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Y1S2- Cardio, Resp, Loco > Locomotor > Flashcards

Locomotor Flashcards

1
Q

development of long bones

A

Bond forms as a cartilage first → blood vessels invade cartilage → cartilage remains in growth plate → adult bone

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2
Q

what cells invade cartilage during development with blood vessels?

A

osteogenic cells

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3
Q

diaphysis

A

shaft of the long bone

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4
Q

epiphysis

A

distal and proximal ends of bone

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5
Q

metaphysis-

A

regions in a mature bone where the diaphysis joins the epiphysis, in a growing bone this is the region occupied by the epiphyseal growth plate

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6
Q

Why is repair of connective tissue so poor/non-existent?

A
  • Poor vascular supply
  • Very low synthesis rates of some tissue components
  • Loss of cell-matrix interactions- leads to irreversible loss of phenotype
  • Integration of repair tissue very poor
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7
Q

common features of connective tissues

A
  • Low density of highly specialised cells sensitive to the physico-chemical environment
  • Complex ECM
    • Fibres- eg. collagen
    • Ground substance- unstructured filling material which is made of proteoglycans
    • Interstitial fluid
  • ECM turnover (synthesis/degradation) by cells throughout life
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8
Q

resident cells in connective tissue

A

fibroblasts in most CT but chondrocytes in cartilage

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9
Q

resident cells in bone

A
  • Osteoblasts- produce bone
  • Osteocytes- a mature osteoblast surrounded by a bone matrix
  • Bone lining cells
  • Osteoclasts- function in resorption and degradation of existing bone
  • Osteoprogenitor cells- osteoblast precursors
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10
Q

components of ECM

A
  • Collagens- fibrillar proteins resist tensile stresses- “rope”
  • Proteoglycans (also call ground substance- unstructured material)- composed of glycosaminoglycans which swell and resist compressive forces
  • Interstitial fluid- complex composition
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11
Q

what is mechanical stability of tissue controlled by?

A

synthesis/degradation of ECM. Cells link to the ECM by integrins.

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12
Q

epiphyseal growth plate

A
  • Specialised zone of cartilage
  • Lies between epiphysis and metaphysis
  • Site of continued endochondral ossification during growth
  • Longitudinal growth: regulated by complex networks of nutritional, cellular, paracrine and endocrine factors (including growth hormone, IGF-I, thyroid hormone, glucocorticoids, androgens and oestrogens)
  • Rapid growth occurs at puberty and when there is plentiful nutrition and closes after
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13
Q

diaphysis- cortical or cancellous?

A

most cortical and little cancellous bone

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14
Q

epiphysis- cortical or cancellous?

A

predominantly cancellous bone

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15
Q

cortical/ compact bone function

A
  • Provides most structural support

* Resists bending and torsion stresses (less likely to fracture)- thicker in mid part of bone

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16
Q

macroscopic histology of cortical bone

A
  • Osteons/ Haversian canals

- Volkmann’s Canals

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17
Q

Osteons/ Haversian canals

A
  • Main structural unit of cortical bone
  • Bone cylinders 2-3mm long
  • 8-15 concentric lamellae 0.2mm wide
  • Axis parallel to long axis of bone
  • Central cavity with blood vessel and nerve
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18
Q

Volkmann’s Canals

A

• Carry blood vessels from periosteum (dense layer of vascular connective tissue enveloping bones expect at the surface of joints) to haversian system

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19
Q

cancellous/trabecular bone features

A
  • Found inside cortices
  • Provides large surface area for metabolic functions
  • Provides strength without disadvantage of weight
  • Arranges along lines of maximum mechanical stress: allows transmission of loads, support areas of maximum stress
  • More metabolically active than cortical bone due to larger surface area
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20
Q

macroscopic cancellous bone histology

A
  • Forms interconnecting network of plates/trabeculae with marrow between
  • Arranges along lines of maximum mechanical stress
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21
Q

osteoid

A
  • Unmineralized bone matrix- produced by osteoblasts

* Type I collagen

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22
Q

non collagenous protein in osteoids

A
  • Osteocalcin- marker of bone formation
  • Osteonectin
  • Osteopontin
  • Growth factors
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23
Q

microscopic lamellar bone

A
  • Type I collagen fibres laid down in parallel sheets/lamellae
  • Structurally very strong
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24
Q

microscopic woven bone

A
  • Collagen fibres randomly arranged

* Mechanically weak formed when bone is being produced rapidly eg. foetus or fracture

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25
Q

formation of osteoblasts from stem cells

A

Formation and proliferation for preosteoblast cells from stem cells requires signalling through the Wnt-frizzled-Lrp5-betacatenin signalling pathway. Osteoblast differentiation is controlled by the transcription factors Runx2 and osterix.
In absence of factors, no osteoblasts formed.

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26
Q

osteoblasts function and lifespan

A
  • Produce and deposit osteoid
  • Regulate osteoclast differentiation/ function: RANKL-RANK interactions
  • Life span of 6 months
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27
Q

osteocytes features

A
  • Most common in bone
  • Reside in lacunae in cortical and trabecular bone- connect to other osteocytes, osteoblasts and osteoclasts via long cytoplasmic process
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28
Q

function of osteocytes

A

Regulation of bone remodelling
• increased expression of RANKL
• production of sclerostin- inhibited by PTH and mechanical loading

• Responds to increasing PTH levels by inducing rapid calcium release (osteolytic osteolysis)

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29
Q

osteoclasts function

A
  • Bind to mineralised bone surface using integrins

* Resorb bone by production of acid to release calcium and proteases to breakdown organic matrix

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30
Q

osteoclast biomarkers of bone resorption

A
  • Detected in blood or urine
  • Type I collagen fragments: N- and C- terminal cross linked telopeptides
  • Tartrate resistant acid phosphatase- expressed by osteoclasts
  • Bone sialoprotein (BSP)
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31
Q

osteoclast features

A

• Monocyte/macrophage derived multinucleate giant cells

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32
Q

how are osteoclast precursors expressed?

A

growth factors: M-CSF and TNF produced by stromal cells induces expression of osteoclast precursors

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33
Q

RANK-RANKL interactions

A

RANK is a cell membrane receptor expressed by osteoclasts and precursors. It is activated following binding to RANKL which is expressed by stromal cells, osteocytes and osteoblasts.
This induces the proliferation of mononuclear precursors and induces them to become osteoclasts. It also increases the osteoclast activity.

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34
Q

what is intramembranous ossification? sites?

A
  • Osteoid deposition on mesenchymal cells within a fibrous membrane to increase bone thickness
  • Formation of skull, maxilla, parts of clavicle/mandible
  • Subperiosteal bone growth
  • Fracture repair
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35
Q

process of intramembranous ossification

A

A. Mesenchymal stem cell proliferation in fibrous tissue, formation of cluster/ nodule
B. Differentiation into osteoblasts- formation of ossification centre, production of osteoid (woven)
C. Mineralisation of osteoid, osteoblasts embedded in matrix- osteocytes
D. Blood vessels become entrapped/grow in, bone remodelled into lamellar trabecular bone

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36
Q

endochondral ossification

A
  • Osteoid deposition on a cartilage framework to lengthen bones
  • Development of most of the skeleton
  • Growth plates
  • Fracture repair
  • Programmed changes in chondrocyte: hypertrophy, matrix vesicles, type X collagen secretion, chondrocyte death
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37
Q

primary centre of ossification

A

genetically predetermined sites and times of ossification in diaphysis of cartilage bones in utero

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38
Q

how is a primary centre of ossification formed?

A

Hyaline cartilage model→ periosteum forms → formation of a bone collar → chondrocyte hypertrophy and secretion of alkaline phosphatase → matrix calcification → osteo-progenitor and blood vessel ingrowth → primary centre of ossification

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39
Q

where are primary and secondary centres of endochondral ossification?

