At the end of this chapter and any recommended reading the student should be able to:
1. understand the basic structure and function of cells and how they are vulnerable to toxic substances;
2. understand the structure and function of the systems of the human body;
3. understand how body systems are vulnerable to toxic substances;
4. use the knowledge gained to better understand the content of other chapters of this book, and
5. apply acquired knowledge in the analysis and management of hazardous situations.
This appendix is designed to provide basic knowledge about the structure and function of the human body for those who have received no formal education in medicine, biological sciences, or human biology. Readers will find this section useful for understanding the terminology used in the main body of the book, as will lecturers on the Essentials in Toxicology for Health Protection course. The appendix is also designed to stimulate interested health professionals to learn more of the disease states and disorders of organs and systems in the body that follow exposure to toxic chemicals.
The human body can be divided into a number of systems on the basis of both structure (anatomy) and function (physiology). Each of these systems can be affected by exposure to toxic agents and some play an essential role in combating toxic effects.
The information presented will describe the essentials of normal function of body systems and so provide reference points for the toxic effects described in other chapters.
A2 Cells: the fundamental building blocks of body systems
Humans have evolved from life forms that were originally just single cells in the primordial ocean. The function of the whole body depends on providing each of its 30 trillion cells with a suitable chemical environment, water, and oxygen. The cells of the body require a constant environment which is independent of changes in the outside world. This is ensured by the chemical composition of the extracellular fluid in the body, which bathes each of the cells.
For the amount of a substance in the body to remain constant, the amount gained each day must not exceed the amount required by the cells to function and that is excreted or lost from the body each day.
If intake exceeds the amounts required by cells daily to function normally and that of loss, there will be an imbalance. The amount of this imbalance will determine whether the cells will function abnormally (dysfunction or malfunction).
It will also determine whether cells would multiply abnormally (producing growths—tumours or malignancies) or die. This is the basis of toxicology, where the amount taken by the body is in excess of its needs and/or exceeds the amount that can be lost from the body by normal mechanisms, resulting in malfunction, disease, or death.
The amounts of foreign substances that enter the body depend on ingestion and absorption from the gut, the amounts inhaled (taken in during breathing), and the amounts absorbed through the skin. Foreign substances may cause toxic effects by entering the cells directly or from the fluid that surrounds them.
Toxic substances can also enter by other means, such as when venomous animals bite or sting.
The essential points about the structure and function of body cells are shown in Box A1.
A2.1 Specialized cells
Cells in the body have developed from primary stems cells to perform specific functions (e.g. muscle cells for movement, nerve cells for transmission of impulses or messages, liver cells for metabolism). This process is called cell differentiation. Approximately 200 distinct types of such cells can be identified in the human body. In the body cells migrate to different locations, adhere to each other, and form multicellular structures or tissues (e.g. muscle tissue, nerve tissue, epithelial tissue, and connective tissue). Different types of tissues come together in varying proportions and arrange in differing forms, such as layers or bundles, to form organs, such as the heart and kidney. Most organs possess similar functional sub-units, each contributing to the functions of an organ. Organs with similar functions are often grouped together as systems. There are 10 organ systems in the human body classified on the basis of both structure (anatomy) and function (physiology). Each of these systems can be affected by environmental toxic agents whilst some play an essential role in protecting the human body or minimizing harm following toxic environmental exposures.
A2.2 Body systems
Specialized cells give rise to the systems that make up the body, which are:
1. the nervous system, comprising the central nervous system and peripheral nervous system, including the autonomic nervous system (sympathetic and parasympathetic nervous systems), neurotransmitters, and the neuromuscular junction
3. the heart and circulation (the cardiovascular system), including blood and blood components, blood pressure, and the blood vessels
5. the liver, including normal functions and the important feature of the metabolism of foreign substances (xenobiotics)
6. the kidney and reproductive system
7. the endocrine system, i.e. the production and role of hormones in the body
8. the immune system and body defence mechanisms.
In addition to these systems the body comprises cartilage, bone, ligaments, tendons, and skeletal muscles, which support and protect and allow movement of body.
Finally, all these systems are enclosed inside the skin, which can be regarded as an organ in itself. It is constantly being renewed and provides protection against injury and dehydration, defence against entrance of foreign substances, and regulation of body temperature.
A3 The nervous system
The main functions of the nervous system are to monitor, integrate (process), and respond to information from inside and outside the body. The nervous system controls or regulates many body functions essential to life such as breathing (respiratory centre), circulation (vasomotor centre), hormonal secretions, temperature, and indirectly the activity of the lungs, blood vessels, heart, kidneys, and several other organs. Fundamentally, the role of the nervous system is to maintain normal body function by making the necessary adjustments or responses to changes that may eventually cause harm or ill-health.
The nervous system controls body functions and receives information from the outside world by means of transmission of electrical impulses passing along nerve cells (neurons). In various parts of the system these signals are passed from cell to cell by special relay stations called synapses, where the signal is passed by a chemical messenger. These chemical messengers are called neurotransmitters. Special synapses are found at the end of nerves which pass a signal directly onto an organ, also through a neurotransmitter. Synapses can be regarded as being amplifiers of the electrical signals transmitted through the nervous system.
Overall, the nervous system consists of the central nervous system (CNS), comprising the brain and spinal cord, and the peripheral nervous system (PNS), which is composed of nerves extending to and from the CNS. The major constituent systems of the central and peripheral nervous systems, shown in Box A2, are described in the following sections.
A3.1 The central nervous system
The brain and spinal cord are made up of dense accumulations of nerve cells and their associated fibres. The cell bodies give rise to grey matter and the fibres, with a special coating called myelin, make up the white matter. The whole central nervous system is carefully protected. Three connective tissue membranes called meninges enclose the brain and the spinal cord. These meninges cover the nerves entering and leaving the brain and the spinal cord to varying lengths. The meninges also enclose blood vessels and venous sinuses (large veins into which blood drains from the nerve cells). Meninges retain cerebrospinal fluid (CSF), which is a watery liquid similar, but not identical, in composition to blood plasma, which supports, cushions, and nourishes the brain. The meninges form artitions within the skull and brain. Inflammation of these lining membranes gives rise to the serious condition called meningitis whilst inflammation of the brain tissue itself (nerve cells) is referred to as encephalitis.
The major regions of the brain are the cerebrum, the midbrain, pons, the medulla oblongata, and the cerebellum, which are shown in Figure A1.
The cerebral hemispheres are the uppermost part of the brain and are separated by the longitudinal fissure formed by the meninges. They make up approximately 83% of total brain mass and are collectively referred to as the cerebrum.
The cerebral cortex (cerebrum) constitutes a 2–4 mm thick grey matter surface layer. Because of its many convolutions, the grey matter accounts for about 40% of total brain mass. It is responsible for conscious behaviour and contains three different functional areas: the motor areas, sensory areas, and association areas. Also located internally in the cerebral cortex are the white matter, responsible for communication between cerebral areas and between the cerebral cortex and lower regions of the CNS, as well as the basal nuclei (or basal ganglia), involved in controlling muscular movement and several bodily functions. CSF is contained in the lateral ventricles located in the cerebral hemispheres.
The diencephalon is located centrally within the forebrain (the anterior or front part of the brain). It consists of the thalamus, hypothalamus, and epithalamus, which together enclose the third ventricle (a sac containing cerebrospinal fluid found within the brain which is connected to the lateral ventricles in the cerebral hemispheres and to the fourth ventricle in the brain stem). The thalamus acts as a grouping and relay station for sensory inputs (inputs such as pain, touch, and temperature from the periphery), ascending to the sensory cortex and associated areas. It also mediates motor activities, cortical arousal or wakefulness, and memories. The hypothalamus, by controlling the autonomic (involuntary) nervous system, is responsible for maintaining the body's homeostatic balance, which is commonly referred to as maintaining the internal environment (‘the milieu interior’). This is the environment in which the cells function by maintaining the appropriate balance of electrolytes, ions, temperature, hormones, and all other factors that are associated with normal function. Moreover, the hypothalamus forms a part of the limbic system, the ‘emotional’ brain. The epithalamus consists of the pineal gland and its connections.
A3.1.2 Midbrain, pons, and medulla
The midbrain, pons, and medulla oblongata lie below the diencephalon and are part of the continuing pathways from the cerebral hemispheres to the spinal cord and its nerves. This part of the brain contains collections of neurons that are referred to as ‘nuclei’ or ‘centres’, which control several vital functions such as cardiac (heart) activity and respiration (breathing).
The midbrain, which surrounds the cerebral aqueduct (the duct that conveys the cerebrospinal fluid to the sub-arachnoid space via the fourth ventricle), provides fibre pathways between higher and lower brain centres, and contains visual and auditory reflex and subcortical motor centres. The pons is mainly a conduction region, but its nuclei also contribute to the regulation of respiration and nuclei of some cranial nerves. Cranial nerves comprise 12 pairs of nerves which arise directly from the brain (not from the spinal cord) and leave the brain through apertures or foramina in the skull.
The medulla oblongata has an important role as an autonomic reflex centre involved in maintaining body vital body functions. In particular, nuclei in the medulla regulate respiratory rhythm (the respiratory centre), heart rate (cardiac centre), and blood pressure (vasomotor centre), and contain the nuclei of several cranial nerves. Moreover, the medulla oblongata provides important conduction pathways between the spinal cord and higher brain centres.
The cerebellum, which is located behind the pons and medulla, accounts for about 11% of total brain mass. Like the cerebrum, it has a thin outer cortex of grey matter, internal white matter, and small, deeply situated paired masses (nuclei) of grey matter. The cerebellum processes impulses received from the cerebral motor cortex, various brain stem nuclei, and sensory receptors in order to ‘fine-tune’ skeletal muscle contraction (the muscles that control movement, walking, running etc), thus giving smooth, co-ordinated movements.
A3.1.4 Spinal cord
The spinal cord is the direct continuation of the brain from the brainstem into the vertebral column. It contains the nerve pathways through which messages are sent from the brain (efferent pathways) and to the brain (afferent pathways). Like the brain itself, the spinal cord is composed of central grey matter containing nerve cells and white matter which comprises nerve fibres. Not all messages controlling the body have to go up to the brain and return. The nerves of the grey matter in the cord can act on their own in response to a sensory stimulus. This action is known as a ‘spinal reflex’ and the knee jerk is perhaps the best-known example.
A3.2 The peripheral nervous system
This contains motor nerves that control voluntary movement together with sensory nerves that carry information concerning touch, pain, temperature, and position to the brain.
Nerves arise from nerve cells and the basic structure of a nerve cell is shown in Figure A5.
