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NONSTEROIDALANTIINFLAMMATORY DRUGS

AND ANTIPYRETIC- ANALGESICS

(NSAIDs)

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They have analgesic, antipyretic and

antiinflammatory actions in different

measures.

They act primarily on peripheral pain

mechanisms but also in CNS to raise pain

threshold.

They have various chemical structures but

most are organic acids.

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Mechanism of action:

Inflammation is triggered by the release of

chemical mediators from injured tissues and

the specific chemical mediators vary with the

type of inflammatory process and include

histamine, prostaglandins, bradykinin,

interleukins etc.

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PGE2-vasodilation;-bronchodilation;

- it increases the uterine tone (oxytocic action)

-protective effect on gastric mucosa (it decreases

secretion of gastric acid, increases secretion of

bicarbonate and mucus and stimulates the

circulation);

-increases glomerular filtration through their

vasodilating effect.; it is responsible for maintainingrenal blood flow.

PGF2 -vasoconstriction / vasodilation;

-bronchoconstriction;-it increases the uterine tone.

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PGI2:

synthesized in the endothelial

cells of vessels;

-vasodilation;-bronchodilation;

-it decrease platelet

aggregation;

-inhibits gastric acid secretion;

-it is responsible for

maintaining renal blood flow.

TxA2: -it is preferentially synthesized

in platelets;

-it is the most potent

vasoconstrictor;-it enhances platelet

aggregation;

-it causes bronchoconstriction.

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The major mechanism of action of NSAIDs isinhibition of cyclooxygenase (COX), the enzyme that

converts arachidonic acid (AA) into prostaglandins(PG), prostacycline (PGI2) and thromboxane(TxA2).COX exists in two isoforms:

COX1= constitutive COX which is responsible for thephysiological functions;

COX2=inducible COX; it is induced in macrophages,synoviocytes and fibroblasts by cytokines and othersignal molecules at the site of inflammation.However, COX2 is present (physiologically) at some

sites in brain and in juxtaglomerular cells andendothelium.

Most NSAIDs inhibit nonselectively both COX (1and 2) but some of them are selective / preferentialCOX2 inhibitors.

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Effects of NSAIDs:

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a) USEFUL EFFECTS WITH CLINICAL APPLICATIONS:

EFFECT MECHANISM OFACTION

CLINICAL USESANALGESIC

EFFECT- they reduce pain

of mild to moderateintensity.

Inhibition of

synthesis of

PGE2, PGI2-Somatic pains:

arthralgias, myalgias,

neuralgias, headache,

toothaches;-They are not effectivein visceral pains with

exception of

dysmenorrhoea (due

to an excessive

production of PG,

especially PGF2.)

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EFFECT MECHANISM OFACTION CLINICAL USES

ANTIINFLAMMATO

RY EFFECT-it is moderatedwhen compared to

that

of corticosteroids;-the

anti-inflammatory

effect is more

marked with regard

to the congestive-exudative phase of

inflammation than to

the proliferative

phase.

Inhibition of

synthesis of PGE2,PGI2

-they are used in

the treatment of so called rheumatic

diseases:

rheumatic fever,

abarticular

rheumatism,

rheumatoid

arthritis,

osteoarthtritis,

arthrosis.

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EFFECT MECHANISM OFACTION CLINICAL USES

ANTIPYRETIC

EFFECT

Fever during

infection is produced

through the

generation of

pyrogens

(interferons, TNF)

which induce PG

production in

hypothalamus.NSAIDs reduce bodytemperature in fever

but do not cause

hypothermia innormothermic

Inhibition of

COX and ofPG synthesis ;

but this

mechanism

does not

entirely explain

the antipyretic

effect of

NSAIDs

-hyperpyrexia (> 41 C)

from generalized infections,meningitis, encephalitis;-neurosyphillis;-chronic brucellosis etc.-if the fever is caused by an

infection and it is not so

high (38C) the basic

treatment consists in

administration of

appropriate antibiotics,antipyretics being only an

adjuvant therapy.