A

periosteum* (primary centre) and the growth plate (secondary centre, until the plates fuse)

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40
Q

secondary centres of ossification

A
  • Ossification in epiphysis at or after birth
  • Similar process to that of primary centre formation
  • Line of cartilage between primary and secondary centres= epiphyseal (growth) plate
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41
Q

longitudinal bone growth process

A
  • The cartilage model growth in length by continuous proliferation of chondrocytes
  • Chondrocytes differentiate and hypertrophy
  • Cartilage matric calcifies
  • Blood vessels/chrondroclasts invade and remove calcified cartilage
  • Osteoblasts deposit bone on residual cartilage struts
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42
Q

cessation of bone growth

A
  • Growth stops when the epiphyseal growth plates close
  • Varies at different sites and is genetically determined i.e. Inherited height
  • Oestrogens/androgens initially increase GH secretion in early puberty and increase bone growth but later induce closure of growth plates
  • Premature closure of a growth plate results in a shortened bone
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43
Q

local hyperaemia

A

(excess of blood in the vessels supply) can causes growth arrest
• Infection: osteomyelitis
• Juvenile: chronic arthritis
• Arteriovenous malformation

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44
Q

Achondroplasia

A
  • Mutation in fibroblast growth factor receptor 3 (FGFR3)
  • Receptor constitutively active
  • Decreased chondrocyte proliferation and hypertrophy
  • Limbs are short while the torso is typically of normal length (non-Vitruvian)
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45
Q

Gigantism

A
  • Excess GH production before puberty

* Increased longitudinal bone growth

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46
Q

Acromegaly

A
  • Excess GH production
  • Growth plates closed
  • adults aged 30 to 50
  • Increased bone formation
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47
Q

benefits of bone remodelling

A

maintains the mechanical integrity of the skeleton by removing micro damaged bone and reinforcing bone in areas subject to increased mechanical stress. It is also important for calcium homeostasis.

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48
Q

4 phases of bone remodelling

A
  1. Activation
  2. Resorption (6 weeks)X$
  3. Reversal (1.5 weeks)
  4. Formation/mineralisation (5 months)
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49
Q

Activation in bone remodelling

A

Bone lining cells become rounded and expose bone. They secrete collagenase to remove a thin covering layer of unmineralized bone (osteoid). Osteoclasts are differentiated from mononuclear precursors through the RANKL-RANK interactions and are recruited.

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50
Q

control of activation phase

A

well controlled due to microfractures and mechanical stresses: osteocytes secrete sclerostin leading to increases RANKL expression- increased osteoclast activity and decreased osteoblast activity.

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51
Q

regulation of RANK-RANKL interactions

A

Regulated by osteoprotegrin (OPG) a decoy receptor that binds RANKL
• OPG is secreted by osteoblasts and stromal cells

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52
Q

resorption in bone remodelling

A

Osteoclasts adhere to mineralised bone via αVβ3, the integrin vitronectin receptor.
Actions:
- Form ruffled border (microvillus structure) which increases surface are available for secretion/absorption
- Secretes acid (for removal of calcium hydroxyapatite) and proteases (for removal of organic matrix)

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53
Q

positive regulation of bone resorption

A
  • RANK/RANKL
  • Cytokines including TGFβ, BMPs, FGFs, and IGFs produced locally or released from bone
  • Systemic hormones like PTH
  • Maintenance of the ruffled border
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54
Q

negative regulation of bone resorption

A

local production of OPG and systemically by calcitonin.

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55
Q

what is amount of bone that is resorbed related to

A

osteoclast life span

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56
Q

osteoclast death

A

inhibition of RANKL-RANK interactions. They are replaced by mononuclear cells which lay down a cement line to which the newly produced osteoid adheres to.

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57
Q

reversal phase in bone remodelling

A

Transition from bone resorption to formation is mediated by osteoclast-derived coupling factors which direct the differentiation and activation of osteoblasts in resorbed lacunae to refill it with new bone. Osteoblasts differentiate form bone marrow stromal cells.

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58
Q

role of osteoclasts in reversal phase

A
  • Release of bone matrix derived factors (BMP, IGF) which increase OB formation
  • Cell surface EphrinB2 binds OB EphB4 increasing OB differentiation
  • S1P released by OC increases OB migration
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59
Q

formation phase in bone remodelling

A

Osteoblasts lay down osteoid.
- Directional secretion of type I collagen
- Non collagenous proteins i.e. osteocalcin, IGF, BMPs that regulate osteoclast/osteoblast formation and function
Osteoids stay unmineralized for 15-20 days before immediate mineralisation.

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60
Q

mineralisation phase in bone remodelling

A

Bone mineralisation involves deposition of hydroxyapatite Ca10(PO4)6(OH)2 which is an inorganic mineral of bone and precipitate of soluble Ca2+ and inorganic PO4. The ratio of Ca2+ iPO4 in hydroxyapatite changes with time which makes bone harder but more brittle.

Matrix vesicles= cytoplasmic buds which have accumulated Ca2+ and iPO4 are released from the surface of osteoblasts. - contain alkaline phosphatase and Phospho-1.
MV are deposited on collagen fibres associated with non-collagenous proteins which mediate crystal nucleation.

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61
Q

what does membrane rupture/breakdown and the modulation of ECM composition promote?

A

propagation of hydroxyapatite

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62
Q

local regulation of bone mineralisation

A

Locally: predominantly by availability of extracellular PPi (pyrophosphate):

  • It directly binds to growing hydroxyapatite crystals preventing the apposition of mineral ions
  • Induces osteopontin which is a protein that has mineral binding and crystal growth inhibiting activity and is expressed by osteoblasts
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63
Q

systemic regulation of bone mineralisation

A

Systemically:

  • Regulation of blood Ca2+ and phosphate levels by the parathyroid hormone (PTH) which increases serum Ca2+ and decreases Pi
  • Vitamin D which increases serum Ca2+
  • FGF23- produced by osteocytes and osteoblasts in response to increased Vitamin D, increases renal excretion of Pi and decreases PTH and Vitamin D levels
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64
Q

homonal regulators of osteoclastic bone resorption:

A

PTH (+ve), calcitonin (-ve) and oestrogen (-ve)

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65
Q

Major hormonal regulators of osteoblastic bone formation:

A

PTH (+ve), vitamin D3 (+ve), calcitonin (-ve), oestrogen (+ve), growth hormone (+ve)

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66
Q

disorders of bone remodelling

A
  • Osteoporosis: resorption > formation
  • Paget’s disease of bone: resorption and formation increased
  • Osteopetrosis: resorption decreases
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67
Q

disorders of mineralisation

A
  • Hyperparathyroidism
  • Vitamin D deficiency (osteomalacia, rickets)
  • Tumour induced osteomalacia- increased levels of FGF23
  • Renal osteodystrophy
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68
Q

causes of accelerated bone loss

A

menopause (oestrogen loss), malnutrition, immobilisation, medical endocrine disorders, medication (glucocorticoids), osteoporosis

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69
Q

causes of osteoporosis

A

Primary: old age and post-menopausal status
Secondary: immobilisation, malnutrition/malabsorption, endocrine disease- thyrotoxicosis/Cushing’s syndrome, drugs (eg. corticosteroids, heparin)

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70
Q

what does lower peak bone mass lead to

A

increased fracture risk with normal age related bone loss

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71
Q

osteoporotic bone features

A

Cortical bone: thinner
Trabecular bone: struts thinner and less connected
Both are mechanically weak but normally mineralised.

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72
Q

Paget’s disease of bone definition and clinical features

A
  • Increased and uncontrolled bone turnover → excessive osteoclast activity leads to subsequent increased osteoblast activity
  • thickened, sclerotic bones
    Clinical features:
  • Weak deformed bones
  • Enlarged skull
  • Nerve compression- deafness
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73
Q

pathology of Paget’s disease of bone

A
  • Exaggerated bone remodelling- increased osteoclastic and osteoblastic activity
  • Large multinucleated osteoclasts
  • Lytic, mixed and sclerotic phases
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74
Q

mutation in SQSTM1-

A

abnormal osteoclast function, increased bone resorption

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75
Q

osteopetrosis

A
  • Hard dense bone which is thick and sclerotic
  • Decrease in number or activity of osteoclasts

Bone laid down but not remodelled, in time bone marrow is replaced by bone and haemopoiesis (production of blood cells and platelets, which occurs in the bone marrow) is compromised.

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76
Q

causes of osteopetrosis

A
  • Carbonic anhydrase II deficiency
  • CSF-1 signalling abnormalities
  • Chloride channel mutations
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77
Q

hyperparathyroidism definition

A

Increase in circulation levels of PTH as result of excess production by one or more parathyroid glands and increases serum calcium levels

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78
Q

primary hyperparathyroidism

A

intrinsic abnormality of the parathyroid glands (adenoma)- pathological increase in PTH production

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79
Q

secondary hyperparathyroidism

A

abnormality of calcium homeostasis (chronic renal disease)- results in physiological hyperplasia

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80
Q

PTH importance

A
  • Increases bone resorption- PTH acts on Oblasts to produce RANKL and decrease Osteoprotegerin with activation of Oclasts
  • Increases renal Ca2+ resorption and phosphate loss
  • Enhances Vitamin D conversion to 1,25(OH)2 VitD- increased Ca2+ uptake from GI tract
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81
Q

hyperparathyroidism effect on bones

A

Increased Bone Turnover

  • Increased osteoclastic activity- cortical thinning/ subperiosteal bone erosion
  • Increased osteoblastic activity
  • Fragile bones that easily fracture (osteoporosis)
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82
Q

symptoms and signs of hyperparathyroidism

A
  • Bone and joint pain
  • Kidney stones, excessive urination
  • Abdominal pain
  • Fatigue
  • Depression or forgetfulness
  • Nausea, vomiting or loss of appetite
  • Frequent complaints of illness with no apparent cause
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83
Q

importance of Vit D

A
  • Most active form 1,25(OH)2VitD (calcitriol) acts via VD receptors – present throughout the body
  • Maintains serum calcium levels: increases calcium absorption from GI tract, increases bone resorption by increasing Oclast formation
  • Maintains serum phosphate levels: decreases PTH synthesis, increases FGF23 production
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84
Q

what can vit D deficiency/ resistance lead to?