Nerve cells have a cell body, dendrites and an axon. The nerve cell and its processes are called neurons. The nerve cell and its processes behave like a small electrical battery: the resting voltage inside the nerve cell is –70 mV, one millivolt being one thousandth of a volt. The fluid inside the nerve cell, like that of other cells in the body, contains a high concentration of potassium ions (K+). In contrast, the nerve cell is surrounded by tissue fluid which contains mainly sodium chloride, which gives rise to sodium ions (Na+). In the resting state, the sodium ions are removed from the interior of the cell by the sodium pump. The pump effectively exchanges sodium ions for potassium ions. Both sodium ions and potassium ions diffuse across the cell membrane. Potassium diffuses much more rapidly than sodium, thus generating the resting membrane potential of about –70 mV (interior negative to exterior).
A nerve impulse is a transient event which for a very short period of time alters the permeability of the cell membrane and allows sodium ions to enter the cell. These positively charged sodium ions change the potential inside the cell from –70 mV to +40 mV—a process called depolarization. The sudden change from negative to positive voltage inside the cell is termed an action potential, and is propagated along the cell membrane. Each action potential corresponds to a nerve impulse or message which is conveyed to its destination by the membrane, changing its ‘behaviour’ along the whole nerve, causing a propagation of the nerve impulse.
A nerve impulse lasts about 1 ms and each nerve impulse in both motor and sensory nerves (i.e. nerves that carry messages or impulses to the spinal cord and brain from the peripheral tissues as regards pain, temperature, and touch) is associated with sodium entering and potassium leaving the cell momentarily. Following the action potential, i.e. during the resting phase, there is gradual expulsion of the sodium that entered the nerve cell. The maximum rate of discharge from an anterior horn cell is considered to be approximately 200 impulses a second.
The rate of propagation of an impulse along a nerve or nerve conduction varies with the size of the nerve fibre, the large nerve fibres, with a diameter of 20 μm, have a velocity of conduction of 120 m/s. These large fibres have a sheath made up mainly of fatty material called a myelin (i.e. the nerves are myelinated), and the gaps in this sheath, called nodes of Ranvier, enable a nerve impulse to ‘leap-frog’ down the nerve as the exchange of sodium and potassium ions only occurs at these interruptions in the myelin sheath.
A3.2.1 Autonomic nervous system
The part of the peripheral nervous system that supplies smooth muscles (in contrast to the striated or skeletal muscles found in our limbs etc.) is termed the autonomic nervous system. The autonomic nervous system also controls the heart, the digestive and urinary systems, and the secreting glands such as sweat and salivary glands. In general, the autonomic nervous system is concerned with involuntary nerve impulses. The part of the peripheral nervous system that controls voluntary actions, such as movement, is known as the somatic or motor nervous system.
The autonomic nervous system itself is subdivided into:
1. the sympathetic nervous system
2. the parasympathetic nervous system.
These systems differ in the chemical transmitter involved in the transmission of impulses at synapses. In the sympathetic nervous system the chemical transmitter is predominantly noradrenaline, whereas in the parasympathetic nervous system the chemical messenger is acetyl choline. The actions of these two sections of the autonomic nervous system are shown in Table A1 and Figure A6.
Table A1 Actions of the autonomic nervous system
Pupil of the eye
Air passages, bronchi, and bronchioles
Increased salivary secretion and dilatation of blood vessels
Speeds up, increases force of ventricular contraction
Slows heart rate
Sphincters of the digestive tract
Empties and relaxes internal anal a sphincter
Empties and relaxes internal sphincter
Nil (except salivary gland and external genitalia-vasodilatation)
The sympathetic nervous system
The sympathetic nervous system is active in states of emotional excitement and stress. The system gives rise to what has been called the ‘flight or fight’ reaction.
Increased sympathetic nerve activity causes the heart to beat faster and also increases the force of contraction of the ventricles of the heart (the force with which the heart muscle contracts). These effects cause an increase in the output from the heart (cardiac output) and therefore the blood pressure increases. In addition, the pupils of the eye dilate, the air passages increase in diameter, allowing an individual to breath in more air, and the muscles associated with sweat glands and skin contract, causing the hair to ‘stand on end’ and goose pimples to form. The rate at which breathing occurs also increases because of the excitement of the respiratory centres in the brain. In addition, sympathetic stimulation slows down the contractions of the digestive tract.
Structure of the sympathetic nervous system
The nerve cell (the neuron) in the spinal cord sends a fibre (axon), referred to as the pre-ganglionic fibre, to the ganglion (a collection of nerve cells and their fibres), which is called the sympathetic ganglion. A second fibre starts from the synapse within the ganglion and terminates in the organ (e.g. smooth muscle) it supplies. The preganglionic fibre is covered by a white fatty sheath made of myelin. For this reason, the bundle of pre-ganglionic fibres is called the white ramus. The fibre after the ganglion is termed the post-ganglionic fibre and does not have a myelin sheath, therefore it is grey in colour and is referred to as the grey ramus.
In the spinal cord, the pre-ganglionic outflow takes place between the first thoracic segment and the second lumbar segment. The cells of origin are in the lateral horn of the spinal grey matter in these segments and the fibres leave the spinal cord with the nerves to the voluntary or skeletal or striated muscles. All the fibres from these cells in the lateral horns run to a chain of neurons called the sympathetic chain, which lies very close to the spinal cord. The sympathetic trunk extends upwards towards the neck to the angle of the jaw (superior cervical ganglion of the sympathetic chain) and extends downwards across the back of the thoracic and abdominal cavities to the pelvis.
The chemical transmitters found in the sympathetic nervous system are adrenaline (epinephrine) and noradrenaline (norepinephrine). Chemically, noradrenaline and adrenaline are amines of the benzene derivative catechol and are referred to collectively as catecholamines. Noradrenaline is rapidly removed after release, mainly by re-uptake into the nerve, so that the target organ is capable of responding to further nerve impulses.
Over-activity of the sympathetic nervous system leads to narrowing of blood vessels (vasoconstriction) and consequently a reduction of the blood supply to the organ or tissue. If it is widespread, the narrowing of the blood vessels will lead to an increase in blood pressure (hypertension), profuse sweating, and dilatation of the pupils.
Sympathetic nerve fibres can cause either contraction or relaxation of the smooth muscle of the innervated structure. When noradrenaline causes contraction, the receptor responding to the neurotransmitter is referred to as an alpha receptor. If the action of the sympathetic nerve system is to cause relaxation, the receptor concerned is called a beta receptor. The alpha and beta receptors found in the sympathetic system are called Ahlquist receptors. These can be blocked selectively by either alpha or beta blockers. Blockade of beta receptors in the heart is used to reduce blood pressure. Stimulation of beta receptors in the airways is used in the treatment of asthma to dilate or increase the lumen through which air can move in the small airways or bronchioles of the lung.
In addition there are ganglion-blocking drugs that block transmission at the sympathetic ganglia, thereby preventing the transmission of the nerve impulse from the pre-ganglionic fibre to the post-ganglionic fibre. These ganglion blockers are used to treat very high blood pressure in cases of emergency.
A3.2.2 Parasympathetic nervous system
The parasympathetic fibres originate in the cranial nerves and the lower end of the spinal cord (the sacral region). The 12 cranial nerves have their cells of origin in the brainstem. The third, seventh, ninth, and tenth cranial nerves all contain parasympathetic fibres. The tenth cranial nerve or the vagus nerve is the principal parasympathetic nerve and its stimulation causes a slowing of the heart amongst many other effects, such as those on the stomach and stomach secretions, oesophagus, and the small airways of the lungs.
As in the sympathetic system, the parasympathetic nervous system has two neurons which give rise to the pre-ganglionic and post-ganglionic nerves. However, the post-ganglionic nerve is usually very short. In the heart, the ganglion and the post-ganglionic nerves lie within the organ of innervation, the cardiac muscle.
The neurotransmitter at ganglions (synapses), which are junctions between the pre-ganglionic fibres and the post-ganglionic fibres, in both the parasympathetic nervous system and the sympathetic nervous system is acetylcholine (see Figure A4 of the peripheral nervous system). Acetylcholine is also the neurotransmitter at the post-ganglionic nerve endings of the parasympathetic nervous system, and acts as the neurotransmitter at some post-ganglionic nerve endings of the sympathetic nervous system.
Acetylcholine (ACh) has two distinct actions within the autonomic nervous system and at the neuromuscular junction, which are described as nicotinic or muscarinic. These terms were used since early experimenters applied the two chemicals nicotine or muscarine (found in toadstools) directly to autonomic nerves. Acetylcholine activity in the ganglia of the parasympathetic systems and the neuromuscular junction is called nicotinic, while the activity at the junction between the end of the nerve and the organ supplied, other than skeletal muscle, is termed muscarinic.
Like noradrenaline, the effects of acetylcholine are terminated very quickly after its release. However, for acetylcholine this is due to the activity of the enzyme acetylcholine esterase (AChE) which breaks down acetyl choline. Inhibition of this enzyme is the basis of poisoning by organophosphate pesticides and nerve gases (see Chapter 17).
In most parts of the body, the action of the parasympathetic nervous system is the opposite of that of the sympathetic nervous system (Table A1). Thus it slows the heart rate, lowers blood pressure, constricts the pupils, and constricts or narrows the airways. In addition, the parasympathetic nervous system speeds up digestion and plays an important role in defaecation and emptying of the bladder, and increases secretions from several glands such as the salivary glands and tear glands.
In 1921, the Austrian scientist Otto Loewi discovered the first neurotransmitter. In his experiment (which came to him in a dream), he used two frog hearts. One heart (heart 1) was still connected to the vagus nerve. Heart 1 was placed in a chamber that was filled with saline. This chamber was connected to a second chamber that contained heart 2. Fluid from chamber 1 was allowed to flow into chamber 2. Electrical stimulation of the vagus nerve caused heart 1 to slow down. Loewi also observed that after a delay, heart 2 also slowed down. From this experiment, Loewi hypothesized that electrical stimulation of the vagus nerve released a chemical into the fluid of chamber 1 that flowed into chamber 2. He called this chemical ‘Vagusstoff’. We now know this chemical as the neurotransmitter called acetylcholine.
Neuroscientists (scientists who study the nervous system) consider the following criteria necessary for a chemical to be termed a neurotransmitter:
◆ the chemical must be produced within a nerve cell;
◆ the chemical must be found within a nerve cell;
◆ when a nerve cell is stimulated, the nerve cell must release the chemical;
◆ when the chemical is released it must act on a specialized area, usually in the adjacent or neighbouring nerve cell (the post-synaptic nerve cell) and cause a biological effect where usually there is a change that alters the movement of ions across a cell membrane;
◆ after the chemical is released it must be inactivated—this may occur due to re-uptake of the chemical by the nerve cell that released it or by an enzyme which alters its chemical structure and therefore prevents further action at the receptor or specialized nerve ending; and
◆ if this chemical is applied on the post-synaptic membrane (i.e. the membrane of the adjacent nerve cell), it should produce the same effect as when the chemical is released by a nerve cell.
