyses) of the long bones. The mineral deposits in the spongy bone are arranged as a system of meshwork, like a honeycomb (hence called trabecular meshwork). Bone marrow fill the spaces between the mesh. Red bone marrow is present in the cancellous bone of the femur, humerus and the sternum and is the site for production of the various blood cells.

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TRANSVERSE SECTION OF THE BONE A transverse section of the compact bone (figure 4) shows a wonderful design mapped out in circles. In the centre of each circle is a Haversian canal. The plates of bone (cartilage) or lamellae are arranged concentrically around the central canal. In between the lamella are minute spaces called lacunae. The lacunae contain bone cells and are connected to each other and to the central Haversian canal by minute canals called canaliculi. The trabecular bone has no such characteristic Haversian system.

Figure 21. Haversian system in compact bone COMPOSITION OF THE BONE The bone consists of mineral phase, organic phase and bone cells. Mineral phase: The mineral phase consists of calcium and phosphate which bond together to form crystalline hydroxyapatite [Ca10(PO4)6(OH)2]. This makes up about 40-50% of the bone. Organic matrix: The organic matrix is composed of: Collagen (90-95%) imparts tensile strength and elasticity Proteins (osteocalcin, osteopontin, osteonectin) Ground substance (A gelatinous medium of hyaluronic acid and chondroitin sulphate, which are proteoglycans).

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Bone cells: These are of three types: 1. Osteoblasts

Osteoblasts are bone forming / bone building cells which are responsible for secretion of
the organic matrix and the collagen fibres (called osteoids). This matrix is then subsequently mineralised (by deposition of calcium phosphate). Osteoblasts are mononuclear cells (have a single nucleus), and are found in the inner periosteal layer or osteogenic layer as well as the endosteal layer.

The plasma membrane of the osteoblast has receptors for parathyroid hormone, while the
nucleus has estrogen and vitamin D receptors.

Osteoblasts also secrete an enzyme alkaline phosphatase, which is needed for

mineralization of the bone, and hence is liberated during osteoblastic activity. 2. Osteocytes These are non-functional osteoblasts, which have become trapped in the lacunae and are surrounded by calcified collagen matrix.

The space which they occupy is known as a lacuna. Osteocytes have many processes which reach out to meet osteoblasts probably for the
purposes of communication. From each osteocyte a network of cytoplasmic processes extends through cylindrical canaliculi to blood vessels and other osteocytes. Their functions include to varying degrees: formation of bone, matrix maintenance and calcium homeostasis. They possibly act as mechano-sensory receptorsregulating the bones' response to stress. 3. Osteoclasts

They are responsible for bone cleansing/resorption of bone. The osteoclasts are derived from a monocyte stem-cell lineage.

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Figure 22 Differentiation of osteoclast Osteoclasts mature and migrate to damaged bone surfaces. Upon arrival they attach to the bone surface with the help of sealing zone and secrete from the ruffled border:

o Acid that dissolves the mineral phase o Proteolytic enzymes, which dissolve the matrix
This process, called bone resorption (figure 6), allows stored calcium to be released into systemic circulation and is an important process in regulating calcium balance.

Their function is controlled by hormonal and cellular mechanisms.

Figure 23 Osteoclast scooping out the old bone, leaving a lacuna

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BONE REMODELING

The normal skeleton is constantly being renewed and repaired by a process called bone remodeling. Bone is like a heavily used highway. Because it becomes worn and cracked over time, bone must continuously undergo repair. Its purpose is the release of calcium and the repair of micro-damaged bones (from everyday stress).

Bone remodeling occurs with little change in shape, throughout a person's life It is normal for over 1 million small areas of bone (about 10% of an adult skeleton) to be undergoing remodeling at a time.

In the process of bone remodeling, osteoblasts and osteoclasts work together (referred to as bone remodeling units) under the influence of hormonal and cytokine signalling. The osteoclasts break down, or resorb, old and damaged bone, while osteoblasts form new bone. The steps involved in the process of remodeling are as follows (figures 7):

Reversal

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Figure 24. Bone Remodeling

Figure 25 The bone remodeling cycle

The process of bone formation is followed by a period of quiescence. When there is a mechanical strain on this bone after repeated use, the whole process begins again It takes approximately three weeks for osteoclasts to resorb the appropriate amount of bone. Building new bone takes three to four months.

On the basis of the differences in time for osteoclastic bone resorption and osteoblastic bone formation, there is a continuous bone deficit in the body called remodeling space. Imbalances in this normal remodeling process can lead to osteoporosis and fractures.

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HORMONES REGULATING BONE GROWTH Hormones regulate the growth and consistency of the size and shape of bones. Table 1: Chief Hormones Regulating Bone Growth Hormone Growth hormone Thyroxine, Triiodothyronine Testosterone Estrogen Calcitonin Parathyroid hormone (PTH) i) Secreted Function Important in bone growth during infancy and childhood Growth spurt in boys Growth spurt in girls Homeostasis of blood and bone calcium levels by Anterior pituitary gland Thyroid gland Testes in males Ovary in females Thyroid gland Parathyroid glands

HORMONES REGULATING BONE REMODELING The various endocrine and paracrine influences on the bone remodeling process are summarized in table 2: able 2: Hormones & Paracrine Factors Regulating Bone Turnover Activate Osteoclast Activity PTH Calcitriol Glucocorticoids Thyroid hormones Interlukin-1 Tumor Necrosis Factor Inhibit Osteoclast Activity Calcitonin Estrogen Testosterone Mechanical loading Activate Osteoblast Activity PTH Calcitriol Estrogen Testosterone Mechanical loading Inhibit Osteoblast Activity Interlukin-1 Tumor Necrosis Factor Glucocorticoids

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ENDOCRINE SYSTEM The endocrine system is a system of multiple small organs which involve the release of chemicals known as HORMONES directly into the bloodstream (ductless glands), eg. Pituitary, thyroid & others. Whereas, exocrine glands secrete their products (ENZYMES) into DUCTS (duct glands) eg, sweat glands, salivary glands. Endocrine gland function: regulation of METABOLISM, GROWTH, DEVELOPMENT & PUBERTY Glands in humans are of 2 types, namely - endocrine & exocrine DIFFERENCE BETWEEN ENDOCRINE & EXOCRINE GLANDS EXOCRINE GLANDS DUCTS ARE PRESENT SUSTANCES SECRETED INTO DUCTS SECRETIONS MOVE TO THE SURFACE THROUGH DUCTS EFFECT OVER SHORT DISTANCE SWEAT GLANDS (SWEAT SECRETED ON SKIN SURFACE), SALIVARY INTO GLANDS ORAL (ENZYMES CAVITY) . SECRETED ENDOCRINE GLANDS DUCTS ARE ABSENT CHEMICALS (HORMONES) SECRETED INTO BLOODSTREAM SECRETIONS MOVE BODY & ACT ON THROUGHOUT THEIR THE

RESPECTIVE

RECEPTORS EFFECT THROUGHOUT THE BODY PITUITARY GLAND (HORMONES ACT ON THYROID, GLAND) OVARIES, TESTIS, ADRENAL

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ENDOCRINE GLANDS

Figure.26 Endocrine Glands

Table1: Endocrine glands and Hormones & their Functions

HYPOTHALAMUS Hormone Thyrotropin-releasing hormone TRH Gonadotropin-releasing hormone GnRH Effect Release thyroid-stimulating hormone from anterior pituitary (primarily) Stimulate prolactin release from anterior pituitary. Release of FSH and LH from anterior pituitary.

