Nsaids

NSAIDs

Non Steroidal Anti Inflammatory Drugs

INFLAMMATION

• Inflammation (Latin, inflamatio, to set on fire) is the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants.

• It is a protective attempt by the organism to remove the injurious stimuli as well as initiate the healing process for the tissue.

http://en.wikipedia.org/wiki/Latin

• Burns • Chemical irritants • Frostbite • Toxins • Infection by pathogens • Physical injury• Immune reactions due to hypersensitivity • Radiation • Foreign bodies

CAUSES

The classic signs and symptoms of acute inflammation

English LatinRedness Rubor*Swelling Tumor/Turgor*Heat Calor*Pain Dolor*Loss of function Functio laesa**

http://en.wikipedia.org/wiki/Rubor

http://en.wikipedia.org/wiki/Tumor

http://en.wikipedia.org/wiki/Heat

http://en.wikipedia.org/wiki/Pain

http://en.wikipedia.org/wiki/Functio_laesa

Process of Inflammation

• Inflammation can be classified as either acute or chronic.

• The initial phase of cell injury is known as the acute phase and is mediated by several autacoids like :

– Histamine– 5-HT– Bradykinin– Prostaglandins

• When a tissue is injured, from any cause, prostaglandin synthesis in that tissue increases.

Synthesis of ProstaglandinsCyclo-oxygenase (COX) pathway

Membrane Phospholipids

Phospholipase A2

Arachidonic Acid

Prostaglandins

Thromboxanes

Prostacyclin

COX

• Among the most widely used all therapeutic agents world wide

• They are frequently prescribed for ‘rheumatic’ musculo-skeletal complaints and are often taken without prescription for minor aches and pains

• More than 50 different NSAIDs on the market and none of these is ideal in controlling or modifying the signs and symptoms of inflammation

NSAIDs

• Analgesic• Antipyretic• Anti-inflammatory actions• Compared to Morphine:

– Weaker analgesics– Do not depress CNS– Do not produce physical dependence– No abuse liability

NSAIDs Cont..

• They are also called:– Non norcotic– Non opioid– Aspirin like analgesics

• They act primarily on peripheral pain mechanisms but also in CNS to raise pain threshold

• These drugs are chemically diverse, but most are organic acids.

NSAIDs Cont..

• Non of these steroid • All are analgesic, antipyretic, anti-

inflammatory (expect paracetamol) • Do not produce CNS, RS depression.

• Dose dependent uricosuric action.

• Act by inhibition of PGs except

Nimesulide, Nefopam

Common characteristics of all NSAIDs Cont..

ClassificationNon selective COX inhibitors:

Salicylates Aspirin, Diflunisal

Pyrazolone derivatives Phenylbutazone, Oxyphenbutazone

Indole derivatives Indomethacin, Sulindac

Propianic acid derivatives Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen

Anthranilic acid derivatives Mephenamic acid

Aryl-acetic acid derivatives Diclofenac

Pyrrolo-pyrrolo derivative ketorolac

Preferential COX-2 inhibitors:

Nimesulide, Meloxicam, Nabumatone

Selective COX-2 inhibitors

Celecoxib, Rofecoxib, Valdecoxib

Analgesic –Antipyretics with poor Anti inflammatory action

Para amino phenol derivatives Paracetamol (Acetaminophen)

Pyrazolone derivatives Metamizol (Dypirone), Propifenazone

Benzoxazocine derivative Nefopam

Classification cont..

Non selective COX inhibitors:

Salicylates Aspirin, Diflunisal

Pyrazolone derivatives Phenylbutazone, Oxyphenbutazone

Indole derivatives Indomethacin, Sulindac

Propianic acid derivatives Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen

Anthranilic acid derivatives Mephenamic acid

Aryl-acetic acid derivatives Dicofenac

Pyrrolo-pyrrolo derivative ketorolac

Mechanism of action

• When a tissue is injured, from any cause, prostaglandin synthesis in that tissue increases.

