Drugs, musculoskeletal and joint diseases

MUSCULOSKELETAL EMERGENCIES
MUSCULOSKELETAL DISORDERS
TRAUMA INFECTION NEOPLASTIC DIS. RHEUMATIC DIS., etc

CLINICAL MANIFESTATIONS
PAIN PAIN TENDERNESS EDEMA DEFORMITY, etc

Problems with musculoskeletal and joint diseases

Muscle
Muscle contraction, cramp

Skeleton
Osteoporosis

Joint
Arthritis Gout

Treatment Goals
Reduce pain to where it doesnt adversely impact patients life Treatment without unacceptable side effects Pain Pain alone alone is is not not an an absolute absolute indication for treatment indication for treatment Total removal of pain may not be possible

Gout
Also called gouty arthritis, a systemic disease in which urate crystals deposit in the joints and other body tissues, causing inflammation Primary gout Secondary gout

Tophi

Podagra

Management of gouty arthritis

Asymptomatic hyperuricemia Acute gouty arthritis Chronic or tophaceous gout

Purine nucleotides
hypoxanthine xanthine Uric acid
allopurinol

Xanthine oxidase

Urinary excretion

Alimentary excretion

Tissue deposition in excess Urate crystal Phagocytosis with acute inflammation and arthritis

uricosurics

microtophi

colchicine

NSAID

Colchicine
management of acute gout
Colchicine Effective within the 24 hours of an attack Mechanism of colchicine Inhibit phagocytosis (microtubular system) Affect chemotaxis Affect motility and adhesion of neutrophil Reduce release PGE2 and LTB4 Side effect GI disturbance, blood dyscrasias, myoneuropathy Contraindications Renal dysfunction, liver disease, sepsis, bone marrow dysfunction

Acute Gout Management

FDA approved therapies: indomethacin, naproxen, sulindac, colchicine, allopurinol, sulfinpyrazone Unapproved for Acute Gout:
Variety of NSAIDs Corticotrophin, corticosteroids: for monarticular attacks (IA), polyarticular attacks (IM, PO), when NSAID contraindicated. ACTH has been used since 1949 and may be superior to indomethacin in some trials. Probenecid, Benzbromarone, Sulfinpyrazone losartan (24%) Fenofibrate lowers Urate 19%, increases excretion 36%

AVOID Uricosuric drugs:

Duration of Therapy: 7-30 days PotentiaL adjunctive agents:

MEDICATIONS for GOUT

Drug
NSAIDS (indomethacin, phenylbutazon, coxibs) CORTICOSTEROIDS ineffective (glucocorticoids, prednisone)

MOA
anti-cox-2 anti-prostaglandins (in bone, pmns, macrophages) anti-T cl prolif anti-IL-1,2,6, INF-a/g anti-PAF, LTN, PGs

Dosing
taper dose 2-8 days 12-24 hrs response

Purpose
prophylaxis pain prevention treat acute attack *low tox, hi na/k, bleeding, gi when NSAIDS

give dose to response then taper w/in 1st 12-24hrs relief 6-12 hrs adj dose for hepat & renal pts no use w/uricosurics

rapid dramatic relief prophylaxis suppress symptoms decreases pain of gouty arthritis *gi toxicity, bm supress, skin irrit prophylaxis primary hyperuricemia of gout & 2nd to cancer therapy long term lowers serum uric acid removes crystals from kidney *hypersensitivity, gi, leukopenia, hepat/renal tox

ANTI-GOUT anti-mitotic agent (pmns, macro) (colchicine) anti-tubulin polymerization of attack anti-leukocyte migration blocks lipoxygenase ALLOPURINOL anti-xanthine oxidase decreases synthesis of uric acid decreases purine synthesis

URICOSURICS (Probenecid, sulphinpyrazole)

increase excretion of uric acid blocks reabsorption of uric acid alkalinizes urine

adj dose for renal prophylaxis dec excr pcn, indom long term lowers serum uric acid sulfonurea *ha, nausea, nephrolithiasis no use w/salicyl not for hi uric acid level=stone

