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MSK > Pharmacology of the Musculoskeletal system > Flashcards

Pharmacology of the Musculoskeletal system Flashcards

1
Q

Bone structure

A

• Bone structure; 206 bones in human body

  • 75% inorganic:
  • hydroxyapatite Ca3 (PO4)3OH
  • 99% body calcium stored in bone
  • reservoir - can be released
  • 25% organic:
  • osteoblasts, osteoclasts – bone remodelling
  • osteocytes
  • collagen
  • Calcium metabolism; absorbed from small intestine
  • Vitamin D dependent
  • Renal excretion
  • Site of haematopoiesis; Red marrow
  • Red, white blood cells and platelets
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2
Q

Epiphysis

A
  • Compact bone surface, spongy bone interior
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3
Q

Epiphyseal plate:

A

Junction of epiphysis and diaphysis, site of bone growth during childhood

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4
Q

Spongy bone

A

“trabecular bone” honeycomb structure, filled with bone marrow

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5
Q

Diaphysis

A

Thick collar compact bone, medullary cavity containing

marrow

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6
Q

Compact bone (weight bearing):

A

Outer smooth layer, composed of “osteon”; cylinder of

compact bone, lamellar structure; Canal with blood and nerve fibres

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7
Q

Periosteum:

A

Outer layer protective connective tissue, vascularized; Inner layer osteogenic - osteoblasts and
osteoclasts. Site at which tendons and ligaments attach

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8
Q

Joints

A
  • Multiple types, different classifications
  • Synovial – synovial lining, allowing movement
  • Synarthrosis –fused by fibrous tissue, minimal movement
  • Articular cartilage
  • Covers end of bone; Smooth, low friction
  • Chondrocytes, proteoglycans, collagen, water
  • Deformable but recovers shape
  • Articular capsule
  • Surrounds joint cavity
  • Synovial membrane (synovium)
  • Inner layer of articular capsule, secretes synovial fluid into joint - lubricant
  • Hyaluronic acid
  • Ligaments
  • Extracapsular and Intracapsular (e.g. ACL)
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9
Q

Bone remodelling

A

• Bone remodelling
• Continual turnover to deal with stress
• 25% of trabecular bone remodelled each year; 0.5 g Ca2+ enters/leaves bone/day!
• Bone formation needed to deal with injury
• Osteoclasts
• RANKL binds to receptor “RANK” on osteoclast precursors to promote
differentiation into osteoclasts
• Carry out bone resorption
• Form tight seal and cavity “lacuna” on bone and secrete acid to promote
hydroxyapatite dissociation
• Proteases to degrade organic components
• Osteoblasts
• Reform bone by secreting alkaline phosphatase (hydrolyses pyrophosphate) and vesicles which concentrate Ca2+
• Liberated phosphate recrystallizes bone as hydroxyapatite “calcification”

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10
Q

Hormones regulating - Ca2+ exchange

A
  • Parathyroid Hormone, PTH
  • Ca2+ receptor on parathryoid
  • In GIT:
  • stimulates 25(OH) Vit D →1,25(OH)2 Vit D (“calcitriol”) in kidney
  • 1,25(OH)2 Vit D (calcitriol) stimulates Ca2+ absorption from small intestine
  • Kidney tubules
  • increases Ca2+ reabsorption
  • decreases Pi reabsorption
  • Bone
  • Promotes osteoclast differentiation (↑RANKL) and hence Ca2+ release from bone
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11
Q

Hormones regulating Ca2+ exchange

A
  • Calcitonin
  • Ca2+ reduced (inhibits osteoclasts; increases bone uptake of serum Ca2+; increases Ca2+ deposition in the bones)
  • can be used to treat osteoporosis (slowing bone resorption)
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12
Q

Vitamin D

A
  • Vitamin D3
  • Produced in skin
  • non-enzymatic, UV-B light driven
  • dietary sources too
  • 25 (OH) Vitamin D
  • Enzyme catalysed hydroxylation
  • Liver
  • 1,25 (OH)2 Vitamin D
  • “Calcitriol” - “active form” of vitamin D
  • Enzyme catalysed hydroxylation
  • Kidney
  • Regulated by PTH
  • Promotes Ca2+ absorption in intestine
  • Vitamin D2
  • Ergocalciferol
  • Produced by plants
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13
Q

