3. Subject Lectures Page n.
Histology
Histological structure of cartilages. 2
Histological structure of bone 8
Histological structure of Skeletal & smooth ms. 17
Physiology
Physiology of the neuromuscular transmission & its
modulation.
26
Mechanism of muscle contraction. 38
Smooth muscles 45
Pathology
Pathology of joint diseases. 49
Osteodystrophy. 60
Osteomyelitis. 73
Bone tumors. 80
Soft tissue tumors. 94
Pharmacology
Analgesics & antipyretics. 104
Skeletal muscle relaxant. 127
Disease Modifying Antirheumatic drugs (DMARDs). 133
Parasitology Trichinellosis and Muscular cysticercosis. 146
Microbiology Clostridium & anaerobiosis. 154
Anatomy
Anatomy of the vertebral column. 167
Deep muscles of the back & arm muscles. 169
Shoulder girdle, shoulder joint & axilla. 173
Anterior and posterior forearm muscles. 182
Nerves of the upper limb & injuries. 187
Muscles of the gluteal region and posterior thigh. 195
Muscles of the anterior and medial thigh. 200
Muscles of the leg. 209
Joints of the lower limb. 215
Development and anomalies of vertebral column & limbs. 222
INDEX
5. 2
THE CARTILAGE
It is a special type of connective tissue with firm consistency of the extracellular matrix.
Types of the Cartilage There are 3 types of cartilage:
1. Hyaline cartilage.
2. Yellow elastic fibro-cartilage.
3. White fibro-cartilage.
1. HYALINE CARTILAGE
It is the most common type of cartilage.
Appearance: in fresh state it appears translucent pale blue i.e., hyaline = glassy.
Consistency: firm or rigid with some degree of flexibility.
Structure: it is formed of:
- Perichondrium.
- Cartilage cells = chondrocytes.
- Cartilage matrix.
(I) Perichondrium
- It is a vascular connective tissue membrane which surrounds the cartilage
except at the articular surfaces of the joints.
- It is formed of 2 layers:
(a) Outer fibrous layer: rich in collagen type I, fibroblasts and blood vessels.
(b) Inner chondrogenic layer: It is formed of cartilage forming cells (chondroblast)
which can divide and differentiate into chondrocytes which secrete the cartilage
matrix.
Function of the perichondrium:
1. It acts as source of O2 + nutrients to the cartilage cells.
2. The inner chondrogenic layer is responsible for new cartilage formation.
6. 3
(II) Cartilage cells
There are two types of chondrocytes:
1. Young Chondrocytes:
- They arise from the inner chondrogenic layer.
- They are flat cells with open-face nuclei and pale basophilic cytoplasm.
- They are present singly in their lacunae at the periphery of the cartilage and
parallel to the perichondrium.
2. Mature “old” Chondrocytes:
Site: deep in the cartilage in the form of rows perpendicular to the
perichondrium.
LM:
- Shape: They are oval or rounded “when single” and triangular or
semicircular (when in groups 2, 4, 8).
- A group of cells in a single lacuna are called “cell nests”.
- They have rounded and open face nuclei.
- They have granular, basophilic cytoplasm
EM:
- They contain rER, ribosomes, well developed Golgi.
- The surface show short cytoplasm processes.
Function:
1. They synthesize and secrete: the components of the cartilage matrix
(collagen type II, proteoglycans hyaluronic acid and chondronectin).
2. They are responsible for growth of the cartilage as they can divide.
(III) Cartilage matrix
General characters:
- It is rubbery in consistency.
- It is non-vascular.
- Tissue fluid constitutes 75% of the weight of the matrix.
7. 4
Staining reaction:
- The matrix appears homogenous basophilic by Hx, E due to presence of
sulphated glycosaminoglycans.
- It shows strong PAS positivity.
Components: It is composed of:
(1) Collagen fibres (Type II): Collagen form 40% of its dry weight.
(2) Proteoglycans
Chondroitin 4- sulphate
Chondroitin 6- sulphate
Linked with protein
core
(3) Glycoprotein called chondronectin.
(4) Protein: called chondrocalcin.
Sites of hyaline cartilage:
1. It constitutes the majority of the fetal skeleton.
2. Articular surface of bones.
3. Costal cartilage in the thoracic cage.
4. Nose, trachea, bronchi.
8. 5
2. YELLOW ELASTIC FIBRO- CARTILAGE
It is essentially identical to hyaline cartilage except that:
1. The matrix contains fine elastic fibers in addition to collagen type II fibrils which
responsible for elasticity and flexibility of this type.
2. Fresh elastic cartilage has a yellow color due to presence of elastic fibers. It can
be stained by standard elastic stains e.g. verhoeff’s stains.
Yellow elastic fibro cartilage by H&E and Verhoeff’s stains
Sites:
1. Auricle of the ear.
2. External auditory meatus.
3. Eustachian tube.
4. Epiglottis.
3. WHITE FIBRO CARTILAGE
General characters:
- It is a tissue intermediate between dense C. T. and hyaline cartilage.
- It is white in color in fresh state.
- It is tense and resists stretch due to presence of collagen fibers.
9. 6
Structure:
It differs from hyaline cartilage in:
1. It is not covered by perichondrium but it is surrounded by dense C. T. rich in
blood vessels from which it is nourished.
2. Chondrocytes:
- They are arranged in rows or columns.
- They are present singly or in groups inside their lacunae.
3. Matrix:
- It is acidophilic because it contains bundles of coarse type I collagen fibers in
between them rows of chondrocytes.
Sites:
1. Interverterbral discs.
2. Semilunar cartilage of knee joints.
3. Symphysis pubis.
4. Lips of glenoid cavity.
5. Terminal parts of tendons.
11. 8
THE BONE
Bone is a highly specialized variety of C.T. It forms the skeleton
Constituents of bone
1. Bone cells.
2. Bone matrix.
3. Periosteum.
4. Endosteum.
I- BONE CELLS
There are four Types of bone cells:
1. Osteogenic cells
2. Osteoblasts.
3. Osteocytes.
4. Osteoclasts.
1. OSTEOGENIC CELLS = osteoprogenitor cells
Origin: pericytes.
Sites:
1. Inner osteogenic layer of periosteum.
2. Endosteum.
3. Bone marrow cavities
Structure:
LM: They are flat cells with central flat nuclei and pale basophilic cytoplasm.
12. 9
EM: Rich in ribosomes and rER.
Function: They are capable to divide and give osteoblasts “bone forming cells” during
growth and healing of fracture bone.
2. OSTEOBLASTS
Origin: They arise from activated osteogenic cells.
Structure:
LM: They are small, oval branched cells with eccentric, open face nuclei and deep
basophilic cytoplasm.
EM: They show plenty of ribosomes, rER, well developed Golgi apparatus and
mitochondria.
Sites:
1. Activated inner osteogenic layer of periosteum.
2. Endosteum.
3. Walls of bone marrow spaces.
Function:
They are responsible for bone formation and calcification.
3. OSTEOCYTES
Origin: they are mature osteoblasts
Structure:
LM:
- They are oval, branched cells with oval,
central nuclei.
- The cytoplasm is slightly basophilic rich is
alkaline phosphatase enzyme.
EM:
- They contain rER, ribosomes, Golgi
apparatus, and many cytoplasmic
microtubules.
13. 10
- The cells are present inside lacunae and connected with by processes and these
processes intercommunicate with one another by gap junctions.
Function:
1. They preserve the integrity of the bone matrix and maintain its inorganic
components.
2. They are related to mobilization of Ca+ from the bone to the blood in times
of need.
4. OSTEOCLASTS
Origin: they arise from blood cells called monocytes.
Sites:
On the inner surface of bone where resorption takes place:
1. Bone marrow spaces.
2. Medullary cavities.
3. Endosteum.
Structure:
LM:
- Size: Osteoclast is large cell “20-30 um”.
- Nucleus: It is multinuclated cell “4-50” nuclei
- Shape: It is irregular in shape.
- Cytoplasm: The cytoplasm is foamy acidophilic.
- Border: The cells have striated or brush border facing the bone surface.
EM: The osteoclast shows the following 4-zones:
(1) Ruffled or striated zone.
- It is formed of:
a. Numerous finger like processes projecting from the cell membrane.
b. Collagenous fibrils from the resorped bone matrix.
(2) Clear Zone:
- It is a ring-shaped region under the ruffled part of the cell membrane.
14. 11
- It is rich in actin filaments. It is called clear because it is devoid of cell
organelles.
(3) Vesicular Zone:
- It is a zone of lysosomal vesicles of variable shape and size and contain
acid phosphatase enzyme.
(4) Basal Zone:
- It contains nuclei (4-50) cell organelles (Golgi apparatus & mitochondria)
and cell inclusions.
Function:
1. They are concerned with bone resorption during ossification.
2. They remove bone debris during ossification and after healing of bone
fracture.
BONE MATRIX
General characters:
- It is hard or solid in consistency.
- It is rich in blood supply.
Structure of the bone matrix:
(1) Organic components. (2) Inorganic components.
(1) The Organic components:
- It constitutes about 50% of the dry weight of the bone matrix.
- It includes:
a. bone collagen “Type I”: It constitutes about 90% of the organic component.
b. Sulphated glycosaminoglycans.
c. Glycoprotein = Osteonectin: Which anchor cells with bone matrix.
d. Protein = Osteocalcin: It helps bone calcification.
(2) The Inorganic components:
- It constitutes about 50% of the dry weight of bone matrix.
- It is formed mainly of calcium and phosphorus salts and small amounts of
sodium, carbonate, citrate, iron, Mg.
15. 12
TYPES OF BONES
1. There are two types of bone:
1. Compact bone
2. Cancellous bone.
1. COMPACT BONE
It is solid like ivory with no apparent holes i.e. compact
Sites: a. Shaft of long bones.
b. Outer & inner tables of flat bones of the skull.
c. Outer covering of the vertebrae & ribs.
Structure:
1. Periosteum.
2. Endosteum.
3. Bone matrix.
4. Bone cells.
(I) Periosteum
- It is a vascular C.T. membrane covering the bone from outside.
- It is formed of 2 layers:
a. Outer fibrous layer:
- It is rich in collagenous fibers, blood vessels and fibroblasts.
b. Inner osteogenic layer:
- It is formed of osteogenic spindle-shaped cells when stimulated during growth
or healing of fracture can change into osteoblasts.
Function of periosteum:
1. Provide attachment for muscles, ligaments and tendons.
2. Provide bone with blood supply and nourishment.
3. Inner osteogenic layer is important for formation of bone during its growth and
after its fracture.
16. 13
(II) Endosteum
It is a vascular C.T. membrane that lines the inner surface of the bone, bone
marrow cavities and Haversian canals.
Rich in osteogenic cells, osteoblasts, osteoclasts and blood vessels.
Function of endosteum:
1. It supplies bone with blood supply & nourishment.
2. Its osteogenic cells & osteoblasts & osteoclasts are concerned with
bone formation and resorption during growth & healing after fracture.
(III) Bone matrix and bone cells
The matrix is formed of lamellae of calcified osteoid tissue in which osteocytes are
embedded.
Structure of bone matrix: described before.
Bone lamellae are deposited in regular pattern as follows:
a. Outer “external” circumferential lamellae:
- These lamellae are present under the periosteum and parallel to it.
b. Inner “Internal” circumferential Lamellae:
- These lamellae are present under the endosteum and parallel to the
medullary bone cavity, which contains the bone marrow.
c. Haversian system = Osteon:
- It is the structural unit of the bone.
- It is formed of:-
1. Haversian Canal:
- It runs parallel to the longitudinal axis of the bone.
- It contains loose C.T., rich in blood Vessels, osteogenic cells.
17. 14
2. Concentric bone lamellae:
- It is formed of 4-20 cylinders of
concentric bone lamellae arranged
around Haversian canal.
3. Osteocytes:
- They are found inside their
lacunae in between the bone
lamellae.
d. Interstitial “Inter-Haversian” Lamellae:
It is formed of calcified osteoid tissue present between Haversian systems and
osteocytes are irregularly arranged between these lamellae
Compact bone
18. 15
2. CANCELLOUS BONE
- It looks like – sponge with many holes, so called spongy bone.
