Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

Nonsteroidal anti-inflammatory drugs, usually abbreviated as NSAIDs with analgesic and antipyretic (fever-reducing) effects and which have, in higher doses, anti-inflammatory effects.

The term "Nonsteroidal" is used to distinguish these drugs from steroids, which, among a broad range of other effects, have a similar eicosanoid-depressing, anti-inflammatory action. As analgesics, NSAIDs are unusual in that they are non-narcotic.

Types of NSAIDs

There are two main types of NSAIDs: nonselective and selective.

Nonselective NSAIDs

Nonselective NSAIDs inhibit the enzymes found in the stomach, blood platelets, and blood vessels (COX-1) as well as the enzymes found at sites of inflammation (COX-2) to a similar degree. Nonselective NSAIDs include drugs such as aspirin, ibuprofen, naproxen and dichlorofenac.

Selective NSAIDs09:20:44

Selective NSAIDs (also called COX-2 inhibitors) inhibit the COX enzyme found at sites of inflammation (COX-2) more than the type of enzyme normally found in the stomach, blood platelets, and blood vessels (COX-1). Celecoxib is a selective NSAID

CLASSIFICATION OF NSAIDs

1) NONSELECTIVE IRREVERSIBLE COX INHIBITORS

                   (a) Salicylates           :          Aspirin (Acetyl-salicylic acid)

                                                                 Sodium salicylate

                                                                Methyl salicylate

                                                                 Salicylic acid

                        Others                  :          Olsalazine

2) NONSELECTIVE REVERSIBLE COX INHIBITORS

                   (a) Indole derivatives    :    Indomethacin

                                                                 Sulindac

                   (b)Propionic acid derivatives: Ibuprofen

                                                                       Ketoprofen

                                                                       Flurbiprofen

                                                                       Naproxen

                     (c)Aryl acetic acid derivatives: diclorofenac

                                                                           Aceclofenac

                     (d) Anthracitic acid: Mefenamic acid

                                                           Flufenamic acid

                      (e) Pyrazolone derivatives: Phenyl butanone

                                                                        Oxiphenbutazone

                      (f) Oxicam derivatives    : Tenoxicam

                                                                  Pyroxicam

                      (g) pyrrole-pirole derivatives: ketorolac

                                                                           Tolmethin

                                                                          Oxaprozin

3) SELECTIVE COX-2 INHIBITORS:

                                                 Celecoxib

                                                 Rofecoxib

                                                 Valdexoxib

4) WEAK INHIBITOR OF COX1&COX2

                                                          Nimusalide

5) PREFERENTIAL COX 2 INHIBITORS

                                                         Meloxicam

                                                          Ethodolac

                                                           Nabumethone

6) COX 3 INHIBITOR /REVERSIBLE INHIBITOR OF COX1

                                                           Paracetamol

                                                            Methamizol

7) OTHER NON STEROIDAL DRUGS

                                           Nefopam

3) MORE COX-2 SELECTIVE INHIBITORS

                                             Nimusalide

                                              Etodolak

                                              Meloxicam

                                              Nabumethone

4) COX-2 SELECTIVE INHIBITORS

                                            Celecoxib

                                             Etorcoxib

                                           Valdecoxib

General Mechanism of action

Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) iso enzymes. COX catalyzes the formation of prostaglandins and thromboxane from Arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A₂). Prostaglandins act (among other things) as messenger molecules in the process of inflammation. This mechanism of action was elucidated by John Vane (1927–2004), who later received a Nobel Prize for his work (see Mechanism of action of aspirin

                                       Tissue Injury

                            ↓

           Phospholipids in cell membrane

                          ↓PHOSPHOLIPASE A₂

                               Arachidonic acid

   NSAIDS INHIBITORS (-) ↓cox

                                                 PGG₂    

                          ↓cox

                                    PGH₂      

                  ↙      ↓      ↘ 

      ProstaglandinE₁      prostacyclin     ThrombaxaneA₂

      PGD₂, PGE2, PGF2                 PGI₂                               TXA₂, TXB2

                

Cox-1&cox2

Cox-1 

·         Present in most tissues.