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Growth hormone-releasing hormone GHRH Corticotropin-releasing hormone CRH Growth hormone-inhibiting hormone SS (Somatostatin,) or GHIH Prolactin inhibiting hormone PIH or DA (Dopamine) Prolactin releasing hormone PRH

Release GH from anterior pituitary

Release ACTH from anterior pituitary

Inhibit release of GH and TRH from anterior pituitary

Inhibit release of prolactin and TRH from anterior pituitary

Release prolactin from anterior pituitary

PITUITARY GLAND

(i) Anterior & Posterior (*) pituitary lobe

Hormone Effect Growth hormone GH Prolactin PRL Adrenocorticotropic hormone or corticotropin ACTH Lipotropin Thyroid-stimulating hormone or thyrotropin TSH Follicle-stimulating hormone FSH Luteinizing hormone LH Oxytocin* synthesis of corticosteroids (glucocorticoids and androgens) in adrenocortical cells lipolysis and steroidogenesis, stimulates growth and cell reproduction Release Insulin-like growth factor 1 from liver milk production in mammary glands

stimulates thyroid gland to secrete thyroxine (T4) and triiodothyronine (T3) In female: stimulates maturation of Graafian follicles in ovary. In male: spermatogenesis, enhances production of androgen-binding protein by testes In female: ovulation In male: stimulates production of testosterone Contraction of cervix and vagina release breast milk

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Vasopressin* or antidiuretic hormone AVP or ADH

retention of water in kidneys moderate vasoconstriction

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How the Hypothalamus controls the Anterior Pituitary gland?

According to site of effect 2 types of hormones secreted by the Pituitary gland: Direct effect on body (growth & milk secretion) Acting on other endocrine glands (thyroid, adrenal cortex & gonads) that affect the body

Growth hormone Prolactin (after childbirth)

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What is negative feedback inhibition? NEGATIVE FEEDBACK INHIBITION Hormone secretions by glands that are under the control of the hypothalamus are controlled by negative feedback. When the hormone levels are high, they inhibit the hypothalamus and anterior pituitary, resulting in a decline in their levels.

THYROID & PARATHYROID* Hormone Effect potent form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines, affect protein synthesis less active form of thyroid hormone: increase the basal metabolic rate & sensitivity to catecholamines, affect protein synthesis Calcitonin Parathyroid hormone (PTH)* Bone formation, reduce blood Ca2+ increase blood Ca2+: Activate vitamin D, bone resorption

Triiodothyronine (T3)

Tetraiodothyronine (T4)

Gatrointestinal tract organs Hormone Gastrin (Primarily) Histamine Cholecystokinin Effect Secretion of gastric acid by parietal cells stimulate gastric acid secretion Release of digestive enzymes from pancreas Release of bile from gallbladder hunger suppressant

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LIVER Hormone Insulin-like growth factor (IGF) Angiotensinogen and angiotensin Effect insulin-like effects, regulate cell growth and development vasoconstriction, release of aldosterone

PANCREAS Hormone From cells Effect Intake of glucose, glycogenesis and glycolysis in liver and muscle from blood intake of lipids and synthesis of triglycerides in adipocytes Other anabolic effects glycogenolysis and gluconeogenesis in liver increases blood glucose level Inhibit release of insulin Somatostatin d Islet cells Inhibit release of glucagon. Suppress the exocrine secretory action of pancreas.

Insulin (Primarily)

Islet cells

Glucagon Primarily)

(Also

a Islet cells

KIDNEY Hormone Renin (Primarily) Erythropoietin (EPO) From cells Juxtaglomerular cells Extraglomerular cells Effect Activates the renin-angiotensin system by producing angiotensin I of angiotensinogen Stimulate erythrocyte production

ADRENAL GLANDS Hormone Effect

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Stimulation of gluconeogenesis Glucocorticoids (chiefly Inhibition of glucose uptake in muscle and adipose tissue Mobilization of amino acids from cortisol) extrahepatic tissues Stimulation of fat breakdown in adipose tissue anti-inflammatory and immunosuppressive Mineralocorticoids (chiefly aldosterone) Increase blood volume by reabsorption of sodium in kidneys (primarily) Potassium and H+ secretion in kidney.

Androgens (including anabolic DHEA and testosterone) Fight-or-flight response: Adrenaline (epinephrine) (Primarily) Boosts the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasodilation) Noradrenaline (norepinephrine) Fight-or-flight response: Boosts the supply of oxygen and glucose to the brain and muscles (by increasing heart rate and stroke volume, vasoconstriction and increased blood pressure)

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TESTES Hormone Effect

Androgens testosterone)

(chiefly maturation of sex organs, formation of scrotum, deepening of voice, growth of beard and axillary hair.

PLACENTA (when pregnant) Hormone Progesterone (Primarily) Effect Support pregnancy Inhibit immune response, towards the fetus. Effects on mother similar to ovarian follicle estrogen, development of mammary glands

Estrogens

OVARY These originate either from the ovarian follicle or the corpus luteum. Hormone From cells Effect Support pregnancy Progesterone Corpus luteum Convert endometrium to secretory stage Make cervical mucus permeable to sperm. Inhibit immune response, e.g. towards the human embryo. Antiinflammatory Prevent endometrial cancer by regulating effects of estrogen. Estrogens estradiol) (mainly Granulosa cells, Structural: corpus luteum promote formation of female secondary sex characteristics stimulate endometrial growth maintenance of blood vessels reduce bone resorption, increase bone formation increase hepatic production of binding proteins increase circulating level of some clotting factors, increases coagulation increase platelet adhesiveness Increase HDL, triglyceride, height growth Decrease LDL, fat depositition

Protein synthesis: Coagulation:

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Fluid balance: salt (sodium) and water retention increase growth hormone increase cortisol, SHBG

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THE FEMALE REPRODUCTIVE SYSTEM

The female reproductive organs consist of the ovaries, fallopian tubes, uterus and vagina.

Figure Figure 2728. Parts of the Female Reproductive System OVARY o o The ovaries are a pair of almond shaped, pale white glands. They are present in the pelvic (lower The size of each ovary is about 2.5-3.5 cm in length. All the eggs (ova) in the woman are present within the ovaries. abdominal) cavity.

o The ovaries contain sac like structures called follicles. Each follicle contains an egg or ovum.
Do you know?

A 20-week old female fetus has approximately 7 million eggs. At the time of birth, the number decreases to 2 million. At puberty, a girl has between 3,00,000 to 5,00,000 eggs. But during the reproductive years only about 400-500 eggs mature and are released from the ovary.

FALLOPIAN TUBES

These are also called salpinges or oviducts. They are about 10cm in length. They transport the egg from the ovary to the uterus. Fertilization (union of the ovum and the sperm) usually occurs in the fallopian tubes particularly in the ampulla, which is the widest, longest part, making up about 2/3rd of the length of the tube.

UTERUS It is the site of menstruation, implantation of a fertilized ovum, and development of the fetus during pregnancy. It has the shape of an inverted pear and before pregnancy it is about the size of a fist. It is about 7cm in length.

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The uterine wall is made of 3 layers:

o The innermost layer is called the endometrium o This is surrounded by myometrium, which is the muscle layer o The outermost layer is the perimetrium
On the basis of function, the endometrium can be divided into:

o The outer functional layer o The inner basal layer

The basal layer is permanent while the functional layer increases in thickness during the menstrual cycle and is shed during menstruation. Just after menstruation the endometrium is 1-2mm thick. Just before menstruation the endometrium is about 7mm thick. The endometrium is highly vascular (rich in blood supply). The blood supply to the functional layer increases as the functional layer increases in thickness.

Cervix makes up the lower third of the uterus. It is a narrow portion containing cervical mucus. It opens into the vagina. The cervix is composed predominantly of connective tissue, mainly collagen and has only 10-15% smooth muscle. It changes little during the menstrual cycle and pregnancy until the onset of delivery when a process called cervical ripening (softening of cervix) occurs.