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b) USEFUL / ADVERSE EFFECTS(according to the clinical

situation)

EFFECT USEFUL WITH CLINICALAPPLICATION ADVERSEEFFECTINHIBITION

OF PLATELET

AGGREGATIO

N

-it may be useful by reducing

the incidence of thrombosis in

coronary artery, cerebral

artery, coronary artery bypass

grafts;- for this effect some NSAIDs

(e.g. aspirin) may be used in

primary /secondaryprophylaxis of myocardial

infarction/ prophylaxis of

cerebral ischemic attacks.

-bleedings

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EFFECT USEFUL WITHCLINICAL

APPLICATION

ADVERSE EFFECT

CLOSURE OF

DUCTUSARTERIOUS (DA):DA is kept patent in

the foetus by the

continuous local

production of PGE2and PGI2.DA is closing

after the labour.

-management of

patent ductus arteriousin premature infants:

closure can be

accelerated in a

premature newborn by

i.v. infusion of NSAIDs(e.g.

Indomethacin).The

production of PG in

this situation is not an

inflammatory process

and is probably

dependent upon COX1

rather than COX2

-preterm closure of

ductus arterious at theend of normal

pregnancy

INHIBITION OF

RENIN AND

ALDOSTERON

-in Bartters syndrome

(hyperaldosteronism

and hyperreninemia)-hiporeninemia and

hipoaldosteronism

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c) ADVERSE EFFECTS

a) Gastrointestinal effects:

-Gastric intolerance: gastric pain, gastritis,

bleedings, peptic ulcerations, gastric ulcer (more

frequent than duodenal ulcer).Gastric intolerancecan be minimized with suitable buffering, taking

NSAIDs with meals followed by a glass of water or

antiacids.-Vomiting may occur as a result of CNS stimulation

after absorbtion of large doses of Aspirin.

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b) Renal effects:

*Decrease of glomerular filtration rate with oliguria, anuria, Na+and water retention (especially in patients with underlying

renal diseases and also though rarely-in persons with

normal kidneys.

*Decrease secretion of rennin and aldosteron with fluidretention (caused by inhibition of PG which are also involved

in rennin and aldosteron release).

*Renal lesions: the excessive use of analgesic combinations

especially those that contain phenacetin yield to interstitialnephritis, nefrotic syndrome, papillar necrosis and finally to

renal failure.

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NSAIDs produce renal adverse effects byat least three mechanisms:

-COX1 impairement of renal blood flow andreduction of glomerular filtration ;

-juxtaglomerular COX2 dependent Na+

retention;-rare ability to cause papillary necrosis on

habitual intake.

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c) Hypersensitivity reactions: mediated

probably by leukotrienes not by IgE.

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Classification:

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A) ANTIINFLAMMATORY DRUGS:

1)NONSELECTIVE COX INHIBITORS:

a) Salicylates:Acetylsalicylic acid, Sodium salicylate, Potassium

salicylate, Bismut subsalicylate, Diflunisal.

b)Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.

c) Indole derivatives: Indomethacin, Sulindac.

d)Arylaliphatic acid derivatives:

*Propioinic acid derivatives: Ibuprofen, Ketoprofen,

Naproxen, Flurbiprofen.

* Arylacetic acid derivatives: Diclofenac.

e) Anthranilic acid derivatives (Fenamates): Mephenamic acid,

Flufenamic acid, Niflumic acid, Meclofenamic acid.

f) Oxicam derivatives: Piroxicam, Tenoxicam.

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2.PREFERENTIAL COX2 INHIBITORS.

Nimesulide, Meloxicam, Nabumetone.

3.SELECTIVE COX2 INHIBITORS:Celecoxib, Rofecoxib, Valdecoxib.

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B) ANALGESICS-ANTIPYRETICS with

poor anti-inflammatory

a) Salicylates

b)Para-aminophenol derivatives: Paracetamol.c)Pyrazolone derivatives: Metamizol,

Propiphenazone.

d) Benzoxazocine derivative: Nefopam.e) Pyrrolo-pyrrole derivatives: Ketorolac.

