CENTRAL UNIVERSITY OF ECUADOR FACULTY OF MEDICAL SCIENCES MEDICAL CAREER FARMACOLOGY NSAIDs

Dysmenorrhea

 Patient is a 21 years old female who complains of a dull cramping with her menses each month. Her symptoms have occurred since she began her period at age 13; however, they have been progressively getting worse since age 16.

 Her menses typically lasts five days and comes regularly at 28 day intervals. She has pelvic pain throughout her menses. Every three to four months, she will miss a day of work due to the severe cramping pain.

 She notes that several days prior to her period, she has a feeling of fullness in her lower abdomen and is achy uncomfortable.

 Past Medical History: Obesity Past Surgical History: Right knee arthroscopy , extraction of wisdom teeth, Social History: Pt admits to smoking marijuana from the age of 16-18, denies illicit drug use since. Pt denies tobacco use and rare alcohol use. Pt does not exercise. Pt describes her physical activity as limited to a rare leisurely walk with her friends after work

 Family History: Mother deceased age 54, ovarian cancer; Father, 65, diabetes, obesity, venous stasis; paternal grandparents unknown; maternal grandparents, living, Grandmother breast cancer survivor, otherwise in good health; Grandfather, glaucoma, hypertension

 Physical Exam: Vital signs: Ht: 1.60 m Wt. 78 kg, BMI 30.4, HR 70, BP 135/85, RR 18 General: 21 years old Caucasian female. Good hygiene, cooperative, and pleasant demeanor. Body habitus is overweight

Head - Normal cephalic, atraumatic.No lacerations, bruises, or other discoloration;

Eyes - red reflex intact, 2 cotton wool spots noted on the right retina in the right upper quadrant, no papilledema, Ears - , tympanic membranes intact without erythema or fluid; Nose/Throat - has mild septal deviation to the left, mucosa is moist and pink, good oral hygiene, no erythema, post nasal drip, or sores present in the throat

 Cardio/Pulm: heart rate and rhythm regular without murmurs, gallops, clicks, Abd: abdomen obese, non-tender, although pain near the iliac fossa, no masses palpated, bowel sounds present X 4 quadrants, no masses or polyps palpated on rectal exam, Hemoccult negative

Definition
Abdominal or pelvic pain during menstruation. Can start up to 48 hours before it Usually persists for 48-72 hours.
26 27 28 1 2 3 4 5

Flujo menstrual Dolor

Types of dysmenorrhea
Primary. No identifiable anatomical cause. Spasmodic. Secondary. Associated with an identifiable pathology. Failure.

Primary Dysmenorrhea Acute pain or spasmodic Appear 24 to 48 hours before menstruation and continued until two days after

Secondary Dysmenorrhea Continuing pain and heavy It usually occurs a week before menses and persists throughout the cycle

Frequent in women aged 17 to 25 years

Consult a doctor

Women over age 30 years

Symptom of underlying disease

Pimary dysmenorrhea.
90% of all cases. Starts 6-24 months after menarche. More common in children under 20 years. Up to 50% of adolescents have had it.

Pathophysiology
Increase in endometrial prostaglandin production.
Mainly PGF2 y PGE2.

Thromboxanes increased. Leukotrienes increase. Increased circulating vasopressin.

Prostaglandins Effects
Uterine motility changes.

Local vascular changes Neurosensory changes.

Uterine motility changes

Increased frequency of uterine contractions. Uterine peristalsis arrhythmia. Increased uterine tone at rest (> 10 mmHg). Increasing the strength of uterine contraction (> 120 mmHg).

 Altered uterine vasculature. Vasoconstriction. Decreased myometrial pressure flow. Increased local consumption.

Uterine ischemia (angina uterine). Altered sensitivity. Hypersensitivity nociceptive fibers, products of cell death.

LH

LH

induction COX2 Increases PGs

LH LH progesterona

supression COX2 Dicreases PGs Increases PGDH

COX2 aumento PGs Decreases PGDH = apoptosis = increases K+ y H+ libre

ADH

PGs TBXs

ADH contraction

PGs TBXs

contraction

contraction

ADH

PGs TBXs

isquemia

ADH

pain

PGs TBXs

pain

pain

isquemia

ADH

PGs TBXs

PGs LTs K+ H+

isquemia

ADH

pain

PGs TBXs pain

pain

PGs LTs

isquemia

Classic clinically
Colicky pain, pelvic or lower abdominal. Sign few hours before or at the onset of menstruation. Radiating to the back and external genitalia. General symptoms. Asthenia and adynamia. Headache.

Diagnosis
The primary objectives are: Identify dysmenorrhea. Differentiate between primary and secondary. The clinical history is critical in the diagnosis of dysmenorrhea. Usually both diagnostic purposes can be achieved with the clinical history.