VAGINA It serves as a passageway for the menstrual flow and also for childbirth. It is about 10cm in length. The pH of the vagina is acidic during reproductive age of the women. This pH is due to lactobacilli, which reside in the normal vaginal flora. Glycogen stored in the inner most layer of the vaginal wall provides nutrition to the lactobacilli.

At the end of the vagina is the Vaginal Orifice. The vaginal orifice is surrounded by a membrane called the hymen. The hymen partially closes the vagina.

FEMALE SEXUAL CYCLE / MENSTRUAL CYCLE

During the reproductive years, women go through a menstrual cycle - a cyclical change occurring simultaneously at the ovaries, uterus as well as in the hormone levels, which is repeated every 28-35 days. Menstruation is the periodic or monthly discharge of blood, tissue fluid and mucus from the reproductive organs of sexually mature females. Blood flow usually lasts for 3 to 6 days each month. Day 1 of the menstrual cycle is the first day of menstruation.

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TWO MAJOR EVENTS OCCUR DURING THE MENSTRUAL CYCLE

A single ovum is released every month from the ovary. This is known as ovulation. It takes place midway through the cycle usually on day 14 in a typical 28-day cycle. The endometrium of the uterus is prepared for the implantation of a fertilized ovum or egg by increasing blood supply and storing nutrients for the fetus.

If the ovum is fertilized then there is pregnancy and development of the fetus. If fertilization does not take place, the endometrium loses all the blood and stored nutrients in the form of menstruation. In order to study the menstrual cycle we need to understand three different cycles that occur simultaneously: Hormonal cycle Ovarian cycle and Endometrial cycle.

THE HORMONAL CYCLE A hormone (Hormain means to set in motion or to move on) is a chemical substance or messenger molecule released by an organ or endocrine gland and it has an effect on other cells of the body. The female hormonal system consists of the following hormones, which can affect menstrual cycle: 1. Gonadotropin releasing hormone (GnRH): released by hypothalamus 2. Follicle stimulating hormone (FSH): released by anterior pituitary 3. Luteinizing hormone (LH): released by anterior pituitary 4. Estrogen: released by ovaries 5. Progesterone: released by ovaries The hypothalamus releases GnRH, which goes to the anterior pituitary and stimulates the release of two gonadotrophins, Luteinizing Hormone or LH and Follicle Stimulating Hormone or FSH. These hormones then go to the target organ i.e. the ovary. FSH stimulates the growth of the follicles in the ovaries. The follicles produce estrogen under the influence of FSH. The estrogen in turn enters the bloodstream and by a feedback mechanism decreases the production of GnRH and FSH. Under the influence of the low levels of FSH, one of the follicle continues to mature and secrete large amounts of estrogen When estrogen levels are very high it causes release of LH from the anterior pituitary. LH causes release of the mature egg from the mature ovarian follicle. The release of the egg from the ovary is known as ovulation.

After ovulation, the empty follicle forms a structure called the corpus luteum, which produces progesterone and also some amount of estrogen.

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The function of estrogen and progesterone is to prepare and maintain the endometrium to receive a fertilized egg. Progesterone plays a very important role in the normal functioning of the female reproductive cycle. The word progesterone is obtained from the words pro meaning supporting and gesterone meaning gestation or pregnancy. Normal levels of progesterone are also essential for becoming pregnant and also for maintaining pregnancy.

If the fertilized egg does not implant itself the progesterone level falls and menstruation starts. The whole cycle now begins once more.

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Figure 29. Hormone levels & Changes in the ovary

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THE OVARIAN CYCLE Every month one egg from the ovary is released into the uterus during the process of ovulation. This happens usually around day 14 of a 28-day cycle.

The phase before ovulation is called the preovulatory or follicular phase and the phase after ovulation is called the postovulatory or luteal phase.

Ovarian Cycle Preovulatory or Follicular phase

PREOVULATORY OR FOLLICULAR PHASE There are many ovarian follicles in various stages of maturation. In the ovary the follicles are present as primordial follicles. The primordial follicles contain the ovum surrounded by a single layer of granulosa cells. The cells contain FSH receptors and hence can be stimulated by FSH.

Postovulatory or
LUTEAL PHASE

Figure 30. Formation of Graafian follicle & Corpus luteum

Every month on stimulation by FSH about 10-12 primordial follicles start maturing to form the primary follicles. The single layer of granulose cells divides to form multiple layers. The cells of the primary follicles start producing a fluid called follicular fluid. Follicular fluid contains high levels of estrogen. The follicular fluid collects within the follicle forming a fluid filled cavity called antrum. These fluid-filled follicles are then called antral follicles. As estrogen passes into blood, the blood estrogen levels increase. Hence, by negative feedback mechanism high estrogen levels cause a decrease in GnRH and FSH levels.

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As FSH stimulation decreases, only the largest follicle that has maximum number of FSH receptors continues to develop while the remaining follicles degenerate. This single developing follicle matures to form the Graafian follicle. On the 12th or 13th day of the cycle under the influence of very high levels of estrogen the anterior pituitary secretes LH or luteinizing hormone. On the 14th day LH causes the Graafian follicle to burst releasing the ovum into the fallopian tube in the process of ovulation. Usually ovulation occurs at about the 14th day but in some women it may occur as late as the 21st day. Post-ovulatory or Luteal phase

After ovulation the remaining part of the follicle undergoes a process of luteinization or yellowing under the influence of LH. It is now known as corpus luteum (corpus=body, luteum=yellow). The yellow colour is formed due to the formation of lipids.

Corpus luteum produces large amounts of progesterone and also estrogen. Corpus luteum grows to about 1.5 cm in diameter 7-8 days after ovulation. If there is no fertilization then 12 days after ovulation the corpus luteum loses its lipid and gets converted in to a white colored body called corpus albicans. If fertilization occurs, corpus luteum is maintained for a period of 2 4 months. This will ensure adequate secretion of progesterone to maintain pregnancy till such time that the placenta develops and takes over the secretion of progesterone.

Figure 31. Ovarian Cycle

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THE ENDOMETRIAL CYCLE AND MENSTRUATION As the process of ovulation takes place in the ovary there are simultaneously changes taking place in the uterine endometrium. This endometrial cycle can be divided into:

Endometrial Cycle

Proliferative phase (before ovulation)

Proliferative phase

1) Secretory phase (after Ovulation)

During the follicular phase estrogen (produced by the antral follicles) causes rapid growth or proliferation of the endometrial cells in the functional layer and there is growth of new blood vessels. The deeper basal layer is unresponsive to ovarian hormones.

The endometrium is thus in the proliferative phase. At the time of ovulation the endometrium is 3 to 5 mm thick. The endometrial glands in the cervical region secrete thin, stringy mucus. The mucus strings form channels that help guide sperm in the proper direction from the vagina to the uterus. Secretory phase

After ovulation the endometrium is under the influence of the large quantities of progesterone and estrogen that is secreted by the corpus luteum.

Progesterone opposes the effects of estrogen and hence cellular proliferation slows down and progesterone causes swelling and secretory development of the endometrium (storage of nutrients in the cytoplasm of the cells).

Hence this is the secretory phase of the endometrium. Endometrial cells store high amounts of lipid and glycogen and become swollen. The blood supply also increases. About 1 week after ovulation the endometrium has a thickness of 5 to 6 mm. Towards the end of the secretory phase the endometrial cells become more swollen and these are the predecidual cells. The whole purpose of all these endometrial changes is to produce a highly secretory endometrium that contains large amounts of stored nutrients to provide appropriate conditions for implantation of a fertilized ovum.

MENSTRUATION After the 12th day of ovulation if fertilization has not taken place, the corpus luteum starts degenerating and the levels of progesterone and estrogen start decreasing. Menstruation is a result of reduction of estrogen and progesterone, especially progesterone. A reduction in the levels of progesterone results in increased activity of the enzyme phospholipase A2.