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According to another classification:

1) Aspirin and other salicylates

Aspirin (BayerTM)

Diflusinal (DolobidTM)Salsalate (DisalcidTM)

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2. Non-Selective and traditional NSAIDs Ibuprofen (AdvilTM/MotrinTM/NuprinTM)

Naproxen (AleveTM/AnaproxTM/NaprosynTM)

Ketoprofen (ActronTM)

Indomethacin (IndocinTM)

Diclofenac (CataflamTM)

Sulindac (ClinorilTM)

Ketorolac (ToradolTM) Tolmetin (TolectinTM)

Meloxicam (MobicTM)

Piroxicam (FeldeneTM/FexicamTM)

Meclofenamate (MeclomenTM)

Mefenamic acid (PonstelTM)

Nabumetone (RelafenTM)

Etodalac (LodineTM)

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3. COX-2 specific inhibitors

Celecoxib (CelebrexTM)

4. Non-NSAID Related Analgesic

Acetaminophen (TylenolTM/ParacetemolTM)

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1)Aspirin and other salicylates

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They are derivatives of salicylic acid which

is not used in medical practice because is an

irritating agent.

The most important derivative is

acetylsalicylic acid(aspirin).

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Acetylsalicylic acid(Aspirin)

*It is the prototype of salicylates.

* It is a weak acid with a pKa= 3.5.

* Rapidly absorbed in the stomach* Short serum half life ~15-20 mins

* Metabolized by serum esterases to Salicylic

acid + acetic acid. Both aspirin and salicylicacid exhibit anti-inflammatory activity.

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Aspirin is a NON-SELECTIVE inhibitor of

BOTH COX-1 and COX-2; it irreversibly inhibits

COX-1; Aspirin also acetylates COX-2,

although is a much less potent inhibitor ofthis enzymeisoform )

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Indications

(i) Treatment of mild to moderate pain;(ii) Inflammatory diseases e.g. Rheumatoid Arthritis;

(iii) Fever reduction;

(iv) Prophylactic prevention of cardiovascular events i.e.

MI and stroke (as a prohylactic treatment in theprimary prevention of stroke and myocardial infarctionin individuals at moderate to high risk of CVD; as atreatment in acute occlusive stroke)

(v) Cancer chemoprevention: frequent use of aspirin is

associated with a 50% decrease in the risk of coloncancer:(colonic tumours express large quantities ofCOX-2 ; incidence of colon cancer among regularaspirin users is documented to be much lower.)

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Aspirin Dosage

Anti-platelet activity - 300-500 mg, each two

days / 60 -100 mg / day

Analgesic/Anti-pyretic ~2,400 mg/day

Anti-inflammatory 4,000-6,000 mg/day or 75-

100 mg/kg/day in divided portions producing

steady state serum salicylate c% 15-30 mg/dl.

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Other less well established clinical uses:

-pregnancy induced hypertension and

preeclampsia: imbalance between TxA2 and PGI2is believed to be involved ; aspirin 80-100 mg/daybenefits many cases by selectively suppressingTxA2 production.

-to delay labour;-patent ductus arterious;

-familial colonic polyposis: aspirin suppresses polypformation and affords symptomatic relief in this

rare disorder;-to prevent flushing attending nicotinic acid

ingestion which is due to PG release in the skin.

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Other Salicylates

Salsalate

- Dimer of salicylic acid

- Converted to salicylic acid after absorption

- Competitive inhibitor of COX enzymes

- Used in treatment of mild to moderate pain,

fever and inflammation

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Diflunisal

- difluorophenyl derivative of salicylic acid

- Not converted to Salicylic acid in vivo

- Competitive inhibitor of COX enzymes

- More potent anti-inflammatory agent than aspirin

- Cannot cross the blood brain barrier, hence has

no anti-pyretic effect due to poor CNS

penetration

- Fewer and less intense GI side effects

- Weaker anti-platelet effect than aspirin.

