Locomotion disorders

1
Locomotion disorders

• Martin Votava

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Treatment of locomotion disorders

• Ø    Skeletal Muscle Relaxants
• Ø    Anxiolytic Agents
•     Nonsteroidal anti-inflammatory drugs
• Ø    Analgetics
• Ø    Slow-acting anti-rheumatic drugs
• Ø    Glucocorticoid drugs
• Ø    Chondroprotective drugs
• Ø    Drugs used in gout

3
Rheumatoid Arthritis

• A chronic, systemic autoimmune disease of unknown
  etiology
• Characterized by symmetric, erosive, joint
  synovitis
• Can be Palindromic, Relapsing, or Malignant
• May involve multiple organ systemscardiovascular
  , pulmonary, renal, skin and eyes

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Epidemiology

• Affects 1 of U.S. adults
• 150,000 new cases annually
• 80 of cases occur between 35-50 years
• Female-to-male ratio of 31
• Gender predisposition decreases with increasing
  age
• Costs/year 8.74 billion (1994 dollars)

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RA Joint

• Pannus formation
• Tendon and ligament instability
• Invasion of cartilage and bone surface
• Erosion of bone and cartilage
• Joint instability
• Eventual destruction of the joint

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What diseases are considered in the differential
diagnosis of RA?

• Osteoarthritis
• Spondyloarthritis
• Gout and Pseudogout
• Fibromyalgia
• Polymyalgia Rheumatica
• Systemic Lupus Erythematosus
• Reactive Arthritis

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Functional Classification

• Class I capable of all activities without
  handicap
• Class II Able to conduct normal activities
  despite discomfort or limited mobility of one or
  more joints
• Class III Functional capacity only adequate to
  perform a few of the normal duties of usual
  occupation
• Class IV Confined to bed or wheelchair capable
  of little or no self-care

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Rheumatoid ArthritisExtra-articular
Manifestations

• Dermatologic subcutaneous nodules
• Hepatic elevated transaminases
• Cardiac pericarditis
• Pulmonary fibrosis, nodules, pleural effusion
• Ocular keratoconjunctivitis, scleritis

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Rheumatoid ArthritisLaboratory Abnormalities

• Serologic FindingsAnemia, thrombocytosis, mild
  leukocytosis, positive RF, elevated ESR,
  C-reactive protein
• Synovial Fluid FindingsStraw-colored and
  slightly cloudy fluid, leukocytosis 5,000 to
  25,00/mm3, 85 polymorphonuclear cells

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What laboratory data is consistent with a
diagnosis of RA

• Anemia
• Thrombocytosis
• () Rheumatoid Factor

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Rheumatoid ArthritisTreatment

• Goal
• Prevent disease progression to irreversible joint
  damage
• Maintain Quality of life
• Multidisciplinary approach
• Patient education treatment plan, compliance,
  understanding of disease
• Psychotherapy manage pain and stress
• Rehabilitation exercise, joint protection

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Non-Pharmacologic Interventions

• Goal
• Reduce pain, disability and protect mobility
• Physical Therapy
• Occupational Therapy
• Psychological support for the patient and family
• Surgical Alternatives
• Synovectomy
• Joint replacement

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Pharmacologic Interventions

• Early aggressive treatment
• Control swelling and pain
• Reduce the probability of irreversible joint
  damage
• Agents
• Glucocotricoids
• NSAIDs
• DMARDs
• Biologic response modifiers
• Chondroprotective agents

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NSAIDs NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
15

• are among the most widely used drugs
• major type of effects
• antiinflammatory
• analgesic (reduction of somatic pain)
• antipyretic (lowering of a raised temperature)
• mechanisms of action
• inhibition of arachidonate cyclooxygenase (COX)
• inhibition of biosynthesis of PGs
  and TXs
• COX-1 enzyme expressed in most tissues
• involved in cell-cell signalling and in tissue
  homeostasis
• COX-2 enzyme induced in inflammatory cells
  when they are activated , responsible for the
  production of prostanoid mediators of inflammation