- It is formed of bone lamellae in the form of irregularly arranged bars or
trabeculae which branch and anastomose and separated by bone marrow
spaces of irregular shape and size. These spaces are filled with active red bone
marrow.
Sites:
1. Epiphysis of long bones.
2. Central part of flat bones of the skull.
3. Young embryonic bone.
4. Bodies of vertebrae and sternum.
19. 16
OSSIFICATION
Definition:
It is the process of bone formation, which leads to its growth.
Methods of bone ossification:
1. Intramembranous ossification: It occurs in mesenchymal membranes.
2. Intracartilagenous ossification: It occurs in cartilage model.
INTRACARTILAGENOUS OSSIFICATION
“Growing end of long bone”
Definition:
It is a type of ossification by which cartilaginous model is replaced by bone.
Sites:
Epiphyseal plates of the cartilage
Stages:
Examination of longitudinal section in the growing end of long bone demonstrates the
following stages:
1. Stage of resting cartilage.
2. Stage of proliferation.
3. Stage of maturation and
hypertrophy.
4. Stage of calcification.
5. Stage of invasion.
6. Stage of spongy bone formation.
7. Stage of remodeling and compact
bone formation.
20. 17
THE MUSCLE TISSUE
General characters:
The muscle tissue is formed of a group of muscle fibers.
These fibers have a contractility power due to myofibrils in their cytoplasm.
The plasma membrane is called the sarcolemma.
The cytoplasm is called the sarcoplasm.
The muscle fibers may be:
- Striated.
- Non-striated.
- Voluntary.
- Involuntary.
Types of muscle fibers:
- Skeletal muscle fibers.
- Cardiac muscle fibers.
- Smooth muscle fibers
SKELETAL MUSCLE FIBERS
Types:
Striated (show transverse dark and light band).
Voluntary (under control of will) except:
- Upper third of esophagus.
- Pharynx.
- Cremastric muscle.
Do not branch except: tongue and face.
Sites:
All skeletal muscle attached to skeleton.
Eye.
Tongue.
Pharynx.
Larynx.
21. 18
Structure:
It is formed of cells (fibers) and connective tissue.
A. Connective tissue:
1. Epimysium
- It is a dense C.T. which surrounds the whole muscle.
2. Perimysium
- It is a dense C.T. which divides the muscle into bundles (each bundle contains a
group of muscle fibers).
3. Endomysium:
- It is a loose C.T. which separates the muscle fibers.
Function of C.T.:
1. It contains blood vessels, nerves and lymphatic and give attachment between
muscle bundles.
2. Help the attachment of muscle to tendon, ligament, perichondrium and
periosteum.
B- Skeletal muscle fiber:
LM of skeletal muscle fiber:
L/S:
Single elongated multinucleated cell (syncytium).
Have multiple flattened oval peripherally situated nuclei.
Have regular transverse striation.
The sarcoplasm is acidophilic and contains B-Glycogen granules and myoglobin
pigment.
22. 19
T/S:
Polyhedral in shape.
The nucleus is only seen in some fibers.
The sarcoplasm may show dark areas (Cohnheim's areas) due to grouping of the
myofibrils.
23. 20
E/M of skeletal muscle fiber:
The sarcoplasm show tubular invaginations (T.T.).
It contains:
Smooth endoplasmic reticulum (sarcoplasmic reticulum).
- Plenty of mitochondria.
- Ribosomes.
- B- Glycogen granules.
- Myoglobin pigment.
- Myofibrils
Myofibrils
Definition:
- These are contractile elements which are longitudinally arranged in the sarcoplasm
of the skeletal muscle fiber.
Structure:
- The myofibril shows alternating light and dark bands. The light bands (Isotropic or
I- band) contain actin only and the dark bands (Anisotropic or A- band) contain actin
and myosin. The dark band of one myofibril is present beside those of adjacent
myofibril giving the cross striation seen by light microscope.
- Each dark band is divided at its center by a light disc called H-zone and contains only
myosin.
- Each light band is divided at its center by a dark line called Z-line.
The Sarcomere:
- It is the area between two Z-lines.
- It is the functional contractile unit of a myofibril.
- It includes a whole A (dark band) and ½ of I (light band) on either side.
24. 21
The myofilaments
These are thread-like filaments which are longitudinally arranged in the myofibrils.
Types:
1. Thin Filaments: formed of actin and troponin and tropomyosin.
2. Thick Filaments: formed of myosin protein
SMOOTH MUSCLE FIBERS
Non-striated.
Involuntary Except:
- Ciliary muscle
- Special Muscle in urinary bladder
Site:
Walls of the blood vessels.
Viscera of various systems (G.I.T., G.U.T., and Respiratory system)
Arrangement:
Bundles:
- Branching and anastomosing.
- Separated by C.T.
25. 22
Layers:
LM:
Smooth Muscle Fiber is formed of a single cell.
Shape: spindle (fusiform).
Size: 4-10 um.
Length: 30 um in blood vessels, and up to 500 um in pregnant uterus.
Nucleus: single-central-oval or rod shape, in the widest part (middle part).
Cytoplasm: acidophilic non–striated.
EM:
The cytoplasm:
- Homogenous except for some dark patches (dense bodies).
- It is full of large number of mitochondria, glycogen, RER, Golgi saccules
and ribosomes.
- The myofibrils are not regularly arranged no striation.
- Intermediate filaments (desmosomes and vimitin) are also present in
addition to actin and myosin.
The sarcolemma shows:
- T-tubules which represented by vesicular Caveolae
- Plaques along the inner aspect of the plasma membrane
- Numerous gap junctions and less developed sarcoplasmic reticulum.
- Circular.
- Longitudinal.
- Oblique.
- Spiral.
40. 37
Excitation- Contraction coupling (Mechanism of muscle contraction):
It is the process by which an action potential initiates the muscle contraction.
Excitation contraction coupling involves the following steps:
1. Propagation of the action potential and release of Ca++
ions:
a. Propagation of the action potential in the motor nerve ------> production of an end
plate potential (EPP) ------> generation of an action potential at the adjacent areas
of the motor end plate.
b. This action potential spreads on both sides along the surface of the muscle fiber &
also, along the T tubules which extend deep into the muscle fiber and excites the
whole muscle fiber ++ of DHP receptor------> ++ of ryanodine channels --> release
of Ca2+
ions from the terminal cisternae of the sarcoplasmic reticulum.
c. The released Ca2+
ions diffuse rapidly to the region of the thick & thin filaments.
2. Binding of the cross-bridges between the thick (myosin) and thin (actin)
filaments:
a. The released Ca2+
ions combine with troponin molecules (troponin C) of the thin
filaments ------> weaken the binding of Troponin I to actin -----> movement of
tropomyosin laterally away from its position -------> exposure of the binding sites
presents on actin molecules.
b. Cross bridges (heads) from the thick (myosin) filaments combine with the binding
sites on the actin molecules.
3. Cross-bridge cycling which results in sliding of the thin filaments across the thick
(myosin) filaments:
Cycling of cross-bridges occurs by the following steps:
a. Binding: Cross-bridges on the thick filament bind to actin.
b. Bending: Binding of the cross bridges leads to release of energy stored in myosin
(ATP by ATPase) producing angular movement of the cross bridges i.e. bending of
the cross-bridges and sliding of the thin filaments across the thick filaments.
41. 38
c. Detachment: Detachment of the cross-bridges from the thin filaments which need
energy derived also from ATP.
d. Return to original position: The cross-bridge returns to its original position and
another cycle can occur by binding to another actin molecule and so on.
Cross-bridge cycling occurs so long as Ca++
ions combine with troponin. This leads to
sliding of the thin filaments towards the center of the sarcomere approximating the Z
lines (discs) from each other (the sarcomeres become shorter). The width of the I band
decrease and the H zones become narrower but the width of the A bands do not
change.
N.B.: Rigor mortis is caused by the inability of the cross bridges to detach from actin
due to lack of ATP
4. Relaxation :
Occurs when Ca++
ions are transported into the sarcoplasmic reticulum by an active
process using ATP and Ca-ATPase.
The active Ca++
pump is located in the membranes of the sarcoplasmic reticulum.
Removal of Ca++
ions make troponin return to its original state which causes
tropomyosin to move back and cover the binding sites on actin molecules. Thus,
the cross-bridge cycles stop causing the thin filaments to slide back again to their
original position and the sarcomere to return to their original length.
Changes occurring as a result of muscle contraction:
I. Electrical changes:
Initiation and conduction of action potentials in the skeletal muscles are similar to that
produced in the nerve fibers except for quantitative differences in timing and
magnitude:
Skeletal muscle fibers
Thick myelinated nerve
fibers
Resting membrane
potential
-90 m.v -70 m.v
Firing level (Threshold)
-50 m.v. (after 40 m.v.
depolarization)
-55 m.v. (after 15 m.v.
depolarization)
42. 39
Magnitude of the spike
potential
130 m.v (from -90 m.v.
to + 40 m.v.)
105 m.v (from -70 m.v.
to + 35 m.v.)
Duration of the spike
potential
3-5 m.sec 0.5 - 1 m.sec
Duration of the negative
and positive after
potentials
relatively longer relatively shorter
Velocity of conduction 3-5 meters/sec up to 120 met/sec
II. Metabolic (chemical) changes:
A) During contraction:
1. ATP: Energy of contraction is derived from ATP which is considered the immediate
and only source of energy in this process. The head of myosin (cross bridges)
contain ATPase enzyme which catalyzes the hydrolysis of ATP. (ATP
ADP + P
(phosphoric acid) + Energy).
2. Creatine phosphate: ATP is rapidly reformed from ADP by the addition of
phosphate group from creatine phosphate (Cr-P) (a high energy phosphate
compound).
ADP + Cr~P -------------------> ATP + Cr
ATP and Cr-P represent the stored energy which can be utilized rapidly by the muscle.
The high energy phosphate storage in the muscle is sufficient to allow the muscle to
contract only 50-100 times (8-10 seconds).
3. To maintain muscle contraction, a steady supply of energy is derived from the
following sources:
Anerobic oxidation of glucose
(or glycogen)
Aerobic oxidation of glucose
and free fatty acids (FFA)
Occurs during Sever exercise (when the
muscle is doing work at a faster
rate than the blood can supply
O2 and nutrients muscle
Low or moderate activity (ATP
is produced by the aerobic
oxidation of glucose or FFA)
43. 40
depends on glycogen and
anerobic glycolysis to obtain
energy)
Reaction
Glucose
s)
(Glycolysi
oxidation
Anaerobic
2
Pyruvic. acids+2ATP
Glucose + 6O2
cycle)
s
(Kreb'
oxidation
Aerobic
6CO2 + 6H2O
+ 38ATP
FFA + O2
oxidation
Aerobic
CO2 + H2O + ATP
Advantages Supply ATP at a high rate and
within short time
Great amount of ATP (38 ATP for 1
glucose molecule)
Disadvantages Small amount of ATP (2ATP for
1 glucose molecule)
Slow
Rapid but not economic Slow but economic
- Most muscles contain a mixture of cells, some adapted to use anaerobic glycolysis
which can supply ATP very rapidly (but not economic), and others adapted to use
aerobic metabolism (economic) which is relatively delayed.
4. In exhausted muscles, there is an emergency mechanism for the supply of ATP.
This is done by combining two ADP molecules to reform one ATP molecule and one
AMP (Adenosine Monophosphate) molecule.
ADP + ADP ATP + AMP
B) During recovery:
- At the end of muscular activity, the energy stores in the muscle (ATP, Cr-P and
muscle glycogen) are depleted and the lactic acid is increased in blood.
- Recovery occurs by removal of the lactic acid and regeneration of the energy
stores .
a. Part of the lactic acid (1/5) is oxidized into CO2 and H2O. The energy produced
from this oxidation is used for reformation of ATP and by turn Cr-P.