·         In the GIT, it maintains the normal lining of the stomach.

·         Involved in kidney and platelet aggregation.

Cox-2

·         Present in macrophages and monocytes.

·         Inducible.

·         Responsible for pain and inflammation.

NON SELECIVE IRREVERSIBLE INHIBITORS OF COX

ASPIRIN

Analgesia

→These are the salts or esters of salicylic acid.

           →Salicylic acid itself is a strong irritant.

           →It is one of the oldest analgesic-anti-inflammatory drugs and is still widely used.

           →It is rapidly converted in the body to salicylic acid which is responsible for most of the actions.

  Mechanism of action

·         NSAIDS inhibits cyclooxygenase which is responsible for the synthesis of prostaglandin and thromboxane

·         It also inhibits platelet aggregation

Pharmacological actions

1. Analgesic action

→Aspirin is a weaker analgesic than morphine.

→These are effective only in dull- aching pain of low intensity.

→They do not relieve severe pain like visceral pain.

→They act by preventing the integration of pain sensation in the thalamus But they do not alter the                                         emotional reaction to pain.

2. Anti-pyretic effect

Salicylates do not lower normal body temperature.

Only the elevated temperature is lowered.

Mechanism

Fever is caused by elevated levels of prostaglandin E2, which   alters the firing rate of neurons with in the hypothalamus that control thermoregulation. Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus.PGE2 signals to the hypothalamus to increase the body's thermal set point. Ibuprofen has been shown to be more effective as an antipyretic than acetaminophen. Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E. This is reset for a lower temperature by salicylates

The salicylates produce sweating which also lowers body temperature

3. Anti- inflammatory action

→Aspirin exert the anti-inflammatory action at high doses 3- 6 grams /day

→Signs of inflammation like pain, tenderness, swelling, vasodilatation, and leukocyte infiltration are suppressed.

→Aspirin inhibits cyclooxygenase activity, it diminishes the formation of prostaglandins and modulates those aspects of inflammation in which prostaglandins act as mediators.

→Aspirin inhibits inflammation in arthritis.

4. on respiration

→Salicylates stimulate respiration

→The stimulation is depend on the dose

→Salicylates stimulates respiration directly by stimulating the respiratory Centre

5. Cardiovascular system

No effect at normal dose.

Large doses increase cardiac output to meet increased peripheral O₂ demand and cause direct vasodilatation.

Toxic doses produce paralysis of vasomotor Centre and BP may fall.

6. GI Tract

Salicylates produce nausea and vomiting due to direct stimulation chemoreceptor trigger zone.

Salicylates can also cause gastric ulceration and hemorrhage.

7. Anti- rheumatic effect

Salicylates have powerful anti-rheumatic effect

This effect is produced by reducing pain and inflammation of the joints

8. Blood

Salicylates lower the erythrocyte sedimentation rate (ESR) which is high in rheumatic fever

They also decrease prothrombin level of plasma.

9. Uricosuric effect

Low doses ( 1 or 2/ g day ) may decrease the urate excretion and increase plasma urea concentration

Intermediate doses ( 2 or 3 g / day ) do not alter urate excretion.

Large doses (over 5 g / day) induce urocosuric effect and lower plasma urate levels 

10. Metabolic effects

Salicylates produce uncoupling of oxidative phosphorylation

They produce hyperglycemia and glycosuria

They inhibit the synthesis but enhance the breakdown of fatty acids

Pharmacokinetics

Aspirin is taken through oral administration they are are absorbed from the stomach and small intestine

Adverse reactions

nausea, vomiting , diarrhea , ulceration perforation ,hemorrhage, skin rashes, agranulocytosis, thrombocytopenia , plastic anemia,  headache, difficulty in hearing, drowsiness, lethargy and confusion

Therapeutic Uses

1. It is used as analgesic for light and moderate pain --- 0.3 - 0.6 g - 3 times

2. used as anti-pyretic in fever ---   0.3 - 0.6 g - 3 times

3. Used as anti – inflammatory   & anti-rheumatic & ---4 – 6 g or 75– 100   mg/kg/day in divided doses

4. Anti- platelet effect - 75 – 300 mg / day

5. Used in the treatment of the gout

6. Used in the closure of ductus artereosus

İİ. Non selective reversible inhibitor of cox

Indomethacin

It has anti-inflammatory, analgesic, antipyretic and antigout actions.