A

Vitamin D deficiency can lead to rickets or osteomalacia.

Vitamin D resistance can lead to Vitamin D-dependant rickets type II (receptor mutation).

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85
Q

bone effect of vit D deficiency

A
  • Osteomalacia: decreased mineralisation of bone
  • Rickets: decreased CA2+/ Vit D in childhood, soft bones that deform and fracture easily
  • Serum calcium decreased: decreased phosphate and alkaline phosphatase (affects matrix vesicles in mineralisation)
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86
Q

Autosomal dominant hypophosphatemic rickets

A
  • Mutation in FGF23 gene results in resistance to proteolysis
  • Low serum phosphate, renal phosphate wasting, low 1,25-dihydroxy Vitamin D3
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87
Q

Phosphaturic mesenchymal tumour

A
  • Rare soft tissue tumour that produces excess FGF23
  • Low serum phosphate, renal phosphate wasting, low 1,25-dihydroxy Vitamin D3
  • Decreased bone mineralisation with osteomalacia
  • Excision of the tumour is curative with reversal of clinal and lab abnormalities
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88
Q

Hyperphosphatemic familial tumoral calcinosis:

A
  • Loss of function mutations in FGF23 (or the FGF23 co-receptor α-Klotho)
  • Increased levels of phosphate in the blood (hyperphosphatemia)
  • Abnormal deposits of phosphate and calcium (calcinosis) in tissues
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89
Q

collagen structure

A
  • Each polypeptide chain forms a left hand helix
  • 3 polypeptide chains are wound together in a right handed superhelix
  • There are H-bonds between chains (not within chains as there are in an alpha helix)
  • All collagens contain long stretches of the repeating sequence glycine-proline-4-hydroxyproline
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90
Q

collagen in bone, cartilage and skin

A
  • Bone contains types I, V, XII, XIV
  • Cartilage contains types II, VI, IX, X, XI
  • Skin contains types I, II, III, V, XI
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91
Q

collagen synthesis and processing

A
  1. Transcribed in the nucleus and translated in the ribosomes, like all proteins
    Ends up as pre-pro-collagen
  2. Post-translational modifications in the endoplasmic reticulum (mostly) and the golgi apparatus (latterly)
    Ends up as procollagen
    (Problems here are found in both scurvy and Ehlers Danlos syndrome)
  3. Secreted from the cell, undergoes enzymatic modification
    Ends up as a collagen fibril
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92
Q

where does elastin form elastic fibres

A

ECM protein which forms elastic fibres in lungs, arteries, skin and tendons.

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93
Q

elastin structure

A
  • Contains glycine, proline, alanine but it doesn’t have a triple helix
  • Chains are covalently cross linked by oxidation of lysine sidechains followed by nonenzymatic reaction with other lysines and histadines
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94
Q

how do neutrophils degrade elastin and other ECM proteins

A

Neutrophils can release proteinases that degrade elastin and other ECM proteins: these proteinases are inhibited by a1-antitrypsin (secreted by liver, inactivated by smoking)

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95
Q

what can lead to emphysema?

A

Congenital deficiency of a1-antitrypsin, or its inactivation by smoking

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96
Q

glycosaminoglycans structure

A

unbranched, acidic polysaccharides composed of repeating dissacharide units with attached sulphate groups

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97
Q

proteoglycans structure

A

Proteoglycans contain GAGs covalently attached to core proteins through a tetrasaccharide linked to a serine sidechain in the sequence -SerGlyXGly-

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98
Q

Mucopolysaccharidose

A

are rare hereditary diseases caused by defects in the lysosomal enzymes that degrade GAGS. Partially degraded GAGS accumulate in lysosomes, causing skeletal and other deformities, and often mental retardation

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99
Q

Cartilage structure

A
  • Mostly water (80%) but remaining is collagen (2/3) and glycosaminoglycans (1/3)
  • GAG aggregates are maintained within a mesh of collagen fibrils- allows elasticity and low friction in joints
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100
Q

bone consists of

A
  • 20% collagen; 70% inorganic salts (mainly calcium hydroxyapatite but can also have Mg2+, F–, CO22- and citrate in the crystal lattice); 10% water
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101
Q

scurvy and its symptoms

A

Dietary deficiency of Vit C resulting inactivation of prolyl hydroxylases with consequent failure to synthesis secrete and deposit collagen
Symptoms: fragility of blood vessel walls, petechial haemorrhages, gum inflammation, loss of teeth, poor healing of wounds.

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102
Q

what can result in failure of collagen secretion by fibroblasts?

A
  • Errors in post translational modification (caused by mutations in genes encoding collagen itself or encoding processing enzymes)
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103
Q

why is the collagen structure intolerant of point mutation

A
  • strict requirement for glyXY sequence repeats means that the collagen structure is intolerant of point mutations (particularly in glycine, the smallest aminoacid, and in proline).
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104
Q

Osteogenesis Imperfecta (brittle bone disease)

A
  • Caused by mutation in collagen I

- OI type 1: commonest and least sever, collagen I is deficient but of normal structure

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105
Q

Osteogenesis Imperfecta type 2

A

perinatal lethal, abnormal collagen structure and can lead to crumpled bones in utero

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106
Q

Ehlers-Danlos syndrome

A
  • Heterogenous group of disease where collagen processing is affected
  • EDS type IV= most serious, deficiency of collagen type III may lead to rupture of arteries or intestines, pneumothorax and complications of pregnancy
  • Other forms affect type IV, VII ect.
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107
Q

Marfan Syndrome

A
  • Dominant inherited disease caused by mutations in the gene for fibrillin 1, a glycoprotein that with elastin, forms microfibrils in aorta and ligaments
  • The microfibrils bind a growth factor, TGFbeta and in Marfan syndrome, increased levels of free TGF-beta cause developmental abnormalities
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108
Q

symptoms of Marfan Syndrome

A

Symptoms: disproportionately long extremities (arachnodactyly), craniofacial abnormalities, joint hypermobility; eventually lens dislocation, pneumothorax, or rupture of the aorta may occur.

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109
Q

hyaline cartilage

A

Eg. articular cartilage) on surfaces of moveable joints

  • Glassy, low friction surface
  • Withstands compressive and tensile forces- load bearing
  • Pliable- spreads loads over ends of bone
  • Made of collagen- mainly basket weave
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110
Q

chondrocytes

A
  • Exclusively responsible for synthesis/ breakdown of ECM components
  • Normally synthesise cartilage specific ECM components- collagen type II, aggrecan
  • Specialised matrix surround cells- lacuna or chondon (type VI collagen)
  • Synthesis wide range of degradative enzymes
  • Chondrocytes are phenotypically very unstable- role of the enzyme
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111
Q

difference between chondrocytes and fibroblasts

A

C: type 2, aggrecan
F: type 1, small PGs

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112
Q

Fibrocartilage

A

(eg. intervertebral disc, meniscus)
- Support, prevents bone-bone contact, spread load, limits movement
- Can withstand tensile and compressive forces
- Collagen fibres are thick & have clear parallel orientation and structure
- Cells often in rows, mainly fibroblasts but some chondrocytes

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113
Q

elastic cartilage

A

(eg. auricle of ear, epiglottis)
- Histologically very similar to hyaline
- But contains elastin- highly & reversible deformable
- Ideal for a flexible skeleton
- fibroblasts

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114
Q

what do fibroblasts synthesis

A

elastin, collagens and small PGs

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115
Q

Mosaicplasty

A
  • a method for repairing small areas of degenerate load-bearing cartilage using osteochondral explants
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116
Q

roles of articular cartilage

A

absorbs/ distributes load, protects ends of bone. With synovial fluid, it provides a low friction surface for articulating joints

