The document discusses drugs used to treat musculoskeletal disorders like gout. It begins by describing the musculoskeletal system and different bone types. It then discusses gout in detail, including causes like hyperuricemia, stages of gout progression, symptoms, diagnosis via blood tests and joint fluid analysis. Treatment goals are to relieve acute flares and lower high uric acid levels to prevent further attacks. Lifestyle changes and medications to treat acute flares and lower uric acid are covered, including NSAIDs, colchicine, and corticosteroids.

1. DRUGS USED FOR
MUSCULOSKELETAL
DISORDERS
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Drugs used for Musculoskeletal
disorders
1

2. Introduction
• The musculoskeletal system imparts form and
movement to the human body
• Consists of bones, joints and muscles
• Consists of a rich supply of blood vessels and nerves
Bones
• Provide a framework to support and protect the
body
• Point of attachment with muscles
• Held close together at the joint by ligaments,
which are flexible bands of fibrous tissue
• Store calcium and other minerals
• Produce blood cells within bone marrow
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3. Introduction cont’d
• Osteoblasts are bone-forming cells
• Osteoclasts are responsible for reabsorbing
dead bone tissue
• Bone cells are called osteocytes
• The development of osteocytes and the
hardening process is called ossification
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4. Introduction cont’d
•Bones (continued)
• Different types:
• Short
• Irregular
• Flat
• Long
• Diaphysis — shaft, or long portion, of the
bone
• Distal and proximal epiphysis — two ends of
the bone
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5. Introduction cont’d
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6. Bone Disorders
• The term musculoskeletal disease
embraces a large number of conditions
ranging from localized, benign lesions of
the bone such as the osteochondroma to
generalized disorders such as
osteoporosis, osteomyelitis, rheumatoid
arthritis, gouty arthritis, fracture,
muscular dystrophy, etc
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7. Drug Therapy for
Gout
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8. What is Gout?
• a common metabolic disorder where there is a vast
accumulation of uric acid into the joints
• Leads to the formation of monosodium urate crystal in
various tissues in the body
• causes attacks of arthritis, usually in a single joint (often
the base of the big toe).
• Hyperuricaemia (excess uric acid in the blood) leads to
the formation of uric acid crystals inside joints
• Crystals may also be deposited in the soft tissues in the
ears and around tendons
• More common in middle-aged and older men
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10. Gout Radiograph
http://www.pathguy.com
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11. Gouty arthritis - characteristics
 sudden onset
 middle aged males
 severe pain
 distal joints
 intense inflammation
 recurrent episodes
 influenced by diet
 bone erosions on
Xray
 hyperuricemia
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12. Diagnosis
• Gout is suspected if an attack of arthritis affects
a single joint
• Abrupt onset of severe pain, swelling, and
tenderness that reaches its maximum within just 6–
12 hours, especially with overlying erythema
• A blood test is usually performed;
– a high level of uric acid will suggest gout.
– Hyperuricemia: serum urate > 6.8 mg/dl
• Examination of fluid from the joint may confirm
the diagnosis.
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13. Serum uric acid levels & age
3.0
4.0
5.0
6.0
7.0
8.0
9.0
10.0
11.0
12.0
13.0
10 20 30 40 50 60
Age (years)
Gouty Male
Normal Male
Gouty Female
Normal Female
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14. 1
•Asymptomatic Stage
2
•Acute stage
3
•Intercritical stage
4
•Chronic stage
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15. • urate levels rise in the blood, but
produces no symptoms
ASYMPTOMATIC STAGE
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16. ACUTE STAGE
Severe and sudden onset
Involves one or a few joints
Frequently starts nocturnally
Joint is warm, red, and tender
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17. • symptom-free intervals between gout episodes
• most people have a second attack from six months to
two years, while others are symptom-free for five to
10 years
INTERCRITICAL STAGE
More concentration of uric acid
crystals
Typically no need for drug
intervention at the time
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18. CHRONIC STAGE
Continuous or persistent over
a long period of time
Treatment with ULT
Not easily or quickly resolved
tophaceous gout
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19. PATHOPHYSIOLOGY
 Uric acid is the end product of purine degradation
 Purines originate from dietary purine, conversion of tissue nucleic
acid to purine nucleotides, and de novo synthesis of purine bases
 serum uric acid level dependent upon
 rate of uric acid production
 efficiency of renal uric acid excretion
 Hyperuricemia can be caused by
 impaired renal excretion or
 overproduction of uric acid, and/or
 overconsumption of purine-rich foods that are metabolized to
urate.
 serum urate > 6.8 mg/dl

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20. Cont’d….
