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CENTRAL UNIVERSITY OF ECUADOR
FACULTY OF MEDICAL SCIENCES
MEDICAL CAREER
FARMACOLOGY
NSAIDs
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Dysmenorrhea
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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.
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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 missa day of work due to the
severe cramping pain.
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She notes that several days prior to her
period, she has a feeling of fullness in her
lower abdomen and is achy uncomfortable.
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Past Medical History:Obesity
Past Surgical History:Right knee arthroscopy , extraction of wisdomteeth,
Social History:Pt admits to smoking marijuana from the ageof 16-18, denies illicit drug use since. Pt deniestobacco use and rare alcohol use. Pt does not
exercise. Pt describes her physical activity aslimited to a rare leisurely walk with her friendsafter work
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Family History: Mother deceased age 54,
ovarian cancer; Father, 65, diabetes, obesity,
venous stasis; paternal grandparentsunknown; maternal grandparents, living,
Grandmother breast cancer survivor,
otherwise in good health; Grandfather,glaucoma, hypertension
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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, andpleasant demeanor. Body habitus is overweight
Head - Normal cephalic, atraumatic.No lacerations, bruises, orother discoloration;
Eyes - red reflex intact, 2 cotton wool spots noted on the rightretina 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 moistand pink, good oral hygiene, no erythema, post nasal drip, or sorespresent in the throat
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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
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Definition
Abdominal or pelvic pain during
menstruation.
Can start up to 48 hours before it
Usually persists for 48-72 hours.
1 2 3 4 5282726
Flujo menstrual
Dolor
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Types of dysmenorrhea
Primary.
No identifiable anatomical cause.
Spasmodic.
Secondary.
Associated with an identifiable pathology.Failure.
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Primary Dysmenorrhea Secondary Dysmenorrhea
Acute pain or spasmodic Continuing pain and heavy
Appear 24 to 48 hours beforemenstruation and continued until two
days after
It usually occurs a week before mensesand persists throughout the cycle
Frequent in women aged 17 to 25 years Women over age 30 years
Consult a doctor Symptom of underlying disease
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Pimary dysmenorrhea.
90% of all cases.
Starts 6-24 monthsafter menarche.
More common inchildren under 20years.
Up to 50% ofadolescents have hadit.
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Pathophysiology
Increase in endometrial prostaglandin
production.
Mainly PGF2 y PGE2.
Thromboxanes increased.
Leukotrienes increase.
Increased circulating vasopressin.
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Prostaglandins Effects
Uterine motility changes.
Local vascular changes
Neurosensory changes.
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Uterine motility changes
Increased frequency ofuterine contractions.
Uterine peristalsisarrhythmia.
Increased uterine tone at rest(> 10 mmHg).
Increasing the strength ofuterine contraction (> 120mmHg).
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Altered uterine vasculature.
Vasoconstriction.
Decreased myometrial pressure flow.
Increased local consumption.
Uterine ischemia (angina uterine).
Altered sensitivity.
Hypersensitivity nociceptive fibers, productsof cell death.
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LH
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LH
induction COX2
Increases PGs
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progesterona
LH
LH
supression COX2
Dicreases PGs
Increases PGDH
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COX2
aumento PGs
Decreases PGDH
= apoptosis
= increases K+ y H+ libre
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PGs
TBXs
ADH
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contraction
PGs
TBXs
contraction
contraction
ADH
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PGs
TBXs
isquemia
ADH
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PGs
TBXs
painpain
pain
isquemia
ADH
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PGs
TBXs
isquemiaPGs
LTs
K+
H+
ADH
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PGs
TBXs
isquemiaPGs
LTs
painpain
pain
ADH
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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.
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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.
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INFLAMMATORY
REACTION
ENZYMEACTIVATION
RELEASE OFCHEMICALMEDIATORS
EXTRAVASATION OFFLUID
MIGRATIONDAMAGE CELL
TISSUE REPAIR
THE INFLAMMATIONIS THE RESPONSE OF
LIVING TISSUES TOINJURY
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It is a group of anti-inflammatory non-
steroidal that share therapeutic actions and
adverse effects. Its effects are similar to
those produced by the steroids but withoutits adverse effects.