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117
Q

synovial fluid

A
  • Ultrafiltrate of plasma with hyaluronic acid- lubricant
  • Produced by synoviocytes of synovial membrane
  • Primary source of nutrition and removal of waste for cartilage cells
  • Viscous when joint immobile, warming up exercises increases production/secretion, reduces viscosity
  • Contains a small number of phagocytes
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118
Q

difference btwn tendons and ligament

A
  • Tendons transmit load from muscle to bone
  • Ligaments transmit load/give stability form bone-bone (hold skeleton together)
  • Cells adapt to prevailing mechanical forces by modifying ECM synthesis
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119
Q

thickeness of load and non load bearing cartilage

A
  • Load bearing cartilage is thicker and stronger than non-load-bearing
  • In immobilised joints, cartilage thins and is lost, usually reversible
  • Excessive load/impact can cause matrix damage and chondrocyte death
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120
Q

matrix synthesis and chondrocyte control

A
  • Normal dynamic loading: synthesis = breakdown
  • Greater loading: synthesis > breakdown
  • Less loading: breakdown > synthesis
  • Cartilage degeneration: breakdown&raquo_space; synthesis
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121
Q

static load and dynamic load on chondrocytes

A
  • Static load- depresses synthesis, fluid flow/streaming potentials/ionic composition
  • Dynamic load- stimulates synthesis, high hydrostatic pressure (200x on standing)
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122
Q

fluid loss in different loads

A
  • with static load, over time fluid expression increases

- With dynamic load, stress is too fast for fluid expression to be affected

123
Q

Mechanotransduction-

A

link between changes to the mechanical environment of cells and the cells response

  • Many tissues are required to function correctly
  • They must sense a mechanical stimulus and convert to a biological response
  • Stretch sensed which promotes the creation of tissue- used to equalise leg length
124
Q

how is articular cartilage adapted to withstand load?

A

no vulnerable structure:

  • Avascular
  • Aneural
  • Alymphatic
  • No epithelium at cartilage surface
  • Low cell density
  • Complex ECM (fibre reinforced gel) is highly resilient- adapted to compressive and tensile forces
125
Q

aggrecan

A

monomers of GAG (glycosaminoglycan), highly sulphated and acidic, fixed negative charges
It attracts cations and water, repels anions and swell but only swells to ~20% of total in cartilage as they are restricted by collagens. Gives rise to hydrostatic pressure within ECM.

126
Q

collagen in articular cartilage

A

Hyaline cartilage contains mainly type II and fibrocartilage has mainly type I. In articular cartilage, it has a basket weave structure that is stabilised by minor but important collagens eg. Type IX.

127
Q

proteoglycans in articular cartilage

A
  • mostly aggrecan
  • also small proteoglycans like decorin & fibromodulin but small PGs tend not to be retained effectively by the hyaline cartilage matrix
    It is possible that a PG synthesised exclusively by chondrocytes within the superficial zone (lubricin) could play a role in reducing joint friction.
128
Q

interstitial fluid in articular cartilage

A

controlled by PGs in chondrocytes
More cations and fewer anions compared to synovial fluid. Composition of interstitial fluid can alter with sustained static load, which causes fluid expression- increases PG concentration leading to increased cation concentration and decreased anion concentrations.

129
Q

chondrocytes in articular cartilage

A

Single resident cell type of hyaline cartilage. It is entirely responsible for synthesis/ breakdown of ECM components

130
Q

chondrocyte division

A

no chondrocyte division in skeletally mature healthy cartilage. Chondrocyte proliferation is only evident in late stage osteoarthritis (OA).

131
Q

Turnover of articular cartilage

A

very slow

Cartilage does not repair effectively – connective tissue produced is mechanically incompetent

132
Q

adaption for bipedal locomotion

A
  • Spinal curves
  • Shock absorption of discs
  • Weight bearing axis of hip and knee
  • Tripod arrangement of foot (arches of the foot)
  • Shape of the thorax
  • Soleus slow muscle in leg- maintains posture
  • TA energy absorption- tibialis anterior absorbs energy across the ankle joint as the foot contacts the ground
133
Q

perinatal modes of failure

A
  1. Failure of Segmentation
    Can include congenital scoliosis, wedge vertebra (vertebral compression fracture) or skeletal growths
  2. Failure of Formation
    Fibula Heimelia- part or all of the fibula bone is missing
134
Q

fracture healing

A

Macrophages remove debris → fibrin clot → inflammation and granulation tissue → callus (collar of cartilage and bone surrounding fracture to stabilise outer edges of bone) formation → ossified to woven bone → remodelling

135
Q

direct fracture healing

A

no callus formation but healing is an extension of remodelling, giving rigid fixation, pins may be necessary to immobilise the bone for healing.

136
Q

Rheumatoid Arthritis characteristics

A
  • Chronic symmetrical, predominantly peripheral polyarthritis
  • Joint stiffness (morning and after rest)
  • Joint pain (difficulties with daily activities)
  • Can have exacerbations and remission
  • Joint structure damaged – weak ligaments, tendons and muscles around hands → ↓ grip and manual dexterity
  • Disuse atrophy (wasting of muscles)
  • Subcutaneous nodules
137
Q

Rheumatoid Arthritis effect on bursae

A

bursae- small fluid filled sac lined by synovial membrane with an inner capillary layer of viscous synovial fluid. They form a result of excess rubbing in a particular area that can become inflamed (bursitis) and painful.
Bursa can often be found under the ball of the foot affected by RA.

138
Q

pathology of RA

A
  • Synovial proliferation (cause unknown) but now preventable by early drug treatment
  • Destruction of articular cartilage → loss of movement
  • Tendon invasion → rupture
  • Ligamentous stretching → instability
139
Q

Extra-articular manifestations in RA

A

(more likely in those who have RF factor and/or are HLA-DR4 positive)

  • General weight loss, malaise, fever, lymphadenopathy
  • Skin- rheumatoid nodules
  • Respiratory- rheumatoid nodules, pleural effusions
  • Cardiac- pericarditis, myocarditis, endocarditis
140
Q

outcomes in RA

A
  • Decline in physical function: active disease, permanent joint damage
  • Physical disability
  • Psychological morbidity: anxiety, depression, helpless ness
  • Increased morality
  • Increased atherosclerosis and ischaemic heart disease
141
Q

HLA Class II genes in RA

A

RA is likely to involve a genetic predisposition to the autoimmune reaction, linked to abnormal HLA Class II genes.

associated with production of anti-citrullinated peptide (CCP) antibodies and worse disease outcomes.

142
Q

Rheumatoid Arthritis pathogenesis

A

T cells are activated by APCs. Inflammatory cells (lymphocytes/monocytes/neutrophils) are drawn in with oedema fluid which causes the synovium to swell while the synovial fluid becomes turbid from these presence of neutrophils.
Proliferation of the inflamed synovium forms a pannus (abnormal layer) of granulation tissue over articular cartilage which cuts off its nutritional supply.
Inflammatory mediators like IL-1 and OPGL cause erosion of the cartilage via fibroblasts (MMPs) which further destroys it cushioning ability, leading to bone erosion by IL-1 activated osteoclasts.
Scar tissue between the bone ends can later ossify and immobilise the joint entirely (known as ankylosis).

143
Q

synovial tissue in RA

A
  • Hyperplasia of the synovial lining layer

- Sub lining inflammatory infiltrate of lymphocyte, plasma cells and macrophages

144
Q

biomarkers of RA

A

Circulating IgM antibodies (rheumatoid factors)
- Reasonable sensitivity but not very specific

Anti-cyclic citrullinated peptide (anti CCP) antibodies

  • Only slightly better sensitivity: can predate the onset of symptoms by years
  • Better specifity
145
Q

osteoarthritis

A
  • Heterogenous group of disorders with similar pathological and radiological features
  • Characterised by degeneration of articular cartilage, remodelling of subchondral bone and formation of osteophytes
  • Most common type of arthritis
146
Q

symptoms and signs of OA

A
  • Pain- worse on use of the joint
  • Stiffness- mild in the morning, severe after immobility
  • Loss of movement
  • Pain on movement/restricted range
  • Tenderness (articular or periarticular
  • Bony swelling
  • Soft tissue swelling
  • Joint crepitus- abnormal popping or crackling sound
147
Q

radiological features of OA

A
  • Narrowing of joint space
  • Osteophytosis- bony projection associated with the degeneration of cartilage at joints
  • Altered bone contour
  • Bone sclerosis (stiffening of a tissue) and cysts
  • Periarticular calcification
  • Soft tissue swelling
148
Q

joints that develop OA

A

Spine> DIPJ (Distal interphalangeal joint)> Knee> Hip

prevalence of OA increases with age at all sites

149
Q

Inflammageing

A

chronic, low-grade inflammation characteristic of aging

150
Q

Age related changes in matrix molecule metabolism

A

↓ Type II collagen turnover, ↓ aggrecan turnover, ↓ antioxidant defences

151
Q

Age related physiological changes

A

decrease in proprioception, decrease in muscle strength, changing shape of bones (hip and CMC joint of thumb)

152
Q

Pharma treatment of OA

A

Paracetamol, topical and oral NSAIDs (both non-selective with misoprostol/PPi and selective COX-2), duloxetine, topical capsaicin and IA steroids