 Uric acid may be overproduced because of increased breakdown of tissue
nucleic acids, as with myeloproliferative and lymphoproliferative disorders.
 Cytotoxic drugs can result in overproduction of uric acid due to lysis and the
breakdown of cellular matter
 Dietary purines are insignificant in generation of hyperuricemia without some
derangement in purine metabolism or elimination
 Two thirds of uric acid produced daily is excreted in urine. The remainder is
eliminated through gastrointestinal (GI) tract after degradation by colonic
bacteria
 Decline in urinary excretion to a level below rate of production leads to
hyperuricemia and increased pool of sodium urate
 Drugs that decrease renal uric acid clearance include diuretics, nicotinic
acid, salicylates, ethanol, pyrazinamide, levodopa, ethambutol, cyclosporine,
and cytotoxic drugs.
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22. Uric acid metabolism
cell
breakdown
dietary
intake
purine bases
hypoxanthin
e
xanthine
uric acid
xanthine
oxidase
catalyzes
hypoxanthine
to xanthine &
xanthine to
uric acid
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23. Cont’d
• Deposition of urate crystals in synovial fluid results in
inflammation, vasodilation, increased vascular
permeability, complement activation, and chemotactic
activity for polymorphonuclear leukocytes
• Phagocytosis of urate crystals by leukocytes results in
rapid lysis of cells and discharge of proteolytic enzymes
into cytoplasm
•
The ensuing inflammatory reaction causes intense joint
pain, erythema, warmth, and swelling
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24. Cont’d
 Uric acid nephrolithiasis occurs in 10% to 25% of
patients with gout
 In acute uric acid nephropathy, acute renal failure occurs
because of blockage of urine flow from massive
precipitation of uric acid crystals in collecting ducts and
ureters
 Chronic urate nephropathy is caused by long-term
deposition of urate crystals in the renal parenchyma
 Tophi (urate deposits) are uncommon and are a late
complication of hyperuricemia.
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25. Chronic tophaceous gout
tophus = localized deposit of
monosodium urate crystals
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26. Gout - tophus
classic location
of tophi on helix
of ear
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27. Cause of symptoms
• When monosodium
crystals get into
joints, this illicit a
reaction from the
body’s immune system
• The body macrophages
and neutrophils attack
the monosodium urate
crystals causing
inflammation of the
joint
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28. AMP
ATP
Lactate
Pyruvate
Fructose 1-
Phosphate
Fructose Intake and Urate Excretion
• Dominant dietary source – high-fructose corn syrup (HFCS)
– The principal “sweetener” for humans (found in sugar-sweetened soft
drinks)
• High concentration of fructose causes rapid accumulation of AMP
– Increases the body pool of purines (catabolized to uric acid)
• Lactic acid is a by-product of fructose metabolism
– Lactate decreases urate excretion
HFCS
Fructose
Uric Acid
Purine
Catabolism
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29. Gout - cardinal manifestations
nephrolithiasi
s
nephropathy
arthritis tophi
HYPERURICEMI
A
acute &
chronic
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30. TREATMENT GOALS
• Rapidly end acute flares
– Protect against further flares
– Reduce chance of crystal inflammation
• Prevent disease progression
– Lower serum urate to deplete total body
urate pool
– Correct metabolic cause
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31. Lifestyle Modifications
• Patients should consider lifestyle and dietary
changes to reduce their sUA:
– Losing weight
– Limiting consumption of purine-rich meat
(red meat) and seafood
– Reducing alcohol intake, particularly beer
– Limiting high-fructose corn syrup intake
– avoid peas
– Consuming dairy products: reduce incidence of gout
• Milk proteins have uricosuric properties
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32. Rich in purine SEAFOOD
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33. high-fructose corn syrup is found in
sugar-sweetened soft drinks
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34. Particularly beer can raise sUA upto 1mg/dL
Avoid alcohol
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35. Drugs used to treat gout
allopurinol
probenecid
febuxostat?