It relieves pain and reduces temperature in febrile patients.

Reduces pain and joint swelling in rheumatoid arthritis but does not modify progress.

Mechanism of action

It is a portent inhibitor of cyclooxygenase thus reducing prostaglandin synthesis

Pharmacokinetics

Orally administered, well absorbed through liver, 90% bound to plasma proteins & half-life is 4 – 6 hours

Adverse effects

Adverse effects are high.

Gastrointestinal irritation with nausea, GI bleeding, vomiting, diarrhea and peptic ulcers can occur

Hypersensitivity reactions like skin rashes, leucopenia and asthma in aspirin sensitive individuals

Drug interactions

Indomethacin blunts the diuretic action of furosemide and the anti-hypertensive action of thiazides,  beta blockers and ACE inhibitors by causing salt and water retention

Dose

25 -30 mg

Uses

Rheumatoid arthritis

Gout

Ibuprofen

It is introduced in 1969. It is propionic acid derivatives better tolerated than aspirin.

Its analgesic activity is independent of anti- inflammatory activity and has both central and peripheral effect.

Temperature is reduced in febrile patients

Mechanism of action

It is a potent inhibitor of the enzyme cyclooxygenase resulting in the blockage of prostaglandin synthesis

It also prevents formation of thromboxane A₂ by platelet aggregation

It exhibits anti- inflammatory, analgesic and antipyretic activities

All have similar pharmacodynamics properties but differ considerably in potency and to some extent in duration of action

Analgesic, antipyretic and anti-inflammatory efficacy is slightly lower than aspirin

It is 99% bound to plasma proteins

Adverse effects

Nausea , Vomiting, Gastric discomfort, CNS effects, Hypersensitivity reactions.

Dose

400- 800 mg

Uses: 1. It has analgesic and antipyretic activity

              2. It is used in the treatment of gout

              3. Surgical removal of impacted tooth – a combination of ibuprofen with

                     a muscle relaxant like  chlorzoxaxone is recommended

               4. It is a drug of choice in rheumatoid arthritis because of lesser adverse effects

SELECTIVE COX-2 INHIBITORS

Celecoxib

This is highly selective inhibitor of cox2 enzyme .it is more selective towards cox-2 than the cox-1.

It does not have any inhibitory effect against TXA_{2 at} therapeutic doses

Pharmacokinetics

Orally administered excretion via renal and rectal route

Pharmacological actions

Anti-inflammatory, analgesic, antipyretic, antiplatelet action

Adverse effects

Skin rashes, hypersensitivity, ulceration, hemorrhage, diarrhea, dyspepsia, gastric discomfort,

 Mild hypertension, edema

Contraindications

Celecoxib is contraindicated in patients prone to cardiovascular or cerebrovascular disease.

Therapeutic use

·         Used in rheumatoid arthritis.

·         Used in treatment of osteoarthritis.

COX 3 INHIBITOR /REVERSIBLE INHIBITOR OF COX1

Paracetamol

It is a Para-amino phenol derivative

It has analgesic and antipyretic effects like salicylates

Paracetamol, a metabolite of phenacetin is found to be safer and effective

It has analgesic, good antipyretic and weak anti- inflammatory properties

Due to weak PG inhibitory activity in the periphery, it has poor anti-inflammatory actions

Paracetamol is active on cyclooxygenase in the brain which accounts for its antipyretic action

In presence of peroxides present at the site of inflammation, it has poor ability  

            To inhibit cyclooxygenase

It does not stimulate respiration

It has no action on acid- base balance, cellular metabolism, cardiovascular system and platelet function

It does not produce gastrointestinal irritation and uricosuric effect

It is analgesic and antipyretic of choice especially in patients in whom salicylates or other NSAID are contraindicated

Mechanism of action

Paracetamol exhibits analgesic action by peripheral blockage of pain impulse generation.

It produces analgesic and antipyretic action by inhibiting the action of endogenous pyrogen on the hypothalamic heat regulating centers.