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This enzyme releases arachidonic acid from the cell membrane phospholipids. Arachidonic acid is converted by cyclooxygenase to prostaglandins. Prostaglandins cause vasoconstriction, reducing blood flow to endometrial tissue and decrease in supply of nutrients. This results in ischemia and necrosis in the endometrium, which causes hemorrhages. The hemorrhagic areas grow rapidly over a period of 24 to 36 hours. The mass of separated necrotic tissue and blood in the uterine cavity, plus the uterine contractions caused by prostaglandins result in shedding of the uterine contents as menstrual fluid. During menstruation thus, there is shedding of the functional layer of the endometrium. The first day of menstruation is taken as the 1st day of the menstrual cycle. In normal menstruation about 40ml of blood is lost. Within 4 to 7 days after start of menstruation the endometrium gets re-epithelialized and blood loss stops. As the low estrogens levels gives a feedback signal to the hypothalamus there is increased secretion of GnRH and another cycle starts.

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SUMMARY OF THE FEMALE SEXUAL CYCLE

Figure 32. Menstrual Cycle

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THE MALE REPRODUCTIVE SYSTEM

The male reproductive system comprises

Testes (male gonads) the main organ responsible for production of sperms (Spermatozoa or the male gametes) as well as the male sex hormone (testosterone) A system of ducts, which help in the storage, maturation and transportation of sperms from the testes - the epididymis, the vas deferens, the ejaculatory ducts Accessory glands that produce semen, a fluid needed for nourishing the sperms and help their survival in the female reproductive tract following ejaculation the seminal vesicles, the prostate glands and the bulbourethral (Cowpers) glands.

Supporting structures the scrotum, the spermatic cord, and the penis

Figure 33. The parts of the male reproductive system The sperms, along with the fluid secreted by the accessory glands (semen), are passed out of the reproductive tract following ejaculation through the urethra a common outlet for both, the male reproductive tract and the urinary tract.

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Figure 34. Urethra- the common outlet for reproductive and urinary systems THE TESTES The testes (singular testis) or testicles, a pair of oval glands, about 5 cm in length and 2.53 cm in diameter, are the reproductive glands of the male. Unlike the female reproductive system, where all the reproductive organs are mainly located in the pelvis, in the males, the testes are located in the scrotum. The scrotum: The scrotum is a sac like structure that hangs from the root of the penis and consists of loose skin (which is deeply pigmented), connective tissue, fibrous tissue and smooth muscles(fig 3). It is divided by a vertical septum into two compartments each containing one testis. The scrotum acts as a supporting structure for the testes and epididymis. The location of the scrotum outside the body cavities as well as the contraction and relaxation of the smooth muscles help to provide a temperature of testes that is about 3 C below the body temperature a must for production and survival of sperms.

Spermatic cord Testes

Figure 35: The Scrotum supporting the testes and epididymis STRUCTURE OF THE TESTES The testes are covered by an outer membrane called tunica vaginalis.

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Beneath this is a fibrous covering called tunica albuginea. The tunica albuginea extend inwards, forming septa (singular septum), dividing the testes Each testis has about 200-300 lobules and each of these lobules is made up of 1 to 3 These seminiferous tubules are made up of cells, which develop into sperms by the

into several compartments called lobules. tightly coiled tuberles called seminiferous tubules. process of sperm production (or spermatogenesis). These cells are surrounded by the sertoli cells that nourish and protect the developing sperms. Between the tubules, there are groups of interstitial cells (or Leydigs cells) that secrete the hormone testosterone.

Tunica vaginalis
Figure 36: Internal structure of testes

Figure 37: Seminiferous tubule

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The seminiferous tubules combine together at the upper pole of the testis to form a single,

highly coiled tubule called the epididymis. The spermatic cords: There are two spermatic cords, one on each side consisting of blood and lymph vessels and nerves together with vas deferens all enclosed in a sheath of connective tissue and smooth muscle. The spermatic cord serves as a supporting structure for the testes as it suspends the testes in the scrotum. Functions of the testes To produce sperms the male gametes To produce the male sex hormone testosterone, which brings about the enlargement of the male sex organs at puberty, male secondary sexual characteristics (hair growth, coarsening of voice etc.) spermatogenesis and increases the sexual drive or libido.

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THE DUCTS
The epididymis: The epididymis (plural epididymides) is a comma shaped organ, about 4cm long, located posterior to the testes. It is made up of tightly coiled duct called ductus epididymis (about 6 meter long if straightened out), consisting of epithelial cells and smooth muscles. The epididymis is the site where sperm maturation takes place. It also acts as a storage site for sperms (sperms can be stored for up to a month or more). The vas deferens: The vas deferens, also called ductus deferens or seminal duct is a pair of ducts, about 45 cm long, that convey the sperms from the epididymis to the urethra. It is lined by an epithelial layer and three layers of muscles. The function of the vas deferens is to store the sperms (viable for about a month) and to transport the sperms to the urethra by contraction for ejaculation. The ejaculatory duct: The ejaculatory duct (2 tubes, one on either side) is about 2 cm long, formed by the union of the duct from the seminal vesicle and the vas deferens. They carry the fluid secreted by the seminal vesicles and the sperms into the urethra. The urethra: The urethra in the males provides a common pathway for the flow of urine and semen (secretion of male reproductive organs + sperms). It is about 20 cm long. It consists of 3 parts: 1. The prostatic urethra that originates at the urtheral orifice of the urinary bladder and passes through the prostate gland. 2. The membraneous urethra, the shortest part, extending from the prostate gland to the bulb of the penis 3. The penile (or spongiose) urethra lies within the penis and terminates at the external urethral orifice at the tip of the penis. There are two urethral sphincters: 1. The internal urethral sphincter located at the neck of the bladder above the prostate gland This is made up of smooth muscles 2. The external sphincter surrounding the membranous part of urethra this is made up of skeletal muscles The penis: The penis contains the urethra and is a cylindrical body, consisting of a root, body and glans penis (tip). The body of the penis contains three cylindrical masses of erectile tissue and smooth muscle. It has rich blood supply. It is a supportive organ in the male reproductive system.

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THE ACCESSORY GLANDS

The accessory glands are responsible for secretion of the fluid component of the semen. Seminal vesicles: These are two small pouch-like glands lying on either side of the urinary bladder. Lined by a secretory epithelium, the seminal vesicles secrete a viscous secretion contributing to about 60% of the fluid in semen. This fluid is rich in nutrients to nourish the sperms and maintain their viability and motility. Prostate gland: The prostate gland is a single gland, about the size of a walnut. It is located in the pelvic cavity, below the urinary bladder, in front of the rectum and surrounding the prostatic urethra (fig 6).

1= Peripheral Zone, 2 = Central Zone, 3 = Transitional Zone, 4 = Anterior Fibromuscular Zone. B= Bladder, U= Urethra, SV= Seminal Vesicle Figure 38: The prostate in relation to other organs It consists of glandular tissue (which secretes the prostatic fluid) and stromal (matrix) tissue containing smooth muscles, enclosed in a fibrous capsule .The contraction of the smooth muscles results in propelling the prostatic fluid into the urethra. These tissues are arranged in four zones central, transitional, peripheral and anterior (fig 7).

1. The peripheral zone: It represents 70% of the prostatic volume. It is the zone where the majority (6070%) of prostate cancers form.

2. The central zone:It represents 25% of the prostate volume and contains the ejaculatory ducts. It is the
zone, which usually gives rise to inflammatory processes (e.g. prostatitis).

3. The transitional zone: This represents only 5% of the total prostatic volume. This is the zone where
benign prostatic hypertrophy occurs and consists of two lateral lobes together with periurethral glands. Approximately 25% of prostatic adenocarcinomas also occur it this zone.