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Nonselective NSAIDs
Selective and nonselective
NSAIDs
arachidonic acid
inflammation
physiological activation
COX-1
COX-2
Endoperoxides
(constitutive form)
(inducible form)
proinflammatory prostanoids
prostanoids ensuring physiological functions
Results from inhibition of prostanoids
biosynthesis
COX-2 inhibition
COX-1 inhibition)
Unwanted effects mainly on the GIT and kidney,
decrease in pl.aggregation
Antiinflammatory, analgesic and antipyretic
effects
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Regulation and Expression of COX-1 and COX-2

• COX-1
• Constitutive (Protective)
• Found in all tissues
• Important role in
• GI tract
• Kidneys
• Platelets

• COX-2
• Induced at site of inflammation(Inducible)
• Produced by macrophages, synoviocytes during
  inflammatory process

Vane JR, Botting RM. Semin Arthritis Rheum.
1997262-10.
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the antiinflammatory action of NSAIDs is mainly
related to their inhibition of COX- 2 and it is
probable that their unwanted effects are largery
due to their inhibition of COX-1
All NSAIDs are analgesics and antipyretics but
the degree of anti-inflammatory activity varies.
OTC drugs (over the counter)
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Analgesic effect-- mechanisms in the
periphery against pain associated with
inflammation or tissues damage because of
decrease in PGs production that sensitises
nociceptors to inflammatory mediators
(bradykinin)
central mechanisms (in the spinal cord)
NSAIDs are effective in arthritis
pain of muscular and vascular origin headache,
toothache, dysmenorrhoea in combination with
opioids decrease in postoperative

pain
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• Antiinflammatory effect
• NSAIDs reduce mainly components of the
  inflammatory and immune response in which the
  products of COX-2 action play a significant part
• vasodilatation
• oedema
• pain

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THE SALICYLATES natural products that contain
precursors of salicylic acid such as willow bark
(glycoside salicin) acetylsalicylic acid
sodium salicylate methylsalicylate used in
topical applications diflunisal ASPIRIN
(acetylsalicylic acid) pharmacokinetics well
absorbed, highly bound to plasma proteins
first-pass effect--converted to salicylic acid
in low dose t1/2 4 h, first-order kinetics in
high doses gt4 g/day saturation pharmacokinetics
(danger of overdosage !) pH of urine
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• Unwanted effects
• gastritis with focal erosions and bleeding
• salicylism with repeated ingestion of large
  doses of s
• tinnitus, vertigo, decreased hearing
• Reyes syndrom in children encephalopathy and
  
• hepatopathy that can follow an acute viral
  illness (treated with
• aspirin). RS has a 20-40 mortality
• allergic reactions skin rashes, worsening of
  asthma
• IND
• antiplatelet effects 0.1 g/day
• analgesic effects 0.5 g
  4-6times/day
• for short-term analgesia
• antiinflammatory effects 3.5 - 4 g/day
• for long-term treatment

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• IBUPROFEN
• analgesic, antipyretic and antiinflammatory
  action
• without gastric toxicity
• ind acute pain for short-term analgesia
• OTHER NSAIDs
• for antiinflammatory effects in acute or
  chronic
• inflammatory conditions (e.g. rheumatoid
  arthritis and related
• connective tissue disorders)
• are given in higher doses then that for simple
  analgesia and
• treatment may need to be continued for long
  period
• indomethacin, naproxen can also be used for
  severe pain
• unrelated to inflammation
• flurbiprofen, diclofenac
• more selective for COX-2 nimuselide, celecoxib
  (treatment of arthritis)

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COX Isoform Selectivity of Commercially
Available NSAIDs and Investigational COX-2
Selective Inhibitors
Highly Relatively Relatively
HighlyCOX-1 COX-1 Equally COX-2
COX-2Selective Selective Selective Selective
SelectiveFlurbiprofen Fenoprofen Aspir
in Diclofenac Celecoxib Ketoprofen Piroxicam Ibu
profen Etodolac Rofecoxib Indomethacin Meloxic
am L-743,337 Ketorolac Nabumetone NS-398 N
aproxen Nimesulide Valdecoxib