INFLAMMATORY REACTION

THE INFLAMMATION IS THE RESPONSE OF LIVING TISSUES TO INJURY

ENZYME ACTIVATION

RELEASE OF CHEMICAL MEDIATORS

EXTRAVASATION OF FLUID

MIGRATION DAMAGE CELL

TISSUE REPAIR

What is NSAIDS?
It is a group of anti-inflammatory nonsteroidal that share therapeutic actions and adverse effects. Its effects are similar to those produced by the steroids but without its adverse effects. Their main effects are:
Anti-inflammatory. Analgesic. Antipyretic.

The search is substances that will relieve the pain and lower fever is as old as the man. The history of the Ecuadorian medicine tells us that was in Malacatos, province of Loja the site where it has spread the use of cinchona bark as "febrifuge"

Still the pain, fever, inflammation conditions present in a number of pathological tables is not surprising that NSAIDS are the medications most prescription and consumption, and most were sold freely in pharmacies and other stores.

CYCLE-OXIGENASAS
Inducible, COX-1: constitutive, COX-2: associated with protector of the inflammatory gastric mucosa, processes. It occurs in regulating renal macrophages, function, among monocytes, endothelial others. Its inhibition cells that generate PGs and mediate pain is associated with perception and the damage to the inflammation. gastric mucosa due to the lack of the Their inhibition has an anti-inflammatory "barrier of the effect. It is also gastric mucosa". constitutive in some

territories, such as the

MECHANISM OF ACTION OF NSAIDS

ACT BY INHIBITING THE SYNTHESIS OF PROSTAGLANDINS

PHYSIOLOGICAL
Stimulate inflammatory response

NSAIDS
Inhibit inflammatory response

ANTI-INFLAMMATORY EFFECT

ANALGESIC EFFECT

Stimulates terminations painful

Inhibit terminations painful

ANTIPYRETIC EFFECT

Stimulates the increase of the temperature

Reduces body temperature increased

CLASSIFICATION According to chemical structure:

1.- Salicylates: Acetylsalicylic Acid 2.- Pyrazolone and analogues: Phenylbutazone

3.- Derived Indolaceticos: indomethacin

4.- Derived Arilaceticos: Diclofenac

5.- Aryl Derivatives: Ibuprofen Ketoprofen

6.- Oxicams: Piroxicam

7.- Fenamatos: mefenamic acid

8.- Aminonicotinicos: Flunixin Meglumine.

According to inhibition of the cycle-oxigenasas

1.- Non-selective COX-1/ COX-2: Ibuprofen

2 .- Selective COX-1: indomethacin

3.- Selective COX-2: Meloxicam

EFFECTS
ANALGESIC ACTION
Refers to the inhibition of prostaglandin synthesis to central and peripheral level. At the peripheral level prevents the awareness of nociceptors by reducing the perception of pain and at the central level, stimulating the secretion is endogenous neurotransmitters that inhibit the pain. Also would the reduction of inflammation.

EFFECTS
ANTIPYRETIC ACTION
Corresponds to a consequence of inhibition of prostaglandin synthesis at the central level. Reduces the release of PGE2 to level hypothalamic and reduces body temperature when it is increased .

EFFECTS
ANTIINFLAMMATORY ACTION
Its action is based not only on the inhibition of prostaglandins (important mediators in the inflammatory process ) but who are also responsible for interfering with the signals that trigger the inflammatory cells.

EFFECTS
ACTION

ANTIDYSMENORRHEA
By inhibiting prostaglandins, reduce pain and other symptoms of dysmenorrhea. Decreases the uterine contractility and pressure by inhibiting both the ischemic pain and spasmodic. Also acts to reduce headaches, nausea and vomiting.

Gastrointestinal Disorders
Is frequently nausea, vomiting, abdominal pain , heartburn, constipation among others.

Kidney Failure
It decreases the renal blood flow and glomerular filtration , occurs retention of Na+, K+ and H2O. Increased blood pressure Skin reactions: Urticaria, rash

CONTRAINDICATION
Do not use in patients with hypersensitivity to the drug. Patients with gastrointestinal disorders Patients with concomitant chronic diseases, such as liver, kidney, heart .

TREATMENT
therapeutic objective is reduction of pain

NSAIDs
Simple analgesics are best used as self-treatment of adolescents:

Paracetamol Aspirin Ibuprofen Naproxen

A systematic review of 73 randomized controlled trials concluded that NSAIDs were superior to placebo for the treatment of primary dysmenorrhea pain and reduced the number of days absent from school and work.

Many NSAIDs have been studied for this purpose but there is no literature to indicate the efficacy of either agent to one another.

The choice NSAID is best guided by cost and availability.

Included studies
Included comparisons eligible for the review were as follows: NSAID versus placebo: 41 trials NSAID versus NSAID: 14 trials Two NSAIDs versus placebo: 15 trials Nineteen different types of COX-1NSAIDs Aspirin Naproxen Piroxicam Diclofenac Fenoprofe n Ibuprofen Indometh acin Ketoprofe n Naproxen Nimesulid e Piroxicam.