4. The Anterior Zone: It is made up of predominantly fibromuscular with no glandular structures. 95

The prostate gland secretes the prostatic fluid, which comprises about 25% of semen volume. This is a milky, slightly alkaline fluid, which contains nutrients and other substances needed for the viability of the sperms. The bulbourethral (Cowpers) glands: A pair of pea-sized glands called bulbourethral glands lie below the prostate gland, one on either side of the membraneous urethra. These secrete a fluid, which is alkaline in nature, neutralising the acidic environment in the urethra. Also mucus secreted by these glands, lubricates the urethral lining, preventing injury to the sperms during ejaculation.

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INTERNAL STRUCTURE OF KIDNEYS Each human kidney contains about 1 million nephrons. The nephron is the functional unit of the kidney. Each nephron contains a glomerulus and a renal tubule. The glomerulus consists of a capillary network. Epithelial cells cover these capillaries and the total glomerulus is encased in Bowmans capsule.

Figure 39. Parts of Nephron

The renal tubule consists of a

Proximal tubule Loop of Henle Distal convoluted tubule Collecting tubule

The loop of Henle consists of

Descending segment - this part is highly permeable to water and moderately permeable to most solutes, including sodium. Ascending segment - About 25% of the filtered loads of sodium, chloride and potassium are reabsorbed in this part of the loop of Henle. Large amounts of other ions such as calcium, magnesium and bicarbonate are also absorbed. However it is virtually impermeable to water.

The collecting tubules of several nephrons open into a single collecting duct.

Renal blood supply: Blood flow to the two kidneys is normally about 22% of the cardiac output or 1100ml/min. Because the kidneys remove wastes from the blood and regulate its fluid and electrolyte content they are abundantly supplied with blood vessels.

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Each nephron receives one afferent arteriole, which divides into a capillary network called the glomerulus. The glomerular capillaries then reunite to form the efferent arteriole that drains blood out of the Nephron.

Afferent arteriole: It is the artery that enters the glomerular capsule and divides into extensive capillary network. Efferent arteriole: The glomerular capillaries then reunite to form the artery that comes out from the nephron, which is called as efferent arteriole.

Figure 40. Blood supply to the Nephron Nephrons Perform Three Basic Functions Glomerular filtration: Urine formation begins with glomerular filtration. Approximately 16-20% of the blood plasma entering the kidneys is filtered from the glomerular capillaries into Bowmans capsule. Normal GFR is very high - 125ml/min. The glomerular filtrate is essentially protein free and devoid of cellular elements, including RBCs. As the glomerular filtrate enters the renal tubules, it flows sequentially through the successive parts of the tubule - the proximal tubule, the loop of Henle, the distal tubule and the collecting tubule before it is excreted as urine.

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Figure 41. Basic Mechanisms of Renal Excretion Tubular secretion: Substances not required by the body are eliminated in the urine by this process. Such substances are secreted from the blood vessels into the tubular lumen. Tubular reabsorption: The body reabsorbs filtrate constituents needed by the body to maintain electrolyte and fluid balance. Along this path, some substances are selectively reabsorbed from the tubules back into the blood, whereas others are secreted from blood into the tubular lumen. Eventually the urine that is formed represents the sum of the three basic renal processes as follows: Tubular reabsorption Tubular secretion

Urinary Excretion

Glomerular filtration

Following exchange take place in various parts of the nephron Proximal Tubule Almost all the glucose, bicarbonate, amino acids and other useful substances are reabsorbed along with electrolytes e.g. sodium, potassium, calcium, magnesium etc. Descending loop of the Henle Further reabsorption of mainly water and small quantities of Na+, Cl- and K+ takes place increasing the salt concentration in tubular fluid.

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Figure 42. Exchange in various parts of Nephron Ascending loop of Henle Reabsorption of Na+, K+ and Cl- by Na+/K+/2Cl- transporters. Reabsorption of Mg+2 and Ca+2

Distal tubule

About 10% of filtered sodium chloride is reabsorbed via Na+/ Cl- transporters. Na+ and water are reabsorbed by the stimulation of aldosterone receptors.
Collecting tubule and duct

Stimulation of aldosterone receptors results in Na+ reabsorption and K+ secretion.

Antidiuretic hormone (ADH, vasopressin) receptors promote reabsorption of water.

Role of kidneys in regulating blood pressure: The renal-body fluid system for controlling arterial pressure follows a simple rule: when the body contains too much extracellular fluid, the blood volume and the arterial pressure rise. The rising pressure in turn has a direct effect to cause kidneys to excrete the excess extracellular fluid thus returning the pressure back to normal.

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THE NERVOUS SYSTEM Classification

Figure43. Classification of Nervous System

Nervous System (NS)

Central Nervous System (CNS)

Peripheral Nervous System (PNS)

Brain

Spinal Cord

Autonomic (efferent) (Nerves towards smooth, cardiac muscles)

Somatic (Afferent + Efferent) (Nerves towards & away from skeletal muscles)

Sympathetic Figure 44. Classification of Nervous System THE BRAIN The brain is made up of three parts 1. Cerebrum 2. Cerebellum 3. Brain Stem Mid Brain Pons Medulla Oblongata

Parasympathetic

1. Cerebrum is the largest part of the brain.

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Consist of an: Outer cortex contains nerve cell bodies Inner medulla that consists of the nerve fibres (axons) arising from the neurons. Function

Sensory functions i.e. perception of sight, smell, touch, PAIN, hearing, taste etc. Motor functions i.e. control of the functioning of skeletal muscles Higher functions such as learning, memory, thinking etc.

2. Cerebellum is the second largest part of the brain. Function It is responsible for maintaining the balance and equilibrium. 3. Brain Stem connects the cerebrum to the spinal cord. Consists of:

Mid Brain Nerves connect the cerebrum with the other parts of brain & spinal cord. A group of
nerve originating here travel up to the spinal cord forming the Descending Analgesia Pathway. These nerves RELEASE SEROTONIN at the spinal cord.

Pons - It connects the spinal cord with the brain and bridges other parts of brain. Medulla Oblongata Nerves extend up to the spinal cord forming the Descending Analgesia
Pathway. These axons RELEASE NOREPINEPHRINE at the spinal cord. It also contains vital centres namely cardiac center, vasomotor center, respiratory center, vomiting centre, cough centre. The Limbic System Between the brain stem and cerebrum lie a ring of structures collectively known as the limbic system (thalamus and hypothalamus). Function Connected with emotions such as anxiety and depression.

Peripheral Nervous System

Let us study the Peripheral Nervous System (PNS) in a little detail PNS consists of nerves, which connect the nervous system and various other systems to each other, so they are of two types depending on the DIRECTION in which the MESSAGE or the impulse is carried (conducted).

Sensory nerves (or Afferent) Nerves from various organs to the brain and spinal cord (SENSE THE CHANGE)

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Motor nerves (or Efferent) Nerves from brain and spinal cord to the organs (REACT TO THE CHANGE)

Mixed nerves (Afferent + Efferent) consists of sensory and motor nerve fibers. (SENSE AND REACT)

The Peripheral Nervous System has 2 parts Somatic Nervous System (SNS) somatic nervous system consists of afferent nerves that receive sensory information from external sources, and efferent nerves responsible for muscle contraction

SNS is voluntary i.e. under the control of the will.

Autonomic Nervous System (ANS) This consists of sensory and motor nerves that connect the brain stem and the spinal cord with internal visceral organs e.g. lung, liver, stomach, heart and vice versa. ANS is not under voluntary control.