There are many types of chemical that act as neurotransmitters. The more common neurotransmitters and those of particular interest in toxicology are:
◆ norepinephrine (originally called noradrenaline)
◆ gamma-amino butyric acid (GABA)
◆ glycine, and
◆ glutamate aspartate.
Acetylcholine is found in both the central and peripheral nervous systems. Choline is taken up by the neuron. When the enzyme choline acetyltransferase is present, choline combines with acetyl coenzyme A (CoA) to produce acetylcholine.
Dopamine, norepinephrine, and epinephrine are a group of neurotransmitters called ‘catecholamines’. Each of these neurotransmitters is produced in a step-by-step fashion by different enzymes.
Neurotransmitters are made in the cell body of the neuron and then transported down the axon to the axon terminal. Molecules of neurotransmitters are stored in small packages called vesicles. Neurotransmitters are released from the axon terminal when their vesicles ‘fuse’ with the membrane of the axon terminal, spilling the neurotransmitter into the synaptic cleft.
Neurotransmitters will bind only to specific areas (receptors) on the post-synaptic membrane that recognize them.
A3.3.1 Some neurotransmitters and their effects
Norepinepherine functions in:
◆ arousal, energy, drive
◆ fight or flight.
Norepinepherine deficiencies result in:
◆ lack of energy
◆ lack of motivation
Dopamine functions in:
◆ feelings of pleasure
◆ feelings of attachment/love
◆ sense of altruism
◆ integration of thoughts and feelings.
◆ anhedonia: the loss of the capacity to experience pleasure, which is a core clinical feature of depression, schizophrenia, and some other mental illnesses
◆ lack of ability to feel love, sense attachment to another
◆ lack of remorse about actions
Serotonin functions in:
◆ emotional stability
◆ reducing aggression
◆ sensory input
◆ sleep cycle
◆ appetite control.
Serotonin deficiencies result in:
◆ irrational emotions
◆ sudden unexplained tears
◆ obsessive-compulsive disorder
◆ sleep disturbances.
GABA functions in:
◆ control of anxiety
◆ control of arousal
◆ control of convulsions
◆ keeping brain activity ‘balanced’.
GABA deficiencies result in:
◆ ‘free-floating’ anxiety
◆ racing thoughts
◆ rapid heart
◆ inability to fall asleep
◆ constant ‘fight or flight’ state
A3.4 The neuromuscular junction
The junction between the motor nerve and the skeletal muscle fibre which it supplies is the neuromuscular junction. This is very important both in health and disease for several reasons. Firstly, there is a gap between the nerve fibre endings and the muscle fibres, and the messages across this gap are carried by the neurotransmitter acetylcholine. The acetylcholine is synthesized in the nerve fibre and is discharged when an impulse reaches the end of the nerve fibre. This chemical messenger reaches specialized parts of the muscle fibre called end plates, which contain specific receptors through which sodium ions pass into muscle fibre and produce a change in membrane potential called the end plate potential. This movement of ions—depolarization—spreads to the whole muscle fibre (propagated action potential), causing calcium ion release, and muscle contraction follows.
Acetylcholine stays only for a very brief period at the neuromuscular junction as it is quickly hydrolysed or inactivated by the enzyme acetylcholinesterase. This enables the next impulse to release acetylcholine again and cause another muscle contraction.
The neuromuscular junction functional activity is vulnerable to many toxic substances. Firstly, toxic substances can interfere with the production and release of the chemical messenger acetylcholine. The specialized parts of the muscle fibres may be damaged or altered in disease states such as myasthenia gravis. The enzyme cholinesterase, which restricts acetylcholine in time and space, can be inactivated by several toxic substances, of which the best known are the pesticides belonging to the class of compounds called organophosphates. Some chemical warfare agents (nerve agents), such as sarin, tabun, and soman, also are organophosphates and produce the same effect.
Importantly in medical practice, particularly in the speciality of anaesthesia, drugs are used to prevent transmission at the neuromuscular junction and thus produce muscle relaxation (the drugs used are called muscle relaxants) to facilitate surgery. Historically the Indians of South America used an arrow poison to paralyse their prey during hunting and this arrow poison was refined to become one of the best known muscle relaxants: curare or tubocurarine.
Every muscle in the body consists of muscle fibres, which are the units that cause muscles to contract and enable all forms of motor activity such as walking, running, and talking. Every muscle fibre needs a nerve supply in order to contract. Nerves controlling muscle fibres have their origins in the spinal cord (anterior horn cells) and as there are more muscle fibres than nerve cells, each nerve cell or anterior horn cell innervates more than one muscle fibre. For example in the leg as many as 200 muscle fibres may share a single anterior horn cell. Where eye muscles are concerned, only about five muscle fibres share one anterior horn cell.
These nerves leaving the anterior horn cell are called axons or motor nerves, and branch to supply a group of muscle fibres on reaching the muscle. The anterior horn cell and the muscle fibres supplied by this neuron are called the motor unit. The motor unit forms the basis for voluntary movement (movements which are intentional). If the motor nerve or axon is cut or damaged, paralysis of muscles occurs.
Nerves from the anterior horn cells carry nerve impulses or messages that enable the muscle fibres to contract. If an anterior horn cell discharges slowly or at a very low frequency, the muscles tend to be relaxed or flaccid. When the rate of discharge from the neurons increases, one may see co-ordinated contractions. However, these motor neurons are capable of discharging at very fast rates, usually in disease states, leading to either tremulous contractions (clonus) or sustained contractions (tetanus). Tetanus is also the name given to an infection (lock-jaw) caused by the tetanus bacillus (Clostridium tetani), which occurs when wounds become contaminated with soil/faeces that contain the bacteria. Tetanus was a serious consequence of accidents and war injuries before immunization against the disease became available.
A4 The heart and circulatory system—the cardiovascular system
The heart and the cardiovascular system are involved in the transport of blood. Blood is transported through the body via a continuous system of blood vessels. Blood is pumped away from the heart in arteries and returned to the heart through veins. Arteries usually carry oxygenated blood away from the heart into capillaries supplying tissue cells. The exception is the pulmonary artery, which carries venous blood from the right side of the heart to the lungs. Veins collect the blood from the capillary bed and carry it back to the heart, and carry deoxygenated blood, except for the pulmonary vein, which brings oxygenated blood from the lungs to the left side of the heart (Figure A7).
The circulatory system is divided into:
◆ the pulmonary circulation, which takes unoxygenated blood from the right side of the heart to the lungs and returns to the left side of the heart with oxygenated blood;
◆ the systemic circulation, which takes oxygenated blood from the left side of the heart to all cells in the body and returns unoxygenated blood (i.e. blood from which oxygen has been extracted and which carries carbon dioxide generated in the cells) to the right side of the heart.
The circulation or the cardiovascular system also:
◆ carries food from the digestive tract to the cells to provide nutrition for growth and energy;
◆ carries waste products from cells in the body to the kidneys to enable the body to get rid of (excrete) these unwanted products in the urine;
◆ carries hormones from the glands that produce them (endocrine glands) to other organs of the body, and
◆ carries heat from parts of the body where heat is produced to the skin so that surplus heat can be given off.
A4.1 The heart
The heart is an organ consisting essentially of two pumps, right and left, which circulate blood round the body. Each pump has two chambers: the atrium and the ventricle. The atrium collects blood from either the lungs (the left atrium) or the tissues (right atrium) and passes it through valves to the major pumping chambers, the ventricles. The left ventricle pumps oxygenated blood which has entered the chamber from the left atrium, whilst the right ventricle pumps the blood that has returned from the cells or tissues after extraction of oxygen and nutrients. This blood is pumped through the lungs where carbon dioxide is removed and oxygen combines with the haemoglobin in the red cells. A small amount of oxygen also dissolves in the blood.
Each time the heart beats, each ventricle pumps out about 70 ml of blood, and this volume is termed the stroke volume. The heart beats about 70 times a minute, which is termed the heart rate. This is usually measured in patients by counting the pulse rate at the wrist.
A4.2 Blood vessels and blood pressure
From the left side of the heart, oxygenated blood is pumped by the left ventricle to the aorta, which carries blood to the whole body. From the aorta arise the large arteries and their branches, which carry the oxygenated blood to the various parts of the body. For example, the carotid arteries arising from the aorta supply the brain, and the renal arteries arising from the aorta supply the kidneys. From the arteries blood is transported to smaller vessels called arterioles as it nears the organs or cells for which the blood supply is intended. From arterioles the blood goes into the very thin-walled capillaries that travel between cells providing oxygen and taking up carbon dioxide. Now the blood, which has provided oxygen and nutrition to the cells, passes from the end of the capillaries to the venules, veins, and then to the larger veins (the superior and inferior vena cava) and finally back to the right side of the heart.
The capacity of the venous side of the circulation is much greater than that of the arterial side and often accommodates 75% of the blood volume. This is because the walls of the vessels on the venous side are not as thick and contain less muscle than the vessels on the arterial side. The left ventricle contracts each time the blood is pushed into the aorta and this flow of blood causes a wave of flow commonly referred to as a pulse. This pulse can be felt only in arteries, which are often not visible. Some veins run just beneath the surface of the skin and are visible. The blood flow in them is non-pulsatile.
Blood pressure is the force applied to the wall of the arteries as the heart pumps blood to the cells in the body through the arterioles and capillaries. The measurement of blood pressure is dependent on the amount of blood pumped, which in turn is dependent on the volume of blood in the body (blood volume), the force with which the heart pumps the blood, and the diameter and elasticity of the arteries. This pressure from behind (driven by the left ventricle) is termed in Latin vis a tergo.
In order to have a blood pressure there has to be a flow from the heart (cardiac output) and a resistance to flow on the arterial or systemic side of the circulation. This resistance (the peripheral resistance) determines the blood pressure according to the equation:
blood pressure = cardiac output × peripheral resistance
The resistance to blood flow is mainly in the small arterioles as it is the smaller diameter vessels that offer the greatest resistance to flow through them.
There are two components to a measurement of blood pressure. The first is the systolic pressure, which is the maximum pressure exerted when the left ventricle is contracting. The second component, the diastolic pressure, represents the pressure in the arteries when the left ventricle is refilling. In ‘normal’ people these components are recorded as 120/70 mm Hg (mm of mercury).
The arterioles have smooth muscle in their walls, which is arranged circularly. When the muscle contracts it makes the blood vessels smaller. The sympathetic nervous system provides a nerve supply to these vessels and stimulation of this system causes contraction of the smooth muscle in the walls and thus vasoconstriction and an increase in peripheral resistance and hence of blood pressure. When the arterioles are relaxed or when the sympathetic nerve stimulation is not present, the vessels are vasodilated or there is vasodilation. The diameter of these vessels is directly under control of the sympathetic nerve outflow regulated by the vasomotor centre in the medulla oblongata of the brain.