Their main effects are:
Anti-inflammatory.
Analgesic.
Antipyretic.
What is NSAIDS?
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The search issubstances that willrelieve the pain and
lower fever is as old asthe man. The history of
the Ecuadorianmedicine tells us that
was in Malacatos,province of Loja the
site where it hasspread the use ofcinchona bark as
"febrifuge"
Still the pain, fever,inflammation
conditions present in a
number ofpathological tables is
not surprising thatNSAIDS are the
medications mostprescription and
consumption, andmost were sold freelyin pharmacies and
other stores.
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COX-1: constitutive,protector of thegastric mucosa,regulating renal
function, amongothers. Its inhibitionis associated withdamage to the
gastric mucosa dueto the lack of the"barrier of thegastric mucosa".
COX-2: Inducible,associated withinflammatoryprocesses. It occurs in
macrophages,monocytes, endothelialcells that generate PGsand mediate painperception and the
inflammation. Their inhibition has an
anti-inflammatoryeffect. It is alsoconstitutive in some
territories, such as the
CYCLE-OXIGENASAS
MECHANISM OF ACTION OF NSAIDS
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MECHANISM OF ACTION OF NSAIDS
ACT BY INHIBITING THE SYNTHESIS OF PROSTAGLANDINS
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PHYSIOLOGICAL NSAIDS
Stimulate inflammatory
response
Inhibit inflammatory
response
Stimulates terminations
painfulInhibit terminations
painful
Stimulates the increase of
the temperature
Reduces body
temperature increased
ANTI-INFLAMMATORY EFFECT
ANALGESIC EFFECT
ANTIPYRETIC EFFECT
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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.
CLASSIFICATION
According to chemical structure:
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1.- Non-selective COX-1/ COX-2: Ibuprofen
2 .- Selective COX-1: indomethacin
3.- Selective COX-2: Meloxicam
According to inhibition of the
cycle-oxigenasas
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ANALGESIC
ACTIONRefers 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 endogenousneurotransmitters that inhibit the
pain. Also would the reduction of
inflammation.
EFFECTS
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ANTIPYRETIC
ACTIONCorresponds 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 isincreased .
EFFECTS
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ANTI-
INFLAMMATORY
ACTIONIts action is based not only onthe 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
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ACTION
ANTIDYSMENORRHEA
By inhibiting prostaglandins, reducepain 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.
EFFECTS
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Is frequently
nausea,
vomiting,
abdominalpain ,
heartburn,
constipationamong others.
Gastrointestinal Disorders
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It decreases the
renal blood flow
and glomerular
filtration , occurs
retention of Na+,K+ and H2O.
Increased blood
pressure
Skin reactions:Urticaria, rash
Kidney Failure
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Do not use in patients with hypersensitivity
to the drug.
Patients with gastrointestinal disorders
Patients with concomitant chronicdiseases, such as liver, kidney, heart .
CONTRAINDICATION
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TREATMENTtherapeutic objective is reduction of
pain
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NSAIDs
Simple analgesics are best used asself-treatment of adolescents:
Paracetamol
Aspirin
IbuprofenNaproxen
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A systematic review of 73randomized controlled trialsconcluded that NSAIDs weresuperior to placebo for the
treatment of primarydysmenorrhea pain and
reduced the number of daysabsent from school and
work.
Many NSAIDs have beenstudied for this purpose but
there is no literature toindicate the efficacy of
either agent to one another.
The choice NSAID is bestguided by cost and
availability.
Included studies
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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 NSAID versus paracetamol: one trial NSAID versus paracetamol and placebo: two
trials
Nineteen different types of
COX-1NSAIDs
Aspirin
Naproxen
Piroxicam
Diclofenac
Fenoprofe
n Ibuprofen
Indometh
acin
Ketoprofe
n
Naproxen
Nimesulid
e Piroxicam.