Its weak anti-inflammatory activity is related to inhibition of prostaglandin synthesis in the CNS.

ADME

Rapid absorption through oral administration.  30% protein binding

It is metabolized by the hepatic microtonal enzymes in liver.

Plasma half-life is 2-3 hrs. 

Effects after an oral dose last 3-5 hrs.

It is mainly excreted I urine as conjugation products of glucuronic and sulphuricacids

The ability of the infant liver for glucuronidation of Paracetamol is poor and this results in enhanced toxicity of the drug in neonates

Adverse effects

·         In antipyretic doses, Paracetamol is safe and well – tolerated

·         Nausea and rashes may occur

Dose

0.5     :- 1 g every 4-6 hrs.

Chile 6 – 12 yrs : – 250 – 500 mg every 4-6 hrs

1– 5 years: - 120 – 250 mg every 4 – 6 hrs.

Less than 3 months 10 mg / kg body weight every 4 – 6 hrs.

Maximum dose for adult: – 4 g daily 

Maximum dose for a child: - 4 doses in 24 hrs.

Acute Paracetamol poisoning

When large doses are taken, acute Paracetamol poisoning results.

Children’s are more susceptible because the ability of their liver to metabolite Paracetamol is poor.

10 – 15 grams in adults cause serious toxicity.

Symptoms

                   Nausea,

                   Vomiting,

                   Paracetamol is hepatotoxic and causes severe hepatic damage.

                   Hepatic lesions are reversible when promptly treated.

Mechanism

Small portion of Paracetamol is metabolized to toxic compound – N-acetyl – benzoquinone- imine which is inactivated generally by binding with glutathione in the liver

But when large doses of Paracetamol are taken, larger amounts of the toxic compound are fumed and glutathione in the liver is not sufficient to inactivate it

As a result the toxic metabolite now binds to hepatic proteins resulting in hepatic necrosis

Chronic alcoholics and infants are more likely to develop hepatotoxicity

Paracetamol can also cause nephrotoxicity which may result in acute renal failure in some.

Uses

·         Paracetamol is prescribed in head ache, tooth ache, backache, myalgia etc.

·         Excellent antipyretic.

·         Used in children without any risk.

·         Drug of choice in osteoarthritis.

ANOVA TEST

ANOVA (Analysis of variance test)

Groups	Control	Group A	Group 11	Group 111	Group  1v	Total
	17	19	18	20	24
	21	22	16	23	28
	19	25	17	25	29
	11	18	13	20	25
Observations	4	4	4	4	4	20(n)
Sigma X	68	84	64	88	106	410  (T)
Mean	17	21	16	22	26.5
Sigma X 2	1212	1794	1038	1954	2826	8824
(Signa X)2 /n	1156	1764	1024	1936	2809	8689

Correction factor   Cf    = T²/N   =  (410) 2  

                                                          ------------    =  8405

                                                              20  

Total sum of squares    =  sigma X²   -  c.f  =  8824 – 8405  = 419

B/N groups sum of squares  = ( sigma X²)/n)   -  c.f  =  8689 – 8405  = 284

                                   

Within groups  =  Total sum of square  - between groups sum of squares

                            =  419 – 284  =  135

Degree of freedom

B/n  groups  =  number of groups  - 1   ,  5-1 =4

Total degree of freedom  =  Total observation of all groups – 1

                                                       20 – 1 = 19

Error (df )  Total df  - between groups df  = 19-4 =15

Mean square(b/n groups)  =   B/n groups sum of squares/degree of

                                                                                                        freedom           

                                                  = 284/4 = 71

                                           

Mean square within groups   = 135/15    =  9

F  =  Between mean squares / within groups mean square

     =   71/9  =  7.89

Referring to F – ration table for (4,15) degrees of freedom we get for F = 7.89 , p greater than  0.01 , hence there is a significant difference between groups

For finding out the differences b/n the groups, error mean square Anova is made use by applying dunnets t test

T test formula

Where s2 is the error mean square obtained from Anova

Dunnets  t test to determine effect of drug against control group

Statistic	A	B	C	D
t	1.886	0.472	2.358	4.481

D.F   = 15

*P less than  0.05  ,          ***P less than 0.001

Therefore drug C and drug D  differ significantly from control , but drug D is highly effective

 Tukeys test

Steps

1. Calculate an analysis of variance (e.g., One-way between-subjects ANOVA).
2. Select two means and note the relevant variables (Means, Mean Square Within, and number per condition/group)
3. Calculate Tukey's test for each mean comparison
4. Check to see if Tukey's score is statistically significant with Tukey's probability/critical value table taking into account appropriate df_within and number of treatments.