Acute Gout Management

Drug
NSAIDs COX-2 inhibitors Colchicine

Dose
Indocin* 150 mg/d taper 5-7d Per PDR qd or bid

Common AE
GI toxicity, CNS, HTN, LFTs ?less GI toxicity? RenalHTN,edem

SAE
PUD, renal dz, bleeding, allerrxn PUD, renal, MI, CVA Neuromyopathy, ARF, BM suppression Risk of infection osteoporosis

1.2 mg po then 0.6 Diarrhea, N/V, q1-2h (not to abdominal pains exceed 8mg) IA Methylpred 1040 mg. PO:30-60 qd HTN, BS, fluid retention, insomnia

Corticosteroids

Drug

Dose

Common AE

SAE

* or equivalent anti-inflammatory dose

NSAIDs Contraindicated?
Renal insufficiency
Peptic ulcer disease Congestive heart failure NSAID intolerance

no

NSAIDs Antiinflamatory doses

yes Are Corticosteroids Contraindicated? no

Corticosteroids

Treatment Acute Gout

yes
1
# Joints Involved?

Oral Colchicine Intra-articular PO Steroid

Lipsky PE, Alarcon GS, Bombardier C, Cush JJ, Ellrodt AG, Gibofsky A, Heudebert G, Kavanaugh AF, et al. Am J Med 103(6A):49S85S, 1997

>1 Oral or Intra-articular Steroid

TOXICITY OF NSAIDs
Ototoxic Color blindness Bronchospam

CHF

Hepatotoxic

UGIB UGIB Nephrotoxic

Bleeding

Allergy

Tocolytic

Mechanism of = Mechanism of therapeutic effects adverse effects

Corticosteroids in Acute Gout

Benefits: equal to NSAIDs, less toxic acutely, benefits of local use and aspiration (nonstandard dosing, forms, routes po, IM, SC, IV) Often given w/ CHF, CRI, hx of GI bleed or Monarticular Gout Toxicity: hyperglycemia, hypokalemia, fluid retention, rebound flare Prednisone: 30-50 mg 3-7d then tapered over 10-14 days (rebound?) ACTH IM 40-80 U; Triamcinolone acetonide 60 mg;betamethasone 7

Corticosteroids
management of acute gout Corticosteroids
NSAID and colchicine are contraindicated Prednisone 20-50mg oral 3-20days ACTH 40IU IM once ACTH 40-80IU IM,IV, q8hsubcute q12hqdx3Ds Intra-articular steroids

Corticosteroids in practice
Product Cortisol Prednisone Methylpredn. Triamcinolone Dexamethasone Betamethasone Half life Short Short Short Medium Long Long Mineralocort. Ekv. dse Activity + 20 mg + 5 mg 4 mg 4 mg 0.75 mg 0.6 mg

Colchicine
Alkaloid of the Colchicum species Antiinflammatory effects mediated by ability to inhibit microtubule and PMN activity PK: mean terminal life: 9hrs (IV 19 min 16 hours). Tightly binds microtubules (PMNs). Concentrates liver, spleen & intestine. Excreted in urine and bile. Undergoes enterohepatic recirculation Undergoes demethylation by CYP 3A4 (interacts with cimetadine, terfenidine, EES, ketoconazole, diltiazem, nifedipine, cyclosporine, statins May cross placent. + found in breast milk Off label indications: gout, pseudogout, amyloidosis, familial mediterranean fever, hepatic cirrhosis, dermatitis herpetiformis, Behcets, Sweets syndrome Biologic effects: Binds tubules, inhibits cell migration, adherence, degranulation. Inhibits IL-8, ICAM, E-selectin, L-Selectin., IL-1. Also decreases insulin, thyroid, TSH, amylase, catecholamine synthesis, lysosomal hydrolase release, fibroblast proliferation

Colchicine Advantages
Long history of use (acute and chronic Rxs) Diagnositic specificity (96%); Sensitivity (70%) Faster onset 6-12 hours (IV)
Corticosteroids 12-24 hrs; NSAIDs: 24-48 hours

Tx surgical (NPO) patients, NSAID intolerant/contraindic. Cost ! Yu T. 20 yrs retrospective study 540 pts (518M)
Results: Excellent 82%, Satisfactory 12%, Poor 5% Few were intolerant No cases of renal or hematologic toxicty w/ chronic use Semin Arthritis Rheum 12:256-64, 1982