153
Q

surgical treatment of OA

A

Total joint replacements, osteotomy, knee fusion, knee aspiration and debridement in case of locking

154
Q

osteoporosis definition

A
  • Systemic skeletal disease characterised by low bone mass and deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture
155
Q

common osteoporotic fractures

A

wrist, spine, hip

156
Q

presentation of osteoporosis

A
  • Back pain
  • Thoracic kyphosis
  • Loss of height
  • Fractures
157
Q

drugs with therapeutic effects on osteoporosis

A
  • Bisphosphonates- alendronate
  • raloxifene
  • Oestrogens and analogues
  • Calcium salts
  • Vitamin D
  • Other drugs active on bone: calcitonin, PTH analogues, strontium
158
Q

carpal tunnel syndrome definiton

A
  • Alteration in median nerve function due to pressure on the nerve in the tunnel where it enters the hand (pressure may be due to rheumatoid arthritis which causes swelling)
  • May lead to permanent loss of nerve function
159
Q

risk factors for carpal tunnel syndrome

A
  • Gender (women)
  • Age
  • White race
  • Narrow diameter of carpal tunnel obesity
  • Hormonal: hyperthyroidism, menopause, diabetes, contraceptive pill
160
Q

symptoms and signs of carpal tunnel syndrome

A

Symptoms:

  • Paraesthesia (tingling in nerve distribution)
  • Nocturnal symptoms
  • Provocative features: wrist flexion, hand elevation, Phalen’s test (median nerve is compressed or squeezed at the wrist)
  • Relieving features: shaking hand, running under cold tap
  • Hypoaesthesia (diminished sensation)
  • Muscle wasting
161
Q

neurophysiology

A

measuring speed of conduction in nerve

162
Q

treatment for carpal tunnel syndrome

A
  • Can go away without treatment (common with pregnant women and under 30s)
  • Night splint (keeps wrist straight, takes pressure off median nerve)
  • Steroid injection (brings down swelling around wrist)
  • Operation- open or endoscopic (the operation divides the retinaculum but the nerve still has to recover)
163
Q

ulnar nerve dysfunction process

A

The ulnar nerve is exposed to direct pressure over the medial epicondyle. It is stretched when the elbow flexes. When the elbow flexes it is compressed beneath the fibrous band between the two heads of flexor carpi ulnaris muscle. When the elbow flexes, it may sublux (partial dislocation) medially.

164
Q

presentation of ulnar nerve dysfunction

A
  • Paraesthesia (tingling)
  • Hypoaesthesia (numbness)
  • Weakness of grip
  • Paralysis of affected muscles
  • Clawing of hand
165
Q

treatment for ulnar nerve dysfunction

A
  • Release of compression at elbow

- Occasionally transposition to front of elbow

166
Q

froment’s sign

A

used to test out palsy of the ulnar nerve

167
Q

Dupuytren’s Disease

A
  • Thickening and contracture of the palmar and digital fascia of unknown cause causing palms and digits to be bent over
  • Cordlike contractures in the bands of the longitudinal fibres of the palmar and digital fascia
  • A cellular process involving myofibroblasts
  • Collagen is abnormal: normally type I but in DD type III predominates
  • Has variable patterns
168
Q

Dupuytren’s Disease risk factors

A
  • Genetic influences: familial, racial (Eastern European)
  • Systemic disease: diabetic, cirrhosis of liver
  • Trauma: site of injury
169
Q

Dupuytren’s Disease treatment

A
  • Advice: no contracture means surgery unnecessary
  • Fasciotomy (division of cords) either by surgical release or injection of collagenase
  • Fasciectomy- excision of only diseased fascia
  • Dermofascietomy- removal of diseased palmar fascia which is excised along with any overlying involved skin
  • Amputation
170
Q

why can MCPJ contractors be corrected but not PIPJ?

A

MCPJ (metacarpophalangeal joint at the base of finger) contractures can usually be corrected (no capsular contracture). This because it’s anatomy is one where flexion causes the ligament to be taut and extension leaves it lax.

PIPJ (proximal interphalangeal joint) contractures may be difficult (established capsular contracture). This is because the ligament is lax in flexion but taut in extension

171
Q

Rupture of the Ulnar Collateral Ligament of the Thumb features and treatment

A
  • Poor precision and strength of thumb
  • Important to be seen early on

Treatment

  • Repair the ligament
  • It may have slipped out from beneath the adductor pollicis tend on
172
Q

Osteoarthritis at the trapeziometacarpal joint

A
  • Double saddle joint
  • Laxity may cause abnormal wear at edges of joint because of incongruity
  • Common in middle aged women
  • Various treatments- most can be controlled without operation (analgesics, spontaneous improvement)
173
Q

common problem with metacarpophalangeal joints

A

subluxation and /or ulnar drift. This can be fixed by MCPJ replacements if there is a loss of 3-point grip.

174
Q

Genu Varum/ Valgum

A
  • Angular: bowlegs (varum), knock knees (valgum)
  • Physiological- varum is natural when born
  • Persistent bowing is the most common (varum)
175
Q

apparent bowleg

A

occurs when the child stands with hips and knees fixed (looks like varum) but when the child lies down and extends the hips and knees, the legs are straight.

176
Q

pathology of genu varum

A
  • Asymmetric
  • Resistant to normal change (could be due to rickets)
  • Short stature
  • Varus > 11 degrees
  • Trauma/ systemic
177
Q

treatment of Genu Varum/ Valgum in infants

A

Eight Plate: titanium plates that guide growth

  • Same stiffness as bone so can bend with growth
  • They can slow down growth on one side to allow growth on the other side= corrects deformity
178
Q

presentation of in/out toeing

A 
Presents with:			
-	Clumsy
-	Tipping/ limping
-	‘deformed’
From: femur, foot
Many resolve with growth/ remain asymptomatic
179
Q

pain characteristics

A
  • Acute- trauma, infection
  • Constant- malignancy, chronic infection
  • Morning pain/ pain after inactivity- inflammatory joint disorders
  • Night pain- malignancy, osteoid osteoma, benign growing pains
180
Q

transient synovitis definition and clinical features

A

Non-specific, short term inflammatory synovitis with synovial effusion (accumulation of excess synovial fluid) of the hip joint

Clinical Features:

  • Painful hip/ thigh/ knee
  • Often associated with viral infection
  • Synovial fluid effusion
  • Hip held in flexion, lateral rotation, abduction
  • Exclusion of other conditions
181
Q

Developmental Dysplasia

A
  • Hereditary influence
  • Breach after 32 weeks or Caesarean
  • 1st born
  • Oligohydramnios (deficiency of amniotic fluid)
  • Female: male 5:1
182
Q

DDH Treatment as an Infant

A
  • brace that holds leg flexion and abduction and allows hip to sit down into position
  • If presenting at later stage then surgery is needed
183
Q

perthes disease

A
  • Osteonecrosis of femoral epiphysis by poorly understood non-genetic factors
  • Boys > girls 4:1
  • 4-8 years in majority
  • Lower social class leads to increased risk
    Treatment: Femoral head can be cut down and placed into joint, secured with a plate.
184
Q

Fracture:

A

a disruption in bone continuity, can be displaced or non displaced, articular involvement should be noted, injury mechanism that exceeds maximum force the bone withstand leading to fracture

185
Q

Dislocation:

A

complete loss of continuity of 2 bones forming a joint

186
Q

Subluxation:

A

partial loss of continuity of 2 bones forming a joint

187
Q

Comminution:

A

multiple fragments of bone

188
Q

Sprain:

A

torn ligament

189
Q

4Rs of fracture management

A

Resuscitate- address acute/life-threatening condition of fracture/trauma
Reduce- definitive management of fracture done internally/externally
Restrict- stabilise fracture segment
Rehabilitate

190
Q

massive haemothorax

A
  • > 1500 ml of blood in pleural space
  • Decreased breath sounds, respiratory compromise
  • Large volume loss
    Treatment: needs a chest drain and fluid resuscitation due to shock (insufficient blood flow to the tissues of the body)
191
Q

beck’s triad for cardiac tamponade

A
  • Hypotension: decreased stroke volume
  • Jugular venous distension: impaired venous return to the heart
  • Muffled heart sounds: fluid inside the pericardium
192
Q

treatment for cardiac tamponade

A

pericardiocentesis, under ultrasound guidance

193
Q

tension pneumothorax

A
  • Internal one way valve (air enters but doesn’t escape pleural space)
  • Decreased breath sounds on affected side
  • Increased percussion note (hyper-resonant)
  • Engorged neck veins
  • Reduced lung expansion
  • Deviation of trachea to opposite side
194
Q

tension pneumothorax treatment

A

Treatment: high flow oxygen, needle decompression in 2nd intercostal space, definitive chest drain

195
Q

open pneumothorax

A
  • Sucking chest wound
  • External one way valve
  • Air passes into the cavity through the path of least resistance
  • Treat with oxygen and 3 sided dressing
  • Definitely chest drain- 4th or 5th intercostal space, mid clavicular line
196
Q

flail chest

A
  • 2 or more ribs fractured in 2 or more places
  • Separation of a segment of the thoracic cage that is then unable to contribute to lung expansion
  • Paradoxical movement of a segment of the chest wall
  • Indrawing on inspiration and moving outwards on expiration
197
Q

types of shock

A
  • Anaphylactic
  • Cardiogenic
  • Haemorrhagic
  • Neurogenic
  • Septic
198
Q

what does shock lead to

A

to end- organ dysfunction due to inadequate oxygen availability for tissues (perfusion)

199
Q

possible causes of cariogenic and neurogenic shock

A

Cardiogenic shock in trauma can arise from tamponade/ blunt injury. Neurogenic can be due to spinal injury.