Figure 45. Sensory and Motor Neurons

CELLS OF THE NERVOUS SYSTEM The nervous system is made up of billions of two types of cells Neuroglia and Neurons Neuroglia these support, protect and nourish the neurons (Neuro = Nerve, glia = glue) Characteristics Neuroglia fill half the CNS Smaller than neurons 5-50 times more numerous than neurons Unlike neurons, neuroglia can multiply and divide. In cases of traumatic injury, neuroglia multiplies to fill the spaces formerly occupied by neurons.

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Neuroglia are of 6 different types of which SCHWANN CELLS and OLIGODENDROCYTES are of great importance.

Importance of Schawnn Cell and Oligodendrocyte

Both the Schawnn Cell and the Oligodendrocyte produce a covering around the axon of a neuron. This covering is called myelin sheath. Schawnn Cell produces myelin sheath in PNS. Oligodendrocyte produces myelin sheath in the CNS. The amount of myelin increases from birth to maturity. NEURON

Figure 46. Structure of a typical Neuron Structure of a Neuron: Cell body contains nucleus, mitochondria and other organelles Cell processes (fibers)

Dendrites shorter and usually more in number, carrying impulses towards the cell body.
Axon

Long, unbranched process emerging from the cell body Also called nerve fibre and a bundle of fibres form a nerve1.
Contains axoplasm (cytoplasm) and surrounded by axolemma (plasma membrane) Axon terminates at axon terminals or synaptic knobs.

Synaptic knobs contain synaptic vesicles, which store neurotransmitter. The axon is surrounded by a myelin sheath, which insulates the axon and helps in faster
conduction of nerve impulse.

The myelin sheath is not continuous, unmyelinated part of the axon is called the Node of
Ranvier. Impulses jump from one Node of Ranvier to another.

Nerve = Nerve fibers + blood vessels + connective tissue

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1)

CLASSIFICATION OF NEURON

Functionally neurons are classified as:

Afferent Neurons or Sensory Neurons Transmit nerve impulses from receptors in the skin, sense organs, muscles, joints and viscera to the CNS.

Efferent Neurons or Motor Neurons Transmit nerve impulses from the CNS to effectors, which may be either muscle or glands.

? ?

NO TWO NEURONS ARE DIRECTLY CONNECTED TO EACH OTHER. Then how do they pass the impulse or the message? Let us study . 2) IMPULSE TRANSMISSION

No two neurons are directly connected to each other but there is a gap between them. This GAP is called SYNAPSE

The neuron lying before the synapse is called presynaptic neuron and the neuron lying after the synapse is called postsynaptic neuron. (The neuron, which is sending the impulse, is called presynaptic neuron whereas the receiving neuron is called postsynaptic neuron).

The message from one neuron to the other is carried by some chemicals. Since the chemicals carry or TRANSMIT the message between the NEUrons they are called NEUROTRANSMITTERS. Because the message is transmitted in the synapse the process is called SYNAPTIC TRANSMISSION.

The mechanism of impulse transmission is as follows: When a nerve is stimulated certain changes take place in the axonal membrane, which help in the Opening of Sodium channels along the axon - to help transmit the stimulus to axon terminal. Opening of Calcium channels at the axon terminal, causing entry of Ca into the axon terminal to release neurotransmitter stored in the vesicles. conduction of the nerve impulses to the brain. These are: -

(Note: These calcium channels are made up of five different subunits - 1, 2, , and . The

subunits 2 and are linked together forming 2 subunit.)

Figure 47. Calcium Channel Structural Subunits

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Sensory impulse (tissue injury) Activation of sensory receptors in the periphery (Nociceptors) Opening of Na+ channels Conduction of impulse along axon Impulse arrives at axon terminal Opening of Ca+2 channels Release of neurotransmitter (messengers) Binding of neurotransmitter to postsynaptic receptor Impulse transmission or inhibition

Figure 48. Neurotransmission The released neurotransmitter may bind to the receptor on the postsynaptic neuron leading to either further impulse transmission or inhibition.

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Figure 49. Impulse Transmission Events at the axon terminal and synapse TYPES OF NEUROTRANSMITTERS (CHEMICAL MESSENGERS) The neurotransmitters can be classified depending on the effects they produce. Excitatory Glutamate, substance P, Aspartate Inhibitory GABA, Glycine Both Norepinephrine, Serotonin, Acetylcholine Table 1: Role of neurotransmitters important for understanding our products (ii) Neurotransmitter Glutamate Spinal Cord transmission impulse Serotonin to of the pain brain Cerebral Cortex neuronal activity leading to spread of epileptic seizure Feeling of well being - anxiety and depression Limbic System anxiety

(Ascending Pain Pathway) transmission of pain impulse to the brain (Descending Analgesia Pathway)

Norepinephrine

transmission of pain impulse to the brain (Descending Analgesia Pathway)

Depression

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? ?

(iii) Fate of neurotransmitters what happens to the neurotransmitters after they transmit the message to the post-synaptic receptors? After transmitting the message, the neurotransmitters are INACTIVATED by following mechanisms:

REUPTAKE by presynaptic neuron (back to the place from where they had been released) ENZYMATIC DEGRADATION (destruction) neurotransmitters are mainly destroyed by enzymes. Example: MonoAmine Oxidase (MAO) and Catechol-O-MethylTransferase (COMT) inactivate norepinephrine and serotonin.

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INTRODUCTION
Pharmacology is the science of study of drugs, with reference to history, source, physical and chemical properties, biochemical and physiological effects, mechanism of action, absorption, distribution, metabolism and excretion & therapeutic uses of the drugs. Pharmacology is divided into: -

1. Pharmacokinetics: What body does to the drug, or the effect of the body of the drug- ADME
(Absorption, Distribution, Metabolism and Excretion)

2. Pharmacodynamics: What drug does to the body or the effect of the drug on the body. This
determines the therapeutic effect of the drug.

PHARMACOPOEIA
It is a book containing the list of products used in medicine, with descriptions, chemical tests for determining purity and identity; and formulas for certain mixtures of these substances. USP: United States Pharmacopoeia BP: British Pharmacopoeia IP: Indian Pharmacopoeia NF: National Formulary AHFS: American Hospital Formulary Services

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ROUTES OF DRUG ADMINISTRATION

The route of administration of the drug is determined by the properties of the drug (water or lipid solubility, ionization, etc.) or by need of therapy (rapid onset of action or local action). The three major routes of administration are:

1. Local Applications: Local application of the drug can be in the form of a dusting powder, paste, lotion,
drops, ointment, suppository (vaginal, rectal) and is used for its action at the site of application. Vaginal applications: In vaginal route of administration, the medicated preparations in a wax or gelatin base (vaginal suppositories) are inserted into the vagina e.g. Clingen suppositories. Some drugs, however, are given by the vaginal route for absorption in the blood to producean action e.g. Profine. The absorption at the vaginal site for such drurs is faster and / or better than the oral absorption.

2. Oral or Enteral Route: All routes of administration that pertain to the GI tract are called enteral routes.
This involves administration of the drug via the mouth from where it enters into the GI tract and is then absorbed and enters into the blood circulation. They may be oral solids or liquids. (iv) The oral solids can be of different forms as given below:

a)

Conventional Tablets: Uncoated tablets are without any coating. Sugar/Film coating of tablet is done to mask the taste e.g. Ciprofloxacin. Caplet is a small tablet that is in the shape of a capsule e.g. Doxy-1 Enteric coating of drugs is done to prevent degradation in the stomach. The

degradation occurs in the intestine, hence name enteric coating. (enteron means intestine) e.g. Delisprin tablets

b)

Special Tablets: Soflet is tablet with soft gelatin coating e.g. Ostebon M. Sustained release / Timed release / Controlled release tablets ensure slow release

of the drug into the circulation thereby prolonging its duration of action e.g. Aspitrate G, Bigomet SR Dispersible tablets and granules are given after dissolving into an appropriate solvent (usually water) and are especially useful in children and the elderly e.g. Electral.

c)

Capsules: Hard gelatin capsules have a hard gelatin covering, which can be used for packing Soft gelatin capsules have a soft covering of gelatin e.g. Folinext D, Megasoft Forte,

heat labile substances. e.g. Imax Plus, Imax Forte. Alfa Ostebon. In both cases the gelatin covering protects the inner contents from degradation and contamination.

