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:

• 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?

• 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

• 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

• 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: – 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 Selective and nonselective NSAIDsarachidonic acid

physiological activation

inflammation

Endoperoxides(constitutive form) (inducible form)

prostanoids ensuringphysiological functions

proinflammatory prostanoids

Results from inhibition of prostanoids biosynthesis

COX-1 inhibition) COX-2 inhibitionUnwanted effects mainly on the GITand kidney, decrease in pl.aggregation

Antiinflammatory, analgesic and antipyretic effects

COX-1 COX-2

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 peripheryagainst pain associated with inflammation or tissues damagebecause 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 acidsuch 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: 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

IBUPROFENanalgesic, antipyretic and antiinflammatory action without gastric toxicityind: 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)

Highly Relatively Relatively HighlyCOX-1 COX-1 Equally COX-2 COX-2Selective Selective Selective Selective Selective

Flurbiprofen Fenoprofen Aspirin Diclofenac Celecoxib Ketoprofen Piroxicam Ibuprofen Etodolac Rofecoxib

Indomethacin Meloxicam L-743,337Ketorolac Nabumetone NS-398Naproxen Nimesulide Valdecoxib

Oxaprozin ParecoxibTolmetin

COX Isoform Selectivity of Commercially Available NSAIDs and

Investigational COX-2 Selective Inhibitors

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)

(cont)

Singh G. Am J Med. 1998;105(suppl 1B):31S-38S.

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.

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

Prevention of NSAID-Induced Gastropathy

• 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

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

Pros and Cons of NSAID Therapy

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

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 Unwanted effects CommentsGold compounds skin rashses inhibit mitogen-sodium aurotiomalate mouth ulcerations induced concentrated in macrophages lymphocyteand synovial cells in joints, proliferationeffects 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

Rheumatoid Arthritis: Choice of DMARDs

Drug Side Effectshydroxychloroquine retinal toxicity, diarrheasulfasalazine 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 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

Rheumatoid Arthritis: Choice of DMARDs

Drug Side Effectsgold 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)

Rheumatoid Arthritis: Choice of DMARDs

Drug Side Effectsazathioprine 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 Side EffectsD-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)

Rheumatoid Arthritis: Choice of DMARDs

Drug Side Effectscyclophosphamide 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

• MTX + sulfasalazine

• MTX + hydroxychloroquine (HCQ)

• MTX + sulfasalazine + HCQ

• MTX + gold

• MTX + Azathioprine + HCQ

• MTX + Penicillamine

Rheumatoid Arthritis:Choice of DMARDs

• 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

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

Pros and Cons of Corticosteroid Therapy

New Pharmacologic Agents

• Immunomodulator: – Leflunomide

• Biologic Response Modifiers– Etanercept– Infliximab

• Antibiotics:– Minocycline

Leflunomide/A77 1726 Primary Mechanism of Action

DihydroorotateDHODH

Glutamine+

HCO3+

Aspartate

Orotate

UMP

Pyrimidinenucleotides

DNA/RNA synthesis;glycosylation

Extracellularpyrimidines

Salvagepathway

Leflunomide

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