200
Q

haemorrhagic shock

A

Most common in trauma, the body’s balance between blood loss and compensation is affected

201
Q

Glasgow Coma Scale

A

E=4
V=5
M=6
max 15

202
Q

greenstick fractures

A

incomplete breaks, esp in children

203
Q

predisposing factor to stress fractures in young, active females

A

diet, amenorrhoea, osteoporosis, excessive impact exercise

  • High proteins intake limits Vit C and D absorption
  • Reduced oestrogen levels increase osteoclast activity
204
Q

how does the body compensate through classes 1-3 of haemorrhagic shock?

A
  • RR: increases as lactic acid rises
  • Pulse: tachycardia, HR increases to compensate for falling stroke volume
  • BP – remains fairly constant
  • Urine Output – falls with renal vasoconstriction
  • Peripheries – cool with vasoconstriction
  • Mental State – increasing confusion / agitation with reduced cerebral perfusion
205
Q

what happens in Class 4 haemorrhagic shock?

A
  • RR - falls with fatigue
  • Pulse - tachycardia reaches max, chest pain due to myocardial ischaemia
  • BP – drops dramatically
  • Urine Output – negligible
  • Peripheries – cold, mottled
  • Mental State – confused, comatose
206
Q

permissive hypotension

A
  • Low BP is better in trauma
  • Just enough to keep cerebral perfusion
  • Not enough to start bleeding again
  • roughly 80mmHg systolic
207
Q

most vulnerable areas of bone

A

physis (growth plate where endochondral ossification occurs to lengthen the bones)
apophysis (due to stress on the bone during muscle contraction)
metaphysis (which is less stable as the bone structure changes from solid to weaker)

208
Q

what are epiphyseal fractures (Salter Harris fractures)?

A
  • describes injuries to the physis: transverse and vertical intra-articular fractures (where part of the epiphysis is broken off from the remainder and from the rest of the bone)
209
Q

how do epiphyseal fractures cause osteoarthritis?

A
  • can cause osteoarthritis if not quickly fixed as joint surface would then develop misaligned.
210
Q

what can Salter Harris fractures lead to?

A
  • Sometimes the bone that forms as the fracture heals can cause stunted growth or curving which would need surgically removed
  • Salter Harris fractures can sometimes stimulate growth, leading to uneven limbs
211
Q

common site for acute apophyseal injuries (where it fragments off)

A

trochanters of the femur

212
Q

Osgood-Schlatter’s Disease

A

injury to the tibial tuberosity apophysis. This occurs in very active children where overuse strains the tibial attachment while still growing and possible forms a callus.

213
Q

Sever’s Disease-

A

chronic apophysitis of the heel in children as their bones are not yet fused

214
Q

Little leaguers elbow-

A

injury in the medial chondyle of the humerus

215
Q

functions of anterior cruciate ligament (attaches to the anterior tibia) of the knee:

A
  • prevents joint hyperextension
  • anterior tibial movement
  • tibial over rotation
  • varus/valgus angulation (prevented by collaterals)
216
Q

why are girls more prone to injury of ACL?

A

their pelvic shape gives a more knock- kneed stature (valgus on landing)

217
Q

ACL tears

A

the knee pops, fells unstable, is painful and swells. can scar over but doesn’t help stability

218
Q

diagnosis of ACL tear

A

Tears can be visualised by arthroscopy and are diagnosed using Lachman’s test

219
Q

treatment of ACL tear

A

Surgical reconstruction is used if there is a real requirement for use, otherwise RICE (rest, ice, compression, elevation) and physio.

220
Q

meniscal tears cause

A

knee clicking, locking and chronic pain

221
Q

unhappy triad

A

the damage the anterior cruciate ligament (ACL), the MCL (medial collateral ligament) and a meniscus (medial or lateral)

222
Q

diagnosis of meniscal tears

A

The injury is diagnosed by MRI or McMurray’s test and cartilage lesions are graded 0-4. 4= complete cartilage thickness loss

223
Q

treatment of meniscal tear

A

meniscus has no vascular supply so it can’t regenerate, it is treated as for an ACL tear plus surgery.

224
Q

shin splint

A
  • Exercise induced pain in the anterior lower leg which is treated with rest
  • Can be caused by many conditions eg. compartment syndrome
225
Q

compartment syndrome

A
  • In chronic exertion of a muscle compartment, it’s blood supply increases to meet demand so it expands in size, this increases pressure inside the compartment due to a lack of compliance
  • Pressure reduces blood supply again to cause ischaemia and associated pain
    This can be relieved by a fasciectomy- connective tissue is removed to release the pressure.
226
Q

stress fractures

A
  • Repeated microfractures that are not given sufficient time to repair after impact exercise
  • can cause shin splits
227
Q

flat feet

A

can also cause shin splints which are treated with orthotics (special shoes, maintains length of foot).

228
Q

treatment of stress fractures in female athlete’s triad

A

exercise reduction, analgesics, dietary changes and immobilisation to allow natural healing

229
Q

illiotibial band syndrome

A

overuse injury of the iliotibial band (connective tissue in the lateral thigh). It causes pain and tenderness in that area, especially above the lateral knee.

230
Q

Tennis Elbow- Lateral epicondylitis

A
  • Overuse injury
  • Tendinopathy affecting the origins of the extensors of the forearm (originate at the lateral epicondyle of the humerus)
231
Q

Achilles tendonopathy

A
  • Injury to and pain/stiffness/swelling of the achillies tendon at the heel
  • May be associated with crepitus (creaking) when the ankle is moved
  • Tearing to the achillies tendon is a sudden intense heel pain associated with swelling and bruising even potentially with a snapping sound
  • Inability to plantar flex the foot
232
Q

types of pain: neuropathic, psychogenic

A

Neuropathic (neurogenic)
- Non-nociceptive pain after nerve damage
- Often chronic (eg. phantom limb, disc pain, neuralgia, stroke, diabetes, some tumours)
Psychogenic: pain that occurs after (or is exacerbated by) an underlying psychological disorder, rather than in response to immediate physical injury

233
Q

nociceptors

A

are bare nerve endings found in skin, muscle and deeper viscera. These can directly be activated by:

  • Release of chemicals (histamine, bradykinin, serotonin)
  • Mechanical forces
  • Temperature
  • Tissue injury and inflammation
  • Nerve damage- neuropathy
234
Q

chemicals that activate nociceptors

A

Bradykinin is a well-known chemical that acts via G protein coupled receptors (beta1 & beta2) leading to pain, vasodilation, oedema and activation of membrane bound phospholipase A. Other chemicals that cause pain are serotonin and histamine (from mast cells), K+, lactic acid, H+ and ATP from damaged cells

235
Q

prostaglandins and nociceptors

A

Prostaglandins increased sensitivity to pain but do not cause pain themselves. ie. don’t activate nociceptors

236
Q

peripheral pain fibres

A
  • Myelinated Aδ fibres- rapid transmission at 15 m/s, localised & sharp, fast, intense pains
  • Unmyelinated C fibres- slow transmission 1 m/s, poorly localised & dull slow throbbing burning aching pain
237
Q

nociceptive/inflammatory pain- visceral and somatic definitions

A

visceral- pain due to inflammation of visceral organs eg. appendicitis
somatic- pain due to inflammation from muscle/bone disease or injury eg. fractures

238
Q

neuropathic pain- peripheral and central definitions

A

peripheral- due to peripheral nerve injury/ disease eg. carpal tunnel
central- due to CNS injury/disease eg. stroke

239
Q

cell bodies of peripheral pain fibres

A

dorsal root ganglion

240
Q

where do afferent fibres and nociresponive neurones synapse?

