Lecture for year 2 Medical Students on 15th June 2001 by Professor Omar Hasan Kasule Sr.
A. CONTROL IN ANATOMY
There is centralised master control of physiological functions mediated by the pituitary gland,the hypothalamus, and the CNS. This control has a genetic basis in the form of DNA. DNA has 6x10E9
bits of information called codons. These represent 10E7 genes. Each gene codes for one protein molecule (Bowman p 4.1). Command and control in physiology relate
very well to the concept of tauhid. For efficiency there must be a controlling center otherwise contradictions from many un
coordinated centers of control will lead to failure. An orderly and harmonious universe cannot have more than one master.
Integrity of DNA: Cellular DNA is subjected to constant mutation pressure.
The mutations result in base substitution, deletion, insertion or rearrangement. Mutated cells may be eliminated by the immunological
surveillance system on the basis that they are abnormal or thay may be repaired and return to normal function. Repair processes
preserve the integrity of DNA. The integrity is further preserved by the conservative replication of DNA. Preserving DNA integrity
ensures that control of metabolic processes is constant.
Normal cell growth: The phases of cell growth are: G0 (quiescent stage),
M (variable phase), G1 (gap 1), S (DNA replication) , G2 (gap 2) which is a quiescent stage, M, Mitotic activity is controlled
through the endocrine system (growth factor & growth inhibitoy factors). The reticulo-endothelial system regulates the
optimal number of cells (proliferation, replacement, hyperplasia). Embryonic tissues, skin, blood, and intestinal mucosa have
an abnormal rate of multiplication but within the range of the normal (Bowman p 38.1). Embryonic cells continually divide.
They follow the cell cycle from mitosis to mitosis and are eventually destroyed. Parenchymal cells of all glandular organs
such as the liver, the kidney, and the pancreas are quiescent or stable cells. They have a low level of replication in ordinary
conditions. They can replicate rapidly on injury. Non-dividing (permanent) cells are the neural, skeletal muscle, and cardiac
Abnormal cell growth: Hypertrophy is increase in the size of cells
resulting ion increase or organ size. It could be physiological or pathological. Atrophy is shrinkage in the size of cells
by loss of cell substance. It is caused by decreased work-load, loss of innervation, decreased blod supply, inadequate nutrition,
loss of endocrine stimulation, and aging.In metaplasia there is a change from
one adult cell type to another both being normal cells. Dysplasia is disorganisation of cells. Hyperplasia is excessive growth
in response to a stimulus and is reversible when the stimulus is removed. In neoplasia, control mechanisms are deficient leading
to excessive proliferation. Neoplasia has genetic, physical, chemical, humoral, immune, and viral infectious causes. In benign
neoplasia the cells are well differentiated, are slow-growing, are encapsulated, and are not invasive. In malignant hyperplasia,
the cells are not encapsulated, the edges are not well defined, they are undifferentiated, with increased mitotic activity
and metastases. Malignant tumors are classified according to the tissue: epithelian (carcinoma and adenocarcinoma, papilloma,
adenoma, melanoma), connective tissue (sarcoma, osteoclastoma), nervous tissue (ganglioneuroma, neuroblastoma, neurofibroma,
neurofribrosarcoma), blood (leukemia, myeloma). Tumors cause injury by pressure, erosion, chemicals, (eh phaechromocytoma).
Control of cell growth: Growth factor is involved in cell growth. It
binds to cell receptors causing activation of the protein phosphorylation cascade which leads to entry into the cell cycle.
Cyclins are proteins that modulate the above process. Gorwth is limited by contact inhibition.
PRE-NATAL and POST NATAL GROWTH
Control of embryogenesis: The time-table and pre-determinism of the
growth process result in a constant and predictable outcome. None of the phenomena of growth exceeds its expectations. There
are correlations among physical, intellectual, moral, & social growth. The shaping in the uterine stage is according to
Allah’s wish; He makes it as He likes 3:6. The uterine stage is for a limited period (22:5). The process goes through
pre-determined stages (22:5, , 39:6). Growth in definite stages, twuur (71:4).
Post-natal growth: The 5 stages: intra-uterine, Infancy and childhood,
tufuula), youth, sinn al shudd, middle
age, sinn al rishd, old age, shaikhukhat/
ardhal al ‘umr (16:70).
