Transcript File

NONSTEROIDAL ANTIINFLAMMATORY DRUGS AND
ANTIPYRETIC-ANALGESICS
MS.NAGESWARARAO
DEPT OF MEDICAL PHARMACOLOGY
• All drugs grouped in this class have analgesic, antipyretic and
anti-inflammatory actions in different measures.
▪ In contrast to morphine they are weaker analgesics, do not
depress CNS, do not produce physical dependence and have
no abuse liability.
▪They act primarily on peripheral pain mechanisms, but also
in the CNS to raise pain threshold . They are more commonly
used drugs.
CLASSIFICATION
A. Nonselective COX inhibitors ( traditional NSAIDs )
1. Salicylates:
Aspirin.
2. Propionic acid derivatives: Ibuprofen, Naproxen,
Ketoprofen, Flurbiprofen.
3. Anthranilic acid derivatives: Mephenamic acid.
4. Aryl-acetic acid derivatives: Diclofenac, Aceclofenac.
5. Oxicam derivatives:
Piroxicam, Tenoxicam.
6. Pyrrolo-pyrrole derivative: Ketorolac.
7. Indole derivative:
Indomethacin.
8. Pyrazolone derivatives:
Phenylbutazone,
Oxyphenbutazone.
 B. Preferential COX-2 inhibitors: Nimesulide, Meloxicam,
C. Selective COX-2 inhibitors:
Nabumetone.
Celecoxib, Etoricoxib,
Parecoxib.
D. Analgesic- antipyretics with poor anti-inflammatory
action
1. Paraaminophenol derivative: Paracetamol
(Acetaminophen).
2. Pyrazolone derivatives:
Metamizol (Dipyrone),
Propiphenazone.
3. Benzoxazocine derivative:
Nefopam.
 MECHANISM OF ACTION:
 Prostaglandins, Prostacyclin (PG I2) and thromboxane A2(TXA2)
are produced from arachidonic acid by the enzyme cyclooxygenase
which exists in a constitutive (COX-1) and an inducible (COX-2 )
isoforms.
 Cox-1 is constitutive, found in most tissues such as blood vessels, stomach
and kidney. PGs have important physiological role in many tissues.(GI
protection, platelet function, kidney function , regulation of blood flow and
lowers IOP etc
 COX-2 is induced during inflammation by cytokines and endotoxins, and is
responsible for the production of prostanoid mediators of inflammation,
pain and fever.
 Most NSAIDs inhibit COX-1 and COX-2 nonselectively, , but some
preferential and selective COX-2 inhibitors have been produced
SALICYLATES ASPIRIN (PROTOTYPE)
▪ Aspirin is acetyl salicylic acid. It is rapidly converted in the body to
salicylic acid which is responsible for most of the actions
▪It is one of the oldest analgesic- anti-inflammatory drugs and is still
widely used .
MOA: Inhibits irreversibly both the COX nonselectively
PHARMACOLOGICAL ACTIONS:
 Analgesia- Due to peripheral inhibition of prostaglandin synthesis.
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Relieve pain without causing sedation, tolerance or drug dependence.
They are mainly relieving musculoskeletal pain , dysmenorrhea and
pain associated with inflammation or tissue damage.
 Antipyresis : Inflammation, bacterial infection
Increase in PGE2
Hypothalamus – Raises its temperature set point
Aspirin by inhibiting PG synthesis decreases temperature
They promote heat loss by causing cutaneous vasodilatation and swatting.
 Anti-inflammatory:
 Inhibits PG synthesis at the site of injury . And also affect
other mediators of inflammation –bradykinin , histamine ,
serotonin etc.
 Other mechanisms
 Produce symptomatic relief
 Suppress – Pain
swelling,
vasodilatation.
But they do not affect the progression of underlying disease.
 Antiplatelet aggregation (Antithrombotic effect ):
PGI2
Platelet aggregation
vasodilatation
inhibit platelet aggregation
TXA2
Vasoconstriction
promote platelet aggregation
 Aspirin (low doses 50-325 mg ) by inhibiting TXA2 it prevents platelet
aggregation .
 Aspirin in high doses (2-3g/day) inhibits both PGI2 and TXA2
synthesis, hence beneficial effects of PGI2 is lost.
 Respiration and Acid-base, electrolyte balance:
Anti-inflammatory doses (therapeutic dose)
Stimulation of respiration
Hyperventilation
Respiratory Alkalosis (which is compensated by
excretion of alkaline urine )
At toxic doses –
Respiratory depression
CO2 retention
Respiratory acidosis (later, there is
uncompensated metabolic acidosis )
 Gastrointestinal tract:
 Aspirin irritates the gastric mucosa and produces nausea ,
vomiting and dyspepsia.
 Aspirin also stimulates CTZ and produces vomiting.
 Cardiovascular system:
 Prolonged use of these drugs Causes sodium and water
retention.(inhibit COX-2 in kidney)
 Thus can precipitate CCF and they may also compromise
the effect of antihypertensive drugs.
 Urate excretion :
 Salicylates in therapeutic doses inhibit urate secretion into the renal
tubules and increase the plasma urate levels.
 In high doses, salicylates inhibit the reabsorption of uric acid in the
renal tubules and produce uricosuric effect.