There are many nerve cell groupings that influence the activity of the vasomotor centre. The best known are the baroreceptors, which are found in a special area, the carotid sinus, of each carotid artery (arteries supplying blood to the brain). The higher centres in the brain (regions of the brain where conscious thoughts occur) also influence the activity of the vasomotor centre. Emotional stress and excitement cause stimulation of the vasomotor centre and an increase in blood pressure. Carbon dioxide content in the blood also influences vasomotor centre activity. When the carbon dioxide content and tension are low, as in patients who are breathing rapidly, the activity of the vasomotor centre is reduced. A shortage of oxygen, in contrast, would increase the activity of the vasomotor centre.
There are several factors affecting blood pressure. These include disease of arteries such as thickening or loss of muscle fibres (arteriosclerosis, which usually occurs with ageing), psychological factors such as stress, anger, and fear, kidney disease, and pain. Certain hormonal disorders are also associated with high blood pressure. An increase in blood pressure may occur during pregnancy in some individuals.
A4.3 The blood (haematopoietic system)
An adult has approximately 5 litres of blood in the body. A new born baby has only 300 ml (80 ml per kg body weight). Blood is composed of cells (45%) and plasma (55%). Blood cells are formed in the bone marrow, which is found in cavities of bones. Blood cells can be broadly divided into red and white blood cells and platelets.
Red blood cells
There are approximately 5 million red blood cells per cubic mm of blood. These contain the pigment haemoglobin, which is bright red in colour when combined with oxygen and purple-blue in colour when deoxygenated. Every 100 ml of blood has about 15 g of haemoglobin and this haemoglobin plays an important role in the carriage of not only oxygen but also of carbon dioxide. The life span of the red cell is about 100 days. For the formation of red blood cells (and also of proteins), iron is required, and deficiency of iron leads to iron deficiency anaemia. Other requirements for the formation of red blood cells are vitamin B12 and folic acid. Lack of vitamin B12 and folic acid leads to the formation of abnormally large red blood cells and a state called megalobalstic anaemia.
The hormone erythropoietin, which is formed in the kidney, also plays a role in the production of red blood cells as this hormone is produced in increased amounts when the body is lacking in oxygen, often for long periods of time. This hormone stimulates the bone marrow to produce more red blood cells.
White blood cells
The classification and function of white blood cells is considered in the immunology section (section A11 below).
Platelets have two main functions in the human body. They are able to clump together and block small holes in the blood vessels by forming platelet plugs. This is a very important step in preventing loss of blood or bleeding from blood vessels, particularly after injuries.
Blood clotting is a process by which the body prevents loss of blood from blood vessels. It is initiated by a platelet plug and also by the breakdown of platelets, which causes the release of a factor called thromboplastin and converts a component of the blood called prothrombin to thrombin in the presence of calcium ions. Thrombin acts on another component in the blood called fibrinogen, and changes the fibrinogen to fibrin, which forms the blood clot.
There are a few inherited diseases where the clotting of blood is affected due to lack of specific substances in the person's blood. These diseases include haemophilia and Christmas disease.
Plasma is the straw-coloured fluid in which the blood cells are suspended. It consists of a watery solution of plasma proteins and plasma electrolytes, and all the substances transported in the blood. It also contains the factors or ingredients necessary for blood clotting. If the factors necessary for blood clotting are removed from plasma, the remaining fluid is called serum.
A4.4 Common medical terms used to describe symptoms and signs of heart and blood vessel disorders
Hypotension: an abnormally low blood pressure that can occur following blood loss, failure of the heart to pump efficiently (heart failure), or as a result of toxic effects on the arterioles causing a decrease in peripheral resistance. Abnormally low blood pressure is seen in the clinical state referred to as shock.
Hypertension: defined as a sustained normally high blood pressure. Transient high blood pressures are part of a normal circulation. Hypertension causes a strain on the left ventricle, which has to pump the blood against a higher pressure. Initially the heart muscle increases in size (left ventricular hypertrophy). This can lead to failure of the heart to maintain normal function, i.e. heart failure. High blood pressure may also cause blood vessels to burst. This may occur in the blood vessels in the brain and cause a stroke. If this occurs, it may result in paralysis on the side opposite to the site where the blood vessel burst, due to the anatomy of the nervous system and brain circulation.
Ischaemic heart disease: a disease of the blood vessels resulting in an insufficient supply of the heart muscles with oxygen that is severe enough to cause temporary strain, or even permanent damage to the muscle with death of muscle fibres.
Myocardial infarction: a term used to describe irreversible injury to heart muscle, which results in loss of function or inability of the muscle to pump blood. Common symptoms include crushing central chest pain that may radiate to the jaw or arms. Chest pain may be associated with nausea, sweating, and shortness of breath.
Angina pectoris: a chest pain that occurs secondary to the inadequate delivery of oxygen to the heart muscle. It is often described as a tight, constricting, or crushing pain in the midsternal area of the chest, which may also be felt on the inside of the arms or in the neck. It arises when the blood supply to the heart muscle is reduced, due usually to a partial or complete obstruction of the blood flow in the arteries supplying the heart muscle (the coronary arteries).
Dyspnoea: difficult or laboured breathing; shortness of breath. Dyspnoea is a sign of serious disease of the airways, lungs, or heart.
Oedema: the presence of abnormally large amounts of fluid in the intercellular tissue spaces of the body and usually means demonstrable accumulation of excessive fluid in the subcutaneous tissues. Oedema may be localized, due to venous or lymphatic obstruction or to increased vascular permeability (which may follow stings from insects), or it may be more widespread due to heart failure or renal disease. Collections of oedema fluid are designated according to the site, for example ascites (peritoneal cavity), hydrothorax (pleural cavity), and hydropericardium (pericardial sac). Oedema due to heart failure is usually first detected as a swelling around the ankles (ankle oedema). Oedema may also occur in the back in front of the end of the spinal cord (sacral area), where it is referred to as sacral oedema.
A5 The respiratory system
Respiration or breathing has three main functions:
1. to deliver oxygen to the cells;
2. to eliminate carbon dioxide, and
3. to regulate the pH of the blood.
The oxidation of carbon and hydrogen from food in order to produce energy and heat requires oxygen from the air, obtained through breathing. In the cells, oxygen is delivered to the mitochondria, intracellular structures that are the ‘powerhouses’ of the cells. Mitochondria have cytochromes which combine oxygen, hydrogen, and carbon atoms to generate energy in the form of adenosine triphosphate (ATP), and produce carbon dioxide as a waste product.
At rest, 250 ml of oxygen are absorbed per minute during breathing to satisfy the metabolic requirements of the body. The energy requirements depend on the level of activity of the individual. For example, during heavy exercise, the oxygen requirement may be as high as 5000 ml of oxygen per minute.
The lungs fill the thoracic cavity. During breathing, the thoracic cavity expands and creates a negative pressure. This causes the lungs to expand and sucks air in through the structures shown in Figure A8. This is referred to as inspiration. When the thoracic cavity returns to its normal (resting) size, the lungs also decrease in size and air is forced out through the respiratory tract. This is called expiration.
Physiologically, four phases of respiration are recognized:
1. ventilation: the movement of air to and from the lungs;
2. distribution: air entering the lungs is distributed to all parts, including the small air sacs (alveoli) where gas transfer to and from the blood takes place;
4. internal respiration: blood rich in carbon dioxide and low in oxygen is pumped to the lungs via the pulmonary arteries, by the right ventricle of the heart. Blood low in carbon dioxide but loaded with oxygen is returned to the heart via the pulmonary veins. Matching of ventilation and perfusion (the blood supply to the alveoli—air sacs) within the lung ensures normal gas exchange.
The alternating increase and decrease in the size of the chest during normal breathing is under the control of collections of nerve cells in the medulla oblongata (the respiratory centre). Nerves from the anterior horn cells in the cervical and thoracic regions of the spinal cord supply the muscles of respiration. The main muscles involved are the diaphragm and the intercostal muscles (the muscles between the ribs). These muscles are all striated (skeletal) muscles, which are muscles that are usually under voluntary control (by the somatic nervous system). For this reason, the normal reflex action of breathing can be overridden by voluntary activity, such as taking a deep breath.
The respiratory system can be affected by a wide range of agents, including drugs such as morphine, one of the group of opiates that are compounds derived from or containing the active principles of the poppy (including morphine, heroin, methadone, and codeine), and by many toxic substances such as pesticides (particularly the herbicide paraquat) and nerve gases.
The lungs are elastic structures and outside the thoracic cavity they collapse like deflated balloons. In the thoracic cavity they are fully expanded and fill the cavity. Should air enter the space between the outside of the lungs and the inside of the thoracic cavity, the lungs will collapse and this is referred to as a pneumothorax, which severely interferes with respiration.
A5.1 Definitions of lung volumes and capacities
A number of terms are used to describe the movement of gas during breathing:
◆ Tidal volume (TV): The volume of air breathed in and out in one breath during normal breathing. This is usually around 400–500 ml.
◆ Minute volume (MV): The volume of air breathed in and out during a minute, which is tidal volume multiplied by respiratory rate (rate of breathing per minute). In exercise, the minute volume may increase from the average 6000–8000 ml to 50,000 ml per minute.
◆ Dead space: The region of the lung where there is no exchange of gases.
◆ Alveolar ventilation (AV): This is the volume available for exchange of gases, approximately (tidal volume – dead space) × respiratory rate.
◆ Inspiratory reserve volume (IRV): The volume of air that can be taken in after a normal breath (inspiration) has already been taken, i.e. the volume of air that can be inspired in addition to the tidal volume (approximately 3500 ml in a 70-kg adult).
◆ Expiratory reserve volume (ERV): The volume of air that can be breathed out after a normal expiration, i.e. the additional amount that can be breathed out after the end of a normal breath (approximately 1200 ml in a 70-kg adult).
◆ Residual volume (RV): The volume of air left in the lung after a maximal exhalation, i.e. the amount of air that is always in the lungs after breathing out as far as possible (approximately 1200 ml in a 70-kg adult).
◆ Inspiratory capacity (IC): The volume of air that can be inhaled after breathing out normally, i.e. after exhaling the tidal volume.
◆ Functional residual capacity (FRC): The volume of air left in the lung during normal breathing (approximately 2500 ml in a 70-kg adult).
◆ Vital capacity (VC): The maximum volume of air that can be forced out of the lungs after a maximal inspiration, i.e. the largest tidal volume that the individual is able to make (approximately 4600 ml in a 70-kg adult). This is IRV + TV + ERV.
◆ Total lung capacity (TLC): Volume of air after a maximal inspiration. This is IRV + TV + ERV + RV (approximately 6000 ml in a 70-kg adult).
