NON STEROIDAL
ANTI INFLAMMATORY
DRUGS
Dr.s.Vinodhini
Department of Pharmacology
Perception of painful stimulus Nociception (termed by
Sherrington)
Pain = Nociception + Affective component
Opioid group strongly reduce the distress (affective component)
associated with the pain without strongly affecting the intensity
of nociceptive component.
Under normal conditions, pain is associated with impulse
activity in small diameter (C and A-delta) fibers of
peripheral nerves.
These nerves have endings in peripheral tissues (skin,
muscles and viscera)
These nerve endings respond to stimuli of various kind
(mechanical, thermal, chemical)
Tissue injury is the immediate cause of pain
A variety of local mediators are released following tissue injury
e.g. Bradykinin, Prostaglandin, Histamine
These mediators act on peripheral nerve endings and either
activate them directly or increase their sensitivity of other
mediators.
Primary mechanism of action is their ability to inhibit
Cyclo-oxygenase enzyme
Thus, reducing the formation of Prostaglandins and
Thromboxanes
There are two common isoforms of this enzyme
COX-1 and COX-2
• Algesia (Pain): It is an ill defined sensation usually evoked by an
external or internal noxious stimulus.
• Analgesic: A drug that selectively relieves pain by acting in the CNS
or on peripheral pain mechanism without significantly altering
consciousness
CYCLOOXYGENASE PATHWAY
Classification
A) Non selective COX inhibitors/ conventional NSAIDS
1) Salicylates - Aspirin* , Diflumisal
2) Pyrazolone derivative – Phenybutazone , Oxybutazone
3) Indole derivative – Indomethacin , Sulindac
4) Propionic acid derivative – Ibuprofen*, Naproxen, Ketoprofen
5) Antranicillic acid derivative – Mephenamic acid
6) Aryl acetic acid derivative – Diclofenac*
7) Oxicam derivative – Piroxicam , Tenoxicam
8) Pyrrolo pyrrole derivative - Ketorolac
B) Preferential COX inhibitors
Nimsulide
Meloxicam
C) Selective COX – 2 inhibitors
Celecoxib
Rofecoxib
Valdecoxib
D) Analgesic Anti pyretic with poor anti inflammatory action
1) Para aminophenol derivative – Paracetamol*
acetoaminophen
2) Pyrazolone derivative – Metamizol , Propiphenazone
3) Benzoxazocine derivative - Nefopam
Beneficial effects of NSAIDS
1) Analgesic action
PGE2 + PGI2 NSAIDS
Sensitise Afferent N
Pain
Central action. Inhibition of PG synthesis in spinal dorsal horn
neurons and in brain. Central subcortical action- raising threshold
to pain.
2) Anti- pyretic action
Pyrogens +IL
Interferons+ INF-α
PG synthesis in hypothalamus NSAIDS
Raise temperature set point
Fever
3) Anti inflammatory action
NSAID inhibits
PG secretion
ECAM-1 ICAM-1
Selectins & Integrins
4) Antithrombotic activity
NSAIDS TXA2 Proaggregatory
PGI2 Antiaggregatory
Aspirin- 75- 150 mg/day or 300 mg twice weekly.
