Pharmacology for the Athletic TrainerOver The Counter Medications (OTCs)

NSAIDs

David S. Knitter, MD, FCCP

February 7, 2000

In 1997, the Nonprescription Drug Manufacturers Association (NDMA) published the report of a study conducted by Kline & Co. and subtitled "Economic Benefits of Self-Medication."

“The economic analysis resulted in an estimate that OTC availability for the categories studied resulted in savings to the consumer of $20.6 billion annually when compared with the costs of treating the ailments using physicians and prescription medications. The researchers estimated that nearly two-thirds of the calculated savings could be traced to Rx-to-OTC switched products.”

Because nonprescription products may be used without any medical advice, making patients aware of time limits can be critical in ensuring their safety.

Time Limits on OTC Use

• Sustained use of nonprescription products could mask a serious underlying condition that should be diagnosed.

• If there is no noticeable response by that time, the risk of an adverse reaction outweighs any possible benefit to further use.

• Prevent patients from using them as alternatives to healthier interventions

• The problem should have resolved if the product was used properly and the patient actually had the problem for which the product was indicated.

• Some products may result in addiction if overused

Time Limits on OTC Use

Time Limits for OTC Usage

Medication Category Limit on UseDiarrhea 48 hours

Eye Drops 3 daysSteroid Creams 7 days

Constipation 7 daysHemorrhoid 7 days

Gingival analgesics 7 daysSore throat products 7 days

Headache 10 daysSleep Aids 14 days

Antifungal Creams 14 daysNicoteine Replacement 12 weeks

Diet Aids 3 monthsRogaine 4 - 12 months

• the condition they treat is not easily confused with any other;

• the condition requires lifelong therapy;

• the medications used to treat the condition are fairly safe;

• the medication prevents a problem.

No Time Limits of OTC Use

Examples

• fluorides for dental care,

• antihistamines for motion sickness or allergic rhinitis,

• simethicone for intestinal gas,

• sunscreens to prevent sunburn,

• acne medications

Rise In OTC Sales

Category 1996 ($ inmillions)

2001 ($ inmillions)

% averageannual growth

rateAnalgesics 935.1 1,262.6 7.5

Antifungal(vaginal)

233.0 253.7 14.7

Smokingcessation

53.0 410.0 51.0

ProductPercent of sales dollars of top

21 OTC products

Advil 9.0%

Aleve 4.0

Motrin IB 3.0

NSAID ClassesAcetylated Salicylic

acidNon-AcetylatedSalicylic acid

Acetic acidderivatives

Aspirin DifunisalCholine salicylate

Choline-magnesiumtrisalicylate

Sodium salicylateSalsalate

Magnesium salicylate

IndomethacinSulindacToletin

EtodolacDiclofenac

Propionic Acids Fenamic acids Enolic acids

FenoprofenFlurbiprofenIbuprofen

KetoprofenNaproxenOxaprozin

Meclofenamate Piroxicam

Phenylbutazone

Current OTC NSAIDs• Aspirin

• 325mg not to exceed 4 grams in 24 hours

• Ibuprofen• 200mg not to exceed 1200 mg in 24 hours

– Advil– Nuprin– Mortin AB

• Naprosyn• 200mg not to exceed 600mg in 24 hours

– Aleve

• Ketoprofen• 12.5mg not to exceed 75mg in 24 hours

– Orudis KT

Prostaglandin (PG) Synthesis

• Prostaglandins have been implicated in pathogenesis of inflammation and fever

• Aspirin-like drugs inhibit the biosynthesis and release of PGs

• Inhibition of the synthesizing enzyme (cyclo-oxygenase) is fairly well correlated with anti-inflammatory action Inhibition of COX2 (inducible) may be responsible

for therapeutic effects of NSAIDs Inhibition of COX1 (constituitive) may be responsible

for many adverse effects of NSAIDs

Pain• Direct administration of PGs causes local pain

evidence suggests that PGs (PGE2?)sensitizes pain receptors to bradykinin, a local mediator of pain released during inflammation

• Aspirin is less effective against sharp pain (direct stimulation of nerve endings - no PGs, opioids more effective) than against the dull, throbbing pain of inflammation (involves PGs)

Prostaglandin (PG) Synthesis

Fever • Infection bacterial endotoxins cause release of

endogenous pyrogens from neutrophils

• Tissue damage or inflammation interleukin 1 released by macrophages (principal role is to activate lymphocytes) affects hypothalamus

• Aspirin-like drugs work by increasing heat loss (vasodilatation of peripheral blood vessels) not by reducing heat production

Prostaglandin (PG) Synthesis

Inflammation

• Signs of inflammation - erythema, edema, tenderness and pain

• Damage to microvasculature - leakage of blood components

• Infiltration of leukocytes

• Release of chemical mediators including PGs

• Aspirin-like drugs relieve symptoms not pathology

Prostaglandin (PG) Synthesis

• Diclofenac potassium and sodium

• Diflunisal

• Etodolac

• Naproxen sodium (controlled-release)

• Piroxicam

• Sulindac

• Tolmetin

Possible Future Switches of NSAIDS

Adverse Effects

• Gastrointestinal Effects nausea and vomiting stimulation of CTZ in medulla

gastric bleeding 3-8 ml/day blood loss with 4-5 g aspirin/day vs 0.6 ml in untreated subjects

• Blood Clotting aspirin irreversibly inhibits platelet synthesis of thromboxane A2 (TXA2)

which is required for aggregation

other NSAIDs - reversible effect on clotting

non-acetylated salicylates - no effect on clotting

terminate chronic use of aspirin 1 week prior to elective surgery (most other NSAIDs 24-48 hr)

Adverse Effects

• Salicylism

characterized by tinnitus (may be related to increased labyrinthine pressure or effect on cochlear hair cells, pehaps secondary to vasoconstriction of auditory microvasculature), headache, nausea and vomiting, dizziness and dimness of vision

• Aspirin Hypersensitivity or ”Aspirin Intolerance"

1/4 million in USA

symptoms include rhinitis, profuse watery secretions, bronchial asthma, bronchconstriction, hypotension, vasomotor collapse, coma

non-acetylated salicylates may be used cautiously

Adverse Effects

• Reye's syndrome

rare but often fatal consequence of infection with varicella and various other viruses

salicylates are contraindicated in children and adolescents with chicken pox or influenza

Acetaminophen

• Little or no anti-inflammatory activity

• Mechanism of action is unknown Very weak inhibitor of cyclo-oxygenase

Greater effect in the CNS ??

• Minimal gastrointestinal irritation

• No effect on bleeding time

Acetaminophen Toxicity

• Hepatic necrosis (acute - 10-15 g; >25 g usually fatal)

• Increased incidence of hepatotoxicity in the presence of ethanol and/or fasting (with as little as 4 g/day)

• Ethanol induces hepatic MFO metabolism (pathway 3) shifting reaction toward toxic metabolite (limited glutathione available)

Renal Tubular Necrosis

• Increased risk with lifetime intake • Associated greater than 1000 tablets of acetaminophen • Associated greater than 5000 tablets of NSAIDs • ? effect of aspirin