Oxaprozin Parecoxib Tolmetin
Vane JR et al. Annu Rev Pharmacol Toxicol.
19983897-120.
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• Unwanted effects
• gastrointestinal disturbances
• dyspepsia, diarrhoea, nausea, vomiting
• one in five chronic users gastric damage
  (risk of
• serious hemorrhage and/or perforation)
• PGs inhibit acid secretion and have
  protecting action on
• 
  the gastric mucosa
• skin reactions (from mild rashes, urticaria to
  more serious
• 
  reactions)
• renal reactions
• acute renal insufficiency reversible on
  stopping the drug
• (due to inhibition of PGE2 mediated
  compensatory vasodilatation
• that occurs in response to NORA and ANG II)
• chronic NSAIDs consumption analgesic
  nephropathy
• chronic nephritis, renal papillary necrosis
  (renal hypertension,
• malignancies)

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NSAID-Induced Upper GI Toxicity

• Estimated prevalence of dyspepsia is 10-60
• Use of nonselective COX-2 NSAIDs is associated
  with a significantly increased risk of gastric
  and duodonal ulcers
• Endoscopic ulcer point prevalence is 10-30
• Upper GI ulcers, gross bleeding, or perforation
  caused by NSAIDs appears to occur in 2-4 of
  patients treated for 1 year
• Majority of patients hospitalized for
  NSAID-induced ulcer complications have no warning
  symptoms

Singh G. Am J Med. 1998105(suppl 1B)31S-38S.
(cont)
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NSAID-Induced Upper GI Toxicity

• NSAID use is associated with significant
  morbidity and mortality
• Approximately 107,000 hospitalizations per year
• More than 16,500 deaths per year
• Relative risk does not decline with long-term
  therapy

Singh G. Am J Med. 1998105(suppl 1B)31S-38S.
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Prevention of NSAID-Induced Gastropathy

• Is inflammation present?
• Misoprostil
• Omeprazole
• Not H2-Blockers
• COX-2 selective NSAIDs

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Criteria for NSAID Selection

• Record of efficacy and safety (experience, length
  of time on the market)
• Patient characteristics and concomitant disease
  states (minimize risks in high risk patients)
• Pharmacodynamic/pharmacokinetic profiles
• Dose - Dosing interval
• Price

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Pros and Cons of NSAID Therapy

• Cons
• Does not affect disease progression
• GI toxicity common
• Renal complications (eg, irreversible renal
  insufficiency, papillary necrosis)
• Hepatic dysfunction
• CNS toxicity

• Pros
• Effective control of inflammation and pain
• Effective reduction in swelling
• Improves mobility, flexibility, range of motion
• Improve quality of life
• Relatively low-cost

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Rheumatoid Arthritis Disease-Modifying
Antirheumatic Drugs

• DMARDs can alter the progression of RA
• May be initiated within the first 3 months of
  diagnosis if
• Ongoing inflammation despite treatment with
  NSAIDS
• Glucocorticoid dose 7.5 mg prednisone/day (or
  equiv)
• Radiographic evidence of joint destruction
• Presence or development of extra-articular
  disease
• May take 2wks - 6 months for a response

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• Rheumatoid disease (one of commonest chronic
  inflammatory conditions) is a common cause of
  disability.
• The primary inflammatory cytokines, interleukin-1
  and tumour necrosis factor-a , have a major role
  in pathogenesis
• DMARDs improve symptoms and can reduce disease
  activity
• as measured by
• reduction in number of swollen and tender
  joints
• pain score
• disability score
• radiology
• serum concentration of acute-phase proteins

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• The effects
• probably result from inhibition of excessive
  cytokine
• 
  liberation
• are slow in onset
• only have a part to play in progressive disease
  
• are also toxic (the patient must be monitored)