• PGs have TWO major actions:

• They are mediators of inflammation

• They also sensitize pain receptors at the nerve endings, lowering their threshold of response to stimuli and allowing the other mediators of inflammation

• Naturally, a drug that prevents the synthesis of PGs is likely to be effective in relieving pain due to inflammation of any kind

• In 1971 Vane and coworkers made the landmark observation that aspirin and some NSAIDs blocked PG generation.

• This is they do by inhibiting cyclo –oxygenase (COX) enzyme in the pathway for PGs synthesis

Mechanism of action Cont..

Membrane Phospholipids

Phospholipase A2

Arachidonic Acid

Prostaglandins

Thromboxanes

Prostacyclin

COX

Synthesis of ProstaglandinsCyclo-oxygenase (COX) pathway

NSAIDs

COX

• Exists in two isoforms:

1. COX-1 (constitutive)2. COX-2 (inducible)

– Oxidative stress– Injury– Ischemia– Neurodegenerative diseases

Beneficial actions due to PG synthesis inhibition

• Analgesia• Antipyresis• Antiinflammatory• Antithrombotic• Closure of ductus arteriosus

Shared toxicities due to PG synthesis inhibition

• Gastric mucosal damage• Bleeding• Limitation of renal blood flow/Na+ & water

retention• Delay/prolongation of labour• Asthma and anaphylactoid reactions in

susceptible individuals

Salicylates - Aspirin

• Prototype

• Acetylsalicylic acid

• It was obtained from ‘willow bark’ (Salicaceae) but

is now synthesized

• Methyl salicylate is a volatile liqiud derivate. (Counter irritant)

• Irreversible inhibitor of COX

• Nonselective inhibitor of COX

Aspirin – Pharmacological actions

1. Antiinflammatory action:

Potent Exerted at high doses (3-6g/day or

100mg/kg/day) Signs of inflammation are suppressed Acts mainly by inhibiting PG synthesis


2. Analgesic action:

• Mild analgesic effect ≤ codeine

• Effective in non -visceral pain

• Inhibition of peripheral PG synthesis


3. Antipyretic action:• Reduces body temperature in fever• Resets the hypothalamic thermostat• Rapidly reduces fever by heat loss• But does not decrease heat production

4. Metabolic effects:• These are significant at only at antiinflammatory

doses• ↑ Cellular metabolism• increased heat production• ↑ Utilization of glucose

3. Respiration:• Stimulated at therapeutic doses by peripheral and

central actions• Hyperventilation is prominent in salicylate poisoning• Further raise causes respiratory depression and death

due to respiratory failure

4. Acid -base and electrolyte balance:• Significant changes at antiinflammatory doses• Hypokalemia, Respiratory alkalosis(400µg-

500µgstimulation of respiratory centre inc. pO2), compensated respiratory alkalosis(most pts), respiratory acidosis(higher doses500µg to 1mg medullary depress,inc.pCO2 ), uncompensated metabolic acidosis(poisoning) and dehydration(poisoning).


5. CVS:• No direct effect in therapeutic doses• Larger doses increase Cardiac Output (3g)• Toxic doses depress VMC

6. GIT:• Irritate gastric mucosa and cause epigastric distress,

nausea and vomiting• Also stimulates CTZ• “Ion trapping”• Heart burn, dyspepsia, gers.astritis, erosion,

Gastric ulcers.


Asp Asp

Acid

pH 1.5pH 7.1Gastric

mucosal cell

7. Effect on platelets/coagulation:

• TXA2 enhances platelet aggregation

• PGI2 decreases it

• Low doses(80-100mg/day) An anticoagulant effect with a prolonged BT


8. Urate excretion:

• Dose related effect is seen• <2gm/day- urate retention and antagonism of all other

uricosuric drugs• 2-5gm/day- variable effects, often no change• >5gm/day- increased urate excretion• Not suitable in chronic gout- high doses are not

tolerated


9. Local irritant effect:

• Cause irritating to the skin & mucosa and destroys epithelical cells

• Keratolytic effects

10. Endocrine effect:• Large dose stimulate adrenal cortex by hypothalamus

inc adrenocortico steroid production• L.Dose dec. thyroid uptake of iron cause goitre.