5) Dutus arteriosus closure
PGE2 & PGI2 Keep ductus open unknown mech
closes it at birth
6) Dysmenorrhoea
PGE2 Contraction intermittent pain of
uterus ischaemia
Adverse effects and toxicity
1)Gastric mucosal damage
PG Mucosal & HCO3- secretion
NSAIDS Mucosal ischemia Gastric pain
enhanced acid mucosal
secretion ulceration
2) Bleeding
3) Limitation of renal blood flow
Hypovolemia Oppose ADH
Renal perfusion PG Vasodilation Na +loss
Tubular reabs
NSAIDS decrease COX-1 dependent renal blood flow
4) Delay/ Prolongation of labour
PG Trigger labour & facillitates its prolongation
NSAIDS Delays or retards labour
5) Asthma and Anaphylactoid reaction
Diversion of AC to LTs
6) Hepatic damage
NSAIDS raises transaminase hepatic failure
7) CNS Manifestations
Headache, mental confusion, behavioural disturbances, seizures
precipitation
Aspirin
Pharmacological action
1) Analgesic, antipyretic, anti-inflammatory, antiplatelet
2) Metabolic effects (at anti-inflammatory doses)
3) Respiratory failure
- At anti-inflammatory doses Resp. stimulated
- At higher doses Resp. depression Resp. failure
4) Acid base and electrolyte imbalance
5) CVS
Large Doses increased cardiac output
Toxic doses depresses vasomotor BP
centre
6) GIT
Nausea vomitting & epigastric distress (irritation & CTZ)
Back diffussion of gastric acid
Occult blood loss
7) Urate excretion
8) Blood - bleeding time doubles
PHARMACOKINETICS
• Absorption from stomach and small intestine
• Metabolism in gut wall, liver, plasma and other tissues
• Plasma bound ~ 80%
• t1/2 =15-20 mins
• Elimination = urine
Adverse Effects
1) Gastric mucosal damage & peptic ulceration
2) Hypersensitivity and idiosyncrasy
3) At Anti inflammatory dose (3-6 gm/day)
- Salicylism syndrome
- Liver Damage
4) Reye’s syndrome = Hepatic encephalopathy in children having
viral infection
5) Acute salicylate poisoning
- Dose in adults 15-30 gm
- Serious toxicity at serum levels > 50 mg / dl
Manifestations
- Vomiting, Dehydration
- Hallucination
- Hyperpyrexia
- Convulsions
Treatment
Symptomatic and supportive
- External cooling
- Maintain electrolyte balance = i.v. fluid with Na+ K+ HCO3-
and glucose
- Gastric Lavage
- Forced alkaline diuresis or hemodialysis
- Blood Transfusion and Vit K (if bleeding occurs)
• SYMPTOMS OF ASPIRIN SENSITIVITY
Precautions and Contraindications
In patient with peptic ulcer, bleeding tendencies
In children suffering from viral infection
In chronic liver disease
In Pregnancy - Low birth weight babies
- Prolonged labour
- blood loss
- Pre Mature closure of ductus arteriosus
In G-6-PD deficiency = hemolysis
Interactions
Displace plasma bound drugs - warfarin
- naproxen toxicity
- sulphonylureas
- methotrexate
Patients on oral anticoagulants – bleeding tendencies
uric acid level - tubular secretion
- Antagonises uricosuric action of probenecid
Blunts diuretic action of furosemide & thiazides
USES
1) Analgesic(0.3-1.5 g)
2) Antipyretic
5) Rheumatoid arthritis
6) Osteoarthritis
7) To delay labour
8) To close patent ductus arteriosus
9) Prevention of colon cancer
Propionic acid derivatives
Ibuprofen
Antipyretic analgesic & antiinflammatory action is lower than aspirin
A/E : Milder , some CNS & GI manifestatons
Uses : 1) analgesic & antipyretic – used in dysmenorrhea
(400-600mg)
2) R.A. , O.A. & Other musculoskeletal disorders
3) Indicated in soft tissue injuries
Aryl Acetic Acid Derivative
Diclofenac Na
Has good tissue permeability & conc in synovial fluid is high
A/E : Mild epigastric pain & ulceration, bleeding, kidney
damage rare
Uses : R.A. O.A. , ankylosing spondylitis, dysmenorrhoea (50mg TDS)
Aceclofenac
• Moderately selective COX-2 congener of diclofenac.
• Enhancement of glycosaminoglycan synthesis–
chondroprotictive action.