Lactic acid
Oxidation
Pyruvic acid
cycle)
s
(Kreb'
Oxidation
CO2+ H2O + ATP
ATP + creatine
Cr-P + ADP
44. 41
b. The other part of the lactic acid (4/5) diffuses to the blood stream and then to
the liver where it is converted into blood glucose (through the Cori cycle).
Muscles take glucose from the blood stream and changes it into muscle
glycogen.
- At the end of recovery, the energy stores in the muscle (ATP, Cr P and muscle
glycogen) are reformed again, and the lactic acid is removed.
PH. Changes in the muscle during contraction:
1. At first, the pH changes towards the acidic side due to the release of phosphoric
acid.
ATP
ATPase
ADP + Phosphoric acid + Energy
2. Then the pH changes towards the alkaline side due to the release of creatine from
the Cr-P.
ADP + Cr-P ATP + creatine
3. Lastly, the pH changes towards the acid side due to the release of lactic acid from
the anaerobic oxidation of glucose.
Glucose (ms glycogen)
s)
(Glycolysi
oxidation
Anaerobic
2 lactic acid + 2ATP
III. Thermal changes:
- During contraction, the heat production in the muscle is markedly increased
(about 100-1000 times) compared with the heat production during rest.
- During contraction, 40-50% of the energy liberated as a result of hydrolysis of
ATP is converted into work.
- The remaining 50-60% of the energy is liberated as heat at the onset of and
during contraction of the muscle.
IV. Mechanical changes:
- There are two types of muscle contraction:
1- Isotonic contraction 2- Isometric contraction
Occur when muscle contract against light or
moderate load
contract against heavy load
Muscle Shortens Not shortens
45. 42
Load Move Note move
Work Done (work = weight of load x
distance of movement)
No work done
Mechanical
efficiency (% ratio of
work to total energy
expenditure)
Maximum (40-50%) i.e. energy
is converted into work and
heat
Zero i.e. energy is converted
into heat only
Muscle tension Increase at 1st
then maintained
constant during major part of
contraction (isotonic)
Markedly increased
O2 and nutrient
requirement
Greater lesser
46. 43
Mechanism of isometric
contraction:
-The muscle is supposed to be
composed of 2 components:
* Contractile components
(sarcomere), and Elastic
components:
- one in series with
contractile components&
- A second elastic element in
parallel with the two
components.
-The parallel elastic element present in the sarcolemma and the series elastic
element may be present in the tendon, connective tissues or in the cross-
bridges (in the hinge regions of the myosin).
- When the muscle contracts against a heavy load (isometric contraction), the
contractile components shorten, at the same time the elastic components
are stretched to the same degree. So, the length of the muscle remains
constant, but its tension is markedly increased.
Length – tension relationship
- The tension developed during isometric cont. depend on the length of the
ms during experiments
- A maximum tension is obtained when the length of the muscle is nearly equal
to the resting length of the muscle in the body (optimal length)
- The tension decreases when the muscle length is longer or shorter than
normal body length (optimal length)
- At optimal length (when sarcomere length is 2-2.2m) maximum number
of cross bridges connecting thin and thick filaments.
- At lengths longer or shorter than optimal length degree of overlap between
thin and thick filaments decreases and number of cross bridges between thin
and thick filaments decrease decrease contraction i.e decrease tensions
47. 44
Pacemaker:
Some fibers in cardiac and smooth muscles are pacemaker cells that
spontaneously generate APs which are conducted by gap junctions into
other muscle fibers.
Nerve terminals are often restricted to pacemaker cells.
It often receives nerve supply from both divisions of autonomic nervous
system (sympathetic and parasympathetic).
They do not initiate AP, but they modify the inherent activity either by
increase or decrease
48. 45
Skeletal Muscle Cardiac Muscle Smooth Muscle
Appearance: Striated No striations
Regulation: Nervous control
Pacemaker cells,
controlled by:
nervous & hormonal
control
• Nervous
• Hormonal
control
Action
potential:
Spike
AP:
No plateau
Plateau
(Due to inward Ca+2
current)
No plateau
Upstroke
due to:
inward Na current
inward Ca+2
current
49. 46
Excitation contraction coupling in smooth muscles:
It involves the following steps:
1. Release of Ca++
ions:
in the intracellular Ca2+
concentration inside the muscle fiber which comes
from:
a. The sarcoplasmic reticulum:
b. The extracellular calcium: (by opening of Ca2+
channels)
Which may be:
1. Opening of voltage-activated Ca2+
channels by spread of an action
potential on the plasma membrane.
2. Opening of chemically-activated sensitive Ca2+
channels binding of a
chemical transmitter with its specific receptor on the plasma membrane.
2. Contraction:
a. Ca2+
binds to calmodulin (a calcium binding protein whose structure is
related to troponin) forming calcium-calmodulin complex.
Source of Ca+2:
SR
via action
potential
on T
tubules
SR
Via Ca+2 (Ca+2
induced
calcium
release)
SR
Via inositol
triphosphate
(IP3)
______ ECF
via DHP Ca+2
channels
in T tubules
ECF
via voltage
gated
Ca+2
channels
Regulatory
Proteins:
Troponin Calmodulin
Speed of
contraction:
Fast to slow Slow Very slow
50. 47
b. The calcium-calmodulin complex binds to and activates an enzyme known
as myosin light chain kinase (MLCK).
c. The active enzyme (MLCK) then uses ATP to phosphorylate myosin light
chain (MLC).
d. The cross-bridges of the phosphorylated myosin are able to bind to actin
molecules and undergo cross bridge cycling i.e. sliding of filaments and
shortening of muscle fibers (the dense bodies??? come closer to each
other).
3. Relaxation:
a. the intracellular Ca2+
concentration by an active transport of Ca2+
ions:
b. Into the sarcoplasmic reticulum (through Ca2+
-ATPase) OR out of the cell
across the plasma membrane (through Ca2+
-Na+
exchanger).
a. When the intracellular Ca2+
decreases, myosin light chain kinase (MLCK)
enzyme becomes inactive WHILE myosin phosphatase enzyme becomes
active.
b. Active myosin phosphatase removes phosphate from myosin light chain
(MLC). So, the cross-bridge cycle stops, and relaxation occurs by sliding
of filaments to their original position.
51.
52. 49
Joint diseases
Normal synovial joint structure
- Synovial joints have a joint space that allows for a wide range of motion.
Situated between the ends of bones formed via endochondral ossification, they
are strengthened by a dense fibrous capsule reinforced by ligaments and
muscles.
- Synovial membrane contains Type A synoviocytes; specialized macrophages
and Type B synoviocytes; similar to fibroblasts and synthesize hyaluronic acid
and various proteins.
- Synovial fluid is therefore a hyaluronic acid–rich plasma filtrate that acts as a
viscous lubricant and provides nutrition for the articular hyaline cartilage..
- Hyaline cartilage an elastic shock absorber and wear-resistant surface.
Chondrocytes secrete degradative enzymes in inactive forms and enrich the
matrix with enzyme inhibitors.
- Diseases that destroy articular cartilage do so by activating the degradative
enzymes and decreasing the production of their inhibitors, leading to matrix
breakdown.
54. 51
Acute suppurative arthritis
Microorganism:
Staph aureus and Strept pyogenes
Routes of infections:
- Hematogenous.
- Penetrating wound.
- Nearby osteomyelitis.
Osteoarthritis (Degenerative arthritis)
Definition: A degenerative disease of articular
cartilage that may be primary or secondary.
Primary osteoarthritis: It is of unknown cause,
it affects the elderly and it occurs in a normal
joint.
Secondary osteoarthritis: Predisposing factors:
1. Intra articular abnormalities: 2. Extra articular abnormalities:
- Congenital hip dysplasia.
- Damage of the articular cartilage by
trauma, inflammation
- Bowing legs.
- Malunion of a fracture.
- Obesity.
Joints affected: Large joints e.g Hip joint in males, Knees & hands in females.
Peak age: 60-80 years.
55. 52
Pathogenesis: Degenerative changes which may be primary due to aging or
secondary to mechanical stress.
- Fragmentation of articular surface and thinning of the cartilage
- Calcification of cartilage margins
- Extensive loss of cartilage with formation of osteophytes and cystic
degeneration of underlying bone.
Pathology
1.Synovial membrane: Congestion and non-specific chronic inflammation.
2.Articular cartilage: The central part undergoes degeneration and separation
exposing the underlying bone.
3.Bone: Thickening and sclerosis of exposed bone, Small bony projections are
formed at the joint periphery “osteophytes.
56. 53
Rheumatoid arthritis (Autoimmune/Seropositive arthritis)
Definition: Chronic systemic autoimmune disease affecting peripheral joints and
other organs in the body.
Joints affected: Small joints of hands and feet.
Peak age: 30-40 years.
Sex: More in females.
Pathogenesis: Autoimmune
[Production of anti-IgG antibodies
(rheumatoid factor) leads to Ag-Ab
reaction initiating inflammatory
reaction in the joints].
57. 54
Pathology:
1. Synovial membrane:
- Chronic inflammation which creeps over
the articular cartilage.
- A synovial biopsy reveals prominent
lymphoid follicles, synovial hyperplasia,
and villous folds (pannus).
- Organization of pannus leads to fibrous
ankylosis.
2. Articular cartilage:
- Erosion of the articular cartilage mainly at the periphery.
3. Bone: Increased osteoclastic activity and osteoporosis.
Local effects:
Stiffness, Swelling, Deformity, and Pain, Limitation of Motion
Systemic effects:
1. Rheumatoid nodules: Subcutaneous nodules
2. Internal organs:
- Vasculitis - Lymphadenopathy - Secondary amyloidosis
3. Serology:
- Rheumatoid factor (RF): +ve in 85% of cases
- Anti-nuclear antibodies (ANA) in juvenile cases that affect younger age group.
58. 55
Marked synovial hypertrophy with
formation of villi
Subsynovial tissue containing a dense
lymphoid aggregate
Rheumatoid nodule Rheumatoid nodule composed of central
necrosis rimmed by palisaded macrophages.
60. 57
Gout (Metabolic arthritis)
Definition: Increased serum uric acid leads to deposition of uric acid crystals in
joints. This leads to inflammation with foreign body giant cell reaction (Tophi).
Joints affected: Most first attacks are monoarticular and 50% occur in the first
metatarsophalangeal joint of the big toe.
Peak age: usually appears after 20 to 30 years of hyperuricemia.
Sex: More in males.
Pathogenesis: The basis for crystal
formation is not known, but studies suggest
that degradation of articular cartilage
proteoglycans, which normally inhibit
mineralization, allows crystallization around
chondrocytes.
Pathology:
Swollen inflamed joint of the big toe.
M/E: Uric acid crystals deposited surrounded by inflammatory cells.
61. 58
Gouty tophus—an aggregate of urate
crystals surrounded by reactive
fibroblasts, mononuclear
inflammatory cells, and giant cells.
Needle-shaped urate crystals are
easily identified under polarized light.
Tumors:
Pigmented villo-nodular synovitis
(Diffuse type)
Giant cell tumor of tendon sheath
(Localized type)
62. 59
Tenosynovial giant cell tumor
ME: Fibroblasts + histiocytes with hemosiderin pigment + giant cells.
Ganglion cyst (Synovial cyst)
Definition: Cystic structure containing mucoid material.
Joints affected: hand and wrist.
Peak age: Any age.
Sex: more in females.
Pathogenesis: unclear but may be Myxoid degeneration of connective tissue
after trauma.
Pathology:
- Is a small sac of fluid that forms over a joint or tendon. Inside the cyst is a
thick, sticky, clear, colorless, jellylike material.
- Uni or multilocular cystic structure.
- Dense collagenous walls with foci of myxoid changes.
- No true epithelial lining.
63. 60
Osteodystrophy
Definition: It is disturbance of bone growth.
Types of osteodystrophies:
A. Congenital
B. Acquired:
Hereditary Acquired
- Osteogenesis Imperfecta
- Osteopetrosis
- Achondroplasia
Fibrous dysplasia
- Paget’s disease
- Osteoporosis
- Radiation osteodystrophy.
- Renal osteodystrophy.
- Endocrinal osteodystrophy.