Lung capacities are defined as sums of volumes, thus:
◆ inspiratory capacity = IRV + TV
◆ vital capacity = IRV + TV + ERV
Spirometry is the direct measurement of lung volumes from a subject breathing spontaneously. Lung volumes as determined by spirometry are illustrated in Figure A9.
A5.2 The carriage of oxygen and carbon dioxide
The alveoli of the lungs contain oxygen, carbon dioxide, nitrogen, and water vapour. These four together make up a pressure equal to the total barometric pressure of 760 mm Hg. The water vapour when it is fully saturated exerts a partial pressure of 47 mm Hg. The other three gases (oxygen, carbon dioxide, and nitrogen) also exert partial pressures depending on the proportion of each in the mixture. In the alveoli of the lung, the pressure of these gases is measured as the total barometric pressure (760 mm Hg) minus the pressure of the water vapour (47 mm Hg), resulting in a pressure of 713 mm Hg. Oxygen contributes 14% and carbon dioxide contributes 6% to this pressure, therefore the pressure due to the oxygen is 14% of 713, i.e. 100 mm Hg.
Gases diffuse across membranes in amounts that are determined by the difference in the partial pressures of that gas between the two compartments. With a partial pressure of 100 mm Hg in the alveoli, oxygen diffuses into the blood with a lower oxygen tension, which is brought by the pulmonary artery, and this continues until the partial pressure in the blood reaches equilibrium with the alveolar gas. The blood leaves the lungs with a tension of 100 mm Hg and usually arrives at the capillaries with a similar tension of oxygen. As the blood flows through the tissue capillary it comes into contact with the tissue fluid with a much lower oxygen tension (e.g. 40 mm Hg). The tension of oxygen in the tissue fluid is low because oxygen is being continually taken up by cells for metabolism.
As the blood flows through the capillary, the oxygen tension falls to 40 mm Hg (the pressure of the surrounding tissue fluid) and returns to the right side of the heart (to the right atrium and ventricle) with an oxygen tension of 40 mm Hg. Then it comes into contact with alveolar air with an oxygen tension of 100 mm Hg and equilibrium occurs when the tension of oxygen in the blood reaches 100 mm Hg and thus becomes referred to as arterial or oxygenated blood.
Gases carried in the blood are now measured routinely. This process is referred to as blood gas analysis and indicates the partial pressure of oxygen and carbon dioxide in the blood and also measures the pH of the blood. These measurements provide valuable information about disease processes and the effects of treatment.
The quantity of oxygen carried in the blood depends on the affinity of oxygen to haemoglobin, found in red blood cells. Haemoglobin allows far more oxygen to be carried than would be possible than in solution alone. One gram of haemoglobin has the ability to combine with 1.34 ml of oxygen. Thus a person who has 15 g of haemoglobin in every 100 ml of blood would theoretically be able to carry approximately 20 ml of oxygen in every 100 ml of blood. This is termed the oxygen capacity of the blood. In venous blood that is returning from the tissues via the veins to the right side of the heart, only 14 ml of oxygen are present in every 100 ml of blood. As noted above, the tension has fallen to 40 mm Hg. Thus, as blood passes through the tissues 5–6 ml of oxygen is taken up by the tissues; during exercise this amount is much more.
Carbon dioxide carriage
The tension of carbon dioxide in the lungs is 40 mm Hg whilst in the tissues it is 46 mm Hg. Therefore as the blood passes through the capillaries in the lung, carbon dioxide diffuses into the alveoli due to the difference of tension of the carbon dioxide in the venous blood and that in the alveoli. Therefore carbon dioxide moves in a direction opposite to that of oxygen in the alveoli of the lungs. The carbon dioxide content of the blood leaving the lungs is 48 ml carbon dioxide per 100 ml blood. As it passes through the cells and tissues, the carbon dioxide content increases to 52 ml of carbon dioxide per 100 ml of blood.
What emerges from the above is that the changes in oxygen content are greater than the changes in carbon dioxide content. This is because carbon dioxide is not only a waste product. An adequate level of carbon dioxide has to be maintained in the blood in order to maintain an acceptable blood pH (a measure of the acidity) to enable cells to function normally (normal range 7.36–7.42).
Carbon dioxide is carried in the blood in three ways, firstly in simple solution as carbonic acid and secondly as sodium bicarbonate in the plasma and potassium bicarbonate in the red blood cells. Thirdly, it is carried as neutral carbamino protein, mainly with haemoglobin in the red cells.
The transport of the acid-gas carbon dioxide in the blood is closely associated with the maintenance of the normal blood pH. Carbon dioxide dissolves in water, or plasma, and forms carbonic acid. This weak acid is in equilibrium with its salt, the bicarbonate ion. The ratio of bicarbonate ions to molecules of carbonic acid defines the acidity of the blood. Under normal circumstances, this ratio is 20:1. Bicarbonate ions are produced in red blood cells in systemic capillaries as carbon dioxide diffuses into these cells and forms carbonic acid. The formation of carbonic acid is catalysed by the enzyme carbonic anhydrase. Bicarbonate ions diffuse from the red cells to the plasma, being replaced by chloride ions moving into the red cells. Hydrogen ions produced during the formation of bicarbonate ions are buffered by haemoglobin in its deoxygenated state. This process is precisely reversed in the capillaries of the lung; bicarbonate ions enter red cells, chloride ions leave red cells, and hydrogen ions released from oxygenated haemoglobin combine with bicarbonate ions to produce carbonic acid, carbonic anhydrase catalyses the formation of carbon dioxide, and water from carbonic acid and the carbon dioxide diffuses out of the cell into the plasma. Note that carbonic anhydrase catalyses both the formation and breakdown of carbonic acid; the direction of the reaction is defined by the law of mass action and the rate of the reaction is controlled by the catalyst, i.e. carbonic anhydrase.
A5.3 Common signs, symptoms, and terms used for disorders of lung or respiratory function
This is a state in which there is excess of carbon dioxide and lack of oxygen in the body. This occurs when respiratory function or activity is insufficient to meet the demands of the body or when there is obstruction to respiration, e.g. during strangulation, or when an individual is breathing in a confined space when the expired air has to be inhaled. Asphyxial states stimulate respiration or breathing, as carbon dioxide is a potent stimulus of the respiratory centre, as is a lack of oxygen.
This is defined as a shortage of oxygen without a concurrent shortage of carbon dioxide. This is very often encountered when there is insufficient oxygen in the inspired air or when for some reason the tissues are deprived of the normal amount of oxygen, possibly because of poor circulation or a blood clot. In this case, tissue hypoxia results and if this occurs in the heart muscle it results in heart attacks or ischaemic heart disease. Hypoxia also depresses brain function as the brain is dependent on sufficient oxygen supplies for the proper functioning of nerve cells. When hypoxia of the brain occurs, a person becomes disorientated, loses all sense of danger, loses consciousness, and coma sets in. For example, this happens when carbon monoxide displaces oxygen from haemoglobin and deprives the tissues of oxygen.
Hypoxia may be due to a decreased amount of oxygen in the air breathed in (inspired oxygen), as at high altitude, or to lung disease when the oxygen cannot enter the red blood cells in the blood that flows through the lungs.
In contrast to asphyxia, where an individual will struggle to breathe with all the available resources in the body, in hypoxia the individual will soon lose control and become unconscious.
If the supply of oxygen to the brain cells is interrupted for more than 4 minutes (as seen when the heart ceases to pump blood effectively, commonly referred to as cardiac arrest), the nerve cells in the brain may be irreversibly damaged and ‘brain death’ may result. If there is a deficiency of haemoglobin to transport the oxygen, as is seen an anaemic patients due to either poor nutrition or prolonged blood loss, the term used is anaemic hypoxia. The hypoxia associated with carbon monoxide poisoning is an anaemic hypoxia as there is insufficient haemoglobin to transport the oxygen due to its preferential binding with carbon monoxide, which has an affinity about 250 times greater for haemoglobin than oxygen.
If blood flow through the body tissues is slow, there is insufficient oxygen for the cells to function. This is referred to as stagnant hypoxia.
Finally the cells may be unable to utilize the oxygen brought to them by the blood due to the enzymes within the cells being inactive or destroyed. This occurs in cyanide poisoning, where vital enzymes such as the cytochromes are destroyed by the cyanide and the cells cannot extract the oxygen in the blood.
A5.3.3 Pulmonary oedema
In the lungs, the pulmonary arterial systolic pressure is usually 25 mm Hg compared to about 130 mm Hg in arteries arising from the aorta from the left ventricle. When the pressure in the left atrium or pulmonary veins is elevated (for example when the atrium cannot empty its contents to the left ventricle either because the atrium muscle is not contracting in the normal manner or when there is an obstruction to the flow of blood from the atrium to the ventricle such as narrowing ostenosis of the valve between the two chambers, commonly referred to as mitral stenosis), the pressure in the pulmonary capillaries could be exceeded to such an extent that fluid passes from the capillaries into the alveoli. This fluid would interfere with diffusion of gases. The presence of fluid in the alveoli or in the lung created in this way is referred to as cardiac pulmonary oedema. Pulmonary oedema leads to difficulty in breathing (as there is insufficient oxygen and accumulation of carbon dioxide, which are both stimuli for the respiratory centre) and the patient will become dyspnoeic, that is conscious of breathing and difficulty in breathing, and breathless. Pulmonary oedema may also occur due to the action of poisonous gases such as chlorine or phosgene, where the structure of the alveolar walls and capillaries are damaged, leading a leakage of fluid into the alveoli. If the left side of the heart fails, the heart muscle on the left side of the heart does not function or contract adequately and there is a build up of pressure in the pulmonary veins bringing blood from the lungs. This type of fluid accumulation in the lung is called toxic pulmonary oedema.
Cyanosis is a bluish discolouration, especially of the skin and mucous membranes, caused by an excessive concentration of deoxygenated haemoglobin (haemoglobin not bound to oxygen) in the blood. A point of interest to those in countries where anaemia is very common, is that the haemoglobin levels may be so low that the amount of haemoglobin without oxygen (deoxygenated haemoglobin) is insufficient to cause cyanosis.
A6 The gastrointestinal system
Food or water entering the body through the mouth passes down the oesophagus and enters the stomach. From the stomach, partially digested food passes on to the duodenum, jejunum, and ileum (small intestine). That which has not been absorbed proceeds to the caecum and then to the ascending, transverse, descending, and sigmoid colon (large intestine), the rectum and finally the anal canal (Figure A10).
In the mouth, saliva is produced by three paired salivary glands: parotid, submandibular, and sublingual. Saliva is secreted by these glands, usually in response to the thought, site, taste, or smell of food. Secretion of saliva is under the control of the parasympathetic nervous system. Thus when there is over-activity of the parasympathetic nervous system and there is more secretion of the neurotransmitter of that system (acetylcholine), there will be excessive secretions, for example as in organophosphorus insecticide poisoning. If the action of acetylcholine on the receptors is blocked by drugs such as atropine, dryness of the mouth results.