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Others include:

sodium thiosalicylate,

choline salicylate,

magnesium salicylate and

methyl salicylate (Oil of Wintergreen-

constituent of muscle liniments)

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Aspirin/Salicylates Pharmacokinetics

They are rapidly absorbed from the stomach and upper small

intestine; Salicylates enter the serum in 530 mins and reach peak

serum concentrations in 1-2 hrs;

All salicylates (except diflunisal) cross the blood brain barrier

and the placenta, hence diflunisal is ineffective as an anti-pyretic agent;

-Salicylates are 50-90% protein bound and can therefore

affect the blood concentrations of other highly protein-bound

drugs e.g. warfarin; - Salicylate is metabolized in the liver to water-soluble

conjugates that are rapidly cleared by the kidney

- Salicylates are excreted in the urine as free salicylic acid

(10%) or as salicylate-conjugates (90%)-

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Excretion of free salicylate is extremely variable anddepends on the dose and the pH of the urine

Salicylate is secreted in the urine and can affect uric acidsecretion.

* At low doses (4g/d) aspirin blocks thereabsorption of uric acid by the proximaltubules,thereby promoting uric acid secretion in theurine.

Because of these effects of aspirin on uric acidlevels, the drug is not given to individuals with gout

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ADVERSE EFFECTS*GI tract (Most common side effect of all

NSAIDs)- Symptoms include epigastric distress, nausea and vomiting

- NSAID treatment can lead to GI bleeding (5-10% mortalityrate)

- NSAID treatment can aggravate and promote developmentof gastric & duodenal ulcers

- Gastric damage caused by two effects:

a) Direct damage to gastric epithelial cells caused byintracellular salicylic acid

b) Inhibition of COX-1-dependent prostaglandin synthesis inthe stomach, which normally acts to prevent damagecaused by gastric acid and digestive enzymes

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These adverse effects can be ameliorated

by co-administration ofMisoprostol (a PGE1

analog) that promotes gastric mucous

production and thereby acts to prevent

damage to the stomach wall or by

Omeprazole (a proton pump blocker).

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* Kidney(A) Aspirin can cause hemodynamically-mediated acute

renal failure

Aspirin treatment inhibits prostaglandin synthesisthereby allowing the vasoconstrictors to actunopposed leading to decreased renal blood flow,renal ischemia and ultimately acute renal

failure- Usually reversible following discontinuation of the drug

(B) Acute Interstitial Nephritis and the NephroticSyndrome(Exact mechanism unknown)

(C )Analgesic Nephropathy/Chronic InterstitialNephritis(Associated with chronic daily overuse of drugover many years)

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* Increased Bleeding

- By blocking TXA2 production aspirin prolongs

the bleeding time

- Aspirin is therefore contraindicated in

hemophilia patients and individuals about to

undergo surgery(1 week in the

case of aspirin)

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* Exacerbation of hypertension and heart failure

- Not seen with low-dose aspirin, only with high-

dose aspirin- High-dose aspirin promotes vasoconstriction,

which can lead to increased blood pressure in

patients with pre-existing hypertension- Increased vasoconstriction can also increase

cardiac afterload resulting in further decreased

cardiac output in patients with pre-existing heart

failure

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****Reyes Syndrome (- unique Aspirin sideeffect)

- Reyes syndrome is a rare, often fatal liverdegenerative disease with associated

encephalitis- Not seen with other NSAIDS, only with aspirin

- It is associated with the administration of aspiringiven during the course of a febrile viral infectionin young children (e.g. chickenpox, influenza etc)Because of this aspirin is not generallyadministered to young children

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* Hypersensitivity*GOUT-As a general rule Aspirin and the salicylates

are not given to patients with a prior history ofGOUT

*Salicylate toxicity

-excessive consumption of aspirin is very toxic andcan result in death; - Aspirin intoxication occurswith doses of >10-30 g (adult) or > 3g (child)

- Mortality: Acute exposure ~2%; Chronic Exposure~25%

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Symptoms

*Early: nausea and vomiting, abdominal pain, lethargy, tinnitus and

vertigo*Late: hyperthermia, hyperventilation, respiratory alkalosis, metabolic

acidosis, hypoglycemia, altered mental status (agitation, hallucinations

and confusion), tremors, seizure, cerebral edema and coma.

