Transcript Bez nadpisu

Locomotion disorders
Martin Votava
Treatment of locomotion
disorders
 Skeletal Muscle Relaxants
 Anxiolytic Agents
Nonsteroidal anti-inflammatory drugs
 Analgetics
 Slow-acting anti-rheumatic drugs
 Glucocorticoid drugs
 Chondroprotective drugs
 Drugs used in gout
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 systems:
cardiovascular, pulmonary, renal, skin and eyes
Epidemiology:
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Affects 1% of U.S. adults
150,000 new cases annually
80% of cases occur between 35-50 years
Female-to-male ratio of ~ 3:1
Gender predisposition decreases with
increasing age
• Costs/year ~$8.74 billion (1994 dollars)
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
What diseases are considered in the
differential diagnosis of RA?
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Osteoarthritis
Spondyloarthritis
Gout and Pseudogout
Fibromyalgia
Polymyalgia Rheumatica
Systemic Lupus Erythematosus
Reactive Arthritis
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
Rheumatoid Arthritis:
Extra-articular Manifestations
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Dermatologic: subcutaneous nodules
Hepatic: elevated transaminases
Cardiac: pericarditis
Pulmonary: fibrosis, nodules, pleural effusion
Ocular: keratoconjunctivitis, scleritis
Rheumatoid Arthritis:
Laboratory Abnormalities
• Serologic Findings:
Anemia, thrombocytosis, mild leukocytosis,
positive RF, elevated ESR, C-reactive protein
• Synovial Fluid Findings:
Straw-colored and slightly cloudy fluid,
leukocytosis 5,000 to 25,00/mm3, 85%
polymorphonuclear cells
What laboratory data is consistent with a
diagnosis of RA
• Anemia
• Thrombocytosis
• (+) Rheumatoid Factor
Rheumatoid Arthritis:
Treatment
• 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
Non-Pharmacologic
Interventions:
• Goal:
– Reduce pain, disability and protect mobility
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Physical Therapy
Occupational Therapy
Psychological support for the patient and family
Surgical Alternatives
– Synovectomy
– Joint replacement
Pharmacologic Interventions
• Early aggressive treatment:
– Control swelling and pain
– Reduce the probability of irreversible joint damage
• Agents:
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Glucocotricoids
NSAID’s
DMARDs
Biologic response modifiers
Chondroprotective agents
NSAIDs
NONSTEROIDAL
ANTI-INFLAMMATORY DRUGS
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
Nonselective NSAIDs
arachidonic acid
physiological
activation
COX-1
(constitutive form)
Selective
and nonselective
NSAIDs
inflammation
COX-2
Endoperoxides
(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
Antiinflammatory, analgesic
and kidney, decrease in pl.aggregation and antipyretic effects
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. 1997;26:2-10.
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)
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
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
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 >4 g/day saturation pharmacokinetics (danger of
overdosage !) pH of urine
Unwanted effects:
• gastritis with focal erosions and bleeding
• salicylism with repeated ingestion of large doses of s:
tinnitus, vertigo, decreased hearing
• Reye´s 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:
• analgesic effects:
0.1 g/day
0.5 g 4-6times/day
for short-term analgesia
• antiinflammatory effects: 3.5 - 4 g/day
for long-term treatment
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)
COX Isoform Selectivity of
Commercially Available NSAIDs and
Investigational COX-2 Selective Inhibitors
Highly
COX-1
Selective
Relatively
COX-1
Selective
Flurbiprofen Fenoprofen
Ketoprofen Piroxicam
Equally
Selective
Aspirin
Ibuprofen
Indomethacin
Ketorolac
Naproxen
Oxaprozin
Tolmetin
Relatively
COX-2
Selective
Highly
COX-2
Selective
Diclofenac
Etodolac
Meloxicam
Nabumetone
Nimesulide
Celecoxib
Rofecoxib
L-743,337
NS-398
Valdecoxib
Parecoxib
Vane JR et al. Annu Rev Pharmacol Toxicol. 1998;38:97-120.
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)
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. 1998;105(suppl 1B):31S-38S.
(cont)
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. 1998;105(suppl 1B):31S-38S.
Prevention of NSAID-Induced
Gastropathy
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Is inflammation present?
Misoprostil
Omeprazole
Not H2-Blockers
COX-2 selective NSAIDs
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
Pros and Cons of NSAID
Therapy
Pros
• Effective control of
inflammation and pain
• Effective reduction in
swelling
• Improves mobility, flexibility,
range of motion
• Improve quality of life
• Relatively low-cost
Cons
• Does not affect disease
progression
• GI toxicity common
• Renal complications (eg,
irreversible
renal insufficiency, papillary
necrosis)
• Hepatic dysfunction
• CNS toxicity
Rheumatoid Arthritis:
Disease-Modifying Antirheumatic Drugs
• DMARDs can alter the progression of RA
• May be initiated within the first 3 months of
diagnosis if:
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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
Rheumatoid disease (one of commonest chronic inflammatory
conditions) is a common cause of disability.