Vitamin D

A

• Vitamin D receptor (VDR) is a transcription factor
• Binds Vitamin D in cytosol, forms dimer with RXR
• Shuttles to nucleus and recognises specific DNA sequences
• Increases expression of genes involved in Ca2+
absorption
• TRPV6 – Ca2+ channel
• Calbindin – Ca2+ transport protein
• PMCA1b - Ca2+ pump
• Increases RANKL expression in osteoblasts
• Activates osteoclasts

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14
Q

Metabolic bone diseases

A

• Group of disorders where there is some disturbance of
bone formation/resorption
• Osteoporosis - common; backpain, loss of height, fracture
• Paget’s disease - common; deformity of long bones, pain in hips
• Osteomalacia - uncommon; generalized bone pain, muscle weakness

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15
Q

Osteoporosis

A
  • Generalized reduction of bone mass
  • increased fragility, predisposition to fracture
  • 230,000 fractures related to osteoporosis

Reduction of bone mass in mid-late adult life
• ↓0.7% bone mass p.a.
• Decreased formation and Increased resorption
• Bone Fragility →fracture from mild trauma

Post menopausal women
• Osteoporosis more prevalent
• Reduced estrogen causes:
• Increased osteoclast activity
• Increased RANK & RANKL expression
• Estrogen normally represses RANKL expression
• Decreased osteoclast apoptosis → ↑resorption cavities
• Increase osteoblast apoptosis →↓ bone production

• Results in increased remodelling of trabecular bone

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16
Q

Denosumab

A

• Humanized monoclonal antibody; binds RANKL, reduces osteoclast number and hence bone turnover

Indications
• Osteoporosis
• Bone loss in cancer

ADR
• Atypical femoral fracture due to excessive bone demineralisation
• Osteonecrosis of jaw
• Hypocalcemia

Contraindications
• hypocalcaemia

17
Q

SERMS

A

Mechanism
• Selective estrogen receptor modulators; Act as either estrogen receptor agonists or antagonists in different tissues
• Depends on other cofactors in transcription factor complex (co-repressors, co-activators)
• Allows tissue-specific effects
• Increase in osteoblast activity & decrease in osteoclast activity; reduces risk of vertebral fractures

Raloxifene
• Estrogen receptor agonist in bone, estrogen receptor antagonist in breast
- useful for treating women with/risk of breast cancer and osteoporosis

Indications
• Osteoporosis

ADR
• Hot flushes, Increased risk venous thrombosis

Contraindications
• hypocalcaemia

18
Q

Osteomalacia

A

Osteomalacia
• Termed “Ricketts” in children
• Vitamin D deficiency
• lack of sunlight
• dietary deficiency - although diet is generally poor source of Vitamin D in UK
• Causes defects in bone mineralization, muscle weakness
• soft, weak bones, pain from small fractures, risk of fracture
• Can also occur in patients taking P450 inducers (e.g. epilepsy) leading to increased calcitriol metabolism

19
Q

Kidney disease and Pagets

A

Chronic kidney disease
• Hypocalcemia caused by:
• Decreased synthesis of 1,25 (OH)2 Vitamin D3
in kidney→↓Ca2+ absorption
• Decreased Pi secretion in kidney leading to Ca2+ complexation
• Hypocalcemia causes secondary hyperparathyroidism:
• increased PTH production→↑bone resorption (osteoclasts)
• Decreased synthesis of parathyroid Ca2+ sensors - alters set point for Ca2+ to stimulate PTH secretion, so less responsive to altered Ca2+
• Net effect is increased bone resorption → fracture risk

Paget’s disease
• Distortion of bone turnover, resulting increased bone size, altered shape and weakness
• Cause unknown

20
Q

Pagets Disease

A

• X-ray shows increased bone thickening on right side
of pelvis
• increased osteoblastic activity

21
Q

Vitamin D supplements

A

Indications
• Hypoparathyroidism, osteomalacia

Alfacalcidol (1a-hydroxycholecalciferol)
• rapid onset, useful for quick adjustment plasma Ca2+ e.g. hypoparathyroidism