steroids
NSAID’s
colchicine
Acute Arthritis Drugs Urate Lowering Drugs
rest + analgesia + time
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36. 1. NSAIDs
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37. NSAIDs
37
• Agents of first choice for acute gouty
arthritis
– Benefits derive from suppressing of pain and
inflammation
• All of the NSAIDs are effective for gout
trt, but paracetamol has no anti-
inflammatory effect
– Commonly used drugs are:
• Indomethacin
• Naproxen
• Diclofenac sodium
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38. MOA of NSAIDs
• The primary effect of the nonsteroidal antiinflammatory
drugs (NSAIDs) is to inhibit cyclooxygenase (COX or
prostaglandin synthase - PGHS), thereby impairing the
ultimate transformation of arachidonic acid to prostaglandins,
prostacyclin, and thromboxanes
• COX-1 is expressed in most tissues, but variably
• It is described as a "housekeeping" enzyme, regulating normal
cellular processes (such as gastric cytoprotection, vascular
homeostasis, platelet aggregation, and kidney function)
• COX-1 activity is stimulated by hormones or growth factors
• COX-2 is constitutively expressed in the brain, kidney, bone,
and probably in the female reproductive system
• Its expression at other sites, including the cardiovascular
system, is increased during states of inflammation or,
experimentally, in response to mitogenic stimuli
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40. 2/7/2023 Drugs used for Musculoskeletal disorders 40

41. NSAIDs
• Indomethacin can inhibit urate crystal
phagocytosis by decreasing the
migration of granulocytes into the
inflammatory area
– it may replace colchicine
• Aspirin in therapeutic low doses is
contraindicated as it compete with uric
acid secretion in proximal tubule
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42. NSAIDs
• Adverse effects
– better tolerated as compared with colchicine
• GI ulceration
• impaired renal function
• fluid retention, and increased risk of cardiovascular
events
• almost all of the above AEs are due to ed PG secretion
– since the duration of treatment is brief, the risk
of these complications is low
• Contraindicated in:
– Renal disease
– PUD
– GI bleeders
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43. 2. Colchicine
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44. 2/7/2023 Drugs used for Musculoskeletal disorders 44

45. OVERVIEW
A plant alkaloid
Used for the treatment of acute gouty
attacks and prophylaxis
Neither a uricosuric nor an analgesic agent,
yet relieves pain in acute attacks of gout
Prophylactic effect which reduces the
frequency of acute attacks
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46. MECHANISM OF ACTIONS
Binds to tubulin - disrupt migration of
granulocytes to affected area
diminishes PMN phagocytosis of
crystals, thereby prevents release of
chemotactic factors and cytokines
from neutrophils
reduces inflammatory response to
deposited crystals
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47. Colchicine
• Colchicine is approved for:
- Treatment of gout flares
- Prophylaxis of gout flares
• Colchicine is not an analgesic medication
and should not be used to treat pain
from other causes
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48. Adverse effects
• dose-related & more common when patient
has renal or hepatic disease
• Diarrhea is a common adverse effect. May
cause nausea, vomiting ,abdominal cramps
– Common with oral dose
• Chronic use may cause alopecia, bone
marrow depression, peripheral neuritis,
myopathy
• Also affect fertility
• Preg risk Category C
• fetal harm
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49. Contraindication & Precaution
• Contraindicated in pregnancy
• Should be used with caution in
hepatic , renal or cardiovascular
diseases.