Rationale of staged growth: The staged and relatively slow growth and
changeis necessary to allow interaction with and learning from the environment
since the fetal stage and the later period of childhood are learning and adaptation processes to the environment. Relations
established among organs and tissues in the embryological period correlate with later physiology and pathology. Embryological
blood supply and innervation persist even when organs migrate to new positions. Some embryological organs and tissues disappear
after serving their function.
Growth and decline: It is a constant law that phenomena of growth and
renewal co-exist with those of degeneration and decay. The overall result is determined by which of the two phenomena is dominant
at a particular time. Human cells are growing and are increasing by mitosis but at the same time old and effete cells are
broken down. The human body declines and degenerates toward old age, ardhal al umr (p 16:70, 22:5, 36:78). This overall
physical decline occurs despite daily renewal of cells.
Concept of life-span or half-life: Every living things has a maximum
life-span. This applies to cells, sub-cellular organelles, tissues and whole organisms. In biology life-span is expressed
as half-life which is a mesasure of the time taken for a 50% decay. Half-lfe (T1/2) for albumin is 15-20 days, platelets 8-14
days, erythrocytes 120 days. Erythrocytes are replaced at the rate of 2 million a second. Exponential decay is a constant
of nature and is considered one of the sunan. The exponential distribution.
B. CONTROL IN PHYSIOLOGY, BIOCHEMISTRY, PHARMACOLOGY
BALANCE AS THE OBJECTIVE OF CONTROL
The various control mechanisms in the body aim at maintaining an optimal balance.
If the balance is disturbed, patho-physiological disturbances occur.
PHENOMENA OF BALANCE
FLUID BALANCE: The following distribution systems are involved
in fluid balance: distributiion between tissues, distribution between the intra-cellular fluid (ICF) and extra-cellular fluid
(ECF), and the acid-base balance. The organs involved in integrated homeostatic control are the kidneys, the alimentary system,
the respiratory system, and the cardio-vascular system. Both neuronal and endocrine controls are involved in these organs.Water is 66% of adult body weight; if adipose tissue is excluded this proportion becomes
73.2%. The ratio of water distribution between ICF and ECF is 1:2 for adults and 1:1.5 for infants. The extracellular fluid
compartment consists of: interstitial fluid, lymph,blood plasma, and transcellular
fluids such as CSF, synovial fluid, acqueus humor, endo and periluymph, peritoneal fluid, perocardial fluid, pleural fluid,
and alimentary secretions. Osmotic pressure is the main determinant of fluid distribution. A tight water balance is maintained
between water losses and water intake. Water loss of 1.1 liters a day is accounted for as follows: vapour in expired air 0.4
L/.day, skin evaporation 0.4L/day, sweat 0.1-0.8 L/day, feces 0.2l/day and urine 1 l/day. Water intake is 0.8 l/day from diet,
0.4 l/day as metabolic water, and the balance from fluid intake.
ELECTROLYTE BALANCE: The chemical composition of the extra-cellular
fluid compartment is maintained constant. Differential concentrations across permeable membranes are temporary. Electrolytes
are transported across the membranes to restore the balance and remove the chemical or electrical gradient. (a) Sodium balance:
The daly dietary intake is 2.5 - 15 g as Sodium Chloride. It is lost in feces 0.3 g /day and in sweat which can be up to 20
g/day in hot climates. The lymphatic system removes excess sodium from tissues and returns it to the circulation. Excess sodium
leads to fluid retention.
IRON BALANCE: Total iron in the body is 2-6 g. It is lost at a
rate of 0.5 mg/day as part of cells being shed off. The dietary intake is 15-20 mg of which only 0.5-2.0 mg is absorbed. Menstrual
iron loss is 17.5 mg in 35 ml, 0.6 mg/day. Pregnancy and chronic bleeding increase iron needs.