Mechanism:

Salicylates trigger increased respiration resulting in an initial respiratory

alkalosis followed by a compensatory metabolic acidosis

Acidified blood promotes the transport of salicylates into the CNS

resulting in direct toxicity, cerebral edema, neural hypoglycemia,

coma, respiratory depression and death

Treatment for salicylate intoxication:

Mild cases- symptomatic treatment and increasing urinary pH to enhance the

elimination of salicylate; Severe- gastric lavage & administration of iv fluids

and dialysis

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2)Traditional NSAIDs

They all have a common mechanism of

action and exhibit very similar efficacy

and adverse drug effect profiles.

l i

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General Properties:

- All traditional NSAIDs are reversible competitiveinhibitors of COX activity;

- All traditional NSAIDs work by blocking the

production of prostaglandins;- Traditional NSAIDs are mostly NON-SELECTIVE COX

inhibitors and inhibit both COX-1 and

COX-2 to varying degrees;

- All traditional NSAIDs exhibit anti-inflammatory,anti-pyretic and analgesic effects.

Ph ki i f di i l

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Pharmacokinetics of traditional

NSAIDs

*most traditional NSAIDs are weak acids and are

well absorbed in the stomach and upper

intestine

*highly protein bound 90-95%- therefore can

interact with other protein-binding drugs e.g.

warfarin

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*specifically accumulate in the synovial fluid

and at other sites of inflammation i.e. ideally

suited for the treatment of arthritis

* metabolized by the liver

* Mostly excreted by the kidney- hence drugs

can accumulate in patients with impaired

renal function resulting in increased risk of

adverse effects

K f f l d di i l

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Key features of selected traditional

NSAIDs

Ibuprofen (AdvilTM/MotrinTM/NuprinTM)

equipotent with aspirin and better tolerated(GIbleeding occurs less than with aspirin)

- potent analgesic and anti-inflammatory properties- rapid onset of action 15-30 mins- ideal for

treatment of fever and acute pain

- Low doses are effective as an analgesic

- High doses required for anti-inflammation

- commonly prescribed OTC for analgesia

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Clinical uses: soft tissues injuries, fractures,vasectomy, tooth extraction, postpartum andpostoperatively , dysmenorrhoea, rheumatoid

arthritis, osteoarthritis, other musculoskeletaldisorders, specially where pain is moreprominent than inflammation;

Flurbiprofen is more effective than ibuprofen

and it is also used as an ocular anti-inflammatory (as eye drops).

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Naproxen (AleveTM/AnaproxTM/NaprosynTM) -20x more potent than aspirin

- rapid onset of action- 60 mins- ideal for anti-pyretic use

- long serum half life of 14 hrs/twice daily dosing

- low incidence of GI bleeding

- considered to be one of the safest NSAIDs

- naproxen may be more valuable in acute goutand it is also recommended for ankylosingspondylitis.

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Indomethacin (IndocinTM)- 10-40X more potent than aspirin as an antiinflammatory

- also inhibits neutrophil migration- most effective NSAID at reducing fever

- not well tolerated (50% of users experience sideeffects);one side effect is pulsatile frontal headache

hard to relief;- should only be used after less toxic drugs prove

ineffective

- can delay labor by suppressing uterine contractions

- drug of choice to promote closure of patent ductusarteriosus in prematures (by i.v. infusion)

- It is available as tablets, syrup, ointments, ophthalmicsolutions, vials.

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Sulindac (ClinorilTM) - equipotent to aspirin

- closely related to indomethacin- less

potent/fewer adverse effect

- it is a prodruginactive itself but converted in

the body to an active sulfide metabolite;

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Ketorolac (ToradolTM)- relatively weak anti-inflammatory activity and potent

analgesic ;

- It inhibits PG synthesis and is believed to relieve pain

by a peripheral mechanism.- used as i.v. analgesic for moderate/severe post surgical

pain; it may also be used for renal colic, migraine andpain due to bony metastasis

- can be used as replacement for opiod analgesic e.g.morphine

- It is administered orally, i.m. or i.v. Continuous use formore than 5 days is not recommended.