Only two types of COX-2
NSAIDS were evaluated
Etoricoxib Meloxicam
D f NSAID
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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)
Etoricoxib (120 mg), Meloxicam (7.5 to15mg),
both 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 :
COX-1NSAIDs
Doses of NSAIDs
EFFECTS OF
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INTERVENTIONSPAIN RELIEF
1) NSAIDS VERSUS PLACEBO.
There were 41
trials
The studies analysed a totalof 2121 women, 1631 incrossover trials and 490women in parallel trials.
NSAIDs were significantlymore effective than placebo
at producing moderate orexcellent pain relief (OR4.50, 95% CI: 3.85-5.27;
I2=53%).
The most precise findingwas for naproxen (OR 3.67,
95% CI: 2.94 to 4.58; 16studies, I2=52%).
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Compared withplacebo diclofenac
reduced pain by65% (MD 65.96,95% CI: 55.70-
76.22, two studies)
Meloxicam by 34%(MD 34, 95% CI:15.88-52.12, one
study.
The other 8 studiescompared 7
different NSAIDsversus placebo,using 5 different
pain scales.
In all cases NSAIDswere significantly
more effective thanplacebo inproducing
moderate/excellentpain relief and/or inreducing pain scores
with the exceptionof aspirin (for whichthere was only one
relevant study)
1) NSAIDS VERSUS PLACEBO.
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They compared the following NSAIDs versus placebo:
aspirin, diclofenac, fenoprofen, ibuprofen,indomethacin, naproxen, nimesulide, piroxicam.
All NSAIDs were significantly more effective thanplacebo
Aspirin which was not found to be not significantlydifferent to placebo
EFFECTS OF
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2) NSAIDS VERSUS NSAIDsINTERVENTIONS
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
There were fifteen, none of which compared
the same two NSAIDs.They made the following comparisons:
2) NSAIDS VERSUS NSAIDS
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Diclofenacreduced pain on aVAS 100 point scale
significantly more thanmeloxicam
Fenoprofen reduced painintensity significantly more
than aspirin
Naproxen reduced painscores significantly morethan Ibuprofen and was
significantly more likely toachieve effective pain
relief than ketoprofen
Other head-to-headcomparisons between
NSAIDs showed nostatistically significant
difference between them.
One found indomethacinsignificantly more effectivethan aspirin and one foundno statistically significant
difference betweennaproxen and diflusinal
2) NSAIDS VERSUS NSAIDS
3) NSAIDS VERSUS PARACETAMOL
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3) NSAIDS VERSUS PARACETAMOL
Resulted in a statistically significant difference in theproportion of women reporting good, excellent or
complete pain relief, favouring NSAIDs overparacetamol (OR 1.89, 95% CI: 1.05-3.43).
Naproxen vsparacetamol
(1 studio )
Ibuprofen vsparacetamol(2 studies )
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DISCUSSION
Overwhelming evidence of the efficacy of NSAIDs in relieving thepain of dysmenorrhea
The review was unable to determine what is most effective NSAIDsfor dysmenorrhea or whether individual NSAIDs have a similarlyeficacioa.
Also it was found that the pain relief efficacy of NSAIDs is superior toparacetamol.
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Tolerability and Safety of NSAIDs
More adverseeffects thanplacebo:
Headache
Dizziness
Dryness
Sleepiness
Gastrointestinal Effects
Indomethacin
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Indomethacin
Neurological sideeffects
Dexketoprofen
Gastrointestinal
side effects
Naproxen
More likely tocause the two
Etoricoxib
No different fromthe effectivenessof naproxen
Meloxicam
Less effective in
relieving painthan diclofenac
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Among NSAIDs no significantdifference was found
between adverse
NSAIDs are a very effectivetreatment for dysmenorrhea,
but q women using themneed to be aware of the side
effects they entail.