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50. 3. Corticosteroids
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51. Glucocorticoids
51
• highly effective for relieving an acute
gouty attack
• Candidates for glucocorticoid therapy
include
– patients who are hypersensitive/
contraindicated to NSAIDs/Colchicine
– patients with severe gout that is unresponsive
to NSAIDs/Colchicine
• should be avoided in patients prone to
hyperglycemia
– Worse glycemic control
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52. Glucocorticoids
• Methods of adminstration
- Parenteral
- Oral
- Intra-articular :- in patients with only one or two actively
inflamed joints
• Prednisolone
- 1mg/kg PO as a single dose -OR-
- 20-40 mg PO QD taper by 5-10mg every 3 days until dose
complete
• Methylprednisolone
- 40 mg intra-articular single dose
• Triamcinolone acetonide
- 40 mg intra-articular as a single dose
- 60 mg IM every 1 to 4 days as needed
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53. Urate-lowering Therapy
• Prevents disease progression
• Lower urate to the target sUA < 6 mg/dl :
– Depletes total body urate pool & deposited crystals
• RX is lifelong & continuous
• MED choices:
– Xanthine oxidase inhibitors
– Uricosuric agents
• prevent arthritis, tophi & Kidney stones
• These drugs have no role to play in managing acute gout
– Since they can precipitate acute gout & prolong attack of gout
53
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54. Prevention of
recurrent
attack
Inhibitors of uric
acid synthesis
Allopurinol
Febuxostat
Uricosuric drugs
- Probenecid
-Sulfinpyrazone
-Large doses of
aspirin
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55. Inhibition of uric acid synthesis
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56. Allopurinol
• Structural analog of hypoxanthine &
xanthine
• Competitive inhibitor of xanthine oxidase
• Xanthine and hypoxanthine are more soluble and
better excreted renally
• Allopurinol is metabolized to oxypurinol
• Oxypurinol accumulates—may be responsible for
antigout effects
• Oxypurinol is not well absorbed orally
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57. Allopurinol
• Historically, the drug of choice for
treatment of chronic tophaceous gout
• effectively blocks formation of uric acid
– Decreases serum and urinary uric acid levels
• Can work in pts with renal insufficiency
• supplied - 100 mg & 300 mg tablets
• pregnancy category C
57
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58. Uric Acid Production
• About two-thirds of uric acid is generated
endogenously by the body, while one-third
comes from purines in the diet
Purine
Catabolism
Xanthin
e
Oxidas
e
Xanthine
Oxidase
Urate
Oxidase
(Uricase)
End product for humans, higher
primates, reptiles, birds, and some
mammals
End product for
the majority of
mammals
Hypoxanthine Xanthine Uric Acid Allantoin
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59. Uric acid metabolism and site of action of
allopurinol
cell breakdown
dietary intake purine bases
hypoxanthine
xanthine
uric acid
allopurinol
inhibits xanthine
oxidase
allopurinol
allopurinol
oxypurinol
59
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60. Therapeutic Uses of Allopurinol
• It is drug of choice in patients
with: tophi
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disorders
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61. • For high serum uric acid in patients
with impaired renal functions
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62. • In patients with uric acid
stones or nephropathy
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63. • used to prevent increased uric acid
levels in patients
receiving cancer chemotherapy
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64. Side Effects (most common)
exacerbation of
an acute attack of gout
due to mobilizing flare
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65. Maculopopular skin rash
extremely serious problem
prompt recognition required
first sign usually skin rash
progression to toxic
epidermal necrolysis & death
Allopurinol hypersensitivity
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66. nausea, diarrhea
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67. Side Effects (less common)
Body : fever, headache CVS : vasculitis
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68. Thrombocytopenia Epistaxis
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69. Stevens-Johnson syndrome
target skin lesions
mucous membrane
erosions
epidermal necrosis with
skin detachment
sometimes bleeding in
the mucous membranes
of the eyes, mouth, nose,
and genitals.