A

in the dorsal laminae of spinal cord. They ascent the spinal cord in the contralateral spinothalamic tracts.

241
Q

spinal wind up

A

chronic potentiation of the depolarisation in spinal neurones due to repetitive activation of C fibres meaning that further activation can cause prolonged response (hyperalgesia) because of priming (NMDA receptor based response)

242
Q

inhibitors of cord pain sensitivity

A
  • Metenkephalin and β-endorphin acting at GPCR opioid receptors (μ,δ,κ) which inhibit glutamate and substance P release at C fibres by blocking voltage-gated Ca2+ channels (opioid activation reduces cAMP, opens K+ channels to hyperpolarise neurons)
  • Noradrenaline and 5-HT (serotonin)
  • GABA and glycine
243
Q

what can opiod receptors respond to

A

endogenous metenkephalins and exogenous opiods like morphine

244
Q

Higher brain centres involved in pain:

A

thalamus, cerebral cortex (cognitive response, eg. removing body from point of damage), limbic system (emotional response)

245
Q

gate control theory of pain

A

The activity of neurones that transmit pain in the spinal cord can be influenced (inhibited) by other factors that may reduce transmission of impulses to the brain and these include

  • Descending nerve impulses from the thalamus and cerebral cortex, areas of the brain that regulate thought and emotions
  • Other local sensory inputs such as rubbing the skin around an affected area (NB the use of TENS)
246
Q

excitatory and inhibitory influences of spinal cord transmission

A
  • Excitatory: substance P, glutamate

- Inhibitory: GABA, glycine

247
Q

excitatory and inhibitory influences of descending pathways

A
  • Inhibitory – 5-HT, noradrenaline, enkephalin

- Excitatory descending pathways

248
Q

Target receptors for opioids

A
  • Agonists to mimic endogenous analgesics
  • Antagonists to block algogens (pain)
  • Drugs to block synthesis of transmitters
249
Q

analgesics

A

drugs that relieve pain without blocking nerve impulse conduction or markedly altering sensory function

250
Q

paracetamol and molecular action

A
  • Cyclooxygenase inhibitor
  • Structure similar to aspirin (NSAID) but different pharmacological effects: has analgesic and anti-pyretic effects but NO ANTI-INFLAMMATORY EFFECT, no peripheral NSAID adverse effects

paracetamol acts centrally to inhibit the cyclo oxygenase (COX) enzyme which synthesises prostaglandins from arachidonic acid. This decreases sensitivity to pain signals and it also increases the bioavailability of 5-HT, inhibiting pain transmission Maximum daily dose = 4g.

251
Q

Classifications of analgesics:

A
  • Simple analgesic: paracetamol
  • Opioid analgesic: codeine/dihydrocodeine (weak), morphine (strong)
  • NSAIDs: aspirin (non-selective, irreversible), ibuprofen (non-selective), celecoxib (COX-2 selective)
252
Q

paracetamol indications, dose and adverse effects

A

Maximum daily dose = 4g.
Indications: mild-moderate pain, pyrexia
Adverse effects: hepatotoxicity in overdose, which is treated with n-acetylcysteine

253
Q

what can paracetamol be combined with?

A

codeine (co-codamol) and dihydrocodeine (co-dydramol).

254
Q

GCPR opiod receptors and sites of action

A
  • mu (μ) receptors: main receptors analgesic effects
  • delta (δ) receptors
  • kappa (κ) receptors
    The opioid receptor structure is 7 transmembrane GPCRs.
    Sites of actions include: nociceptive nerve endings, spinal cord, thalamus, midbrain, medulla
255
Q

Ligands for mu opioid receptors:

A
  • Endogenous peptides: enkephalins, endomorphins
  • Full agonists: morphine, methadone, fentanyl
  • Partial agonists: buprenorphine
  • Antagonists: naloxone
256
Q

naloxone

A

opioid antagonist and they have a high affinity for mu receptors, used to treat opiod overdose

257
Q

opioid mechanism

A

act at various levels of the visceral pain pathway via inhibitory opioid receptors. These GPCRs block Ca 2+ channels to inhibit NT release, and open K+ channels to hyperpolarise cells (making depolarisation more difficult)

258
Q

morphine: mechanism of action, indication and administration

A

Mechanism of action: agonists at mu opioid receptors in the spinal cord and brain

Indication: severe visceral pain (eg. MI, post-operative pain)

Administration: can be IV, oral, subcutaneous, intrathecal and begin with lower doses and titrate upwards & review need for analgesia regularly to avoid dependence

259
Q

adverse effects of morphine

A

nausea, vomiting, constipation, respiratory/cough depression (Type 2 respiratory failure), urinary retention, hypotension, miosis, itching and wheal formation (due to histamine release)
tolerance- over time, there is receptor down-regulation which leads to desensitisation

260
Q

NSAIDs mechanism

A
  • Inhibit the formation of pro-inflammatory and hyperalgesic prostaglandins (PGs) by the enzyme cyclooxygenase (COX)
  • Tissue damage leads to inflammation and membrane distortion which activate phospholipase A2 (PLA2) which releases arachidonic acid which is then converted by COX to PGs
  • Predominant effects of NSAIDs are anti- inflammatory and anti-pyretic with some mild analgesic effects
261
Q

similar drugs to morphine

A
  • High efficacy: diamorphine, pethidine, oxycodone, methadone
  • Low efficacy: codeine, dihydrocodeine, tramadol
262
Q

COX-1 and COX-2

A
  • COX-1- constitutive (constantly present) enzyme found widely around the body; it maintains housekeeping PGs (e.g. those that control renal blood flow, platelet activity, gastroprotection)
  • COX-2 is synthesised de novo by inflammatory cells (e,g. neutrophils) to provide PGs, which promote inflammation and repair
263
Q

NSAIDs

A
  • Non-selective: aspirin, diclofenac, indomethacin, ibuprofen
  • COX-2 selective: celecoxib
264
Q

ibuprofen: mechanism of action, indication

A

Mechanism of action:

  • Inhibit COX isoforms to reduce PG formation which reduces pain sesntiivity and ongoing inflammation
  • All but aspirin bind reversibly

Indications:

  • Pain related to tissue injury (eg. trauma, bone pain)
  • Pain related inflammation (eg. rheumatoid arthritis, gout, dental)
  • Pyrexia
265
Q

adverse effects of ibuprofen

A

• Gastrotoxicity (celecoxib), renal impairment, Na+/H2O retention
• Hypertension, bleeding (decreased TXA2-induced platelet aggregation)
Adverse effects depend on vulnerability of patients and ibuprofen should be avoided in elderly unless there is a clear indication.

266
Q

neuropathic pain management

A
  • Antiepileptic drugs: gabapentin, phenytoin

* Antidepressants: amitriptyline

267
Q

carbamazepine: mechanism of action, indication, adverse effects

A

Mechanism of action: blocks voltage gated sodium ion channels in the recovery phase of action potential thereby keeping the channels closed and resistance to activation for a longer time period that usual

Indications:
- Epilepsy
- Neuropathic pain related to neurological damage (eg. nerve fibres, spinal cord, CNS) from processes like trauma, surgery, diabetic neuropathy, cancer and other neuropathies
Adverse effects: drowsiness, dizziness
Symptoms like pain relief and adverse effects should be monitored as well as blood levels.

268
Q

sumatriptan: mechanism of action, indication, AE

A

Mechanism of action: 5HT1 agonists that cause vasoconstriction

Indication:
- Migraine attacks: used during the established headache phase of an attack, preferred treatment in those that fail to respond to conventional analgesics
Adverse effects: tingling, heaviness, pressure, coronary vasospasm
Impact on symptoms should be monitored.

269
Q

local anaesthetics action

A

act by causing a reversible block to conduction along peripheral nerve fibres by blocking sodium channels

270
Q

adverse effects of local anaesthetics

A
  • Result from systemic absorption resulting in excessively high plasma concentrations; severe toxicity usually results from inadvertent intravascular injection or too rapid injection
  • intravascular injection must be avoided due to systemic effects, so it must be given slowly with resuscitation equipment available
  • depression of the CNS and cardiovascular system
271
Q

local anaesthetics drugs

A

lidocaine, prilocaine, bupivacaine, cocaine

272
Q

lidocaine: mechanism, administration

A

Mechanism of action: blocks sodium channels to prevent membrane depolarisation
- Multiple indications
Administration:
- Topical application to skin and mucosa
- Subcutaneous injection (sometimes with adrenaline)
- Deep injection
(not intravascular)

273
Q

Local Anaesthetics plus Adrenaline

A
  • to constrict blood vessels and hence increase the duration of anaesthetic action- activates a1 adrenoreceptors
  • not recommended in digits or appendages due to the risk of ischaemic necrosis
274
Q

Drugs used to treat inflammation:

A
  • NSAIDs eg. aspirin, ibuprofen, diclofenac, indomethacin
  • Corticosteroids eg. hydrocortisone, prednisolone, dexamethasone
  • Other drugs used to treat inflammatory diseases: disease-modifying anti-rheumatic drugs, immunosuppressive drugs
275
Q

natural corticoid action

A

Hypothalamus releases CRF (corticotrofin) which stimulates the pituitary gland to release ACTH which then acts on the adrenal gland. This then releases glucocorticoid such as the natural hormone hydrocortisone (cortisol). Glucocorticoids, to some extent, have mineralocorticoid (adrenal cortex also produces aldosterone, fludrocortisone) effects on the body as well as anti-inflammatory effects. The glucocorticoids have a negative feedback inhibition of the pituitary gland and the hypothalamus.