Problem: Susan Sound predicts that students will learn most effectively with a constant background sound, as opposed to an unpredictable sound or no sound at all. She randomly divides twenty-four students into three groups of eight. All students study a passage of text for 30 minutes. Those in group 1 study with background sound at a constant volume in the background. Those in group 2 study with noise that changes volume periodically. Those in group 3 study with no sound at all. After studying, all students take a 10 point multiple choice test over the material. She begins by conducting a One-way, between-subjects Analysis of Variance. She finds a significant F score. The relevant variables from her ANOVA table are:
MS_within =4.18; M₁ =6; M₂ =4; M₃ =3; df_within = 21; n = 8

EXAMPLES OF THE NULL HYPOTHESIS

A researcher may postulate a hypothesis:

H₁: Tomato plants exhibit a higher rate of growth when planted in compost rather than in soil.

And a null hypothesis:

H₀: Tomato plants do not exhibit a higher rate of growth when planted in compost rather than soil.

It is important to carefully select the wording of the null, and ensure that it is as specific as possible. For example, the researcher might postulate a null hypothesis:

H₀: Tomato plants show no difference in growth rates when planted in compost rather than soil.

There is a major flaw with this null hypothesis. If the plants actually grow more slowly in compost than in soil, an impasse is reached. H₁ is not supported, but neither is H₀, because there is a difference in growth rates.

If the null is rejected, with no alternative, the experiment may be invalid. This is the reason why science uses a battery of deductive and inductive processes to ensure that there are no flaws in the hypotheses.

Many scientists neglect the null, assuming that it is merely the opposite of the alternative, but it is good practice to spend a little time creating a sound hypothesis. It is not possible to change any hypothesis retrospectively, including H₀.

SIGNIFICANCE TESTS

If significance tests generate 95% or 99% likelihood that the results do not fit the null hypothesis, then it is rejected, in favor of the alternative.

Otherwise, the null is accepted. These are the only correct assumptions, and it is incorrect to reject, or accept, H₁.

Accepting the null hypothesis does not mean that it is true. It is still a hypothesis, and must conform to the principle of falsifiability, in the same way that rejecting the null does not prove the alternative. 

PERCEIVED PROBLEMS WITH THE NULL

The major problem with the null hypothesis is that many researchers, and reviewers, see accepting the null as a failure of the experiment. This is very poor science, as accepting or rejecting any hypothesis is a positive result.

Even if the null is not refuted, the world of science has learned something new. Strictly speaking, the term ‘failure’, should only apply to errors in the experimental design, or incorrect initial assumptions. 

DEVELOPMENT OF THE NULL

The Flat Earth model was common in ancient times, such as in the civilizations of the Bronze Age or Iron Age. This may be thought of as the null hypothesis, H₀, at the time.

H₀: World is Flat

Many of the Ancient Greek philosophers assumed that the sun, moon and other objects in the universe circled around the Earth. Hellenistic astronomy established the spherical shape of the earth around 300 BC.

H₀: The Geocentric Model: Earth is the centre of the Universe and it is Spherical

Copernicus had an alternative hypothesis, H₁ that the world actually circled around the sun, thus being the center of the universe. Eventually, people got convinced and accepted it as the null, H₀.

H₀: The Heliocentric Model: Sun is the centre of the universe

Later someone proposed an alternative hypothesis that the sun itself also circled around the something within the galaxy, thus creating a new null hypothesis. This is how research works - the null hypothesis gets closer to the reality each time, even if it isn't correct, it is better than the last null hypothesis.

Gluconeogenesis