- Digital clubbing
- Vitamin D deficiency:
osteomalacia & rickets
64. 61
Osteogenesis Imperfecta
It is a rare hereditary condition.
There is a defect in connective tissue development or maturation. Bone cortex is
formed mainly of woven bone and small areas of lamellar bone.
Clinically:
- Patient is short
- Bone weakness (fractures with mild trauma).
- Patient has blue sclera (the partial visibility of choroid through the thin
sclera).
- Looseness of joints due to laxity of the ligaments.
- It may be associated with dentogenesis imperfecta (brown short teeth)
N/E:
- Osteoporotic vertebra show thinning and dropout of bone spicules.
- Horizontal trabeculae are thinner and there is loss of interconnectivity.
M/E:
- Thinning of the cortex.
- Severe loss of cancellous bone
- Markedly decreased interconnections
- Between the bony trabeculae
66. 63
Osteopetrosis
- It is a rare hereditary condition.
- Called Marble Bone Disease.
- Failure of the osteoclastic activity, thus no remodelling of the bone.
- Obliteration of the marrow cavities.
- Development of secondary anemia.
- The bone is fragile, has poor mechanical properties, thus fractures very
easily.
Osteopetrosis (ME)
Achondroplasia
- It is a disorder of bone growth.
- A common cause of disproportionate dwarfism
- A hereditary condition resulted in abnormally
short stature with short limbs and relatively long
narrow trunk.
- The head is large with prominence of the
forehead, low nasal bridge
67. 64
Fibrous dysplasia
- An acquired disturbance of bone growth characterized by disorganized
mixture of fibrous and osseous elements
- Associated conditions: Skin pigmentation, endocrine dysfunction
(Acromegaly, Cushing syndrome and hyperparathyroidism).
N/E:
- It may be either polyostotic or monostotic.
- Site: In the medulla.
- Color: Grey white.
- Consistency: Gritty with cysts
M/E: Irregular bone trabeculae embedded in a loosely arranged fibrous stroma.
The bony trabeculae are formed of woven bone that lack osteoblastic rimming.
Complications: Deformities of bone and fractures.
Fibrous dysplasia (NE &ME)
68. 65
Paget’s disease of Bone
Acquired disturbance of bone growth characterized by bone resorption & new
bone formation called Osteitis deformans
Clinically: age: after age of 40 years.
Sex: more in males.
Pathogenesis: It passes by 3 stages:
1. Hot Stage: Osteoclasts are over activated by a Virus > +++ bone resorption. So
bone becomes rarified and easily fractured.
2. Mixed stage: Osteoblasts are activated to replace the destructed bone > +++
new bone formation which is irregular thick woven bone.
3. Cold stage: This stage is characterized by little cellular activity.
N/E: It may be polyostotic or monostotic.
Sites: Skull, vertebrae and long bones
The bones show alternating coarse thickened areas and other lytic areas filled with
blood
Causes bone deformities:
- Lion face deformity of skull (leontiasis ossea)
- Kyphosis due to anterior collapse of vertebrae
- Forward bowing of legs.
69. 66
M/E:
- Thick, irregular, plate-like bony trabeculae with multiple osteoclasts at the
margin with several resorption cavities. The marrow space is filled
with fibrovascular tissue containing scattered osteoclasts.
- The thickened bony trabeculae show mosaic appearance
Complications:
1. Fractures.
2. High output heart failure due to local increase of bone blood flow.
3. Malignancy: Mainly osteosarcoma (of old age). Other malignancies:
Fibrosarcoma, chondrosarcoma and giant cell tumor.
Paget’s disease of bone (ME)
70. 67
Vitamin D Deficiency
Rickets
Defect in bone mineralization in childood.
Age: It starts after 6 months (after exhaustion of calcium stores formed during
intrauterine life).
Etiology: Deficiency of vitamin D, C and phosphorous due to:
- Insufficient exposure to sunlight.
- Decreased intake or absorption of vitamin D.
- Pre-maturity due to increased demands of Ca and due to defective
hydroxylation of vitamin D in the liver.
Pathogenesis of rickets:
Defective calcium level → cartilage is not calcified → cartilage cells don't
degenerate, continue to proliferation & lay down chondroid matrix → ticking of
ends of long bones
New bone → irregular & poorly calcified
N/E of Rickets:
- Enlarged soft epiphysis (cut with knife).
- The line between epiphysis and diaphysis is irregular.
M/E of the cartilage plate in cases of rickets:
- The resting zone is relatively normal.
- The proliferating zone is widened and disorderly arranged.
71. 68
- The zone of provisional calcification is poorly defined.
- Minimal amount of bone is formed.
- Areas of proliferating cartilage extend on the expense of metaphysis.
Clinical picture:
General lesions:
1. Protrusion of the abdomen
2. over weight due to limited movement
3. Generalized lymphadenopathy and
splenomegaly.
4. Anemia
5. Delayed standing, sitting and
walking.
6. Increased susceptibility to infections.
Skeletal changes:
1.Skull:
- Delayed closure of fontanelles and
sutures.
- Craniotabes (flat occipital bone due
to pressure).
- Square shaped head and frontal
bossing.
- Delayed dentition.
2.Chest:
- Rosary chest (prominence of the
costochondral junctions).
- Pigeon chest (Flattening of the
sides and protrusion of the
sternum).
- Harrison’s sulcus (a horizontal
groove at the lower part of the
chest at the site of attachment of
the diaphragm).
3.Vertebrae: Kyphosis, lordosis or
scoliosis
4.Pelvis: Trifoil pelvis.
5.Long bones: Bowing of legs and prominence of epiphyseal cartilage.
72. 69
Osteomalacia
Definition: Defective bone mineralization in adult.
Causes: Vitamin D deficiency.
- Insufficient exposure to sunlight
- Increased demands (repeated pregnancies & lactation)
Pathogenesis: Failure of calcification of bone matrix resulting in bone softening.
Clinical picture:
- Lumbar lordosis.
- Bending of femur and tibia.
- Contracted pelvis.
Rickets (left) vs normal (right) (ME)
75. 72
Osteoporosis
Definition: It is reduction of bone mass to a level below that required for normal
bone support. However, mineralization is normal.
Causes:
Localized:
Prolonged
immobilization
(paralyzed
limb).
Generalized:
1. Senile: Occurs in postmenopausal women and elderly
men.
2. Scurvy: Vitamin C is essential for the synthesis and proper
structure of collagen
3. Collagen disturbances (Osteogenesis Imperfecta)
4. Endocrinal.
Radiation osteodystrophy
- Exposure of the growth cartilage plate to radiation field leads to premature
closure of epiphysis.
- Renal osteodystrophy
- Damaged glomeruli lead to Phosphate retention
- Tubular damage lead to decreased 1,25-dyhydroxy vitamin D
- With renal failure there is decreased intestinal absorption of Ca: hypocalcemia
Endocrinal osteodystrophy
- Steroids lead to increased rate of bone resorption.
- Hyperthyroidism > increase rate of bone resorption.
- Hyperparathyroidism lead to mobilization of calcium from bone
76. 73
Digital clubbing
It affects mainly the fingers. Nails are
elongated, curved, raise and cyanotic.
Phalanges are thickened with subperiosteal
new bone formation.
Causes: Hypoxia, toxaemia, chronic lung
diseases.
Osteomyelitis
Definition: inflammation of bone and marrow
Types of osteomyelitis
Duration of the illness
Acute osteomyelitis: present with symptoms duration of a few days or weeks
Chronic osteomyelitis: longstanding infection over months or years
Mechanism of infection
- Hematogenous
- Non hematogenous (by direct implantation of the organism).
77. 74
Acute Osteomyelitis
I. Acute suppurative hematogenous osteomyelitis:
Age & site:
- The majority are children because the disease tends to affect areas of rapid
growth and of increased risk of trauma (as lower end of femur, upper end of
tibia).
- Adult cases vertebrae is affected involving two adjacent vertebrae with
intervertebral disk (may occur pelvis, long bones and clavicle).
Organism:
- 80% due to Staphylococcus aureus.
- Strep. Pyogens.
Pathogenesis:
Organisms reach the bone through the blood stream from a septic focus.
The metaphysis is affected, because:
1. It is actively growing
2. Highly vascular
3. Its veins and sinusoids are wide with marked slowing of blood stream which
helps stasis of bacteria for a long time and helps post traumatic thrombosis.
78. 75
Pathogenesis:
1. Trauma: It leads to extravasation of blood and, bacteria into the medullary
cavity.
2. Suppuration: Pus is formed, because bone is rigid structure does not allow
swelling. Pus finds its way to the surface of the bone, forms a subperiosteal
abscess, reach the surface to form a sinus.
3. Bone necrosis: It involves the superficial layers of bone. Endosteal vessels
supply the deep ones. Necrosis results from:
a. Acute ischemia.
b. Effect of bacterial toxins.
c. Inflammatory vascular thrombosis.
d. Septic granulation tissue formation
e. Separation of septic necrotic tissue (Sequestrum): This occurs by
osteoclastic resorption where septic granulation tissue is found. Small
sequestra are resorbed completely.
f. New bone formation (Involucvrum): It is formed under the loosely
attached and elevated periosteum.
ME:
1. Osteonecrosis with surrounding neutrophils; Bone necrosis is recognized by
the absence of osteocytes within lacunae.
2. Osteoclastic activity causing scalloping of bone.
3. Subperiosteal new woven bone with osteoblastic rimming (involucrum).
The woven bone is haphazardly arranged.
Marrow exudate, marrow necrosis, and intravascular thrombi.
79. 76
Complications:
1. Spread:
- Direct to nearby joint (if the metaphysis is intracapsular) and other soft
tissues.
- Blood spread due to septic thrombophlebitis.
2. Chronic suppuration.
3. Patholoical fractures
4. Retardation of growth from damage to the epiphysial cartilage.
81. 78
2-Acute suppurative non hematogenous osteomyelitis
- It occurs in adults.
- It affects the diaphysis.
Chronic Osteomyelitis
Definition: Longstanding infection of bone lasting months to years;
characterized by low grade inflammation and presence of dead bone or fistulous
tract.
Etiology: Chronic osteomyelitis is frequently the result of either inadequate
antibiotic treatment or the incomplete surgical debridement of necrotic bone.
Most common organism: Staphylococcus aureus.
Sites: Usually unifocal disease:
- Tarsal and metatarsal bones and toes
- Femur and tibiofibular
- Spine, sternum and pelvis
Chronic multifocal osteomyelitis
- It is a variant of osteomyelitis in children and young adults,
- It is characterized by low-grade fever, local swelling and pain, and radiologic
findings suggesting osteomyelitis.
- Multiple asymptomatic sites of involvement.
Causes:
- Infected compound fracture causing direct inoculation.
- Direct spread from a nearby septic focus
82. 79
- The lesions occur mainly in the metaphyses of tubular bones and in the
clavicles.
- Cultures are negative for bacterial, fungal, and viral organisms.
- The clinical course is characterized by intermittent periods of exacerbation
and improvement during several years.
Clinically,
- The main symptom is usually a purulent discharge from a sinus over the
affected bone
- Pain.
- Remissions and exacerbation of symptoms.
- Bone is palpably thickened, and associated overlying scars or sinuses
ME:
- Fragments of necrotic bone and
chronic inflammatory cells with
predominance of plasma cells.
- Fibrous tissue deposition in marrow
space.
Complication:
- Pathological fracture: due to bone weakness.
- Deformity: in children if the focus of infection destroys the epiphyseal plate.
- Rarely; amyloid disease.
- Rarely; squamous cell carcinoma related the opening of the sinus.
83. 80
Bone tumors
1. Bone forming tumors:
Benign Malignant
- Osteoma
- Osteoid osteoma
- Osteoblastoma
- Osteosarcoma
Osteoma
Age: Adults
Site: Facial bones (skull, jaws & paranasal
sinuses).
Number: Single or multiple
Clinical picture: Local mechanical problems
as:
- Sinus obstruction.
- Visual defects and
- Cosmetic deformity.