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Applicaps are small tubules containing the drug for direct application in the eye e.g.

Chlormycetin Applicaps. The oral liquids are also of different forms like Suspensions, Dry Syrup, Syrup, Solutions and Emulsions.

3. Parenteral Route: Routes of administration of drugs to produce a systemic effect (via the blood) other
than the GI tract are called parenteral routes.

a) Inhalation: Here the drug is given directly through the nasal route with the help of an inhaler e.g.
Salbutamol for asthma.

b) Injection: Injections are given in case of drugs which cannot be given orally due to extensive
metabolism in the liver e.g. Nitroglycerine or in the case of hospitalized patients or where it is necessary that drugs reach the site of action rapidly e.g. Profine injection, Meganeuron injection, Fibrokinase. There are different administrative routes of injectables: Intradermal: This is given under the layers of the skin e.g. BCG vaccine. Subcutaneous: The drug is injected below the skin. This route is only used for drugs Intramuscular: The drug is injected into the muscle layer e.g. aqueous solutions. Intravenous (IV): Drugs are given directly into the vein to produce rapid action and

that do not irritate the skin e.g. Insulin.

100% drug concentration in the blood can be obtained e.g. Ofler IV. Intrathecal: It involves introduction of drugs such as spinal anesthetics into the spinal Intraperitonial: Injection is given into the peritoneal cavity. This route is used in infants cord. These drugs act directly on the central nervous system. for giving fluids like glucose saline, as the peritoneum offers a large surface from which they are readily absorbed. Intramedullary: Introduction of the drug into the bone marrow. Intraarticular: Certain drugs are administered directly into the joint for the local action

e.g. Hydrocortisone acetate for treatment of rheumatoid arthritis. The different packs for of injectables are:

Ampoules (single-use packs): e.g. Meganeuron and Profine injection Vials (multiple use packs) Pre-filled syringes

Light sensitive drugs are stored in amber coloured containers.

c) Sublingual Administration: A tablet containing the medication is placed under 111

the tongue and is allowed to dissolve in the mouth. The drug thus gets absorbed directly into the systemic circulation via the buccal mucous membrane e.g. Sublingual nitroglycerin (onset of action 30 secs).

PACKAGING OF ORAL SOLIDS

The different types of packs available are:

1. 2.

Blister Pack: The tablet is visible within a blister on one side or both sides are opaque Strip Pack: (a) Aluminium foil: Both sides of the pack are covered by aluminium foil (b) Alu-Alu packing: The strip has blisters but both sides are covered by aluminium foil.

3.

Bottle Pack: Drugs susceptible to sunlight are kept in amber bottles. PACKAGING OF LIQUID DOSAGE FORMS

Syrups:

Bottle Packing: e.g. Imax syrup

Light sensitive drugs are stored in amber coloured containers.

PHARMACOKINETICS Absorption of the drug

Absorption is the transfer of a drug from its site of administration to the bloodstream. Depending upon its chemical properties, the drugs may be absorbed from the GI tract by passive absorption or active absorption.

1. Passive Absorption: The drug moves along the concentration gradient i.e. from a region of higher
concentration to that of lower concentration. This process does not require energy.

2. Active Absorption: This mode of drug entry involves specific carrier proteins that extend across the
membrane. It requires energy. The movement of the drug, in this case, can be against the concentration gradient i.e. from a region of lower concentration to a region of higher concentration. FACTORS AFFECTING ABSORPTION

1. Physical state of the drug: Liquids are better absorbed than solids. 2. Lipid and water solubility: At the cell surface, the lipid soluble drugs penetrate more rapidly than
water-soluble drugs.

3. Particle size: The smaller the particle size, the better the absorption. 112

4. Disintegration time: It measures the rate at which the tablet or capsule breaks up into granules of the
drug.

5. Dissolution rate: The rate at which the drug gets dissolved in the gastrointestinal fluids. This is a good
in vitro parameter to measure the bioavailability of the drug.

6. pH: Unionized form of drug gets absorbed more quickly than ionized form. Hence, acidic drugs are
rapidly absorbed from the stomach as due to acidic pH they do not get ionised e.g. Barbiturates. The reason aspirin causes gastric irritation is because it gets ionized to form acetyl and salicylate ions that get trapped in the gastric mucosa and cause irritation. Hence, it is enteric-coated to prevent this side effect. Basic drugs are not absorbed until they reach the alkaline environment of the small intestine. The alkaline environment keeps the drug in an unionized form, facilitating its absorption.

7. Surface area for absorption: The surface area for absorption is much greater in the intestine than in
the stomach.

8. Blood flow: The more the blood flow to the absorption site, the greater is the absorption of the drug.

Bioavailability of the drug

Bioavailability is the amount of drug that reaches the systemic circulation to produce action. It is measured by AUC (Area under curve)

Cmax
Tmax

Figure 50. determination of bioavailability of a drug Bioavailability is 100% for intravenously administered drugs and is generally less than 100% for orally administered drug, since the drug has to pass through the biological membranes. Hepatic First Pass Metabolism

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Many drugs undergo significant first pass metabolism that reduces their bioavailability. Drugs from the GI tract reach the liver via the portal circulation. Here the drugs are metabolized. The drug then enters into the systemic circulation. Drugs may be metabolised to a great degree when they pass through the liver for the fist time and hence the process is called First Pass Metabolism.

H E P A T IC F IR S T P A S S M E T A B O L IS M

Figure

51.

Difference according to

in route

drug of

metabolism

administration (Oral vs. IV)

First pass following results: The prodrug can be converted into the active drug. e.g. Simvastatin.

metabolism can give the

The drug can be rendered ineffective e.g. 90% of nitroglycerin gets metabolized in the liver; hence it is given as IV or sublingually.

Distribution of the drug

Distribution is the process by which the drug reversibly leaves the blood stream and enters the extracellular fluid and/or the tissues. It is affected by Blood Flow: Higher the blood flow, more the distribution. Capillary permeability: The greater the permeability, the higher the distribution. In the brain, however, the junctions in the capillary are very tight resulting in a barrier called the blood-brain barrier. This anatomical barrier prevents entry of most of the drugs that are polar or ionized into the brain. Lipidsoluble drugs readily enter into the CNS as they dissolve in the membrane of the endothelial cells.

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Figure 52. Permeability of blood vessels in the liver & brain PROTEIN BINDING Drugs bind to the plasma proteins like albumin and globulin. Reversible binding of drugs to these proteins holds the drug in the form of a depot. The drug is released slowly depending upon the amount of drug getting metabolized and excreted. Thus, the proteins act as a reservoir for the drugs maintaining a constant amount of free drug in the circulation e.g. Glimepiride, Pioglitazone. Higher protein binding of the drug prolongs its duration of action as it stays in circulation for longer time.

Metabolism of the drug

Drugs are often eliminated by biotransformation and/or excretion into urine (kidney) or bile (faeces). The liver is the major site for drug metabolism, but some specific drugs may undergo biotransformation in other tissues. In the liver, the drugs are either converted to prodrug to active drug or into its active/inactive metabolites e.g. pioglitazone is converted into its active metabolites in the liver.

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Metabolism of the drug is to render it as water-soluble as possible so that it can be efficiently excreted by the kidney. With this aim, the lipophilic drugs are converted into water-soluble ones. This is normally done by the cytochrome P450 system of enzymes. If water solubility is not achieved completely, the drugs are further conjugated with substances available in the body itself such as glucuronic acid, sulfuric acid, acetic acid or an amino acid to increase its water solubility. The kidney then excretes the highly polar compounds formed.