• Well absorbed• Poor water solubility is the limiting factor• Solubility is more at higher pH• Rapidly deacetylated in the gut wall, liver, plasma and

other tissues to salicylic acid• 80% bound to proteins• Vd=0.17L/kg• Slowly enters the brain but freely crosses placenta

Aspirin – Pharmacokinetics

• Conjugated in the liver by glycine and glucuronic acid• Excreted by glomerular filtration as well as tubular

secretion• t1/2 of aspirin as such is 15-20min• Together that released salicylic acid is 3-5hrs• Metabolic processes get saturated over therapeutic

range• t1/2 of antiinflammatory doses may be 8-12hrs• While that during poisoning may be upto 30hrs• Thus elimination is dose dependant

Aspirin – Pharmacokinetics

a) Gastrointestinal:• Most common• Epigastric distress, Nausea, Vomiting• Increased occult blood loss in stools• Gastric mucosal damage and peptic ulcer

b) Rey’s syndrome• Occurs in infants and children• Occurs when aspirin given during viral infections• Characterized by liver damage and encephalopathy• Replaced by acetaminophen in such condition to

reduce fever

Aspirin – Adverse effects

c) Hypersensitivity:• Though infrequent, these can be serious• Reactions include; rashes, urticaria, angioedema,

rhinorrhoea, asthma and anaphylactoid shock

d) Salicylism• High doses(at antiinflammatory doses) or chronic use

of aspirin may induce a syndrome characterised by tinnitus, hearing defects, blurring of vision, dizziness, headache and mental confusion

• Effects are reversible



e) Acute salicylate poisonig:• More common in children• Fatal dose in adults estimated to be 15-30gm, but

considerably low in children• Serious toxicities seen at serum levels >50mg/dl

Manifestations are:

vomiting, dehydration, electrolyte imbalance, acidotic breathing, hyper/hypoglycemia, petecheal hemorrhages, restlessness, delirium, hallucinations, hyperpyrexia, convulsions, coma and death due to respiratory and cardiovascular failure


Treatment:

• Symptomatic and supportive• Gastric lavage• i.v. infusion of Na+, K+, HCO3 and glucose(dextrose-5%)

• Vitamin K 10mg i.v.• Peritoneal dialysis or hemodialysis


contraindications

• Peptic ulcer

• Ulcerative colitis

• Gout

• Renal failure

• Patients hypersensitive to salicylates

• Hemophilias

Aspirin – Contraindications

Drug interactionsAspirin – Drug interactions

Uses

1. As analgesic

2. As antipyretic

3. Antiinflammatoryi. Acute rheumatic fever

ii. Rheumatoid arthritis

iii. Osteoarthritis

4. Cardio protective

Aspirin – Uses

• As analgesic and antipyretic: 0.3-0.6gm, 6-8 hourly

• Acute rheumatic fever: 75-100mg/kg/day in divided doses/4-6 days 50mg/kg/day/2-3wks- maintenance dose

• Rheumatoid arthritis: 3-5gm/day

• Cardio protective: 80-100mg/day

Aspirin – Doses(oral)

a) Sodium salicylate:• Aspirin alternative in rheumatic fever• But now is obsolete

b) Methylsalicylate (Topical):• Used topically as a counterirritant in muscle and joint

pain, in the form of liniments and ointments• Systemic absorption can lead to toxicity

c) Salicylic acid (Topical):• Used as keratolytic and corn remover• Combined with benzoic acid (Whitefield ointment) for

local use in epidermophytosis

Other clinically used Salicylates

These are:• Aminopyrine and antipyrine• Phenylbutazone and oxyphenbutazone• Analgin (dipyrone)