ACID-BASE BALANCE: There are 3 mechanisms for balance of H+. (i)
buffer systems based on carbon dioxide and ionisable proteins (ii) regulation of carbon dioxide elimination by the lungs (iii)
electrolyte secretion by the kidneys. The following equations show the equilibrium equations for the buffer systems (a) :
CO2 + H2O <--à H2CO3<--à H++HCO3- (b) HbO2 + CO2 + H2O ßà HHb + HCO3-+ O2 (c) Protein+ <--à H++ HCO3-. Acidosis (metabolic and respiratory) and alkalosis (metabolic & respiratory) are conditions
of imbalance that are rapidly corrected by the body. Respiratory acidosis arises due to accumulation of carbon dioxide that
arises in hypoventilation. Respiratory alkalosis airses when there is low carbon dioxide pressure in the alveoli in cases
of hyperventilation. Metabolic acidosis arises in cases of lactic acidosis. Metabolic alkalosis arises when bicarbonates are
ingested. The kidney plays a role in acid-base balance by regulating the excretion or reabsorption of HCO3- and H+.
ENTROPY (DISORDER) AND EQUILIBRIUM: Energy is needed for maintenance,
reproduction, and other functions under the rubric 'catabolic'. ATP is the link between energy-producing and energy-utlising
systems. There is inter-conversion between various forms of energy. There is also exchange of energy with the external environment.
Entropy is the degree of disorder or randomness in the system. All processes chemical or biological tend toward maximum disorder,
entropy. Equilibrium is achieved when disorder is maximum. The relation between change in free energy available for work,
G, enthalpy (change in heat content), H, and change in entropy can be described mathematically.
HEATENERGY BALANCE: The
first law of thermodynamics state sthat energy can not be created or destroyed (law of conservation of energy). It can only
be interchanged from one form to another.The chemical energy of glucose covalent
bonds can be converted to the chemical energy of ATP. The chemical energy of ATP can be converted to mechanical energy of
muscle contraction. The law of conservation of energy applies to human metabolic processes. According to the 1st
law of thermodynamics, there is energy balance in a closed system. The energy output = external work + energy storage + heat.
Metabolic rate = energy per unit time. Efficiency = work done/total energy expended. Heat balance is controlled basically
by physico-chemical factors.Heat is produced by: metabolism (catabolic break-down
of macro molecules), food intake (specific dynamic action of food), and muscle activity. The amount of heat produced by metablism
can be measured by direct calorimetry or indirectly by measuring oxygen and carbon dioxide consumption/production. About 85%
of all heat produced is from 5 organs only: liver, muscle, brain, heart, and kidneys. Metabolic rate is more related to surface
area than to weight. Other factors of metabolic rate are: age (lowest in infants and elderly), hormonal status (thyroid, anterior
pituitary, adrenaline), habitat, amount of brown fat, mental state (anxiety), shivering, food intake, work and exercise, and
body temperature. Heat is lost by radiation, conduction, vaporisation of sweat, respiration, urination, and defecation. Heat
can be gained or lost by conduction, convection, and radiation.
TEMPERATURE BALANCE: There are mechanisms to make sure that the
body temperature stays within the acceptable range (Ganong p 230). Pathogenesis of fever (Ganong p. 231). Humans are homoimothermic
(ie bofy temperature is within a narrow range). Poikilothermic animals such as reptiles and amphibia have body temperatures
that vary with external temperature. Heterothermic animals are able to suspend the homoimothermic state and go into hibernation.
Normal human body temperature is 37 degrees centigrade. There are regional differences: rectum is 0.3and the axilla is 0.6 degrees below the mouth. The temperature of blood leaving the liver is 0.2 degrees
higherthan blood entering the liver. Testes are 1 degree below rectal temperature
since spermatogenesis is inhibited below 36 degrees. A circadian rhythm has been described with temperatures being lowest
in the morning and highest in the afternoons and evenings. The temperature rises on ovulation, work, and exercise.
BALANCE BETWEEN COAGULATION AND FIBRINOLYSIS: The processes of
coagulation and fibrinolysis are kept in finely tuned balance. Hemostasis refers to control of blood coagulation which stops
bleeding from injured blood vessels. It has three components: platelets which plug the injury, the coagulation process, and
the contraction of the vascular smooth muscles that cuts off blood supply to the injured area. Coagulation is the process
of stopping bleeding; its eventual product is the clot that plugs the injured blood vessel. The change of prothrombin to thrombin
is a result of a series of events (a cascade) triggered by contact with a 'foreign' substance; the amplification factor in
the cascade could be as much as a million. Thrombin causes the change of fibrinogen to fibrin that is the basis of the clot.