Cholecalciferol (vit D3), ergoclaciferol (vit D2)
• slower onset because of need for hydroxylation

• PK: absorbed po

Dose according to [Vit D]plasma
• Vitamin D insufficiency (50-75 nM) – low dose
• Vitamin D deficiency (< 50 nM) – higher dose

22
Q

Issues with Vitamin D supplementation

A
  • Vitamin D can accumulate in fat; prolonged activity (months after single high dose)
  • Metabolised by P450 24-hydroxylase (see previous slide – enzyme inducing drugs causing vitamin D deficiency)
  • ADR
  • Hypercalcaemia; Children overdose on vitamin D reported (several symptoms)
  • Caution
  • Excreted into breast milk; Monitoring of plasma Ca2+ may be appropriate for higher doses
23
Q

Calcium

A
  • Indications:
  • Acute hypocalcaemia
  • infusion of Calcium gluconate
  • Monitor [Ca2+] and adjust
  • Start oral Ca2+ therapy for maintenance
  • Chronic hypocalcaemia
  • Oral Calcium carbonate or citrate
  • Additional treatment as necessary see previous slides
  • Vitamin D in Vitamin D deficiency
  • Alfacalcidol, calcitriol in Hypoparathryoidism
  • ADR
  • Arrhythmia, confusion, polyuria…..
  • Interactions
  • Avoid with digoxin
24
Q

Bisphosphonates

A

• e.g. Alendronate

  • Mechanism
  • Accumulates in bone
  • Inhibits osteoclasts (causes apoptosis) reduced bone resorption
  • Inhibition of mevalonate pathway (farnesyl diphosphate synthase)
  • Indications
  • Osteoporosis; Slow loss of bone density, risk of fracture
  • Bone metastatic cancer: Hypercalcaemia due to metastasis, bone damage to metastasis
  • Paget’s disease
  • PK
  • Poor oral bioavailability; IV administration possible in cancer
  • Distribution/Elimination: Some drug absorbed into bone, only release after bone resorbed; Rest excreted unchanged (renal)
25
Q

Issues with bisphosphonates

A
  • ADR
  • Osesophageal irritation (po)
  • Osteonecrosis of jaw (usually only with prolonged use)
  • Caution
  • Avoid with antacids and Ca2+ – reduced po absorption

• Contraindications
• Hypocalcaemia
• Avoid if eGFR less than 35 mL/minute/1.73 m2
.
• GI disease
• Patients should report; any oral problems (see ADR); thigh/hip pain - possibility of atypical femoral fracture if excessive bone demineralization

• Falling out of favour due to ADRs/ poor bioavailability and advances in therapy

26
Q

Osteoarthritis

A
  • Most common joint disease
  • Affects at least one joint in 2/3 population over 75, usually weight bearing joints (hip, knee). Results from disorder of articular cartilage leading to loss of cartilage
  • Underlying bone exposed and remodelled new bone growth
  • loss of joint mobility
  • Treatment
  • Pain management with paracetamol, codeine, NSAIDS
  • New biological approaches being developed
27
Q

Rheumatoid arthritis

A
  • 1% of population, typically in 40-60 year olds
  • Autoimmune disease
  • systemic inflammation, may see inflammatory processes outside joints
  • Increased mortality due to cardiac disease (esp. ischaemic heart disease)
  • Wrist, shoulder, knee
  • Repeated remission and relapse, worsening at each relapse
  • Antigen
  • Unknown arthritogenic antigen induces self-perpetuating immune response
  • Exogenous, endogeous?
  • Autoantibodies to IgG and collagen, not clear these are causative
  • Genetic predisposition
  • linked to certain MHC alleles
28
Q

Rheumatoid arthritis

A
  • Infiltration and accumulation of CD4+ T cells in synovium
  • T cells release cytokines (e.g. TNF and IL-1) stimulating B cells (autoantibodies), recruit additional leukocytes eg neutrophils,
  • Macrophages – stimulating proliferation of synovial cells
29
Q

Rheumatoid arthritis

A
  • Proliferation of synovium cells; “hyperplasia”
  • Forms folds linked together by fibrin