Phenylbutazone:• Potent antiinflammatory drug• Poorly tolerated by many patients• Causes GI, hepatic, renal and fatal hematologic,

agranulocytosis toxic effects• Gives rise to various drug interactions• Hence now it is rarely used

Pyrazolone Derivatives

Oxyphenbutazone:• Metabolic degradation product of phenylbutazone• Less gastric irritation than phenylbutazone• It shares all toxic effects of phenylbutazone

Analgin (Dipyrone, Novalgin):• Has potent analgesic antipyretic but no antiinflammatory

actions• Has no advantage over aspirin• Toxic effects are similar to phenylbutazone

Pyrazolone Derivatives Cont…

Indomethacin:• Potent antiinflammatory agent• Has antipyretic, analgesic and anti-inflammatory actions• Effective in gout, rheumatoid arthritis, ankylosing spondylitis

and osteoarthritis.• Given orally, absorbed well• Mainly metabolized by liver and excreted by kidneys• Its action is more prolonged than its t1/2

• Headache is the most common adverse effect, followed by giddiness, mental confusion, blurring of vision, depression and psychotic disturbances.

• Total daily dose is 50-150mg in divided doses (Indomethacin 25mg cap) after food.

Indole Derivatives

Tocolytic agent: As effective as MgSo4

It dec. preterm birth significantly by arresting premature uterine contractions

Dose; 25mg 2-3 times a day.

Sulindac:

• Fluorinated derivative of indomethacin• It is a prodrug and has a longer duration of action• Given orally in the dose of 100-200mg twice a day

Indole Derivatives Cont..

These are:

Ibuprofen, naproxen, flurbiprofen and ketoprofen• Analgesic, antipyretic and anti-inflammatory properties

similar to Aspirin• Better tolerated orally• Adverse effects are lower than aspirin and indomethacin• Highly bound to plasma proteins (92-99%)• ADR: cause GI disturbances such as epigastric pain,

nausea, sensation of fullness in the stomach and heartburn

• Less frequently they may cause CNS symptoms

Propionic acid Derivatives

Mefenamic acid:

• Useful in chronic and dull aching pains• No advantages over other NSAIDs• Weaker analgesic than aspirin• Adverse reactions include gastric upset, diarrhoea,

dizziness, headache, skin rashes, hemolytic anemia • Dose is 500mg 2-3 times a day• Used in Dysmenorrhoea

Anthranilic acid Derivatives (Fenamates)

Diclofenac:

• Probably has greater activity than other NSAIDs• Extensively bound to plasma proteins, t1/2 is 1-2hrs

• Accumulates in the synovial fluid- probably responsible for its longer duration of action than its t1/

2

• Incidence of adverse reactions is 20%• Adverse effects similar to propionic acid

derivatives+elevation of liver enzymes

Arylacetic acid Derivatives

Piroxicam:

• Structurally different from other NSAIDs• Given orally, well absorbed, has long t1/2 (38-45hrs) –

administered OD• Commonly causes GI and CNS disturbances• Has been used to treat rheumatoid arthritis, ankylosing

spondylitis, osteoarthritis and acute gout• Has no advantages except a longer duration of action

Oxicam Derivatives

Ketorolac:

• Has less antiinflammatory activity• IM. 20-30mg (single dose) is a moderately effective

analgesic in patients with moderate to severe postoperative pain

• IV ketorolac has been as effective as, and have fewer side effects than morphine in surgical and chronic cancer pain

• Has longer duration of action (t1/2 5hrs)

• Metabolised in liver and excreted by kidneys

Pyrollo pyrollo Derivatives

• The commonly used drug is Paracetamol (Acetaminophen)

• Potent antipyretic and equianalgesic with aspirin in therapeutic doses but devoid of significant antiinflammatory effect

• Does not produce gastric irritation, acid –base imbalance, electrolyte disturbances nor does it affect blood clotting

• Hence is preferred to aspirin as an analgesic antipyretic• Absorption, fate and excretion:• Rapidly absorbed on oral administration• Peak plasma levels are reached within ½ an hour to

1hour

Para aminophenol Derivatives

• Metabolised in the liver and excreted in urine as conjugation products of glucuronic and sulfuric acids

• Poor metabolism in infants- enhanced toxicity

Adverse effects:• At recommended therapeutic doses (500-1000mg) in

healthy subjects is well tolerated

Hepatic and renal toxicity:• Larger doses (7-10gm) produce extensive hepatocellular

damage and renal tubular necrosis, and may cause death

Para aminophenol Derivatives Cont..