The fibrinolytic system acts opposite to the coagulation system. It is triggerred at the same time as the coagulation system
by damage to tissues. Plasminogen is activated to change to plasmin (fibrinolysin). Anti-plasmin in serum and platelets controls
the small amounts of plasmin that are formed spontaneously. Urokinase and similar substances in tears, sweat, milk, and other
secretions are plasminogen activators. Once a clot is formed fibrin is covered and plasmin does not reach the inside.
BALANCE OF SYMPATHETIC AND PARASYMPATHETIC SYSTEMS: Balance between
sympathetic NS (flight or fight) vs parasympathetic (resting function or quiet activity). The balance is responsible for control
of: HR, BP, GIT motility, bladder control, sweat glands, erector pilli muscles, smooth muscles of blood vessels
BALANCE BETWEEN LEFT AND RIGHT BRAIN HEMISPHERES: The left and
right brain hemispheres are connected by the corpus collosum. There is continuous communication between the right and the
left brains. There is clear dominance by either hemispehere.Injuries to one hemisphere or to the joining corpus collosum lead
to specific clinical manifetations. It is interesting that many functions depend on the balance between the two hemispheres.
Whe one hemisphere is injured, the othert ione seems to take over some of the functions that would otherwise be lost.
EQUILIBRIUM OF CHEMICAL REACTIONS: Equilibrium reactions: Hassel-bach
law. Enzyme kinetics. Cytochromes are found in all cells except RBC and skeletal nmuscles. They catalyse the oxidation of
various compounds. Structure closely follows function. Little changes lead to big differences.
BALANCE BETWEEN ANABOLISM AND CATABOLISM: The 4 processes in protein
synthesis: transcription, post-transcription, modification, translation, post-translation modification..
PHENOMENA OF CONTROL IN PHYSIOLOGY, BIOCHEMISTRY, PHARMACOLOGY
CONTROL OF THE HEART BEAT: The heart rate is a balance between
opposing effects of the sympathetic and para-sympathetic nervous systems. If both were eliminated the heart would beat at
an intrinsic rythm of 110/minute. If the sympathetic system alone were eliminated, the heart rhythm would be 60-70/minute.
If the parasympathetic system were eliminated the rythm would be 160/minute. The cardio-regulatory and cardio-inhibitory centers
in the medulla are under cortical control. Baro-receptors in the carotid sinus, the aortic arch,, and the wall of the left
ventricle have control on the heart rate. Heart rate decreases in sl;eep and increases on exercise, fever, and stimulation.
Sinus bradycardia is found in athletes and sinus tachycardia is found in infants. The electrical activity of the heart and
the cardiac conduction system (SAN, AVN, internodal pathway) ahev a role in controlling the heart rate. The electrical impulse
starts from SAN through the inter-nodal tract to the bundle of His, the purkinje network, to the ventricular muscle. The speed
of conduction is controlled and is variable. Atrial systole is before ventricular systole. Concept of pacemakers as automatic
cells. There is a hierarchy among pacemakers.
CONTROL OF VOMITING: The stimuli for vomiting are from: intra-cranial
pressure receptors, GIT receptors (chemical or pressure), labrynth, and the cerebral cortex (chemo-receptor trigger zone).
The vomiting center is in the medulla oblongata. Nausea is sensation of anticipation of vomiting. Salivation is the first
act. Deep inspiration is followed by increased intra-abdominal pressure. The epiglottis is closed and the soft palate is raised.
Abdominal muscles contract in a co-ordinated way.
CONTROL OF SWALLOWING:
CONTROL OF COUGHING: Sneezing is due to mechanical and chemical
irritation. The hiccup is involuntary rapid inspiration of the diaphragm with the glottis closed. Yawning is prolonged inspiration
with the mouth open and the pharynx dilated. It is due to fatigue and psych0-social factors.
CONTROL OF GAGGING:
CONTROL OF POSTURE: Integration in the brain and spinal cord. Motor
cortex. Cortico-spinal and cortico-bulbar. The extrapyramidal system. Postural reflexes,
CONTROL OF MICTURITION:
CONTROL OF DEFECATION: Distention of the sigmoid colon leading
to awareness of need for defecation. The presence of stool in the rectum relaxes the internal anal sphincter. The external
anal sphincter is under voluntary control. Contraction of abdominal muscles helps expel the stool.