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Diclofenac:It is an analgesic-antipyretic - anti-inflammatory agent similar

in efficacy to naproxen. It inhibits PG synthesis and has short lastingantiplatelet action.

Diclofenac is a protective agent on articular cartilages incomparison with other NSAIDs which have when administered forlong periods damaging effects on articular cartilages.

It is employed in rheumatoid and osteoarthritis, bursitis,

ankylosing spondylitis , postsurgical and posttraumatic pains, gout,genital inflammations etc.

Side effects: are generally mild: epigastric pain, nausea,headache, dizziness, rashes.

Ketodolac:It is used topically in the treatment ofseasonal allergic conjunctivitis.

Etodolac

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Flufenamic acid: It is an anti-inflammatory agent used in rheumaticdiseases, in thrombophlebitis.

Mephenamic acid:

It is used mainly as analgesic in dysmenorrhoea, in muscle, joitand soft tissue pain where strong anti-inflammatory action is not

needed.It exerts peripheral as well central analgesic action.It may be useful is some cases of rheumatoid and

osteoarthritis but has no distinct advantage.It also has anti-inflammatory and antipyretic actions.

Diarrhoea is the most important dose related side effect.

It is available as capsules, syrup, orally suspension.

Meclofenamic acid: it used in arthrosis.

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Piroxicam:It is a long acting potent anti-inflammatory agent also with

good analgesic antipyretic action.It is a reversible inhibitor of COX.Inaddition it decreases the production of IgM rheumatoid factor.

It is used as short term analgesic as well as long term anti-

inflammatory drugrheumatoid and osteoarthritis, ankylosing spondylitis,acute gout, musculoskeletal injuries, dysmenorrhoea etc.

Common side effects are: nausea, anorexia, but generally it is bettertolerated and less ulcerogenic.

It is available as 10/20 mg capsules, ampulas, topical gel.

Tenoxicam:It is a congener of piroxicam with similar properties and uses.

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ADVERSE EFFECTS

Very similar with salicylates. They also may

cause-

* modest worsening of underlying

hypertenstion

* Elevated liver enzymes; Liver failure rare

Increased risk with sulindac (27/100,000

prescriptions)

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3) Selective COX-2 inhibitors

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Since inflammation is associated withincreased COX-2 activity and aspirin and thetraditional nonselective NSAIDs are associatedwith significant adverse effects, drugs thatspecifically target COX-2 were developed.

The underlying hypothesis being that thesedrugs should exhibit anti-inflammatory activity

without the serious adverse effects of aspirin andthe traditional NSAIDs that are associated with

the inhibition of COX-1.

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*Celecoxib (Celebrex)

*Rofecoxib (Vioxx) withdrawn Dec 2004 dueto increased MI & stroke

*Valdecoxib (Bextra) withdrawn April 2005due to increased MI & stroke

*Other coxibs: PARECOXIB( the only available fori.m. injection), LUMIRACOXIB, ETORICOXIB

( ARCOXIA).

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Features of Celecoxib (Celebrex)- Selectively inhibits COX-2 not COX-1

- Anti-inflammatory, anti-pyretic and analgesic properties similar to

traditional NSAIDs- Associated with fewer GI side effects (does not inhibit COX-1 in the

stomach)

- No effect on platelet aggregation as does not inhibit COX-1

- Similar renal toxicities to traditional NSAIDs due to constitutive

expression of COX-2 in kidney- Recommended for the treatment of rheumatoid arthritis and

osteoarthritis

- However- no evidence that Celecoxib is any more efficacious thantraditional NSAIDs

- May be indicated in patients with increased risk of GI complications- Approved for the treatment of colon cancer

COX-2 inhibitors and increased

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COX-2 inhibitors and increased

cardiovascular riska) Several large clinical trials have shown that both Rofecoxib and