The primary inflammatory cytokines, interleukin-1 and tumour
necrosis factor-α , 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
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
Drugs
Unwanted effects
Comments
--------------------------------------------------------------------------Immunosuppressants 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
Drugs
Gold compounds
Unwanted effects
skin rashses
Comments
inhibit mitogensodium 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%
nauzea, vomiting,
proteinuria
is known to have
metal-chelating propert
and decreases IL-1 gener.
chloroquine
blurring of vision decreases leukocyte
retinopathies
chemotaxis, lyozomal
enzyme release
Rheumatoid Arthritis:
Choice of DMARDs
Drug
hydroxychloroquine
sulfasalazine
Side Effects
retinal toxicity, diarrhea
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)
Rheumatoid Arthritis:
Choice of DMARDs
Drug
methotrexate
Side Effects
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
Rheumatoid Arthritis:
Choice of DMARDs
Drug
gold salts
Side Effects
bone marrow suppression,
rash, stomatitis, proteinuria
diarrhea, edema
• Administered IM (50 mg) on a weekly basis for 35 months, followed by less frequent dosing
• Requires close monitoring of bone marrow and
renal toxicity
• PO dosing 3-6 mg qd (auranofin)
Rheumatoid Arthritis:
Choice of DMARDs
Drug
azathioprine
Side Effects
bone marrow suppression,
hepatotoxicity, GI symptoms
• AZA is used when disease activity persists on
other DMARDs
• May be safer than MTX for patients > 65 years
with renal insufficiency
• PO dose: 50-100 mg qd (max 2.5 mg/kg/day)
Rheumatoid Arthritis:
Choice of DMARDs
Drug
D-penicillamine
Side Effects
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)
Rheumatoid Arthritis:
Choice of DMARDs
Drug
cyclophosphamide
Side Effects
bone marrow suppression
hemorrhagic 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)
DMARD Combinations
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MTX + sulfasalazine
MTX + hydroxychloroquine (HCQ)
MTX + sulfasalazine + HCQ
MTX + gold
MTX + Azathioprine + HCQ
MTX + Penicillamine
Rheumatoid Arthritis:
Choice of DMARDs
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Cost
Dosing regimen
Compliance
Comorbid disease states
Toxicity profile and monitoring requirements
Severity and prognosis of patient
Rheumatoid Arthritis :
Glucocorticoids
• Potent rapidly acting anti-inflammatory agents
• Used as “bridge therapy” until DMARD’s
become effective; local injection is efficacious and
less toxic than DMARD’s
• Low dose systemic therapy may slow the rate of
joint damage and is effective in refractory RA
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
Pros and Cons of Corticosteroid
Therapy
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
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 steroidinduced osteopenia
New Pharmacologic Agents
• Immunomodulator:
– Leflunomide
• Biologic Response Modifiers
– Etanercept
– Infliximab
• Antibiotics:
– Minocycline
Leflunomide/A77 1726
Primary Mechanism of Action
DHODH
Dihydroorotate
Orotate
Salvage
pathway
UMP
Extracellular
pyrimidines
Leflunomide
Glutamine
+
HCO3
+
Aspartate
DNA/RNA synthesis;
glycosylation
Pyrimidine
nucleotides
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%,  LFT’s 10%, rash 8%,
alopecia 7%
Etanercept:
• soluble receptor for TNFα
• Indication:
– To reduce signs/symptoms of moderate to severe active
RA in patients who have had an inadequate response to
one or more DMARD’s
• 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
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)
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
Antibiotics:
Minocycline
• Tetracyclines first advocated for RA in
1960’s
• Minocycline:
– inhibits metalloproteinases which destroy
cartilage
– 3 Clinical Trials have shown statistically
significant improvement in patients w/RA
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 LFT’s 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 DMARD’s
Chondroprotective agents
• Glukosamine sulphate
• Chondroitine sulphate
• Hyaluronic acid
• Diacereine
Rheumatoid Arthritis:
Prognosis
• Progressive in 2/3 of patients resulting in disabling
and destructive disease
• Poor Prognostic Factors:
– Male, age >50, poor functional capacity, positive RF,
presence of nodules, HLA-DR4
• 3-10 year decrease in survival in 50% of patients
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
Chronic gout
• Uricosuric agents (probenecid,
sulfinpyrazon)
• - reabsorption of uric acid in the proximal
tubule is decreased
• Inhibition of synthesis (allopurinol)
• inhibititor of xanthine oxidase