• This is a major problem in paracetamol poisoning• Liver toxicity is due to N-acetyl-P- benzoquinone imine

which normally turns harmless by conjugation with glutathione

• Early manifestations are just nausea, vomiting, abdominal pain and live tenderness with no impairment of consciousness

• After 12-18hrs centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycemia that may progress to coma


paracetamol

N-acetyl benzoquinone imine

Glutathione conjugate of toxic metabolite(non toxic, excreted)

Cell proteins get covalently Bound to toxic metabolite→cell death

Oxidation of SH groupOf hepatic and renal Cell proteins

Methionine orN-acetylcysteineConjugates of toxic metabolite

For normal therapeutic doses

In toxic doses

Treatment

Glutathione

Glutathione


Treatment:• Patient is brought early (within 16hrs of ingestion)• Vomiting should be induced or gastric lavage done• Activated charcoal is given orally or through tube to

prevent further absorption• Other supportive measures, as needed, should be taken

Specific:• N- acetylcysteine 150mg/kg should be infused i.v. over

15min, followed by the same dose i.v. over next 20hrs


Nefopam:

• Different from other NSAIDs since it has atropin like actions

• Effective in traumatic and post operative pain, and in musculoskeletal pain not responding to other NSAIDs

• Atropine like adverse effects • Contraindicated in epilepsy

Benzoxazocine Derivatives

These are:

Nimesulide, Meloxicam, Nabumatone

Nimesulide:• Relative weak PGs inhibitor with COX-2 selective action• Other mechanisms implicated are reduced superoxide

generation by neutrophils, inhibition of PAF synthesis and free radical scavenging action

• Gastric and other adverse effects are similar to other NSAIDs

Has been reported to cause nephrotoxicity and hepatotoxicity Not licensed in some developed countries And it has been withdrawn from others Use should be avoided especially in children and old persons

Pref COX-2 inhibitors

• Selectively block COX-2 activity more than COX-1 activity

• Less action on stomach, blood vessels and kidneys

This group includes:

Celecoxib, Rofecoxib and Valdecoxib• Given orally, absorption is complete• Established analgesic- antiinflammatory NSAIDs• They have to be shown effective in treatment of

osteoarthritis and rheumatoid arthritis• Their major advantage is that they cause fewer gastric

ulcers and do not inhibit platelet aggregation• Stomach friendly

Selective COX-2 Inhibitors

Adverse effects:• The most common adverse effects are nausea, vomiting,

dyspepsia, abdominal pain, diarrhoea and edema of the lower extremities

• Share some of the renal adverse effects of non selective COX inhibitors and renal toxicity

• Hence their use should be restricted to patients who do not tolerate other NSAIDs

Selective COX-2 Inhibitors Cont..

Recently, the use of rofecoxib and valdecoxib has been reported to be associated with increased incidence of MI and stroke

Hence, they have been withdrawn by the original manufacturers

Currently all the selective COX -2 inhibitors are under suspicion regarding their long term toxicity

They have been described as drugs with “marginal efficacy, heighted risk and excessive cost compared with traditional NSAIDs”

Selective COX-2 Inhibitors Cont..

• Diclofenac 1% gel• Ibuprofen 10% gel• Naproxen 10% gel• Ketoprofen 2.5% gel• Flurbiprofen 5% gel• Nimesulide 1% gel• Piroxicam 0.5% gel

Topical NSAIDs

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Health & Medicine

Nsaids