The food formed into a bolus in the mouth passes down the oesophagus due to propulsive contractions of the muscle of the oesophagus, which are controlled by another parasympathetic cranial nerve, the vagus. Then the food enters the stomach where digestion begins aided by secretions (pepsin and hydrochloric acid for digestion of proteins) from the cells lining the stomach wall. The secretions of the stomach are also under the control of the vagus nerve and a hormone called gastrin.
At regular intervals of minutes, small quantities of food pass through an opening at the distal end of the stomach, called the pyloric sphincter, to the duodenum. The contents of a stomach usually empty in about 4 hours. However, with a very fatty meal, the emptying of the stomach becomes much slower due to the release of a hormone called enterogastrone.
Stomach ulcers and duodenal ulcers, commonly referred to as peptic ulcers, occur because pepsin, which aids in digesting proteins, acts on the cells of the stomach wall. Digestion of stomach wall cells is aided by the presence of hydrochloric acid, which is also secreted by the cells lining the stomach.
A6.1 The pancreas
The pancreas is a gland which sends its secretions into the bloodstream and also into the duodenum. The secretion of insulin and glucagon, which are necessary for the control of blood sugar in the human body, is from the pancreas. The secretions from the pancreas which enter the duodenum are known as the pancreatic juices and contain the enzymes trypsinogen and chymotrypsinogen, which are precursors of the protein-splitting enzymes trypsin and chymotrypsin.
Pancreatic secretion is also under the control of the vagus nerve. Insulin secretion is from specialized cells called the Islets of Langerhans. Failure to produce sufficient insulin results in diabetes mellitus.
Secretions from the liver also enter the duodenum via the bile duct. The bile is stored and concentrated in the gall bladder, which also contracts due to the action of the vagus nerve, and can also contract due to the action of some hormones. The bile constituents may concentrate and give rise to gall stones. Inflammation of the gall bladder is referred to as cholecystitis.
A6.2 The small intestine
The small intestine is concerned primarily with the absorption of sugars or carbohydrates and produces the related enzymes maltase, sucrase, and lactase. Although the nerve supply to the small intestine is both from the parasympathetic and sympathetic nervous systems, these nerves regulate motility or contractions of the small intestine (peristalsis) and have no role in the production of the digestive enzymes. The absorption of food takes place mainly in the small intestine. Amino acids and fats are also absorbed here.
A6.3 The large intestine
The main function of the large intestine is the absorption of water, sodium and other minerals. 90% of the fluid coming from the small intestine is removed here to form semi-solid faeces which may contain important biomarkers following toxic exposure. The large intestine is not essential to life.
A6.4 Common medical signs, symptoms, and terms used for gastrointestinal disorders
Dyspepsia: the impairment of the function of digestion, usually applied to epigastric discomfort following meals.
Peptic ulcer: an ulcer in the wall of the stomach or duodenum resulting from the digestive action of the gastric juice on the mucous membrane, when the latter is rendered susceptible to its action.
Cholecystitis: acute or chronic inflammation of the gallbladder.
Gall stones: stones within the gall bladder, usually of cholesterol (non-opaque) or of calcium bilirubinate (bilirubin), opaque and commonly associated with haemolytic anaemia (sickle cell disease, spherocytosis, thalassaemia). Gall stones are considered to have an increased incidence in individuals commonly referred to as having the five Fs: fat, female, fertile, flatulent, and over 40.
Pancreatitis: an acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease. Less commonly it may be associated with hyperlipaemia (increased fat content in blood), hyperparathyroidism (increased activity of the parathyroid glands), abdominal trauma (accidental or operative injury), vasculitis, or uraemia (increased content of urea in blood usually due to kidney disease).
Ileus: distension of the intestines, usually due to an obstruction such as a tumour. When a lesion causes a cessation of peristalitic movements in the intestines, the term paralytic ileus is used.
A7 The liver
The liver is the chemical factory of the body, both producing essential molecules and modifying and detoxifying ingested toxic substances (Figure A11).
The main functions of the liver are given below.
◆ Production of essential proteins such as albumin.
◆ Synthesis of factors that are involved in the clotting of blood.
◆ Maintaining the level of sugar in the blood. The excess carbohydrate absorbed by the blood from food is converted to glycogen, which is also formed from excess fat and protein. The liver glycogen maintains the normal blood glucose level in the blood when glucose is used up by the cells.
◆ Formation of urea from the ammonia which collects after amino acids have been used up (deaminated). The urea is eliminated through the kidney.
◆ The bile salts produced by the liver along with products from an anatomically closely related organ, the pancreas, play a vital role in digestion and absorption of fat. The liver also stores fat-soluble vitamins (A and D).
◆ The destruction of used red blood cells and removal of the breakdown product of haemoglobin (bilirubin) in the bile via the bile duct to the intestine (duodenum). The liver stores vitamin B12, which is necessary for the maturation of blood cells.
◆ In relation to toxicology, the liver plays a vital role by modifying the toxicity of foreign substances (toxins, drugs) that gain entry into the body by any route. Some drugs used in medical treatment are administered as pro-drugs, which depend on the liver to produce the active drug through the action of liver enzymes. The liver also has the ability to bind toxic substances to other compounds to make them more water soluble and thus enable to kidney to excrete them from the body.
One of the important roles of the liver, as noted above, is the formation of bilirubin from the red cells that die. Approximately 200 mg of bilirubin, which is insoluble in water, are made each day. It is bound to albumin and brought to the liver, where the albumin is replaced by glucuronic acid (an acid made from glucose), which makes the bilirubin water soluble. The water-soluble complex passes down the bile duct, which is the channel through which the liver eliminates its waste products, into the intestine (duodenum). Water-soluble bilirubin is responsible for the characteristic colouration of the faeces.
The failure to excrete bilirubin gives rise to yellowish discolouration of the whites of the eyes, the skin and nails, and mucosal membranes, which is called jaundice. Jaundice is essentially a sign of liver failure. Several toxic compounds, such as some pesticides, solvents such as carbon tetrachloride, and dry-cleaning fluids, damage the liver cells and prevent them from functioning normally to bind the bilirubin to the glucuronide. There are many drugs used in the treatment of disease which also damage the liver cells and are termed hepatotoxic. For example, high levels of the common drug paracetamol can cause liver damage, liver failure, and jaundice. Another common and important cause of damage to liver cells which often results in liver failure is excessive alcohol (ethanol) consumption.
In liver failure, jaundice occurs, the blood urea falls (as urea is no longer formed from ammonia), there is insufficient production of proteins, of which albumin is the most important, which may lead to swelling of ankles or oedema (as proteins are essential to maintain plasma osmotic pressure, which keeps fluid within capillaries), and blood clotting will be impaired. The most important effect is that the blood will not have sufficient glucose for cells to function normally.
In addition, when liver cells fail to function properly, their ability to make foreign substances less toxic by metabolic enzymes fails and the toxicity of some drugs used in medicine, such as morphine, is increased.
A7.2 Role of the liver in metabolism of xenobiotics
Humans are constantly and unavoidably exposed to foreign chemicals or xenobiotics, which include both synthetic and natural chemicals such as medical drugs, industrial chemicals, pesticides, pollutants, plant alkaloids and plant metabolites, and toxins produced by moulds, plants, and animals.
The physical property that enables many xenobiotics to be absorbed through the skin, lungs, or gastrointestinal tract is their fat solubility or lipophilicity. Lipophilicity is also an obstacle to their elimination as they can be readily reabsorbed. Another important consideration is that lipophilicity facilitates the entry of toxic substances into cells. Therefore, the elimination of xenobiotics often depends on their conversion to water-soluble compounds by a process called biotransformation, which is catalysed by enzymes in the liver and other tissues. An important result of biotransformation is the conversion of a lipophilic substance to one that is more water soluble (hydrophilic) (see phase 1 and phase 2 reactions below).
This transformation is probably one of the most important defence mechanisms of the body. Xenobiotics such as drugs exert beneficial effects and others may cause deleterious effects, as in the case of poisons. The effect a xenobiotic produces in the human body is dependent on its physicochemical properties and thus the results of xenobiotic exposure would be altered by this process of biotransformation.
Some drugs must undergo biotransformation to be effective because the metabolite of the drug and not the drug itself produces a therapeutic or beneficial effect. Similarly, some xenobiotics undergo biotransformation to produce their harmful or toxic effects. However, in the vast majority of situations, biotransformation terminates the effectiveness of the xenobiotic in the human body, be it beneficial or harmful. In the context of toxicology, this means that many potentially toxic substances are made relatively innocuous by biotransformation by liver enzymes. These are predominantly the cytochrome P450 group of isoenzymes, which are responsible for the majority of oxidation reactions that xenobiotics undergo.
The enzymes catalysing biotransformation reactions often determine the intensity and duration of the action of drugs and play a key role in chemical toxicity. The xenobiotic biotransforming enzymes catalyse two types of reactions. These are:
Phase I reactions: addition of a functional group (e.g. –OH, –NH2, –SH, or –COOH) to produce a slight increase in water solubility or hydrophilicity.
Phase II reactions: include glucuronidation, sulfation, acetylation, methylation, conjugation with glutathione and conjugation with aminoacids (e.g. glycine, taurine, glutamic acid). These reactions cause a large increase in water solubility and thus increase the excretion of the xenobiotic, for example:
Morphine, heroin, and codeine are all converted to morphine-3-glucuronide. In the case of morphine, this is a result of direct conjugation with glucuronide. In the instance of heroin and codeine, conjugation with glucuronic acid is preceded by phase I biotransformation—hydrolysis or deacetylation—with heroin and demethylation involving oxidation by cytochrome P450 isoenzymes with codeine.
A7.3 The cytochrome P450 enzyme system
The liver is the organ with the highest concentration of enzymes catalysing biotransformation reactions. These enzymes are also located in the skin, lungs, nasal mucosa (mucosa of the nose), eyes, and gastrointestinal tract. In the liver and in most other organs, they are located in the cells, primarily in the endoplasmic reticulum (microsomes) or in the soluble fraction of the cytoplasm, with a smaller concentration in the mitochondria, nuclei, and lysosomes.
Amongst the phase I biotransformation enzymes, the cytochrome P450 system is responsible for most oxidation reactions and is probably the most versatile, detoxifying more xenobiotics than any other enzyme system.
In humans, about 40 different microsomal and mitochondrial P450 enzymes play a key role in catalysing reactions in the following areas:
◆ the metabolism of drugs, environmental pollutants and other xenobiotics;
◆ the biosynthesis of steroid hormones;
◆ the oxidation of unsaturated fatty acids to intracellular messengers, and
◆ metabolism of fat-soluble vitamins.