EXCRETION OF THE DRUG

Removal of drug from body may occur via a number of routes, the most important being through the kidney into the urine. Other routes include bile, intestine, skin, lungs or milk in nursing mothers. Renal Excretion: Glomerular Filtration Rate: Normal GFR - 125 ml/min Proximal tubular secretion. Distal tubular reabsorption.

Figure 53. Drug elimination by kidney

Terms used in pharmacokinetics

Cmax- Peak plasma concentration of the drug Tmax- The time at which the Cmax is achieved T1/2- Time during which the drug concentration is reduced to 50% of its maximum concentration. Protein binding- Percentage of drug bound to plasma proteins like albumin. AUC: Area under concentration time curve- determines the bioavailability

PHARMACODYNAMICS
It is the study of drug effects on the living body. Most of the drugs used clinically produce their effects by interacting with cell receptors. Receptor: Macromolecule (e.g.protein) with which a drug binds to produce its effects; it is usually specific for a drug. It is the part on the cell which receives the drug. The receptor may be:

1. Extracellular: Present on the cell membrane insulin receptors. 116

2. Intracellular: Present within the cell e.g. nuclear PPAR receptors that are present on the
nucleus. Agonist: Has affinity (ability to bind to the receptor) and intrinsic activity (capable of producing a response). If the receptor is the lock, the agonist is the key that opens the lock e.g. adrenaline, noradrenaline, acetylcholine, PPAR agonist is pioglitazone. Antagonist: Has affinity but no intrinsic activity (incapable of producing a response). It has a blocking action on the particular receptor i.e. if the antagonist binds to the receptor, the agonist cannot bind or produce its effects on the receptor. The key enters the keyhole but is not able to open the lock e.g. Atenolol (beta blocker) PARAMETER Selectivity Affinity Intrinsic activity Example AGONIST Adrenaline ANTAGONIST Atenolol

Parameters to judge therapeutic efficacy & safety

Bioequivalence: Two related drugs are bioequivalent if they show comparable bioavailability and similar times to achieve peak blood concentrations e.g. Amlosafe, Amlogard and Stamlo (all are containing Amlodipine) are bioequivalent. So the molecule is the same, only brand names are different. Therapeutic Equivalence: Two similar drugs are therapeutically equivalent if they have comparative safety and efficacy e.g. Lovastatin 10mg is therapeutically equivalent to Simvastatin 5mg, Glimepiride 2mg is therapeutically equivalent to Glibenclamide 5mg. So the comparison among the same class of drugs. The median lethal dose or LD50: This is the dose (mg/kg), which would be expected to kill half of the population being tested. The LD50 is different for different species. The median effective dose or ED50: This is the dose (mg/kg), which produces a desired response in 50% of the population. Therapeutic Index: It is the ratio of LD50/ ED50. Higher the therapeutic index, safer the drug

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Therapeutic window: The concentration of the drug at which it is therapeutically effective without being lethal. It is the difference between Minimum Toxic Concentration (MTC) and Minimum Effective Concentration (MEC).

MTC

MEC

Figure 54. Window of Steady state: entering the amount of drug leaving the circulation is same. Shelf Life: Time in which the active conc. of the drug drops to 90% of the original value (at the time of manufacturing) i.e. Delisprin 75 mg will reduce to 67.5mg. Shelf life helps to determine the expiry date. Figure 55. Predicted plasma concentration of drug given by repeated oral administration

Therapeutic Formulation A Amount of drug circulation and

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COMMON TERMINOLOGIES IN THERAPEUTICS

Side effect: It is a mild extension of the therapeutic action of the drug e.g. At therapeutic doses bradycardia with atenolol and hypoglycemia with sulphonylureas. Adverse effect: It is the unpleasant or harmful effect of the drug that requires termination of drug administration. e.g. Neutropenia with Ticlopidine Toxic effect: It occurs when the drug concentration rises much higher than therapeutic range that can be fatal. It can be due to reduced excretion, higher drug intake or overdose. Acute: For a Short time Chronic: For a long time Contraindications: Drug should not be prescribed under any circumstances. Precautions: If the drug is given, caution should be exercised. Hypersensitivity: A state of altered reactivity where the body reacts with an exaggerated immune response to a foreign substance. Anaphylaxis: A type of hypersensitivity where a sensitized individual exposed to an antigen shows urticaria, pruritis, followed by vascular collapse and shock. Tachyphylaxis: Rapid decrease in response to a drug after administration of a few doses. In Vitro: Vitreous means glass; within a test tube or in an artificial environment. In Vivo: Within the living body. Teratogenic: Drug that adversely affects the developing child (foetus) in the womb of the mother. Carcinogenic: Capable of producing cancers. Mutagenic: Capable of causing genetic change. Blood Brain Barrier: An anatomical barrier in the CNS that allows the entry of highly lipid soluble drugs. E.g. Diazepam, Propanolol. Blood Retinal Barrier: An anatomical barrier in the eye between the retina and the blood vessels supplying the retina Placental Barrier: An anatomical barrier which allows only certain substances to pass through the placenta Loading Dose: The drug is given in a large quantity to achieve a fast steady state concentration Bolus: A single large intravenous dose e.g. Solokinase Additive: The final therapeutic response of two concomitantly administered drugs is the addition of therapeutic response of individual drugs e.g. Amlodipine+atenolol (Amlosafe AT) Synergistic: The final therapeutic response of two concomitantly administered drugs is more than the addition of therapeutic response of individual drugs e.g. Sulphamethoxazole and trimethoprim, Megasoft E.

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TYPES OF DOSAGE REGIMEN

o.d. b.i.d. t.i.d q.i.d. SOS Preprandial Postprandial Once a day Twice a day Thrice a day Four times a day At bed time As and when needed Before meals After meals - Amlosafe, Meganeuron OD Ofler Halocef Ampicillin Simchol Paracetamol Glybovin Bigomet

h.s. (hora somnis)-

CLINICAL TRIALS
A clinical trial is a controlled study to evaluate a new drug, new drug combination, or a new treatment for a particular disease. The results from clinical trials are used to decide if a new treatment is effective to be marketed to all patients with a particular disease. Clinical trials are performed with the following objective: Is the drug in question effective? Is the drug effective in acute or chronic use? Is the drug safe on acute or long-term use? What are the adverse reactions? Is the drug safe in special population like - geriatrics and/or in pregnancy?

COMPARISON OF DRUGS
Placebo: Inert dosage form, having all the physical characteristics similar to formulation containing active drug. It is also called as Dummy. It is used to compare efficacy, safety and tolerability. Cohort: A subgroup or group of volunteers. Control: The group of volunteers who are given placebo is the control Open study: When both the volunteer and investigator know which tablet is placebo and which contains active drug. Blind: To prevent against any bias Single blind: When the investigator knows which tablet is placebo and which contains active drug but the volunteer is unaware of the fact Double blind: When neither the investigator nor the volunteer knows which tablet is placebo and which contains active drug

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Parallel design: When a group of volunteers are given drug or simultaneously

placebo or two different drugs

Cross over: After group I is given drug A and group II is given drug B the groups are crossed over and now group I is given drug B and group II is given drug A Multicentric: When the trial is conducted at many centers Meta analysis: The data of multicentric trials are pooled and analysed Significant: The difference in response is not by chance but due to the actual efficacy of the drug. It is denoted by p<0.05, 0.001 Prospective: When a trial is done to find out the major benefit or outcome e.g. Prospective analysis of benefit of lisinopril in MI GISSI-3 Retrospective: When, after the trial is completed, results are tracked for some parameter e.g. What was the benefit of lisinopril in diabetics who suffered from MI

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