84. 81
NE:
- Well circumscribed round or oval
bony mass,
- white and firm attached to bone
cortex
ME:
- Admixture of mature lamellar
and woven bone patterns.
Osteoid osteoma
Age: Adults
Site: metaphysis of long bone
Clinical picture: Severe pain (tumor cells secrete Prostaglandin E2) relieved by
aspirin.
Radiology: Radiolucent center (nidus) surrounded by dense sclerotic bone
NE: Well circumscribed round or oval bony mass in the cortex.
85. 82
ME:
- Central nidus is formed of vascularized fibroconnective tissue surrounded by
interlacing trabeculae of Woven Bone lined by osteoblasts
- Periphery of dense reactive bone (sclerosis)
86. 83
Osteoclastoma
Similar to osteoid osteoma
Site: vertebrae.
Clinical picture: Less pain.
Radiology: Radiolucent larger size (>2
cm)
ME:
Nidus: osteoid bone prominently lined by osteoblasts + highly vascular C.T.
stroma, and multinucleated giant cells.
Absent or minimal surrounding sclerosis (reactive bone).
Osteosarcoma
The most common primary malignant tumor of bone.
87. 84
C/P:
- Pain
- Pathological fracture
- Aggressive behaviour, recurrence.
- Direct spread and early blood spread to the lungs
Radiology: Destructive, mixed lytic and sclerotic mass with infiltrative margins with
characteristic sunray appearance and Codman triangle
NE: Fusiform mass with hemorrhage and necrosis which occupies the medullary
cavity then passes to the bone cortex, and elevates the periosteum, may infiltrate
soft tissue around
88. 85
ME:
Direct deposition of osteoid matrix
(glassy eosinophilic) by tumor cells in a
lace-like pattern is diagnostic.
- Malignant osteoblasts
(pleomorphism, large
hyperchromatic nuclei, mitosis).
- Bizarre and giant tumor cells and
abnormal mitotic figures
89. 86
2. Cartilage forming tumors
Benign:
- Osteochondrma
- Chondroma
Malignant:
- Chondrosarcoma
Osteochondroma (exostosis):
Osteochondroma is a benign cartilage-capped tumor that is attached to the
underlying skeleton by a bony stalk.
Age: 10-30 years
Site: Metaphysis of long bone especially around the knee
Number: Most are solitary, multiple in multiple hereditary exostosis syndrome
Clinical picture: Slowly growing mass, may be painful if fractured or compressed
nerve
NE: sessile or pedunculated mass, and they range in size from 1 to 20 cm.
90. 87
ME: Cap of mature hyaline cartilage with underlying bone trabeculae separated by
bone marrow.
91. 88
Chondroma:
Usually occur in bones of endochondral origin.
Age: 10-30 years
Site: Medullary cavity of small bones of hands and feet
Number: Solitary, can be multiple in syndromes
Clinical picture: Asymptomatic or can produce pain or deformity, may turn
malignant
NE:
Chondromas are usually smaller than
3 cm and are gray blue and
translucent.
ME: Composed of well-
circumscribed nodules of hyaline
cartilage containing benign
chondrocytes.
92. 89
Chondrosarcoma
The second most common primary malignant tumor of bone.
C/P:
- Pain
- Pathological fracture
- Recurrence.
- Direct spread and early blood spread
to the lungs.
Age: 30-60 years
Site: Pelvis, shoulder and ribs
Radiology: Large mass with “Popcorn
calcification”.
NE: large bulky nodules of glistening,
translucent cartilage with spotty
calcifications and necrosis.
ME: Malignant chondrocytes with
pleomorphism and increased mitotic figures
in a chondroid matrix infiltrating the bone
marrow with entrapment of normal bony
trabeculae.
93. 90
3. Tumors of Unknown Origin:
Locally aggressive Malignant
Giant cell tumor Ewing sarcoma
Giant Cell Tumor
Age: Adults (20-40 years)
Site: Epiphysis of long bones
(distal femur and proximal tibia)
Radiology: Expanding lesion
Soap Bubble appearance.
Clinical picture: Pain, pathologic
fracture, Arthritis like symptoms
as, if close to joint.
ME: consisting of numerous
osteoclast-type giant cells with
100 or more nuclei with uniform,
oval mononuclear tumor cells in
between. The tumor lacks bone
or cartilage.
94. 91
Ewing Sarcoma
Ewing sarcoma called primitive neuroectodermal tumor (PNET).
The second most common bone sarcoma in children.
Age :10-20 years
Site: Diaphysis of long bone
Clinical picture: painful enlarging
masses
Pathogenesis: EWSR and FLI1
mutations
Radiology: destructive lytic tumor
with reactive bone deposited in an
onion-skin fashion
ME: Sheets of uniform small,
round cells that have scant
cytoplasm. Homer-Wright
rosettes (round groupings of cells
with a central fibrillary core) may
be present.
95. 92
4. HematopoieticTumors
Plasma cell myeloma (multiple myeloma)
Proliferation of neoplastic plasma cells in the
bone marrow which leads to lytic
lesion/lesions in the bone
- One lytic lesion = Plasmacytoma (solitary
myeloma)
- Multiple lytic lesions = Multiple myeloma
Age: old age
Site: Skull, vertebrae, ribs, pelvis, long bone.
Clinical picture:
- Solitary plasmacytoma: Pain
- Multiple myeloma: CRAB: hypercalcemia, renal impairment, anemia and
bone fracture
ME: Plasma cells in sheets, sometimes
with prominent nucleoli or inclusions
containing immunoglobulin.
96. 93
Secondary Bone Tumors
- More common than primary.
- Reach bone by blood
- Primary sites are breast, prostate, lung, thyroid and kidney.
- Most bone metastases are →osteolytic (produce bone destruction)
Except cancer prostate that may be → osteosclerotic (tumor secrete factors
stimulate osteoblasts).
Age: Adults
Sites: Multifocal in axial skeleton and proximal part of appendicular skeleton (due
to presence of vascular red marrow.
97. 94
Soft tissue tumors
- Soft tissue refers to non-epithelial tissue excluding the skeleton, joints,
central nervous system, hematopoietic and lymphoid tissues.
- Soft tissue includes: adipose tissue, fibrous tissue, smooth and skeletal
muscles, blood and lymph vessels and peripheral nerves.
Classification of soft tissue tumors: clinically, soft tissue tumors are classified
into:
1. Benign, self-limited lesions that require minimal treatment
2. Intermediate grade, locally aggressive tumors with minimal metastatic risk
3. Highly aggressive malignancies (sarcomas) with significant metastatic risk and
mortality.
Pathologic classification integrates morphology (e.g., muscle differentiation),
immunohistochemistry, and molecular diagnostics.
Tumors of adipose tissue:
Lipoma
- Lipoma: is a benign tumor of fat.
- The most common soft tissue tumor in
adults.
Age: Adulthood uncommon in childhood
Site: Most common locations include back,
shoulder, neck, and abdomen
98. 95
Clinical picture: Slowly growing, mobile soft mass in the subcutaneous tissue;
occasionally found in deeper tissue.
NE:
- Soft, well-circumscribed, lobulated tumors that are are thinly encapsulated
- Cut surface shows soft, pale, yellow, homogeneous, mature-appearing adipose
tissue.
ME:
- Lobular architecture with thin,
internal fibrous septa with thin,
fibrous capsule.
- Lobules are composed of mature
adipose tissue with cells that vary
only slightly in size with small,
eccentric, compressed nuclei (signet
ring appearance).
IHC: S100 protein positive
Liposarcoma
- Liposarcoma ia a malignant tumor
of adipose tissue.
- Liposarcoma is one of the most
common sarcomas of adulthood.
Age: 50-60 years
99. 96
Site: deep soft tissue and peritoneum.
Clinical picture: Recurring rapidly growing large mass.
NE: well circumscribed but not encapsulated, may have a mucoid cut surface or
a bright yellow appearance mimicking lipoma.
ME: The diagnostic cell is the lipoblast; appears as a mononuclear or
multinucleated cells. The nucleus is often centrally located but exhibit small sharp
indentations by multiple small lipid vacuoles.
IHC: S100 protein positive.
Tumors of fibrous tissue
Fibromatosis
Fibromatosis: Tumor of intermediate grade
(locally aggressive).
100. 97
Types:
Superficial fibromatosis
Age: Adults, male > female
Site: palmer, planter, penile
Deep (Desmoid type) fibromatosis
Age: teenagers to adults more in females.
Site: Abdominal or in head & neck and limbs.
Clinical picture: Small, slow-growing,
subcutaneous nodule or thickening
NE: Single or multiple, gray-white, firm
nodules
ME: Fascicles of bland fibroblasts,
surrounded by abundant dense collagen.
IHC: β-catenin positive.
Tumors of skeletal muscles
Rhabdomyosarcoma
Rhabdomyosarcoma is a malignant mesenchymal tumor with skeletal muscle
differentiation.
Types:
- Alveolar rhabdomyosarcoma
- Embryonal
- Pleomorphic
101. 98
Age: Alveolar and embryonal rhabdomyosarcoma is the most common soft tissue
sarcoma of childhood and adolescence. Pleomorphic rhabdomyosarcoma is seen
predominantly in adults.
Site: The pediatric forms often arise in the sinuses, head and neck, and
genitourinary tract.
NE: Soft gray infiltrative mass
ME:
Embryonal rhabdomyosarcoma: is formed
of sheets of both primitive round and
spindled cells.
Alveolar rhabdomyosarcoma: a network of
fibrous septae divide the cells into clusters or
aggregates, creating a resemblance to
pulmonary alveoli.
The tumor cells are uniformly round with
little cytoplasm
102. 99
Pleomorphic rhabdomyosarcoma: is
characterized by numerous large, sometimes
multinucleated, bizarre eosinophilic tumor
cells.
IHC: Desmin & myogenin positive
Tumors of smooth muscles
Leiomyoma
A benign tumor of smooth muscle, is most common in the uterus but can arise in
any soft tissue site.
Age: cutaneous type in adolescent and young adults
Site: Skin, deep soft tissue, GIT and uterus.
Clinical picture: Clinical presentation depends on location and can range from
painful cutaneous swellings to deep masses in the extremities and abdomen.
NE:
- Typically measures less than 2 cm; deep tumors may be larger
- Sectioning shows a firm, trabeculated, gray-white, bulging surface
ME: Well-differentiated smooth muscle cells arranged in interlacing fascicles. The
cells have Eosinophilic cytoplasm and oval, blunt-ended nuclei with perinuclear
vacuoles. No atypia or mitotic activity.
IHC: SMA & desmin positive.
103. 100
Leiomyosarcoma:
A malignant tumor of smooth muscles.
Age: Adults, females more than males.
Site: the deep soft tissues of the extremities and
retroperitoneum.
Clinical picture: painless firm masses
NE:
- Relatively well-circumscribed, fleshy mass with a gray-white, whorled, cut
surface.
- Focal hemorrhage, necrosis, or cystic change may be seen.
ME: They consist of eosinophilic spindle cells with
blunt ended, hyperchromatic nuclei arranged in
interweaving fascicles.
Cellular pleomorphism may be minimal to
marked.
Mitotic rate usually 5 mitotic figures/10 hpf, IHC: SMA & desmin positive
104. 101
Tumors of peripheral nerves:
Schwannoma:
Schwannomas are benign encapsulated tumors of peripheral nerves.
Age: Any age, mainly adults
Site: it may occur in soft tissues, internal organs, or spinal nerve roots.
C/P: slowly growing painless tumor
NE: circumscribed encapsulated masses abutting an adjacent nerve.
ME:
Presence of dense hypercellular areas (Antoni A areas) and hypocellular, myxoid
areas (Antoni B areas)
- Nuclear palisading around fibrillary processes (Verocay bodies)
- Cells are spindled and contain elongated, wavy nuclei with tapered ends
- Hyalinized vessels are characteristic
IHC: S100 protein positive.
105. 102
Tumors of uncertain origin
Synovial sarcoma:
Misnomer because this malignancy is only rarely found within joints
Age: 20-40 years
Sites: Mostly in lower extremities, but any site could be affected including viscera.