The liver microsomal P450 enzymes involved in xenobiotic biotransformation belong to three main P450 gene families: CYP1, CYP2, and CYP3. The level and activity of each P450 enzyme varies from individual to individual due to genetic and environmental factors.
It is important to remember that the activity of the CYP isoenzymes can be altered by several agents. For example, there are many drugs that increase the activity of the isoenzymes and these are called enzyme inducers. Similarly some xenobiotics can inhibit the activity of CYP450 isoenzymes and these are called enzyme inhibitors. The induction of CYP450 isoenzymes by drugs such as phenobarbital (a barbiturate used primarily in the treatment of epilepsy) or rifampicin (an antibiotic used in the treatment of tuberculosis) can prevent the effectiveness of the oral contraceptive drug ethinyl oestradiol.
A7.4 Common medical signs, symptoms, and terms associated with liver dysfunction
Jaundice: a yellowing of the skin (and whites of eyes) by bilirubin, a bile pigment, frequently caused by a liver problem.
Ascites: an accumulation of serous fluid within the inner lining of the abdominal cavity (the peritoneal cavity), which causes a ‘bulging’ abdomen.
Hepatic encephalopathy: a term used to describe the deleterious effects of liver failure on the central nervous system. Features include confusion, dementia, and often unresponsiveness (coma). A common cause is alcoholic cirrhosis.
A8 The kidney
The kidneys are two bean-shaped organs about the size of a fist lying below the rib cage. Although they are small in size (about 0.5% of the body weight), the kidneys receive approximately 20% of the blood that is pumped out from the heart via the renal arteries. The main parts of the kidney are an outer lightly coloured cortex and an inner darker medulla (Figure A12). The renal (kidney) pelvis is the funnel which collects the urine from nephrons (the basic functional unit of the kidney) and enables the urine to flow to the ureters. The ureters are the tubes that carry the urine from the kidneys to the urinary bladder.
The blood brought to the kidneys by the arteries is filtered under pressure by a part of the nephrons (Figure A13). There are approximately one million nephrons and each nephron is a thin long convoluted tube, surrounded by capillaries, which is closed at one end, where the filtering takes place. The filtered fluid is then absorbed from within the nephron, according to the needs of the body. The cells of the tubules also have the ability to secrete waste substances into the lumen of the tubule of the nephron into the urine. These waste substances include many toxins and drugs.
The kidney plays a key role in the elimination of waste products and unwanted substances from the blood. The blood supply and blood vessels and the structure of the kidney enable the entire blood volume of an individual to be filtered 20–25 times a day. The ‘cleaned’ blood is returned to the circulation by the renal veins.
Essentially, three basic processes take place in the nephron: filtration, absorption or reabsorption, and secretion or excretion.
The principal function of the kidney is to produce urine, which is excreted from the body and ensures the maintenance of the correct chemical environment (milieu interior) for body cells: water balance, electrolyte balance, and the pH of the blood. It has other functions such as producing substances necessary for the formation of red blood cells (erythropoetin), converting vitamin D to an active form which promotes the absorption of calcium from the intestine, and also producing some hormones associated with the regulation of blood pressure.
Urine normally contains surplus water and electrolytes, waste products such as urea, which is formed from the amino acids, uric acid, which is produced from nucleic acids and purines, and creatinine from muscle. Urine also gets rid of excess amounts of acids or alkalis that have either been ingested or are formed following metabolic processes.
It is important to note that most toxic substances and even beneficial substances such as drugs that are used in treatment are eliminated in the urine and the measurement of the relevant constituents can confirm either the use of drug(s) or the exposure to toxic compounds. Thus examination and analysis of the urine is an important investigation in toxicology and acts as a biomarker of exposure. The amounts excreted in the urine may also be an indicator of the severity of exposure to a toxic substance.
A8.1 Common symptoms associated with disease of the kidneys
Anuria: the complete suppression of urinary secretion by the kidneys.
Uraemia: in current usage, this is the entire constellation of signs and symptoms of chronic renal failure leading to increased urea in the blood. These include nausea, vomiting, anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic ‘frost’ on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, oedema, mental confusion, and acid base and electrolyte imbalances.
Dysuria: painful or difficult urination.
Oedema: the presence of abnormally large amounts of fluid in the intercellular tissue spaces of the body, usually applied to demonstrable accumulation of excessive fluid in the subcutaneous tissues. Oedema may be localized, due to venous or lymphatic obstruction or to increased vascular permeability, or it may be systemic due to heart failure or renal disease. Collections of oedema fluid are designated according to the site, for example ascites (peritoneal cavity), hydrothorax (pleural cavity), and hydropericardium (pericardial sac).
Haematuria: the presence of blood in the urine.
Proteinuria: the presence of proteins in the urine.
A9 The reproductive system
The reproductive system in the male comprises the testes, penis, and associated ducts and glands. In the female it includes the ovaries, uterine tubes, uterus, vagina, and mammary glands. A detailed consideration of the reproductive system is not possible in a text of this length but overall it involves the production of sperm cells and their transfer to the female. In the female, fertilization of ova (eggs) takes place and the uterus provides a suitable environment for the developing embryo (foetus). The reproductive system is very important toxicologically since the dividing cells of the early developing foetus are vulnerable to drugs and other toxic substances, leading to malformations. The drug thalidomide, used in the 1960s, was the first known example of damage to the foetus in this way, leading to babies being born with partial or total absence of limbs, a condition called phocemelia.
A10 The endocrine system and the production of hormones
The activities of the organs of the body are primarily controlled by nerve impulses. The other important mode of control of activity is by hormones. These are chemical messengers produced by endocrine glands. They enter the bloodstream directly following secretions by the glands and are brought to all parts of the body by the cardiovascular system. Most organs are under the influence of both nerve impulses and hormones.
The word ‘hormone’ is derived from the Greek word hormao, which means to excite. A hormone is a naturally occurring substance secreted by specialized cells that affects the metabolism or behaviour of other cells possessing functional receptors for the hormone. Hormones may be hydrophilic, like insulin (from the pancreas), in which case the receptors are on the cell surface, or lipophilic, like steroids (from the adrenal cortex), where the receptor can be intracellular. Thus hormones are substances which circulate in the blood and bring about an effect on distant organs.
The main endocrine glands are:
◆ parathyroid glands
◆ ovaries in the female
◆ testes in the male
◆ placenta during pregnancy
◆ pancreas, which is both exocrine and endocrine (secretions of exocrine glands reach the bloodstream through ducts whilst those of endocrine glands reach the bloodstream directly).
A10.1 Pituitary gland
The pituitary gland lies in a bony cavity in the skull called the pituitary fossa. The posterior part of the pituitary is suspended by a structure called the pituitary stalk from a part of the brain called the hypothalamus. The gland has two parts: the anterior pituitary or adenohypophysis, and the posterior pituitary or neurohypophysis (Figure A14). Whilst the posterior pituitary has neural or nerve connections with the brain, the anterior pituitary has vascular connections with the brain.
A10.1.1 The posterior pituitary
The posterior pituitary is composed mainly of nervous tissue descending from the hypothalamus and produces two hormones:
◆ antidiuretic hormone (vasopressin), and
◆ oxytocic hormone (oxytocin).
Antidiuretic hormone (ADH) is involved intimately with water balance as it controls or regulates the amount of water that is reabsorbed in the kidney. Large doses of ADH cause high blood pressure or hypertension as it causes vasoconstriction or contraction (narrowing) of blood vessels. The amount of ADH secreted is controlled by the amount of water in the blood. If the body is short of water, more ADH will be secreted and more water will be reabsorbed by the kidney tubules and less urine will be formed.
The posterior pituitary may fail to produce ADH, in which case the condition is called diabetes insipidus. In this condition excessive amounts of urine are formed and lost from the body and patients are always very thirsty.
The oxytocic hormone
The oxytocic hormone is only important during pregnancy. It causes contraction of the pregnant uterus and facilitates the ejection of milk during lactation.
A10.1.2 The anterior pituitary
The hormones released by the anterior pituitary gland are:
◆ growth hormone;
◆ thyrotrophic hormone;
◆ adrenocorticotrophic hormone, and
This hormone stimulates the growth of bone and muscle tissue during childhood. If there is excessive production of this hormone before puberty (when the long bones fuse with the growing ends or epiphyses and no further increase in growth can occur), gigantism results. Insufficient production causes dwarfism. Increased production after puberty leads to an increase in the size of facial bones and the bones of the hands and feet—a condition called acromegaly.
A10.2 Thyroid-stimulating hormone and the thyroid gland
The thyroid-stimulating hormone acts on the thyroid gland in the neck and stimulates the release of the thyroid hormones thyroxine and tri-iodothyronine. The thyroid hormone stimulates metabolism by acting on the cells to speed up the rate at which food is used up and converted to heat and energy. The thyroid gland is unique in that it stores its hormones as a colloid in small vesicles in the gland. The other glands store their secretions in the cells themselves. The formation of the thyroid hormone requires iodine ingested in the diet. In regions where populations may encounter a deficiency of iodine in their diets, the addition of iodine to salt (iodized salt) has helped in the prevention of thyroid disease, particularly the enlargement of the thyroid gland known as goitre. Deficiency of the thyroid hormone (also called hypothyroidism) in a child causes cretinism, where the development of the nervous system is affected and the child is mentally retarded. In an adult, deficiency of thyroid hormone causes myxoedema, where the body temperature is low, the heart rate is slow, brain activity is sluggish, and there is deposition of fluid-like material under the skin. The face and eyelids become puffy.
If there is increased production of thyroid hormone (hyperthyroidism), metabolism is stimulated and more heat is produced, the heart beats faster, and the heart excitability is increased, which may give rise to disorders of heart rhythm (cardiac arrhythmias). In this situation, which is called thyrotoxicosis, the person is irritable, anxious, and nervous. They lose weight although the appetite is good. They often have protrusion of the eye balls (exophthalmos).
In addition, the thyroid gland produces calcitonin, which is important in the regulation of calcium balance.
Parathyroid glands are adjacent to the thyroid gland but are not controlled by the secretions of the anterior pituitary gland. There are four parathyroid glands, two on either side of the thyroid. The hormones from the parathyroid gland control the calcium levels in the blood. Another factor affecting the blood calcium level is calcitonin, which as stated above is a secretion of the thyroid gland. Calcitonin acts by trapping calcium in the bones. Another important factor determining the level of blood calcium is vitamin D.
With increased activity of the parathyroids (hyperparathyroidism), the plasma level of calcium increases to about 20 mg calcium per 100 ml of blood from a normal of 5.5 mg of calcium per 100 ml of blood. This calcium comes from the bone and the kidney gets rid of it from the body. Thus the bones become thin and fragile, and are likely to fracture more easily than normal bones with sufficient calcium.
