Drugs,

musculoskeletal
and joint diseases

MUSCULOSKELETAL EMERGENCIES
MUSCULOSKELETAL
DISORDERS

CLINICAL
MANIFESTATIONS

TRAUMA

PAIN
PAIN

INFECTION

TENDERNESS

NEOPLASTIC DIS.

EDEMA

RHEUMATIC DIS., etc

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

allopurinol

Xanthine
oxidase

xanthine
Uric acid

Urinary
excretion

Alimentary
excretion

Tissue deposition
in excess
Urate crystal

uricosurics

colchicine

Phagocytosis
with acute
inflammation and
arthritis

microtophi

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.

AVOID Uricosuric drugs:

Probenecid, Benzbromarone, Sulfinpyrazone

Duration of Therapy: 7-30 days

PotentiaL adjunctive agents:

losartan (24%)
Fenofibrate lowers Urate 19%, increases excretion 36%

MEDICATIONS for GOUT

Drug

MOA

Dosing

Purpose

NSAIDS
(indomethacin,
phenylbutazon,
coxibs)

anti-cox-2
anti-prostaglandins
(in bone, pmns, macrophages)

taper dose 2-8 days

12-24 hrs response

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

CORTICOSTEROIDS
ineffective
(glucocorticoids,
prednisone)

anti-T cl prolif
anti-IL-1,2,6, INF-a/g
anti-PAF, LTN, PGs

give dose to response

when NSAIDS

then taper

rapid dramatic relief

ANTI-GOUT anti-mitotic agent (pmns, macro)

(colchicine)
anti-tubulin polymerization of attack
anti-leukocyte migration
blocks lipoxygenase

w/in 1st 12-24hrs

prophylaxis
suppress symptoms
decreases pain of gouty arthritis
*gi toxicity, bm supress, skin irrit

ALLOPURINOL

anti-xanthine oxidase
decreases synthesis of uric acid
decreases purine synthesis

adj dose for hepat &

renal pts
no use w/uricosurics

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

relief 6-12 hrs

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

Acute Gout Management

Drug

Dose

Common AE

SAE

NSAIDs

Indocin* 150 mg/d

taper 5-7d

GI toxicity, CNS,
HTN, LFTs

PUD, renal dz,

bleeding, allerrxn

COX-2
inhibitors

Per PDR qd or bid

?less GI toxicity?
RenalHTN,edem

PUD, renal, MI,

CVA

Colchicine

1.2 mg po then 0.6 Diarrhea, N/V,

q1-2h (not to
abdominal pains
exceed 8mg)

Neuromyopathy,
ARF, BM
suppression

Corticosteroids

IA Methylpred 1040 mg.

PO:30-60 qd

Risk of infection
osteoporosis

Drug

Dose

HTN, BS, fluid

retention,
insomnia

Common AE

* or equivalent anti-inflammatory dose

SAE

NSAIDs Contraindicated?

NSAIDs
Antiinflamatory
doses

no

Renal insufficiency
Peptic ulcer disease
Congestive heart failure
NSAID intolerance

yes
Are Corticosteroids
Contraindicated?

Treatment
Acute Gout

no
Corticosteroids

yes
1

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):49S-85S, 1997

# Joints
Involved?

>1
Oral or
Intra-articular
Steroid

TOXICITY OF NSAIDs
Ototoxic

Bronchospam

Hepatotoxic

Bleeding

Allergy

Color blindness

CHF

UGIB
UGIB
Nephrotoxic

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
40IU
IM
once
ACTH
ACTH
40-80IU
IM,IV, q8hsubcute q12hqdx3Ds
Intra-articular steroids

Corticosteroids in practice
Product

Half life

Mineralocort. Ekv. dse

Activity
+
20 mg

Cortisol

Short

Prednisone

Short

5 mg

Methylpredn.

Short

4 mg

Triamcinolone

Medium

4 mg

Dexamethasone

Long

0.75 mg

Betamethasone

Long

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 II (24-72h)

Recovery

Stage 1 (<24h)

Stage II (24-72h)

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)

100

300

600

800

Oxy (mg)

100

300

600

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