• Cells become invasive, form “pannus”
• covering and destroying articular cartilage, tendons and joint capsule
• Macrophages, recruited neutrophils and synovial cells release proteases,
destroy proteins in cartilage and bone

  • Osteoclasts activated by RANKL (elevated in RA) degrade bone.
  • joint damage, destruction of joint capsule and tendons causes deformities
30
Q

Treatment

A

• Early treatment with Diseasemodifying anti-rheumatic
drugs (DMARDs)
• e.g. methotrexate; sulfasalazine; gold; hydroxychloroquine; ciclosporin

• Joint replacement
• Anti-TNFα drugs
• Enteracept, infliximab,
adalimumab

31
Q

Gout

A
  • Pain caused by crystals of sodium urate in joints
  • Sparingly soluble
  • 6.8 mg/L
  • Plasma concentration
  • 4-6 mg/L
  • Crystals can form in joints
  • Esp. great toe
  • Lower temp
  • Synovial fluid more acidic than plasma
  • Can form white/yellow lumps in skin “tophi”
  • Uric acid is product of purine metabolism
  • Renal secretion
  • 90% filtered reabsorbed by URAT1 transporter in kidneys
32
Q

Gout

A
  • Accumulation of uric acid leads to formation of sodium urate crystals in joints
  • Immune responses lead to acute/chronic inflammation
33
Q

Gout

A
  • Patients affected
  • with polymorphisms in genes regulating purine synthesis and degradation, URAT1
  • Drugs which increase renal uric acid reabsorbtion (eg diuretics)
  • Purine rich diet (red meat)
  • Several stages
  • 1st phase: Asymptomatic, elevated urate
  • Acute gout: Sodium urate induces inflammation (“gouty arthritis”)
  • Very painful – therapy aims to control this
  • Intercritical phase
  • Asymptomatic, elevated urate
  • Chronic phase
  • Recurrent attacks, several joints affected
  • Therapy aims to modify urate metabolism and restore [urate]
34
Q

NSAIDS

A
  • Used to treat pain & reduce inflammation in gout
  • Naproxen, Ibuprofen, diclofenac
  • See pain and analgesia lecture
  • Colchicine (see later) may be used if these are contraindicated
35
Q

Xanthine oxidase inhibitors

A
  • Allopurinol
  • Used in chronic gout
  • Inhibits xanthine oxidase, increasing urinary secretion of hypoxanthine and xanthine
  • Reduced [urate] in plasma
  • ADR
  • Hypersensitivity, possibly developing to Stevens-Johnson syndrome in rare cases
  • Drug interactions
  • Affects metabolism of purine based drugs that are metabolized by xanthine oxidase
  • Mercaptopurine
  • Azathioprine
  • Inhibits metabolism of warfarin
  • Febuxostat
  • Recently licensed
36
Q

Colchicine

A
  • Indications
  • Used in chronic gout, sometimes in acute gout
  • Inhibits microtubule polymerization
  • Prevents intracellular transport (“trafficking”) mediated by microtubules
  • Inhibitors neutrophil inflammatory response
  • ↓ transport of phagocytosed urate crystals
  • ↓ synthesis and secretion of chemotactic factors particularly LTB4
  • ↓ motility and adhesion
  • Pharmacokinetics
  • Excreted by PgP and undergoes enterohepatic recirculation
  • Metabolised by p450 3A4

ADR
• GI disturbances
• Diahorrea see PK
• turnover of GI epithelial cells see mechanism
• myelosuppression through inhibition of mitosis see mechanism
• Peripheral neuropathy

Caution
Low therapeutic window

Contraindications
• Advanced renal failure (cannot be removed by haemodialysis)

Drug interactions
• P450 inhibitors
• PgP inhibitors

37
Q

Neuromuscular junction

A
  • Neuromuscular blockers
  • principal use as adjunct to general anaesthesia
  • e.g. suxamethonium
  • See anaesthesia lecture
  • Myasthenia gravis
  • Auto-immune disease, antibodies to muscle nAChR
  • Causes muscle weakness
  • Potentiate activity of acetylcholine with acetylcholinesterase inhibitors e.g. pyridostigmine

MSK (6 decks)

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