C/P: Presents as a deep-seated, often painful mass; has often been present for
years
NE:
A well-circumscribed mass with a gray
white or variegated cut surface; rapidly
growing tumors tend to be more
infiltrative.
ME: monophasic or biphasic.
106. 103
Monophasic synovial sarcoma
Consists of uniform spindle cells with scant cytoplasm and dense chromatin
growing in short fascicles.
The biphasic type contains glandlike structures
composed of cuboidal to columnar epithelioid cells in
addition to the spindle cell component
- CK in epithelial component
- CD99 in either or both components, TLE1
Summary of IHC in soft tissue tumors
- S100 protein is positive in tumors of adipose tissue and neural tissue.
- Desmin positivity indicate muscle differentiation
- Myogenin is positive in tumors of skeletal muscle origin
- SMA is positive in tumors of smooth muscle differentiation.
- β catenin positivity is chareteristic for fibromatosis
- CD99 and TLE1 positivity are characteristic for synovial sarcoma.
109. 106
Classification of NSAIDs
Acetylsalicylic acid (Aspirin)
Pharmacokinetics:
Oral absorption is complete; most of absorption occurs from the stomach
and upper GIT.
Aspirin is rapidly deacetylated in the gut wall, liver, plasma and other
tissues to release salicylic acid which is the major circulating and active
form.
Slowly enters brain but freely crosses placenta.
The metabolites are excreted by glomerular filtration & tubular secretion
(How to increase excretion of aspirin?)
Mechanism of action:
Aspirin is non-selective and irreversible COX inhibitor leading to
inhibition of both prostaglandins (PGs) and thromboxane A2 (TXs).
Other NSAIDs, which reversibly inhibit COX-1 and COX-2.
110. 107
Mechanism of action of NSAIDs
Pharmacological effects:
1. Analgesic action:
For mild to moderate intensity
pain (not severe pain).
Analgesic effect is mainly due to
peripheral inhibition of PG
production.
Relieve pain without causing
sedation, tolerance or drug
dependence
2. Antipyretic effect:
Aspirin is antipyretic but NOT
hypothermic agent i.e. it can
lower elevated body
temperature but not normal
body temperature.
Mechanism:
Decrease PGE2 synthesis in
the hypothalamus.
Decrease the hypothalamic
response to interleukin-1
(endogenous pyrogen).
Cutaneous VD and increase
sweating.
111. 108
3. Anti-inflammatory, anti-immunological and anti-rheumatic effects
Suppress signs and symptoms of inflammation such as pain, tenderness,
swelling, vasodilatation and leukocyte infiltration
Mechanism:
By inhibition of COX enzyme, it ↓ synthesis of PGs and TXs, and possibly other
inflammatory mediators leading to:
Decrease inflammatory cell activation and chemotaxis.
Decrease capillary permeability.
Decrease hyaluronidase enzyme and inhibits spread of inflammation.
Stabilize lysosomal membranes of inflammatory cells.
4. Hematologic effects:
Antiplatelet action (small dose aspirin 75-150mg)
Aspirin inhibit platelet aggregation
Mechanism
Irreversible inhibition of COX enzyme → ↓ TXA2 → ↓ platelet aggregation.
Irreversible acetylation of platelet cell membranes → ↓ platelet adhesions.
Decrease platelet ADP synthesis → decrease platelet accumulation
Why small dose aspirin?
Vascular endothelium produces PGI2 (prostacyclin) that causes VD and
inhibition of platelet aggregation
Platelets produce TXA2 that causes VC and increase platelet aggregation
In high doses (> 300 mg), aspirin inhibit both vascular PG12 and platelet
TXA2.
In small doses (75-150 mg), aspirin inhibits only platelet TXA2 synthase
enzyme selective antiplatelet action.
112. 109
Questions:
QI: if a patient taking aspirin has to undergo a surgical operation, when must
he stop aspirin before the operation?
He must stop aspirin at least 7 days before the operation because platelet COX-
I is IRREVERSIBLY inhibited (i.e. platelet aggregation is permanently inhibited)
and the patient has to synthesize new platelets (life span of platelets is 7-10
days).
Q2: If this patient needs urgent operation, what is the next step?
He must receive fresh blood, or packed platelet transfusion.
Q3: If this patient was taking an NSAID other than aspirin, when must he stop
this drug before the operation?
Any time because all NSAlDs other than aspirin inhibit COX enzyme
REVERSIBLY (i.e. platelet aggregation is not permanently inhibited).
5. GIT effects:
Acute gastric ulcer:
- Due to ingestion of large doses of salicylates [trapping of salicylate ions inside
the gastric mucosal cells leading to acute, painful gastric bleeding].
113. 110
Chronic gastric ulcer:
- Occurs as a result of chronic ingestion of salicylates. Due to chronic inhibition
of the protective PGE1, PGE2 and PGI2 synthesis leading to chronic ulceration
and chronic blood loss.
6. Renal effects:
Analgesic nephropathy: due to chronic abuse of analgesics, which produce
chronic renal ischemia due to decrease synthesis of renal PGE2 and PGI2
Salt and water retention: due to decrease RBF and increase aldosterone.
Antagonize diuretic effect of diuretics and antihypertensive effects of β-
blockers: due to decrease synthesis of PGE2.
Uric acid excretion: low doses decrease uric acid secretion
7. Hepatic effects:
Mild hepatic effect:
- Dose-dependent, reversible and asymptomatic.
- There may be mild increase in serum transaminases (SGOT and SGPT).
Severe hepatic injury: “Reye’s syndrome”:
- It is a rare and fatal condition occurs if aspirin is used to control fever of some
viral infections (e.g. influenza) in children below 12 years old.
8. Metabolic effects:
High doses cause uncoupling of oxidative phosphorylation → tachycardia and
hyperpyrexia
9. Uterus:
Prolongation of pregnancy and delay of labour due to inhibition of PGs
necessary for uterine contraction during labour.
The use of NSAIDs after 20 weeks of pregnancy is not recommended.
114. 111
10. Respiratory effects:
Low toxic doses: produce metabolic acidosis → compensatory
hyperventilation to wash excess CO2 → prolonged respiratory alkalosis.
High toxic doses: produce metabolic acidosis together with inhibition of RC →
death from severe acidosis.
11. CVS effects:
Therapeutic doses: NO significant effect on the CVS.
Toxic doses: inhibit VMC leading to circulatory failure.
Therapeutic uses:
1. Analgesic: in headache, arthritis, rheumatic pain
2. Antipyretic
3. Anti-inflammatory and anti-rheumatic: in rheumatic fever, rheumatoid
arthritis, osteoarthritis, etc.
4. Antithrombotic: in ischemic heart disease, deep vein thrombosis, AF, etc.
Adverse effects:
1. GIT:
Epigastric pain, nausea and
vomiting.
Acute and chronic gastric ulcers
2. Renal:
Analgesic nephropathy & Salt and water
retention.
The diuretic effect of loop diuretics and
antihypertensive effects of β-blockers.
3. Hepatic:
Mild reversible hepatic injury in
adults.
Severe hepatic injury in children:
“Reye’s syndrome”.
4. Blood:
Increase bleeding tendency.
Displacement of other drugs from
plasma proteins.
5. Reproductive functions
Prolongation of pregnancy and
delay of labour.
6. Hypersensitivity reactions:
Bronchospasm (aspirin asthma), in
patients with bronchial asthma.
115. 112
Contraindications:
1. GIT disorders: peptic ulcer and gastritis
2. Chronic liver diseases: (those patients have bleeding tendency).
3. Hemorrhagic disorders: hemophilia, thrombocytopenia, etc.
4. Severe hypertension: risk of fatal bleeding.
5. Chronic renal diseases: aspirin may aggravate renal failure
6. Gout: small dose may inhibit uric acid excretion (aspirin).
7. Pregnancy: long-term therapy may delay labour.
8. Before surgery: aspirin must be stopped at least 7 days before surgery.
9. Children <12 years old: Fear of Reye’s syndrome.
Other NSAIDS
Diclofenac
One of the most widely used NSAIDs.
It is less gastric irritant than other NSAIDs but more Nephrotoxic. (A dose
of 150 mg/day can impair renal blood flow and GFR).
It is often combined with PGE analogue misoprostol to decrease gastric
ulceration.
Topical gel is available for local rheumatic pain and osteoarthritis of the
knee and hands.
Sulindac and ketorolac
Both have minimal effect on platelet aggregation.
Sulindac is a prodrug and has long t½.
Ketorolac is a potent analgesic but it can cause severe GIT bleeding.
Ibuprofen, fenoprofen, ketoprofen
No reported interactions with oral anticoagulants
Ibuprofen is a good alternative to aspirin in children with flu fevers.
116. 113
Long-term use of ibuprofen is associated with an increased incidence of
hypertension in women.
Fenoprofen has been reported to induce nephrotic syndrome
Indomethacin
It is a very potent COX inhibitor but relatively more toxic than other
NSAIDs.
It is approved to speed the closure of patent ductus arteriosus in
premature infants (otherwise it is not used in children); it inhibits the
production of PGs which prevent closure of the ductus.
Patent ductus arteriosus
Piroxicam
It has long t½ (~ 45 hours).
Like aspirin and indomethacin, bleeding and ulceration are more likely
with piroxicam than with other NSAIDs.
Selective COX-2 inhibitors
Celecoxib, etoricoxib, meloxicam
Selective COX-2 inhibitors are newer forms of NSAIDs that directly target
COX-2 enzyme responsible for inflammation and pain.
117. 114
Celecoxib is approximately 30 times more potent at inhibiting COX-2 than
COX-1.
Meloxicam is slightly selective for COX-2 than COX-1 enzyme.
Risk benefits
Selectivity for COX-2 reduces the risk of peptic ulceration but does not
seem to affect other adverse-effects of NSAIDs (especially the risk of renal
failure).
Selective COX-2 inhibitors may also increase the risk of cardiovascular
accidents (myocardial infarction, thrombosis and stroke) due to relative
increase in TXA2 and platelet aggregation (TXA2 is formed by COX-1
where PGI2 is formed by COX-2).
Rofecoxib (Vioxx®) and valdecoxib were withdrawn from the market in
2004 and 2005 respectively because of these potential adverse effects.
118. 115
Analgesic Antipyretic
Acetaminophen (Paracetamol)
Pharmacokinetics:
Absorption:
Complete and rapid from GIT with peak levels after 30 min.
Metabolism:
Liver by conjugation.
At high doses,(oxidation) it is converted into toxic metabolite (N-acetyl-
benzoquinone) by CYP450 that is responsible for hepatotoxicity.
Excretion:
Mainly renal.
Non-selective COX
inhibitors Selective COX-2 inhibitors
Mechanism: They inhibit COX-1
(non-inducible) and
COX-2 (inducible)
enzymes
They inhibit COX-2 (inducible)
enzyme only
Pharmacological
effects:
Both classes have equal analgesic and antipyretic effects
Gastric side
effects:
Frequent Less frequent
Renal side
effects:
Frequent Frequent
Thrombotic
complications:
Decreased ( ↓TXA2)
(due to decreased
platelet aggregation)
Increased (↓PGI2)
(due to increased platelet
aggregation)
Hypersensitivity
reactions:
Frequent Less frequent
119. 116
Mechanism (The exact mechanism of action remains unclear) (Theories)
Acetaminophen may inhibit the COX pathway in the central nervous
system but not peripheral tissues by inhibiting a splice variant of COX-1,
also called COX-3, but this has not been confirmed in humans.
The analgesic properties may be due to a stimulating effect on the
descending serotonergic pathways in the central nervous system (CNS).
Acetaminophen or one of its metabolites can activate the cannabinoid
system.
Pharmacological effects:
Acetaminophen has analgesic and antipyretic properties without
peripheral anti-inflammatory properties.
Therapeutic uses:
1. As analgesic and antipyretic when aspirin is contraindicated (e.g. patients
with peptic ulcer, haemophilia, etc).
2. Acetaminophen can be administered in pregnancy with greater safety
than aspirin.