Valdecoxib are associated with a significantly increased risk ofheart attack and stroke; similar findings have also beenreported for Diclofenac and Meloxicam two traditionalNSAIDs that exhibit preference towards COX-2 inhibition

b) This increased cardiovascular risk is believed to be caused by

the selective inhibitory effect of these COX-2 inhibitors onthe endothelial production of the anti-thromboticprostaglandin PGI2 (prostacyclin). (N.B. COX-2 isconstitutively expressed in endothelial cells).

c) Since these COX-2 inhibitors do not inhibit COX-1, they do not

block the production of the platelet-derived prothromboticprostaglandin TXA2.

Hence these drugs shift the TXA2/PGI2 balance towardsincreased platelet aggregation.

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Other disadvantages

d) COX-1 isoenzyme may also have a role in

inflammation selective COX-2 inhibitors

may not have a broad range of efficacy as

nonselective COX inhibitors;e) Juxtaglomerular COX-2 is constitutive ;

inhibition of this can cause salt and water

retention;

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4) Non-NSAID analgesics

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Acetaminophen- An important ANALGESIC drug in the treatment of mild to moderate pain &

Fever

- Anti-pyretic and analgesic activity (equivalent to Aspirin)

- No anti-inflammatory activity because acetaminophen does not inhibitperipheral COX-2

- No anti-platelet activity because acetaminophen does not inhibit PlateletCOX-1

- Only a very weak inhibitor of COX-1 and COX-2 in peripheral tissues- thoughtto be due to the inhibitory effects of high concentrations ofhydroperoxides in the periphery

-Reduced Adverse effects compared to NSAIDs due to lack of effect onperipheral COX-1

- Most potent effect are on the pain and thermoregulatory centers of the CNS

-- Well absorbed orally and is metabolized in the liver- Peak blood levels are achieved in 30-60 mins with a serum half-life of 2-3

hrs.

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Acetaminophen: Indicationsa) Mild to moderate pain not associated with inflammation (Dosage 325-500

mg x 4 daily)b) Used for the relief of pain associated with headaches, muscle aches andmild forms of arthritis

c) Alone is not an effective therapy for arthritis. However, may be used as anadjunct therapy together with NSAIDs.

d) Preferred analgesic in patients that are allergic to Aspirin, or where

salicylates are poorly toleratede) Preferred Analgesic/Anti-pyretic in children with viral infections (to avoid

Reyes syndrome)

f) Preferred Analgesic/Anti-pyretic in patients with hemophilia or a history ofpeptic ulcer- does not affect the bleeding time or promote GI bleeding

g) Does not affect uric acid levels, therefore can be used together with

Probenecid in the treatment of gouth) Should not be taken with alcohol as together they can cause serious liver

damage

Acetaminophen: Adverse effects and

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Acetaminophen: Adverse effects andtoxicity

a) At normal doses (4g/day) Acetaminophen is essentially free of

adverse effectsb) Larger doses might result in dizziness, excitement and disorientation

c) High doses or long administration causes analgesic nephropathywith papillary necrosis, tubular atrophy followed by renal fibros

d) Ingestion of very large doses (>15 g) acetaminophen can be fatal

due to severe hepatotoxicitye) Hepatotoxicity is due to the build up of the toxic metabolite

Nacetyl- p-benzoquinoneimine that is caused by theacetaminophendependent depletion of hepatic glutathione

Treatment is with N-acetyl cysteine (given within 8-10 hrs ofoverdose), which works by replenishing cellular glutathione

levels

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Metamizole (ALGOCALMIN, NOVALGIN)It is a potent and promptly acting analgesic and

antipyretic but poor anti-inflammatory and not uricosuric.

It is used in headache, toothache, neuralgias,

dysmenorrhoea. It is also an antispatic agent.It can be given orally, i.m. as well as i.v.

The risk of agranulocytosis is present but is not soobvious.Gastric irritation, pain at site injection site occurs.Occasionally i.v. injection produces precipitous fall in blood

pressure.