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Non Steroidal Anti Inflammatory Drugs

NSAIDS

Lecturer: Mahamoud Garaad


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.
CAUSES
• Burns
• Chemical irritants
• Frostbite
• Toxins
• Infection by pathogens
• Physical injury
• Immune reactions due to hypersensitivity
• Radiation
• Foreign bodies
The classic signs and symptoms
of acute
inflammation

English Latin
Redness Rubor*
Swelling Tumor/Turgor*
Heat Calor*
Pain Dolor*
Loss of Functio laesa
function **
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.
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Membrane phospholipids
Cosrticosteroids
Phospholipase
Arachidonic acid

Lipoxygenase COX NSAIDS

Leukotienes Prostaglandins Thromboxane Prostacyclin

Prostanoids
Synthesis of Prostaglandins
Cyclo-oxygenase (COX)
pathway
Membrane Phospholipids
Phospholipase A2

Arachidonic Acid

COX

Prostaglandins
Thromboxanes
Prostacyclin
NSAID
s
• 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.


NSAID
s
• Analgesic
• Antipyretic
• Anti-inflammatory actions
• Compared to Morphine:
– Weaker analgesics
– Do not depress CNS
– Do not produce physical
dependence
– No abuse liability
NSAID
s
• They are also called:
– Non narcotic
– 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.
Common characteristics of all
NSAIDs

• 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
Classificati
on
Non selective COX inhibitors:
1. Salicylates Aspirin, Diflunisal
2. Pyrazolone derivatives
Phenylbutazone
,

Oxyphenbutazo
ne
3. Indole derivatives Indomethacin, Sulindac
4. Propianic acid Ibuprofen, Naproxen,
derivatives Ketoprofen, Flurbiprofen
5. Anthranilic acid Mephenamic acid
8. Oxicam derivatives
derivatives Piroxicam,
Tenoxicam.
6. Aryl-acetic acid Diclofenac
derivatives
Classificati
on
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
Non selective COX inhibitors:
Salicylates Aspirin, Diflunisal
Pyrazolone derivatives Phenylbutazone
,
Oxyphenbutazo
ne
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

Piroxicam, Tenoxicam.
Oxicam derivatives
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
Synthesis of
Prostaglandins Cyclo-
oxygenase (COX) pathway

Membrane Phospholipids
Phospholipase A2

Arachidonic Acid

NSAIDs COX

Prostaglandins
Thromboxanes
Prostacyclin
COX

 Cyclooxygenase (COX) is found bound to the endoplasmatic


reticulum. It exists in 3 isoforms:
COX-1 (constitutive) acts in physiological conditions.
COX-2 (inducible) is induced in inflammatory cells by
pathological stimulus.
COX-3 (in brain).
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COX-
1
 It is responsible for the Physiologic production of
prostanoids.
 It is enzyme that regulates the normal cellular
processes (via production of PGs) such as
 Gastric cytoprotection
 Vascular homeostasis
 Platelet aggregation
 Kidney function.
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.
• 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
Aspirin – Pharmacological
actions
2. Analgesic action:

• Mild analgesic effect


≤ codeine
• Effective in non -
visceral pain
• Inhibition of
peripheral PG
synthesis
Aspirin – Pharmacological
actions
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
Aspirin – Pharmacological
actions
5. 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
6. Acid -base and electrolyte balance:
• Significant changes at antiinflammatory doses
• Hypokalemia, Respiratory alkalosis.
Aspirin – Pharmacological
actions
 7. CVS:
 No direct effect in therapeutic doses
 Larger doses increase Cardiac Output (3g)

 8. GIT:
 Irritate gastric mucosa and cause epigastric
distress,
nausea and vomiting
• Also stimulates CTZ
• Heart burn, dyspepsia, erosion,
Gastric ulcers.
Aspirin – Pharmacological
actions

9. Effect on platelets/coagulation:
• TXA2 enhances platelet aggregation
• PGI2 decreases it
• Low doses(80-100mg/day) An anticoagulant effect with
a prolonged BT
Aspirin – Pharmacological
actions
10. Local irritant effect:
• Cause irritating to the skin & mucosa and destroys
epithelical cells
• Keratolytic effects

11. Endocrine effect:


• Large dose stimulate adrenal cortex by hypothalamus
inc adrenocortico steroid production
• L.Dose dec. thyroid uptake of iron cause goitre.
Aspirin –
Pharmacokinetics
• 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
• 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
Aspirin – Adverse
effects
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
Aspirin – Adverse
effects
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
Aspirin – Adverse
effects
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
Contra-indication aspirin

• Peptic ulcer

• Ulcerative colitis

• Gout

• Renal failure

• Patients hypersensitive to salicylates

• Hemophilias
Aspirin – Uses

1. As analgesic
2. As antipyretic
3. Antiinflammatory
i. Acute rheumatic fever
ii. Rheumatoid arthritis
iii. Osteoarthritis
4. Cardio protective
Aspirin –
Doses(oral)
• 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
Other clinically used
Salicylates
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
Pyrazolone
Derivatives
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
Indole
Derivatives
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
• 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
Propionic acid
Derivatives
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
Anthranilic acid Derivatives
(Fenamates)
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
Arylacetic acid
Derivatives
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
Oxicam
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.
Pyrollo pyrollo
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
Para aminophenol
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
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
Treatment:( toxicity)
• 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
Benzoxazocine
Derivatives
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
Pref COX-2
inhibitors
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
Selective 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
 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”
Topical
NSAIDs
• Diclofenac 1% gel
• Ibuprofen 10% gel
• Naproxen 10% gel
• Ketoprofen 2.5% gel
• Flurbiprofen 5% gel
• Nimesulide 1% gel
• Piroxicam 0.5% gel
Thank
you