Adverse effects:
At therapeutic doses: acetaminophen is well-tolerated but may cause:
1. Skin rash& drug fever (as allergic reactions).
2. Long term use may lead to renal failure.
In toxic doses:
Dose-dependent hepato-toxicity (centrilobular necrosis): It occurs with large
doses (about 15 gm in adults and 4 gm in children)
Mechanism of hepatotoxicity
Paracetamol is metabolized in the liver by conjugation into glucuronide
and sulphate conjugates.
A small proportion of the paracetamol is metabolized by cytochrome
P450 enzymes into the toxic metabolite, N-acetyl-p-benzoquinoneimine
(NAPQI).
120. 117
When there are adequate stores of the anti-oxidant, glutathione, NAPQI
is conjugated to form non-toxic metabolites.
In the case of paracetamol overdose, the initial conjugation pathway is
exceeded and greater production of NAPQI occurs. Glutathione stores
become depleted and NAPQI concentrations accumulate resulting in
hepatocyte damage and potentially the development of fulminant liver
failure.
Clinical symptoms of toxicity (e.g. vomiting) occur within 24 hrs but signs
of hepatic damage (e.g. jaundice) occur after 2-6 days.
Mechanism of paracetamol toxicity
Treatment of toxicity with paracetamol
1. Gastric lavage with activated charcoal.
2. Sulfhydryl donors (acetylcysteine) to restore hepatic glutathione. It must be
started within 8 hours of toxicity (Acetylcysteine replenishes glutathione
stores, allowing NAPQI to be metabolized and preventing further liver
damage).
3. Haemodialysis: better within the first 12 hrs after ingestion.
121. 118
4. Following treatment with acetylcysteine, repeated checks for renal and
liver function. If there is significant renal or liver impairment, a further
infusion of acetylcysteine
5. Patients with severe hepatic dysfunction consider liver transplant.
Glucocorticoid pharmacology
Regulation of Adrenal Hormones
The 2 adrenal glands are responsible for producing:
Mineralocorticoids (e.g., aldosterone) which regulate fluid and electrolyte
balance.
Aldosterone production is regulated by the renin-Angiotensin system.
In the renal tubules, aldosterone binds to and activate specific mineralocorticoid
cytoplasmic receptors ↑ Na+ and water reabsorption & ↑ K+ excretion.
Glucocorticoids (e.g., cortisol) which are essential for carbohydrate
metabolism and response to stress.
Cortisol production is regulated by the hypothalamic-pituitary-adrenal (HPA)
axis.
1. The hypothalamus releases CRH (corticotrophin-releasing hormone) in
response to various stimuli.
2. CRH stimulates the anterior pituitary to release ACTH (corticotrophin).
3. ACTH then stimulates the adrenal cortex to produce cortisol.
4. As serum cortisol levels increase, synthesis and secretion of CRH and ACTH
decrease via a negative feedback loop.
122. 119
Physiologic Effects of glucocorticoids
Cortisol bind to specific cytoplasmic receptors translocated to the nucleus
↑ or ↓ transcription of specific genes
various anti-inflammatory, anti-allergic and metabolic effects of
glucocorticoids:
↑ Liver gluconeogenesis
(↑ formation of glucose
from amino acids) an
anti-insulin effect.
↑ Protein catabolism
muscle and skin wasting &
osteoporosis.
↑ lipolysis abnormal fat distribution
Corticosteroid Drugs (classification)
Fludrocortisone:
A mineralocorticoid used as replacement therapy in patients with primary
adrenal insufficiency (Addison disease).
Semisynthetic glucocorticoid drugs
Uses:
Most commonly, used as anti-inflammatory drugs for treatment of a
wide range of inflammatory, allergic, autoimmune disorders.
Whenever possible, topical or inhalational administration is preferred
because it avoids most systemic adverse effects
Less commonly, used as replacement therapy in the treatment of adrenal
insufficiency (e.g., cortisone & hydrocortisone)
124. 121
Glucocorticoids
Anti-inflammatory Effects
Glucocorticoids have multiple actions on several types of leukocytes:
1. Suppress activation of T lymphocytes & macrophage
2. ↓ Production of cytokines by activated T helper cells & macrophages.
3. ↓ Release of inflammatory chemical mediators from mast cells and
eosinophils e.g., histamine, prostaglandins & leukotrienes.
4. Stabilize lysosomal membranes of neutrophils and prevent the release of
catabolic enzymes.
5. Cause vasoconstriction and ↓ capillary permeability and inflammatory
edema.
6. ↓ Number of circulating lymphocytes, eosinophils, basophils, and
monocytes.
7. ↑ Number of RBCs, platelets, and WBCs.
125. 122
Other effects
1. ↓ Growth in children.
2. ↑ development of peptic ulcer
3. Promote fat redistribution.
Increase visceral, facial, and
supraclavicular fat. “Moon face”
and “buffalo hump”
4. Antagonize Vitamin D effect on
calcium absorption.
5. Stimulates structural/functional development of fetal lungs.
6. Behavioral disturbances: Initially insomnia and euphoria followed by
depression or psychosis.
7. Suppress pituitary release of ACTH (long-term use of glucocorticoids
suppress the hypothalamic-pituitary-adrenal axis.
Indications
1. Treatment of Inflammatory, Allergic, and Autoimmune Disorders
Autoimmune disorders as: systemic lupus erythematosus, multiple sclerosis and
ulcerative colitis.
N.B. beclomethasone an inhaled glucocorticoid 1st
-line therapy of
bronchial asthma
Mometasone topical in the nose for allergic rhinitis
126. 123
Topical steroids allergic & autoimmune dermatologic conditions.
2. Cancer
Treatment of lymphocytic leukemias and lymphomas
3. Respiratory Distress Syndrome in premature infants.
4. Replacement therapy in adrenocortical insufficiency
N.B. Most commonly, adrenal insufficiency results when steroid drugs are
stopped suddenly after being used for a prolonged time.
Replacement therapy in adrenocortical insufficiency
Replacement therapy for primary adrenocortical insufficiency (Addison
disease) is caused by adrenal cortex dysfunction.
Replacement therapy for secondary or tertiary adrenocortical
insufficiency these disorders are caused by a defect in CRH production
or in ACTH production.
Hydrocortisone is used for treatment of replacement therapy. 2/3 of the
daily dosage of hydrocortisone is administered in the morning and 1/3 in the
afternoon, mimicking the normal circadian variation in cortisol levels.
Pharmacokinetics
Absorption:
Glucocorticoids are highly lipid soluble well absorbed after oral
administration.
Glucocorticoids are highly bound to corticosteroid-binding globulin and
albumin.
127. 124
Metabolism:
Glucocorticoids are oxidized by cytochrome P450 enzymes and conjugated
with sulfate or glucuronide in the liver before undergoing renal excretion.
Administration:
Orally to treat mild-moderate allergic conditions, autoimmune disorders
and cancers.
Parenterally (IV or IM) to treat acute adrenal insufficiency, acute allergic
reactions, and emergencies.
Glucocorticoids are often more effective when they are initially given in large
doses then gradually tapered over several days until treatment is discontinued.
N.B. Alternate-day therapy is a dosage schedule that appears to reduce adverse
effects and produces less suppression of the hypothalamic-pituitary-adrenal axis
by allowing more time for recovery between doses.
Side effects
1. Administration of therapeutic doses of glucocorticoids > 2 weeks results
in Iatrogenic “Cushing syndrome”.
Moon face & buffalo hump.
Increased hair growth (hirsutism)
Weight gain
Muscle wasting and weakness
Osteoporosis.
128. 125
Dermatologic changes acne (steroid acne), bruising, and thinning of
the skin.
2. Metabolic changes hyperglycemia and hypertension.
3. Na+
retention, K+
loss, and hypertension more common with cortisone or
hydrocortisone have greater mineralocorticoid activity than other
glucocorticoids.
4. Mood changes Euphoria or psychosis.
5. Exacerbate peptic ulcers.
6. ↑ susceptibility to infection
7. Ophthalmic cataracts and glaucoma
8. Acute Adrenal suppression due to negative feedback mechanisms
The degree of suppression is related to the dose and length of therapy.
When therapy is discontinued, the dose must be gradually tapered.
130. 127
Skeletal muscle relaxant
Classification:
1. Centrally acting:
A. Benzodiazepine→ Diazepam
B. GABA derivative→ Baclofen
C. α 2 receptor agonist→ Tizanidine
2. Peripherally acting:
Drugs acting at neuromuscular junction (NMJ)
A. Depolarizing neuromuscular blockers→
Succinylcholine
B. Non depolarizing neuromuscular blockers
→Tubocurarine
C. Inhibitor of Ach release →Botulinum toxin
Direct acting skeletal muscle relaxant
→Dantrolene
Centrally acting skeletal muscle relaxant
A. Diazepam (valium):
The only FDA approved benzodiazepines for treatment of spasticity and
muscle spasms and not often recommended as a first-line.
Mechanism
Binds to GABAA receptors and potentiates GABAergic activity by increasing
chloride conductance, which results in presynaptic inhibition in the spinal cord.
Adverse effect
The main disadvantages are sedation and dependence and abuse.
B. Baclofen
Mechanism
1. An analogue of GABA that bind GABA B receptors presynaptic and
postsynaptic. Presynaptic GABA B reduces glutamate release, inhibits
neurotransmitter release.
2. Baclofen also has an analgesic effect, probably by inhibition of the release
of substance P in pain pathways.
131. 128
Adverse effects
1. Sedation, drowsiness, confusion, depression, dizziness, ataxia, seizure.
2. Nausea, gastrointestinal disturbances.
3. Sudden withdrawal can precipitate hyperactivity and seizures.
C. Tizanidine
Mechanisms
Tizanidine is an alpha 2 -adrenoceptor agonist that inhibits presynaptic release
of excitatory neurotransmitters, reducing the excitability of postsynaptic α-
motor neurons.
Adverse effect
1. Drowsiness, fatigue, dizziness.
2. Dry mouth
3. Hypotension. Tizanidine has only 10% of the antihypertensive activity of
the α 2 -adrenoceptor agonist clonidine.
Uses of centrally acting skeletal muscle relaxant
Spasticity associated with spinal cord injury, hemiplegia, amyotrophic lateral
sclerosis and Multiple sclerosis.
132. 129
Neuromuscular blockers
These drugs block cholinergic transmission between motor nerve
endings and the nicotinic receptors on the skeletal muscle.
They possess some chemical similarities to ACh and they act either as
antagonists (nondepolarizing type)
Or as agonists (depolarizing type) at the receptors on the endplate of the
NMJ.
Non-depolarizing (competitive) NMBs
D-Tubocurarine (prototype)
Semisynthetic derivatives:
Mivacurium, Atracurium, cisatracurium,
Vecuronium, pancuronium
Pharmacokinetics
Absorption and distribution
All members are not absorbed orally
because they are polar compounds
(quaternary amines), they must be given parenterally.
All cannot cross BBB or placental barrier
Metabolism &Duration of action
Atracurium, cisatracurium: plasma hydrolysis by nonspecific esterases,
which is an advantage in hepatic or renal impairment (30-40) min.
Vecuronium: liver (45) min.
Mivacurium: like suxamethonium is metabolized by cholinesterase (15-
20) min).
Mechanism of action
Competitive block of Ach at Nm receptors → muscle paralysis.
Inhibition of ACh hydrolysis by an AChE inhibitor (such as neostigmine will
prolong the action of ACh and rapidly reverse competitive neuromuscular
junction blockade.
Binding locations for centrally acting
skeletal muscle relaxant
133. 130
Reversal of block
Neostigmine
Sugammadex: It is a specific antagonist for the rocuronium and
vecuronium (but not pancuronium) by chelating them in the core and
reducing their plasma concentration. The complex is then eliminated by
the kidneys.
Adverse effects
1. Histamine release leading to hypotension and bronchospasm.
2. Respiratory paralysis in high doses.
Contraindications
1. Bronchial asthma: why?
2. Myasthenia gravis.
3. With aminoglycosides or quinidine (they can aggravate ms paralysis).
Depolarizing (non-competitive) NMBs
Suxamethonium (succinylcholine): It is ester of Ach
Pharmacokinetics
The same as non -depolarizing but it is metabolized by plasma pseudo ChE
enzyme (3-12) minutes after administration.