With decreased production of parathyroid hormone (hypoparathyroidism), the blood calcium level falls, which causes increased excitability of the nerves and of the neuromuscular junctions, leading to a condition called tetany (this has to be distinguished from the disease tetanus, which follows infection with a bacillus Clostridium tetani). In tetany, there is spasm of the hands and feet (carpo-pedal spasm). Increased excitability of the nerve cells in the brain may lead to convulsions.
A10.4 Adrenocorticotrophic hormone and the adrenal gland
The adrenal glands are located on the top of each kidney (see Figure A12). Each adrenal gland consists of a central medulla and an outer cortex.
The adrenal medulla releases the hormones adrenaline and noradrenaline (epinephrine and nor-epinephrine) in response to nerve stimuli that enter the medulla from the sympathetic nervous system. Thus the adrenal medulla is an integral part of the sympathetic nervous system and is intimately involved in the fight or flight responses to stress, where increased sympathetic activity is life saving. It is common to state that a person should have sufficient adrenaline to perform well. The secretions of the hormones from the adrenal medulla are not under the control of the anterior pituitary adrenocorticotrophic hormone (ACTH).
The adrenal cortex has three layers and each layer produces a different hormone and at least two of the layers are controlled by ACTH from the anterior pituitary gland.
The outer layer—the zona glomerulosa—produces aldosterone, which is necessary for reabsorption of sodium in the kidney. An excess of aldosterone causes salt and water retention. The secretion of aldosterone is considered to be regulated by a hormone secreted by the kidney, renin.
The inner two layers of the adrenal cortex—the zona fasciculalta and the zona reticularis—produce hormones collectively known as cortcosteroids. The main corticosteroid secreted is cortisol (hydrocortisone). The corticosteroids have several actions:
◆ they favour the utilization of proteins for the production of heat and energy in preference to the use of carbohydrates;
◆ anti-inflammatory, and
◆ aldosterone-like effects causing retention of sodium and of water and loss of potassium. The salt and water retention may lead to oedema and/or high blood pressure (hypertension).
Cortisol reduces the utilization of carbohydrates for energy, thus the blood sugar level often increases (a diabetogenic effect). When body proteins are broken down, wound healing is impaired and the effect on suppression of immune or inflammatory response can lead to ‘masking’ of infections (which may cause delays in diagnosis) and also an increased susceptibility to infections.
Over-production of the adrenal cortex hormone leads to Cushing's syndrome, which is characterized by a ‘moon face’ that is caused by redistribution of fat and swelling of the face. Redistribution of body fat leads to ‘an egg on match sticks’ appearance with an expanded abdomen and chest with ‘skinny’ limbs, particularly lower limbs, diabetes, and increased blood pressure. The skin tends to bruise easily and purple striae appear on the skin; females develop hirsutism. There may also be psychological changes.
Changes similar to Cushing's syndrome follow treatment with corticosteroids over a period of time for several common disease states. An excessive production of aldosterone leads to Conn's disease, which is associated with muscular weakness, increased loss of potassium, and water in the urine.
Decreased activity of the adrenal gland leads to Addison's disease. This was common following tuberculosis affecting the adrenal gland when both the medulla and cortex were affected. In Addison's disease, sodium and water are lost from the body and this causes a lowering of blood pressure, muscle weakness, nausea, and vomiting. The production of catecholamines (e.g. adrenaline and noradrenaline) is affected and there is increased production of melanin instead. This leads to increased pigmentation, particularly of exposed parts. Episodes of low blood sugar may occur as adrenaline plays an important role in mobilizing glucose, particularly in times of stress.
A11 The immune system
Immunology is the study of the physiological responses by which the body destroys or neutralizes foreign matter or xenobiotics, living and non-living, as well as its own cells that have become altered in certain ways. The ability of the immune response to protect us against bacteria, fungi, viruses and other parasites, and other foreign matter is one of the most important defence mechanisms of the human body.
This immune response—the process by which xenobiotics are destroyed or neutralized—is therefore essential for a healthy disease-free life. The immune response can also destroy cancer cells that arise in the body and also worn out or damaged cells such as old red blood cells or erythrocytes.
Immune responses can be broadly classified into:
1. non-specific immune responses, which recognize in a non-selective manner all foreign substances;
2. specific immune responses against substances that are specifically identified and then attacked.
Bacteria have the ability to cause damage at their sites of invasion or can release into the body fluids (extracellular fluids, of which blood is the most important) toxins that are carried to other parts of the body to cause damage to cells.
The body also needs protection against viruses, which are essentially nucleic acids surrounded by a protein coat. Unlike bacteria, which have their own metabolic processes and can multiply independent of other cells, viruses lack the enzyme processes and other cell constituents such as ribosomes for their own metabolism and energy production. Therefore viruses can only multiply whilst living inside other cells whose biochemical apparatus they make use of. The nucleic acids in the viruses cause the production/manufacture of proteins required for the viruses to multiply and also the energy to multiply.
The cells and associated components that carry out immune responses are collectively called the immune system. Although called a system, it has no anatomical continuity but consists of diverse collections of cells found in both the blood and tissues (cells) throughout the body.
Cells mediating the immune response are the following:
1. White blood cells or leucocytes, including neutrophils, basophils, eosinophils, monocytes, and lymphocytes. The lymphocytes are grouped into B cells and T cells (cytotoxic T cells, helper T cells, and suppressor T cells). White blood cells can leave the circulation or blood (unlike the red blood cells) and enter tissues and function in the tissues.
2. Plasma cells found in peripheral lymph organs. Plasma cells differentiate from lymphocytes in the tissue and are not found in the blood as the name suggests.
3. Macrophages present in almost all tissues and organs are large cells but their structure may vary from tissue to tissue. They are derived from monocytes (white blood cells) that leave the blood vessels to enter the tissues. As their main function is to engulf foreign material, they are strategically located at sites where entry of foreign substances or organisms is likely to take place.
4. Mast cells are also found in all tissues and organs. Mast cells differentiate from basophils that have left the blood vessels and a characteristic feature is that they usually contain large numbers of secretory vesicles and they secrete mainly locally acting chemical messengers such as histamine. These cells are involved in allergic responses such as hypersensitivity reactions.
This is the local reaction of the body to injury or infection which essentially destroys or inactivates the foreign invaders and prepares the body to repair the injury caused. The main role is played by phagocytes, which engulf the foreign material by a process called phagocytosis. Once inside the phagocyte, the foreign substance is destroyed. The important phagocytes are the neutrophils, monocytes, and macrophages.
The usual clinical manifestations of inflammation are redness, swelling, heat, and pain, which are produced by a variety of chemical messengers or mediators. The better known of these mediators are the kinins, histamine, complement, and eicosanoids. The kinins are produced from the plasma protein kininogen whilst histamine is released from mast cells.
Two important mediators, interleukin 1 (IL1) and tumour necrosis factor, are protein in nature and are released by monocytes and macrophages during an inflammatory response.
Complement kills microbes without prior phagocytosis. Complement is always present in the blood albeit in an inactive form most of the time. Activation of complement in response to an infection or tissue injury generates active molecules from inactive precursors and the complement system comprises at least 20 distinct proteins. Complement also stimulates the secretion of histamine from mast cells and effectively increases the blood flow to the injured area and facilitates the movement of phagocytes such as the neutrophils to the injured area from within the blood vessels.
Lymphocytes also circulate in the blood but tend to gather in large numbers in group of organs and tissues called lymphoid organs such as bone marrow, the thymus gland (a gland found in the chest which tends to shrink in size after puberty), lymph nodes, spleen, and tonsils. These cells also concentrate in the lining of the intestine and in the respiratory, genital, and urinary tracts.
The lymphatic system is a network of lymphatic vessels and lymph nodes found along these vessels through which lymph, a fluid derived from interstitial fluid, flows. It constitutes a route by which interstitial fluid can reach the blood vessels or the cardiovascular system. This movement of interstitial fluid as lymph to the cardiovascular system is very important because the amount of fluid filtered out of all the blood vessel capillaries (except those of the kidney) exceed that which is reabsorbed by approximately 4 litres each day. These 4 litres are returned to the venous blood via the thoracic duct in the chest. In the process, the small amount of protein that usually leaks out of the capillaries is also brought back into the circulation by the lymphatic system.
Also important is that the lymph node cells encounter the materials that start off their response, that is the immune response via the lymph flowing through them. Each lymph node is a honeycomb of sinuses (enlargements or sac-like dilations containing lymph) lined by macrophages with large clusters of lymphocytes between the sinuses. The spleen is the largest of the organs containing lymphoid tissue and lies on the left side of the abdominal cavity between the stomach and the diaphragm (the large muscle that is essential for breathing and separates the thoracic cavity from the abdominal cavity).
The other structures with large collections of lymphoid tissue are the tonsils, which are small rounded structures in the throat that often get inflamed in children, resulting in the common condition called tonsillitis.
There are multiple populations and sub-populations of lymphocytes termed B lymphocytes, T lymphocytes, cytotoxic, helper, and suppressor T cells. There are two broad categories of specific immune responses. Firstly, a lymphocyte is programmed to recognize a specific antigen. An antigen is a foreign substance that triggers a specific immune response and is not an anatomical description but is a functional description. The ability of lymphocytes to distinguish one antigen from another is the basis of specific immune responses. Recognition of an antigen implies that antigen becomes bound to the lymphocyte which has receptors for that antigen.
Once the lymphocyte has attached itself to the antigen, it divides into different types of cells, and this takes place at the site where the antigen has attached itself to the lymphocyte. Some of the divided cells will attack the antigens, whilst others may influence both the activation and function of these ‘attack cells’.
The activated cells attack all the antigens that initiated the immune response. Lymphocytes attack the ‘invaders’ in one of two ways: antibody mediated or humoral and cell mediated.
Antibodies are proteins that are both present in the plasma membranes of B cells and are also secreted by them. These antibodies travel along the bloodstream to all parts of the body, combine with the antigens, and direct an attack by phagocytes and complement that eliminates the antigen or the cells bearing them. Antibodies belong to a group of proteins called immunoglobulins.
In cell-mediated immunity, the T lymphocytes and natural killer cells travel to the location of cells bearing on their surface antigens that initiated the immune response and directly kill them.
Two broad generalizations can be made. Antibody-mediated responses carried out by B lymphocytes have a large range of targets and are the major defence against bacteria, viruses, and other microbes and against toxic molecules. Cell-mediated killing by T lymphocytes and natural killer cells is against a more limited number of targets, specifically the body's own cells that have become cancerous or infected with viruses. The helper cells activate both humoral and cell-mediated immune responses. The helper cells are essential for the production of antibodies except in the case of a small number of antigens. Suppressor T cells inhibit the function of both B cells and cytotoxic T cells.
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