CONTROL OF LACTATION:
CONTROL OF PARTURITION: (Bowman p. 20.53)
CONTROL OF CELL MEMBRANE PERMEABILITY: passive diffussion, cellular-facilitated
diffussion, active transport
CONTROL OF GENETIC EXPRESSION: Every human has 23 chromosomes pairs.
The mammalian geneome has 4 x 10E9 base-pairs of DNA. About 0.3% of human DNA is in the mitochondria outside the nucleus.
The DNA content does not correlate with the complexity of the organism. Each cell has the same DNA but expression of some
genes is inhibited by histone. This is the basis for cellular specialisation. Regulation of gene expression enables the organism
to adpt to the environment. Molecules regulate gene expression for example all body cells have genes for insulin but only
pancreatic cells produce it.An operon is a complete regulatory unit of clustered
genes. It consists of structural genes and regulatory genes. Introns are intervening sequences that do not code for any protein.Inducer molecules turn on te transcription of a structural gene whereas co-repressor
s are molecules that inhibit induction.
CONTROL OF HORMONAL RECEPTORS: surface membrane, cytoplasmic, intranuclear.
Endocrine hormones are elaborated in endocrine glands and ae released into the blood stream to exert their action on certain
other tissues. Some chemicals such as serotonin and histamine are referred to as local hormines. Neurotrasnmitters such as
PHENOMENA OF PERIODICITY IN PHYSIOLOGY, BIOCHEMISTRY, PHARMACOLOGY
CYCLICITY: Many phenomena in human biology go though a full circle
and repeat themselves. Nothing illustrates this better than the origin and fate of the human body. Earth is the origin of
all the physical elements of the human body and to it all return. Humans were created from dust, khalq al insan min turab ( , ,
, 22:5, 30:20, 35:11, 40:67, 71:17). They return to the earth on death and
burial (‘awdat al insan ila al turab): 13:5, 16:59, 17:49, 20:55, 23:35,
23:82, 27:68, 37:16, 37:53, 50:3, 56:47, 37:16, 78:40. Humans also go through a social cycle. They start in weakness as infants.
They become strong as young adults before becoming weak again in old age (30:54). The cell cycle has 4 phases: G0, G1, G2,
and S. The mature human female has several cyclical phenomena: ovarian, uterine, cervical, and vaginal cycles. The human menstrual
cycle differs from the estrus cycle in animals.
CIRCADIAN RYTHMS: Circadian rythms in biology also illustrate cyclicity.
ACTH secretion has a circadian rhythm. Wake and sleep alternate. The body temperature changes cyclically between day and night.
Melatonin secretion is also cyclical
PHENOMENA OF CONSTANCY and PREDICTABILITY IN PHYSIOLOGY, BIOCHEMISTRY, PHARMACOLOGY
DIAGNOSTIC TESTS: the principle is that there is consistency and
predictability. Indirect measures of phenomena. Concept of normative distribution. The central tendency. Methods of direct
visualisation of sample eg histology, slides, electron microscopy, x-ray, cat scan, MRI. Serology: agglutination, precipitation,
electropheresis, radioiimunoassay. Measure products of metabolism & their homeostatic levels: primary, intermediate, and
DRUG ACTION: Three stages can
be defined for drug action. The pharmaceutical phase is the disintegration of the drug. The pharmaco-kinetic phase is the
absorption, distribution, metabolism, and excretion of the drug. The pharmaco-dynamic phase involves drug-receptor intercations.
Drugs act at the following levels: molecular, subcellular structures, cells, tissues and organs, intact organism, and interaction
between organisms. The targest of drug action are: enzymes, transport systems, and receptors. Drugs act by specific interference
with metabolic processes (Bowman p 2.29). Almost all drugs act by interference with cell division or cell growth either in
humans or in the pathigens or neoplasms. The agents interfere with synthesis or function of DNA, RNA, arrest of metaphase
or arrest of telophase. The non-specific mechanisms that determine drug action are: osmotic properties, acidity, basicity,
osidising and reducing agents, protein precipitation, physical barriers, adsorbents, surfactants. Chemical bonds (covalent
and electri-static) are intimately bound with drug action. Recptor action may be agonist or antagonist. Structure determines
receptor action. Antibiotics act by inhibiting protein synthesis in micro-organisms but not in humans.