Glucocorticoids then enter cells around the body and interact with glucocorticoid receptors and influence transcription of DNA to mRNA leading to subsequent responses in the body. For one, they can reduce inflammatory response in inflammatory cells and reduce immunological response- there are many responses.

276
Q

exogenous corticosteroid action

A

mimics of natural glucocorticoids (such as cortisol, the stress hormone)that bind to intracellular receptors to inhibit DNA translation of macrophages and T-cells, reduce osteoblast differentiation, increase osteoclast levels and reduce Ca2+absorption

277
Q

prednisolone: mechanism, indications,

A
  • corticosteroid
    Mechanism: inhibit translation of DNA to macrophages and T cells, key cell targets in inflammation
    Indications: Inflammatory diseases (asthma, COPD exacerbations RA, SLE, IBD), allergic emergencies
278
Q

corticosteroid adverse effects

A

skin changes, diabetes, infection, growth suppression, adrenal suppression, osteoporosis, hypertension, myopathy
Monitory and following up is required for long term use, lowest dose should be used for shortest period of time.

279
Q

what can exogenous corticosteroid treatment lead to

A

treatment with exogenous systemic corticosteroids leads to patient’s own internal hypothalamic adrenal gland axis will be shut down, there will be no CRF or ACTH released. This is fine if treatment is continued but stopping means the adaption will take some time which is bad.

280
Q

bone and calcium metabolism

A

Calcium controls cell signalling and contraction. Daily turnover is 700mg Ca2+. Calcium concentration is controlled by interaction of PTH, Vit D and calcitonin.

281
Q

drugs that causes osteoporosis

A

Corticosteriods- Prednisolone:

  • bind to intracellular receptors to alter translation of DNA
  • Macrophages and T cells are key cell targets in inflammation
  • Bone: ↓osteoblast differentiation, ↑osteoclast, ↓Ca absorption

Heparin- (↑osteoclasts, ↓osteoblasts)

282
Q

diagnosis of osteoporosis

A
  • X-rays show loss of trabeculae and cortical thinning
  • Photon absorptiometry may confirm decreased bone density
  • Serum Ca2+, PO43- and alkaline phosphatase usually normal
  • Often first presents with a pathological fracture
283
Q

biphosphonates

A

analogues of the naturally occurring compound, pyrophosphate and reduces bone resorption by osteoclasts by hindering recruitment and stimulating osteoblasts to produce an inhibitor of osteoclast formation.
alsoo absorb onto hydroxyapatite crystals to prevent dissolution

284
Q

alendronate: indications, adverse effects

A

Indications:
• treatment of postmenopausal osteoporosis (70% market)
• prevention (incl. corticosteroid-induced osteoporosis)
• Paget’s disease of the bone
• Malignant bone metastases
Adverse effects:
possible GI upset but well-tolerated
–pills are large so must be taken upright with lots of water and without food to prevent oesophageal rupture.
Jaw pain must be reported due to risk of osteonecrosis
Take care about emergence of symptoms of oesophagitis.

285
Q

oestrogen: effects in bone, adverse and side effects

A
  • Inhibits bone resorption by osteoclasts
  • Reduces hip and spinal fractures in post-menopausal women

Adverse effects: increased risk of endometrial cancer, breast cancer risk, venous thromboembolism, stroke
Side effects: vaginal bleeding, breast tenderness, mood distrubances.

286
Q

raloxifene/ tamoxifen: mechanism, indication, adverse effects

A

Mechanism: oestrogen receptor agonists at some tissue and antagonists at others
Indication: prevention and treatment of osteoporosis , ↑ bone mass and ↓ risk of vertebral fractures only (30-50%)
AE: hot flushes and DVT.

287
Q

smoking in osteoporosis

A

toxins upset body’s hormone balance, destroying oestrogen and calcitonin. Osteoblasts and blood supply (for nutrients) are also damaged. Lastly, smokers tend to have poorerlifestyle habits in general

288
Q

calcitonin use in osteoporosis

A
  • Naturally occurring hormone (thyroid C cells) involved in calcium regulation and bone metabolism
  • Inhibit osteoclasts, slows bone loss, ↑ spinal bone density
  • Used as pain relief after vertebral fractures when other analgesic measures are unsuccessful
  • Side effects: allergic reaction at injection sites
289
Q

teriparatide: PTH- actions, adverse effects

A

• ↑ stimulates new bone formation by osteoblasts and significantly increases bone mineral density
• 70% ↓ vertebral fractures
• 50% ↓ non-vertebral fractures
Adverse effects: nausea, leg cramps, dizziness

290
Q

calcium supplements: intake, adverse effects

A
  • Daily intake should be 1000-1300 mg
  • Oral calcium lactase often given with Vit D
  • Adverse effects: hypercalcaemia→ anorexia, vomiting, polyuria, constipation, weak
291
Q

vitamin D: intake, indications, adverse effects

A
  • Needed for the body to absorb calcium
  • Recommended daily intake between 400-800 IU
  • Indications: prevention of osteoporosis, hypoparathyroidism, renal bone disease, rickets/osteomalacia
  • Adverse effect: hypercalcaemia (nausea, constipation, fatigue, weakness, depression)
292
Q

treatment of Paget’s disease of bone

A
  • Analgesia (NSAIDs)
  • Bisphosphonates will reduce bone turnover
  • Neurological complications and fractures may require surgical intervention
293
Q

treatment of rickets and osteomalacia

A

Vitamin D replacement therapy, phosphate supplements in familial hypophosphatemic rickets

294
Q

synovial fluid in RA

A

cloudy, sterile, ↓ viscosity, ↑ white cells

295
Q

rheumatoid arthritis management

A

initial symptom control (NSAIDs) → remission via DMARDs → short-course corticosteroids for flare-up (due to AEs) → Failure of RA to respond to DMARDs: biological therapy

296
Q

when are DMARDs used?

A

used when rheumatoid arthritis (RA) is confirmed to prevent disease progression and reduce pain/disability. They may take months to achieve their full effect,and allow reduction in NSAID use

297
Q

methotrexate: mechanism, indication, adverse effects

A

mechanism: immunosuppresant, dihydrofolate reductase inhibitor, which blocks DNA synthesis in rapidly proliferating cells (ie immune cells)
Indications: rheumatoid arthritis, psoriasis, Crohn’s, malignancy

Adverse effects: vomiting, diarrhoea, mouth ulcers, hair loss, rash, teratogenic, infection
reduced liver function, pulmonary tox
shouldn’t be given to pregnant, immunosuppressed and live disease patients. Requires regular monitoring (FBC, liver tests).

298
Q

sulfasalazine: mechanism, structure, AE

A
  • Made from aminosalicylate- combo of 5-ASA and sulfapyridine
    Mechanism of action: anti-inflammatory , systemic immunosuppressant activity
    Indications: activity rheumatoid arthritis, IDB
    Adverse effects: rrash, GI upset, reduced leukocytes and platelets, azoospermia, photosensitivity, anaphylaxis (allergic shock), ↓folate
299
Q

hydrocortisone use in RA

A

Hydrocortisone corticosteroid may be injected into joints to avoid systemic effects

300
Q

why are older DMARDs like gold, hydroxychloroquine and penicillamine no longer used?

A

had multiple toxic effects

gold and penicillamine: monitor blood count and urine for proteinuria

301
Q

action of TNF-a antagonists

A
  • Monoclonal antibodies eg. infliximab directly recognise TNF -a
  • Soluble receptor analogues eg. etanercept which are similar to ones TNF-a normally bind on cells to have been produced
302
Q

infliximab: mechanism, adverse effects

A

TNF-αantagonist given by IV in severe active RA. AE: hypersensitivity reaction, latent TB reactivation, cancer. Avoid with pregnancy, breast feeding and severe infection

303
Q

biological therapies

A

cytokine inhibitors

304
Q

fibronectin

A

Acts as an attachment point for anchoring cells in the tissue

Y1S2- Cardio, Resp, Loco (3 decks)

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