Colchicine Dosing
PO: 1.2 mg initially then 0.6 mg q 1-2 hours till GI Sx and/or better (max 6 mg)
Ahern et al. Placebo controlled trial shows colchicine 64% respond within 48 hrs (23% placebo same). Significant differences 18-36 hrs. Colchicine diarrhea developed @ median 24 hours (mean 6.7 mg) GI toxicity in 80% of pts w/in 48 hrs. Toxicity before improvement. Acute use reserved for when NSAIDs/Steroids contraindicated

When to use IV Colchicine? If rapid response, oral use precluded, NSAIDs or steroids contraindicated
Problem is that there is no warning GI symptoms (as with PO). Toxicity depends on total dose over time, size of single dose Rec: 1) 2 mg initially, followed by 1 mg IV q 6 (max 4-5 mg); 2) 2 mg as single IV dose; or 3) 3 mg IV as single IV dose Death: 2% reported by Roberts et al.
20 deaths by Bonnel et al from ODS/FDA

Colchicine Intoxication
Stage 1 (<24h) Stage 1 (<24h) Stage II (24-72h) Stage II (24-72h) Recovery Recovery

*Ben-Chetrit E, Levy M. Sem AR 28:48,1998

Colchicine:Guidelines for Use

IV colchicine should be severely restricted if not banned Removed from licenced clinical use in Great Britain Removed from hospital formulary in many Hospitals Single IV dose < 2-3 mg and cumulative doses < 4-5 mg/7days Give via established intravenous catheter Following IV use, no PO colchicine for at least 7days Give REDUCED (<50%) doses in CRI, liver disease, elderly, prior PO colchicine therapy Lower Doses in elderly (2gm max) and pts w/ renal failure Contraindicated: pregnancy, combined renal and hepatic disease, Creat Clearance <10cc/min, extrahepatic biliary obstruction

Prophylactic therapy
Allopurinol Xanthine oxidase inhibitor Indications
Renal insufficiency Nephrolithiasis Tophi Tumor lysis syndrome Primary metabolic defects

Allopurinol
Effectively reduces serum uric acid (SUA) at doses 300 800 mg daily Active metabolite is oxypurinol
Allopurinol T < 2 hr. Oxypurinol T : 13 - 29 hr.

Limited data on allopurinol/oxypurinol

comparison

Side effect (<2%)

Potentiating imuran marrow suppressive effect Hypersensitivity syndrome Hepatitis Interstitial nephritis

PK Study AAI-US-175
Open-label, dose linearity, fasted/fed, bioequivalence study (N=42) Relative bioavailability of single dose of oxypurinol is about 30% of allopurinol
Oxy (mg) Oxy (mg) 100 100 300 300 600 600 800 800

No data on multiple-dose conversion

Allopurinol Safety
Hypersensitivity reactions (2-4%)
Skin (mild to severe; fatal) Fever, hepatitis, nephritis, hematologic AHS (allopurinol hypersensitivity syndrome) Mechanism: type IV ?

Non-immunologic toxicity
renal, liver animal toxicity: renal, liver, cardiac

Unclear whether hypersensitivity related to allopurinol, oxypurinol or other metabolite

Prophylactic therapy
Uricosuric agents
Probenecid Sulphinpyrazone Benzbromarone

Mechanism
Inhibit renal tubular reabsorption

Prophylactic therapy
Uricosuric agents Side effects
Uric acid crystalluria GI disturbance Allergy Hepatic impairment

Contraindications
Renal insufficiency nephrolithiasis

Uricosuric Therapy:
Creatinine Clearence: <80 mL Probenecid (500mg)
Decreases renal reabsorption of Urate.

Sulfinpyrazone (100mg)
Greater effect than probenecid

*Aspirin antagonizes the effect of both drugs

Probenecid

Prophylactic therapy
When instituting uricosuric therapy
Concurrent colchicine prophylaxis Initial low dose, increase dose gradually Maintain alkaline diuresis Not use in urine volume less than 1400ml/24 hours

Drug-Induced gouty pain

Diuretic
Thiazid

Ethambutol Pyrazinamid Niacin Salicylates Cyclosporin Levodopa NUTRITIONAL FACTORS

Tea Coffee Cocoa Chocolate High purine foods

Gout Quotes
King of diseases and the disease of kings
Hippocrates 450 BC

Love and gout are incurable

1623 Meridia