Mechanism of action
Depolarizing block of Nm receptors → ms paralysis through 2 phases:
Phase 1: initial depolarization →transient ms contraction followed by
paralysis due to maintained depolarization (depolarization block)
Phase 2: the muscle become repolarized again but remains insensitive to
stimulation by acetylcholine (need to increase Ach to be stimulated
(desensitization block)
Reversal of block
Fresh blood transfusion (pseudocholine esterase)
134. 131
Adverse effects
1. Bradycardia due to stimulation of cardiac muscarinic receptors
2. Acute hyperkalemia: It is due to efflux of muscle K+ during depolarization.
3. Sudden rise of IOP due to contraction of the extraocular muscles in
phase1.
4. Postoperative muscle pain.
5. Prolonged respiratory paralysis (apnea) may result from congenital
deficiency of PsChE enzyme (treaded by artificial respiration and blood
transfusion).
6. Malignant hyperthermia.
Contraindications
1. Glaucoma or recent eye surgery: why?
2. Congenital deficiency of PsChE enzyme: why?
Therapeutic uses of neuromuscular blockers
1. Endotracheal intubation: Rapid intubation is the only current use for
suxamethonium, because of frequent unwanted effects, suxamethonium
is replaced by rapidly acting non-depolarizing blockers such as
rocuronium
2. To induce skeletal muscle relaxation during surgical operation.
3. To control convulsion during electroconvulsive therapy (ECT)
Inhibitors of Acetylcholine Release (Botulinum toxin)
Botulinum toxin from the anaerobic bacillus Clostridium
botulinum decreases the release of ACh from neuronal vesicles.
Mechanism of action
It binds a receptor on the presynaptic membrane of cholinergic nerve ending
inhibiting neurotransmitter release.
135. 132
Therapeutic uses:
Injected locally
1. Into skeletal muscles producing local muscle paralysis for 3–4 months
until new nerve terminals develop to treat involuntary movements such
as blepharospasm (spasm of the eyelids), To relieve focal spasticity e.g.
spasmodic torticollis and for cosmetic reasons to temporarily remove
wrinkles.
2. Local injection to reduce excessive axillary sweating (hyperhidrosis)
3. Facial muscles for the prophylaxis of migraine.
4. Intravesical injection to treat severe overactive bladder syndrome.
Dantrolene
Mechanism of action
Dantrolene is an antagonist at the ryanodine receptor (RyR1) that regulate the
release of Ca 2+ from the sarcoplasmic reticulum of skeletal muscle.
Uses
1. Treatment of malignant hyperthermia &neuroleptic malignant syndrome
2. Management of spasticity from disorders (e.g., after strokes, paraplegia,
etc).
Adverse effects
1. Skeletal muscle weakness, dyspnea, dysphasia, somnolence.
2. Dose dependent diarrhea & Dose-related risk of hepatitis.
Malignant hyperthermia.
This is a rare but potentially fatal complication of volatile liquid
anesthetics.
It is genetically determined, and results from a defect in the ryanodine
receptor (RyR1) that regulates release of Ca 2+ from the sarcoplasmic
reticulum in skeletal muscle cells.
136. 133
A sudden increase in intracellular Ca 2+ provoked by an anesthetic
produces tachycardia, unstable blood pressure, hypercapnia, fever and
hyperventilation, followed by hyperkaliemia and metabolic acidosis.
Muscle rigidity may occur.
Treatment is with dantrolene, a RyR1 receptor antagonist
Dantrolene and ryanodine receptors
Disease Modifying Antirheumatic Drugs
(DMARDs)
Rheumatoid arthritis (RA)
RA is an autoimmune, chronic, progressive inflammatory disease; characterized
by symmetric small joint inflammation, swelling, and deformity and systemic
manifestations.
137. 134
Pathophysiology:
Clinical manifestations
Articular manifestations:
Affects mainly small joints of the hands and feet.
Joint involvement is usually symmetric.
Symptoms painful joints and prolonged morning joint stiffness.
Signs warm, tender, swollen, red joints, with limited mobility.
138. 135
Extra-articular manifestations:
The clinical manifestations of RA can extend to include systemic organs e.g.,
pleural effusion, conjunctivitis, anemia, vasculitis, etc.
Diagnosis:
Serological:
Abnormal antibodies "rheumatoid factor“ in 80% of RA patients.
Elevated CRP & ESR
Positive anti-CCP antibodies.
Joint X-ray: Show joint swelling and bony erosions typical of RA.
Drug treatment of RA
Aims of drug treatment are:
To reduce pain, stiffness and improve joint mobility (symptomatic drug
treatment).
To prevent chronic deformity by stopping the inflammation that results in
joint destruction (DMARDs).
139. 136
Symptomatic treatment
NSAIDs and/or corticosteroids are used as a ‘bridge therapy’ provide
symptomatic relief till the therapeutic effect of DMARDs is observed.
1. NSAIDs: analgesic/anti-inflammatory drugs may be used to relief pain.
They are relatively ineffective when used alone in RA they do not prevent
joint damage.
2. Corticosteroids: anti-inflammatory/immunosuppressive.
DMARDs
(Non-biologic & biologic)
Act by various mechanisms to suppress the proliferation & activity of
lymphocytes and macrophages.
1. They prevent disease progression and slow joint destruction by modifying
the immune reactions.
2. They should be started as early as possible (within 3 months of symptom
onset) more favorable outcome.
3. 1 or more DMARDs are used depending on disease severity.
4. There is a lag between starting therapy and observing an effect (3 weeks to
3 months).
5. It is usual to continue NSAIDs/corticosteroids with DMARDs.
140. 137
I. Methotrexate
MOA:
An antineoplastic and immuno-suppressant drug
It is a folic acid antagonist inhibits dihydrofolate reductase enzyme ↓
activation of folate to tetrahydrofolate (FH4 ↓ synthesis of purine and
pyrimidine bases of DNA and RNA.
Immuno-suppressant properties ↓ cytokine production and inhibits
activation & proliferation of T cells and macrophages.
141. 138
Use in RA:
1st
line DMARD it is used in more than 60% of RA cases.
It is given once weekly orally or IM.
The toxic effects of methotrexate can be reversed by the subsequent
administration of folinic acid (leucovorin)
Common adverse effects:
GIT: nausea and mucosal ulceration.
Myelosuppression, esp. leucopenia ↑ infections (periodic CBC)
Hepatotoxicity is common (monitoring liver functions is essential).
Acute pneumonia-like syndrome.
CI in pregnancy.
II. Leflunomide
MOA:
It inhibits the mitochondrial enzyme, dihydroorotate dehydrogenase
(DHODH) inhibits pyrimidine base synthesis suppresses T cell and B cell
proliferation & activation.
Leflunomide an alternative to methotrexate for the first-line
management of RA
Adverse effects:
GIT: nausea & diarrhea
Hepatotoxicity
Reversible alopecia & rash
CI in pregnancy.
142. 139
III. Hydroxychloroquine (anti-malarial drug)
MOA: unknown, but might be:
Inhibition of phagocytic functions.
Stabilization of lysosomal membranes
Side effects:
GIT: diarrhea
Corneal deposits & Retinopathy: the most disturbing toxic effect, rare, is a
result of gradual accumulation of the drug in the retina irreversible retinal
damage with permanent blindness.
Skin discoloration & rash
Hemolysis in G6PD deficiency.
143. 140
IV. Sulphasalazine
MOA:
A prodrug cleaved by gut bacteria 5-aminosalicylic acid & sulphapyridine.
Sulphapyridine is thought to be the principal anti-rheumatic agent.
Adverse reactions:
GIT: nausea, vomiting, diarrhea
Myelosuppression: Occasional leucopenia and thrombocytopenia.
Hemolysis in G6PD deficiency.
V. Cyclosporine
MOA:
Cyclosporine bind cyclophilin inhibit calcineurin inhibit activation of
NFAT (nuclear factor of active T cells) ↓ biosynthesis of IL-2 inhibit T cell
proliferation.
Adverse effects:
Nephrotoxicity
4H HTN, Hyperkalemia, Hirsutism, gingival Hyperplasia
144. 141
VI. Biologic DMARDs
Inflammatory cytokines play a central role in RA.
Biological DMARDs are antibodies and antibody fusion proteins that inhibit the
action of cytokines by blocking the cytokine from binding to its receptor
administered S.C or IV.
Cytokine inhibitors used in the treatment of RA are:
Inhibitor of IL-1 (anakinra),
Inhibitors of TNF-α (infliximab, etanercept, and adalimumab)
Inhibitor of IL-6 (tocilizumab).
These drugs each have a stronger effect than methotrexate.
Methotrexate + any biological agent more effective than methotrexate alone.
145. 142
TNF-α inhibitors (infliximab, etanercept, and adalimumab)
Immunomodulating drugs that exert their effects by binding to and inactivating
TNFα.
TNFα is one of the proinflammatory cytokines produced by macrophages.
Abatacept
A selective costimulation inhibitor (CD80/86 inhibitor) inhibits T-cell
activation.
Anakinra
146. 143
Interleukin-1 receptor antagonist (IL-1Ra) competitively blocks IL-1 receptor
(IL-1R).
Tofacitinib
A Janus kinase (JAK) inhibitor
JAK is an intracellular enzyme that initiates
signal transduction to modulate immune cell
function.
Tocilizumab
An anti–IL-6 receptor antibody It binds
selectively to IL-6 receptors and blocks IL-6
activity.
147. 144
A competitive IL-1
receptor antagonist
Anakinra
IL-1 inhibitor
Complex with
cytokine/cytokine receptor
and prevent its interaction
with corresponding
receptor on immune cells.
Chimeric antibody
Infliximab
TNFα inhibitors Human antibody
Adalimumab
Fusion protein
Etanercept
Humanized
antibody of IL-6
receptor
Tocilizumab
IL-6 inhibitor
Prevent T cell costimulation
Fusion protein
Abatacept
CD80/86
inhibitor
B cell depletion
Chimeric antibody
Rituximab
CD20 inhibitor
Main side effects of TNF-α inhibitors.
Injection/infusion-related reactions
Infections (TB, fungal, sepsis, and reactivation of hepatitis B) never use 2
biologic DEMARDs together.
Increased risk of lymphoma and other cancers.
Contraindications to the use of TNF-α inhibitors.
Acute and chronic infections
Recent malignancies
Live virus vaccination
Demyelinating disorders
Class III or IV heart failure
149. 146
TRICHINELLA SPIRALIS
Geographical Distribution:
Trichinella spiralis is responsible for the disease known as trichinosis. It is
common in carnivorous mammals including rodents and humans. A cosmopolitan
distribution particularly in Europe and United States, it is common in countries
where people eat pork (Pig meat). It is also known in Africa, Southern Asia and the
Middle East. It exists in Egypt.
Habitat:
Small intestine of man, pigs, rodents and some other carnivorous mammals,
(definitive and intermediate hosts).
Reservoir hosts are: Pigs
Morphology: It is a small worm characterized by:
1. Slender anterior end.
2. Cellular oesophagus.
3. Terminal anus or cloaca.
The male measures 1.5 mm by 40µ, its posterior end is ventrally curved with two
lobular caudal appendages and having one set of genitalia.
The female measures 3 mm by 80 µ., its posterior end is bluntly rounded, having
one set of genitalia, the vulva opens at the junction of the anterior fifth with
the rest of the body and is larviparous (viviparous).
The larva has a spear like burrowing tip at its tapering anterior end. It measures 80
to 120 µ by 5.6 µ at birth and grows little until it attains a size of 900 to 1300
µ by 35 to 40 µ.
The mature encysted larva has a digestive tract similar to that of the adult
but the reproductive organs are not fully developed.
Life cycle: Stages of the life cycle: larva trichina capsule adult.
1. The adults live in the small intestine of man and animals specially pigs and rats
(reservoir hosts).
2. After fertilization males die and are expelled. Females penetrate deeply in the