• Dose- 100 mg BD
Drugs Pharmacokinetic Adverse Uses
s Effects
Pyrazolones P.B. = 98% Bone marrow Rheumatoid
Depression, Arthritis,
Phenybutazolone T1/2 = 60 hrs
Agranulocytosis Ankylosing
Oxyphenbutazone Abs = Orally Spondylitis
Indole P.B. = 90% GIT Patent Ductus
derivative T1/2 = 2-5 hrs CNS Arteriosus
Indomethacin Abs = Orally Rheumatoid
Arthritis,
Sulindac Metabolised = Liver
Ankylosing
Excretion = Kidney
Spondylitis
Drugs Pharmacokineti Adverse Uses
cs Effects
Anthranilic acid P.B. = high Diarrhoea, Dysmenorrhoea,
derivative T1/2 = 2-4 hrs Skin rashes, Muscle Joint and
(Fenamate) Abs = Orally Dizziness Soft Tissue pain
Mephenamic acid Excretion = Urine and
Bile
Oxicam P.B. = 99% Same as Rheumatoid
Derivatives T1/2 = 48 hrs Indomethacin Arthritis,
Piroxicam Abs = Orally Ankylosing
Tenoxicam Excretion = Urine and Spondylitis,
Bile Osteoarthritis,
Acute Gout
Drugs Pharmacokinetic Adverse Uses
s Effects
Pyrrolo pyrrole P.B. = high GI Post op pain,
derivatives T1/2 = 5-7 hrs CNS Acute
Ketorolac Abs = Orally and i.m. Increase Musculoskeletal
Serum pain, Renal Colic
Excretion = Urine (60%
tranaminase Migraine(15-30mg
unchanged)
im or iv)
Preferential COX-2 Inhibitor
Nimesulide
Relative COX-2 selectivity
Pharmacokinetics : absorbed orally
P.B. - 99%
t ½ - 2-5 hrs
A/E : G.I. Manifestation , dermatological , CNS Manifestation &
Fulminant hepatitis
Uses : Short lasting painful inflammation , dysmenorrhoea, post
OP pain, asthmatic ,intolerance to aspirin
Selective COX-2 Inhibitor
Inhibits COX-2 without affecting COX -1
low ulcerogenic potential
Platelet aggregation remains intact
Assessment of selective COX- 2 Inhibitor
COX-1 enz may have some role in inflammation so selective COX
inhibitor don’t have broad range efficacy
Ulcer & H pylori stimulates COX-2 secreting PG-- gastroprotective,
so inhibition is injurious
JG COX-2 is constitutive
Its inhibition may lead to Oedema CHF
salt and water retention Rise in BP
COX – 1 TXA2 Proaggregatory
COX – 2 PGI2 Antiaggregatory
• Drugs: Celecoxib, Refecoxib, Valdecoxib
• Should not be used in patients with hepatic and renal failure.
Para-Amino Phenol Derivatives
Paracetamol
Good antipyretic and analgesic action but poor anti-
inflammatory action (0.5-1g tds)
Pharmacokinetics
• t1/2 = 2-3 hrs
• Excretion = Urine
• Adverse Effects = GI Irritation rare
Bleeding rare, Asthma.
• Analgesic Nephropathy
• Pathologial lesions - Papillary necrosis
- Tubular atrophy
- Renal Fibrosis
Acute Paracetamol Poisioning
Dose: > 150 mg/kg (Children)
> 10g/kg (adults)
Fatal Dose: > 250 mg/kg
Mech. of Toxicity
Minor Metabolite: N-acetyl benzo quinoneimine (NABQI)
Large doses: glucoronidation capacity saturated
Necrosis
Rx
Induce emesis
Gastric Lavage
Specific antidote: N-acetyl cysteine 150 mg/kg i.v. followed
by same dose iv over next 20 hrs.
Uses: Fever, Headache, Musculoskeletal pain, dysmenorrhoea
Analgesic Nephropathy
• Renal disease characterized by chronic
interstitial nephritis (CIN) and renal papillary
necrosis(RPN) caused by prolonged and
excessive consumption of analgesic.
New safety concerns
• Stroke and MI ( long term use at high dose)
• Infertility– reversible
• Paracetamol --Asthma
• Antidepressents + NSAID= Greater risk of
intracranial hemorrhage
Selection of NSAID
• Paracetamol
Mild/moderate pain • Low dose ibuprofen
Post op. or short lasting • Ketorolac ,diclofenac,
pain
• Paracetamol
Musculoskeletal pain • Ibuprofen, naproxen,ketoprofen
RA,AS,ACUTE • Naproxen, piroxicam,
GOUT,ACUTE RH.FEVER • Indomethacin, high dose aspirin
• Paracetamol
GI IRRITATION • Cox-2 inhibitors
H/O HS reaction to • Paracetamol or COX-2 inhibitors
tNSAIDS
Paediatric pts • Paracetamol, ibuprofen and naproxen
Pregnancy • Paracetamol
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