69
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70. Drug Interactions
With oral anticoagulant:
Potentiates warfarin
and dicumarol
•inhibits their metabolism
in liver through inhibition
of CYP P450
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71. With anticancer :
6-mercaptopurine
and azathioprine
• inhibits their metabolism
as they are substrate for XO
(doses are reduced up to 75%)
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72. With ampicillin :
Increases frequency
of skin rash
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73. Allopurinol – black box warning
 not recommended for the treatment
of asymptomatic hyperuricemia
should be discontinued at the first
appearance of skin rash or other signs
of an allergic reaction
73
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74. Febuxostat
• Febuxostat is a xanthine oxidase (XO)
inhibitor indicated for the chronic
management of hyperuricemia in patients with
gout
• chemically distinct from allopurinol
• 94% of patients reached urate < 6.0 mg/dl
NC
O
S
N
CH3
CO2H
CH3
H3C
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75. Febuxostat
• Febuxostat is not recommended for the
treatment of asymptomatic hyperuricemia
• Can be used in chronic gout patients with
mild to moderate renal impairment
• Has minimal adverse events and drug
interaction
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76. Febuxostat Dosing and Administration
An increase in gout flares is frequently observed during
initiation of anti-hyperuricemic agents, including Febuxostat. If
a gout flare occurs during treatment, Febuxostat need not be
discontinued.
Usage Dosing
• 40 mg is the recommended starting dose Once daily
• 80 mg is the recommended if sUA
< 6 mg/dL is not achieved after 2
weeks with 40 mg dose
Once daily
• Upon initiation of treatment,
prophylaxis with and NSAID or
colchicine may be beneficial
Up to 6
months
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77. Uricosuric drugs
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78. • Probenecid is a uricosuric drug that
increases uric acid excretion in the urine
• primarily used in treating gout
Probenecid
uric acid
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79. Uricosuric therapy
• probenecid
– Inhibits tubular reabsorption of filtered urate in
kidney
– enhances urine uric acid excretion
• increases urine uric acid level
– decreases serum uric acid level
– moderately effective
– increases risk of nephrolithiasis
• not used in patients with renal disease
79
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80. Drugs Potentially Affected by
Probenecid Therapy
• Ampicillin
• Penicillin
• Nafcillin
• Cephradine
• Cephaloridin
• Salicylates
• Indomethacin
• Heparin
• Dapsone
• Methotrexate
• Rifampicin
Can impair their renal secretion.
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81. Probenecid
81
• S/Es
– frequent, but mild, side effects
– GI effects (nausea, vomiting, anorexia)
• take the drug with food.
– Hypersensitivity reactions—rash
– Renal injury minimized by
• alkalinizing the urine and
• `consuming 2.5 to 3 L of fluid daily
• D/Is
– Aspirin and other salicylates interfere with
the uricosuric action of probenecid.
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82. Sulfinpyrazone
• actions and Uses
– inhibit reabsorption of uric acid, and thereby
enhances uric acid excretion.
– used to reduce hyperuricemia in patients with
chronic gout.
– lacks anti-inflammatory and analgesic actions
• no benefit during an acute gouty attack
– During the first few months of therapy, the drug
may precipitate an acute gouty attack.
• Concurrent use of low-dose colchicine can reduce this
risk
• Adverse Effects
– Gastrointestinal effects (nausea, abdominal pain)
are common but rarely necessitate stopping
treatment
• Take with meals
82
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83. Sulfinpyrazone
83
– exacerbate GI ulcers
• contraindicated in patients with active ulcers
– Kidney stone, reduced by
• alkalinizing the urine and
• having the patient ingest large volumes of fluids
• D/Is
– Salicylates
– as Sulfinpyrazone inhibit hepatic metabolism
of
• tolbutamide (causing hypoglycemia) and
• Warfarin (causing bleeding tendencies).
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84. Uricosuric drugs
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85. Urate-lowering therapy
Gout type
• mild gout
• renal disease
• Nephrolithiasis
• Elderly
• tophaceous gout
Drugs
• Uricosuric
• allopurinol/ Febuxostat
• allopurinol/ Febuxostat
• allopurinol/ Febuxostat
• allopurinol/ Febuxostat
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86. Possible treatments
• If all else fails
• Surgery may be needed to remove uric acid
build up
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87. The end
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