IND rheumatoid psoriatic arthritis
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Drugs Unwanted effects
Comments --------------------------------
------------------------------------------- Immuno
suppressants blood dyscrasias MTX is usual
methotrexate (MTX) carcinogenesis
first-choice azathioprin
opportunistic inf. DMARD cyclosporin
MTX cirrhosis
mucositis
cycl. nephrotoxicity

hypertension -------------------------------------
--------------------------------------------------
sulphasalazine blood dyscrasias s.
is also used for (combination of
rashes chronic
inflammatory sulphonamide colours
urine/tears bowel disease
with a salicylate) orange
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Drugs Unwanted effects
Comments Gold compounds skin
rashses inhibit mitogen- sodium
aurotiomalate mouth ulcerations
induced concentrated in macrophages
lymphocyte and synovial cells in
joints,
proliferation effects appear slowly (in
months) (maximum effects in 3-4months)
penicillamine in 40
is known to have
nauzea, vomiting,
metal-chelating propert


proteinuria and
decreases IL-1 gener. chloroquine

blurring of vision decreases leukocyte

retinopathies chemotaxis, lyozomal

enzyme release

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Rheumatoid Arthritis Choice of DMARDs

• Drug Side Effects
• hydroxychloroquine retinal toxicity, diarrhea
• sulfasalazine bone marrow
  suppression, GI intolerance
• Can be used as initial therapy in milder disease
• Semiannual eye exam for HCQ (macular damage)
• Dosing
• SAS - 1 gram bid or tid
• HCQ - 200 mg bid (maintenance)

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Rheumatoid Arthritis Choice of DMARDs

• Drug Side Effects
• methotrexate bone marrow suppression, hepatic
  and pulmonary toxicity, GI intolerance,
  stomatitis, rash
• Most rapid onset and sustained benefit
• Weekly dose 7.5-15 mg PO
• Close monitoring required

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Rheumatoid Arthritis Choice of DMARDs

• Drug Side Effects
• gold salts bone marrow suppression, rash,
  stomatitis, proteinuria diarrhea, edema
• Administered IM (50 mg) on a weekly basis for 3-5
  months, followed by less frequent dosing
• Requires close monitoring of bone marrow and
  renal toxicity
• PO dosing 3-6 mg qd (auranofin)

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Rheumatoid Arthritis Choice of DMARDs

• Drug Side Effects
• azathioprine bone marrow suppression, hepatoto
  xicity, GI symptoms
• AZA is used when disease activity persists on
  other DMARDs
• May be safer than MTX for patients gt 65 years
  with renal insufficiency
• PO dose 50-100 mg qd (max 2.5 mg/kg/day)

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Rheumatoid Arthritis Choice of DMARDs

• Drug Side Effects
• D-penicillamine bone marrow suppression, rash,
  stomatitis, dysgeusia, proteinuria, autoimmune
  disease
• d-Penicillamine is used if disease activity
  persists on other DMARDs
• Associated with high incidence of lupus,
  myasthenia gravis
• PO dose 125-250 mg qd (max. 1 gram/day)

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Rheumatoid Arthritis Choice of DMARDs

• Drug Side Effects
• cyclophosphamide bone marrow suppression hemorrha
  gic cystitis, malignancy, infertility
• Oral immunosuppressive agent with significant
  toxicity profile
• Used in severe vasculitis and other
  extra-articular involvement
• PO dose 50-100 mg qd (max 2.5 mg/kg/day)

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DMARD Combinations

• MTX sulfasalazine
• MTX hydroxychloroquine (HCQ)
• MTX sulfasalazine HCQ
• MTX gold
• MTX Azathioprine HCQ
• MTX Penicillamine

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Rheumatoid ArthritisChoice of DMARDs

• Cost
• Dosing regimen
• Compliance
• Comorbid disease states
• Toxicity profile and monitoring requirements
• Severity and prognosis of patient

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Rheumatoid Arthritis Glucocorticoids

• Potent rapidly acting anti-inflammatory agents
• Used as bridge therapy until DMARDs become
  effective local injection is efficacious and
  less toxic than DMARDs
• Low dose systemic therapy may slow the rate of
  joint damage and is effective in refractory RA

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Rheumatoid Arthritis Glucocorticoids