NSAID versus paracetamol: one trial NSAID versus paracetamol and placebo: two
trials

Only two types of COX-2 NSAIDS were evaluated Etoricoxib Meloxicam

Doses of NSAIDs
COX-1NSAIDs
Aceclofenac (100 mg daily) Aspirin (650 mg; 4 hrly) Dexketoprofen (12.5 to 25 mg; six hourly) Diclofenac (up to 200 mg daily Etodolac (200 to 300 mg twice daily) Fenoprofen(100 to 200 mg; 4 hourly) Fentiazac (100 mg; twice daily) Flufenamic acid (200 mg; eight hourly) Flurbiprofen (100 mg; twice daily) Ibuprofen (400 mg; three, four or six times daily) Indomethacin (25 mg tablets or 100mg suppositories; three times daily) Ketoprofen (25- 50 mg; six hourly, with or without a loading dose of 25-70 mg) Lysine clonixinate (125 mg; six hourly) Meclofenamate sodium (100 mg; 8 hourly) Mefenamic acid (250 mg; 8 hrly) Naproxen/ naproxen sodium (250-275 mg; four to eight hourly, sometimes with a loading dose of 500-550 mg) Niflumic acid (250 mg; three times daily) Nimesulide (50 to100 mg twice daily) Piroxicam (20-40 mg daily, by tablet or suppository) Tolfenamic acid (200 mg; eight hourly).

Doses of COX-2 inhibitors used :

Etoricoxib (120 mg), Meloxicam (7.5 to15mg), both daily

EFFECTS OF PAIN RELIEF INTERVENTIONS

1) NSAIDS VERSUS PLACEBO.

There were 41 trials

The studies analysed a total of 2121 women, 1631 in crossover trials and 490 women in parallel trials. The most precise finding was for naproxen (OR 3.67, 95% CI: 2.94 to 4.58; 16 studies, I2=52%).

NSAIDs were significantly more effective than placebo at producing moderate or excellent pain relief (OR 4.50, 95% CI: 3.85-5.27; I2=53%).

1) NSAIDS VERSUS PLACEBO.

Compared with placebo diclofenac reduced pain by 65% (MD 65.96, 95% CI: 55.7076.22, two studies)

Meloxicam by 34% (MD 34, 95% CI: 15.88-52.12, one study.

The other 8 studies compared 7 different NSAIDs versus placebo, using 5 different pain scales.

In all cases NSAIDs were significantly more effective than placebo in producing moderate/excellent pain relief and/or in reducing pain scores

with the exception of aspirin (for which there was only one relevant study)

They compared the following NSAIDs versus placebo: aspirin, diclofenac, fenoprofen, ibuprofen, indomethacin, naproxen, nimesulide, piroxicam. All NSAIDs were significantly more effective than placebo Aspirin which was not found to be not significantly different to placebo

EFFECTS OF INTERVENTIONS

2) NSAIDS VERSUS NSAIDs

There were fifteen, none of which compared the same two NSAIDs. They made the following comparisons: Aspirin vs fenoprofen Diclofenac vs - Meloxicam - Ibuprofen -Nimesulide Ibuprofen vs - Piroxicam - Lysine clonixinate Mefenamic acid vs Meloxicam Tolfenamic acid Naproxen vs - Diclofenac - Ketoprofen - Etoricoxib - Flurbiprofen - Ibuprofen - Piroxicam

2) NSAIDS VERSUS NSAIDS

Diclofenac reduced pain on a VAS 100 point scale significantly more than meloxicam

One found indomethacin significantly more effective than aspirin and one found no statistically significant difference between naproxen and diflusinal

Fenoprofen reduced pain intensity significantly more than aspirin

Other head-to-head comparisons between NSAIDs showed no statistically significant difference between them.

Naproxen reduced pain scores significantly more than Ibuprofen and was significantly more likely to achieve effective pain relief than ketoprofen

3) NSAIDS VERSUS PARACETAMOL

Ibuprofen vs paracetamol (2 studies ) Naproxen vs paracetamol (1 studio )

Resulted in a statistically significant difference in the proportion of women reporting good, excellent or complete pain relief, favouring NSAIDs over paracetamol (OR 1.89, 95% CI: 1.05-3.43).

DISCUSSION
Overwhelming evidence of the efficacy of NSAIDs in relieving the pain of dysmenorrhea

The review was unable to determine what is most effective NSAIDs for dysmenorrhea or whether individual NSAIDs have a similarly eficacioa.

Also it was found that the pain relief efficacy of NSAIDs is superior to paracetamol.

Tolerability and Safety of NSAIDs

More adverse effects than placebo:
Headache Dizziness Dryness Sleepiness Gastrointestinal Effects

Indomethacin
Neurological side effects

Meloxicam
Less effective in relieving pain than diclofenac

Dexketoprofen
Gastrointestinal side effects

Etoricoxib
No different from the effectiveness of naproxen

Naproxen
More likely to cause the two

Among NSAIDs no significant difference was found between adverse

NSAIDs are a very effective treatment for dysmenorrhea, but q women using them need to be aware of the side effects they entail.