• Side effects
• Osteoporosis, Cushingoid state, hypertension,
  premature athersclerosis, infection
• Reducing the risk of osteoporosis
• Regular exercise, estrogen therapy, supplemental
  calcium and vitamin D
• Calcitonin or bisphosphonates in patients with
  low bone mass

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Pros and Cons of Corticosteroid Therapy

• Cons
• Does not conclusively affect disease progression
• Tapering and discontinuation of use often
  unsuccessful
• Low doses result in skin thinning, ecchymoses,
  and Cushingoid appearance
• Significant cause of steroid-induced osteopenia

• Pros
• Anti-inflammatory and immunosuppressive effects
• Can be used to bridge gap between initiation of
  DMARD therapy and onset of action
• Intra-articluar injections can be used for
  individual joint flares

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New Pharmacologic Agents

• Immunomodulator
• Leflunomide
• Biologic Response Modifiers
• Etanercept
• Infliximab
• Antibiotics
• Minocycline

48
Leflunomide/A77 1726 Primary Mechanism of Action
DHODH
Salvage
Dihydroorotate
Orotate
pathway
Leflunomide
Extracellular
Glutamine
UMP
pyrimidines

HCO
3

Aspartate
Pyrimidine
nucleotides
DNA/RNA synthesis
glycosylation
49
Leflunomide

• Hepatic metabolism
• Active metabolite inhibits cell proliferation in
  activated lymphocytes results in cell cycle
  arrest
• t 1/2 14 days
• Dose 100 mg/day x3 days then 20 mg qd
• Side effects
• Diarrhea 27, ? LFTs 10, rash 8, alopecia 7

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Etanercept

• soluble receptor for TNFa
• Indication
• To reduce signs/symptoms of moderate to severe
  active RA in patients who have had an inadequate
  response to one or more DMARDs
• Dose
• 10 mg or 25 mg SC twice a week
• Kinetics
• t 1/2 of 25 mg dose 5 days
• Response rate
• 50-70 in moderate or severe RA

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Infliximab

• Monoclonal TNF-? antibody (binds TNF)
• Chimeric mouse-human IgG1
• Well-tolerated and effective in 50 of patients
  with RA
• FDA approved for use w/mtx to reduce s/s of RA
  (inadeq response)

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Infliximab

• Administered as IV infusion 3 mg/kg single dose
  followed with doses 2-6 weeks after the first
  dose, then q8weeks
• Should be used with methotrexate for synergy and
  enhanced duration of response
• Adverse events include increased risk of
  infection, hypersensitivity reactions, and
  formation of auto-antibodies

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AntibioticsMinocycline

• Tetracyclines first advocated for RA in 1960s
• Minocycline
• inhibits metalloproteinases which destroy
  cartilage
• 3 Clinical Trials have shown statistically
  significant improvement in patients w/RA

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New Agents - Place in Therapy

• TNF blockade will likely become a major
  therapeutic advance in treatment of RA
• Leflunomide can be added to MTX if disease
  remains active and LFTs are stable
• Etanercept, and infliximab should be considered
  if disease remains active despite adequate DMARD
  trials (3-6 months at therapeutic doses) or
  significant toxicity precludes continued
  administration of other DMARDs

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Chondroprotective agents

• Glukosamine sulphate
• Chondroitine sulphate
• Hyaluronic acid
• Diacereine

56
Rheumatoid Arthritis Prognosis

• Progressive in 2/3 of patients resulting in
  disabling and destructive disease
• Poor Prognostic Factors
• Male, age gt50, poor functional capacity, positive
  RF, presence of nodules, HLA-DR4
• 3-10 year decrease in survival in 50 of patients

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Drugs used in gout

• artritis (deposit of monosodium urate in joints
  and cartilage)
• excess of meal, drinking (alcohol), gait, stress,
  mild injury
• Acute attack
• Colchicine, Indometacine 

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Chronic gout

• Uricosuric agents (probenecid, sulfinpyrazon)
• - reabsorption of uric acid in the proximal
  tubule is decreased
• Inhibition of synthesis (allopurinol)
• inhibititor of xanthine oxidase