PHARMACOKINETICS
 Absorbed from stomach and small intestines
 Poor water solubility-micro fining enhances absorption
 80 % bound to plasma proteins
 Volume of distribution 0.17L/Kg - 11L
 Conjugated with glucuronic acid and glycine
 Excreted by glomerular filtration and tubular secretion
 In low doses , elimination follows 1st order kinetics and with high doses as
the metabolizing enzymes get saturated ,it switches over to zero order
kinetics.
 Analgesic dose(0.3-1.5 g /day)- t½ 3-5 hours
 Antiinflammatory dose(3-5 g /day)-t½ 8-12 hours
 Anti platelet dose : 50-325 mg/day.
ADVERSE EFFECTS
 Side effects-analgesic dose-nausea, vomiting,epigastric distress, increased
occult blood in stools-gastric mucosal damage, peptic ulceration.
 Ulcerogenic effect is the major drawback of NSAIDs which is prevented /
minimized by taking:
-After food
- buffered aspirin (preparation of aspirin with antacid)
- Misoprostol/H2 blockers /PPIs with NSAIDs
- selective COX-2 inhibitors
 Hypersensitivity and idiosyncrasy are more common with aspirin-
rashes, urticaria, rhinorrhoea, nasal polyps ,angioedema,
bronchospasm and anaphylactoid reaction.
 Aspirin induced asthma (due to incresesd production of LT ) LT
antagonists are effective to treat aspirin induced asthma.
 Anti-inflammatory doses-salicysm-dizziness, tinnitus, vertigo,
reversible
impairment of hearing and vision, excitement and mental confusion,
hyperventilation and electrolyte imbalance. these symptoms are
reversible on stoppage of therapy.
 Reye’s syndrome- Use of salicylates in children's with viral infection
may cause hepatic damage with fatty infiltration and encephalopathy.
Hence these drugs are contraindicated .
 In Pregnancy: These drugs inhibit PG synthesis, there by delaying
onset of labour.
and Increase chances of PPH. In new-borns inhibition of PG s synthesis
results in Premature closure of ductus arteriosus.
 Haemostatic effects:
Prolonged use of salicylates interfere with action of vitamin K in the liver
Decreased synthesis of clotting factors (hypoprothrombinaemia)
Predisposes to bleeding (can be treated by administration of vit K)
 Analgesic nephropathy: mainly seen in renal disease
patients.
 Slowly progressive renal failure / chronic nephritis occurs
on chronic use of high doses of NSAIDs.
 This is mainly due to inhibition of PGE2 mediated
compensatory vasodilatation that occurs in response to
angiotensin-2
ACUTE SALICYLATE POISONING
 More common in children
 Fatal dose in adults is 15-30 g
 Vomiting, dehydration, electrolyte imbalance, acidotic breathing,
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petechial haemorrhages, restlessness,, hallucinations,
hyperpyrexia, convulsions, coma - death due to respiratory failure
+ cardiovascular collapse
TREATMENT symptomatic and supportive
IV fluids with Na, K, HCO3 and glucose
Gastric lavage-alkaline diuresis-haemodialysis
Bleeding-blood transfusion- vit k
External cooling
PRECAUTIONS AND CONTRAINDICATIONS
 Hypersensitivity, peptic ulcer, bleeding tendencies, children suffering from
chicken pox or influenza
 Chronic liver disease-may cause hepatic necrosis
 CHF – sodium and water retention
 Stopped one week before surgery –bleeding
 Taken at or near term may cause- prolonged labour-greater
postpartum blood loss-premature closure of ductus arteriosus (PGE2 &PGI2)
 Bronchial asthma patients
 Avoid high doses in G-6-PD deficiency-may cause haemolysis
Interactions
 Displaces warfarin, phenytoin from protein binding sites
 Alcohol and glucocorticoids increase the risk of gastritis
 Increase risk of bleeding in patients on oral anticoagulant
Clinical uses of NSAIDS:
 Analgesic-(0.3-0.6 g 6-8 hourly)-headache,toothahe, joint pains etc
 Antipyretic-Paracetamol preferred (no Reyes syndrome in children's and
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GIT symptoms are less)
Acute rheumatic fever-4-5 g/day in divided doses-dose reduction after 4-7
days- it reduce fiver , swelling and joint pain.
Rheumatoid arthritis-(3-5 g/day)
Osteoarthritis-Paracetamol is first choice drug.in severe cases NSAIDs are
effective
Post myocardial infarction and post stroke patients-50-150 mg/day –inhibit
platelet aggregation.
Primary prevention of myocardial infarction
 Other uses:
 Medical closure of patent ductus arteriosus (indomethacin is preferred)
 Colon and rectal cancer: regular use of aspirin is reported to reduce the
risk of cancer (COX-2 inhibition in colon)
 To control pruritus and flushing associated with the use of nicotinic acid
(Aspirin will inhibit PGD2 in he skin)
OTHER NSAIDS HAVE SIMILAR MECHANISAM OF ACTION,
PHARMACOLOGICAL ACTIONS, THERAPEUTIC USES AND ADVERSE
EFFECTS. THEY VARY MAINLY IN THEIR POTENCY, DURATION OF
ACTION, ANALGESIC AND ANTIINFLAMMATORY EFFECTS.
PROPIONIC ACID DERIVATIVES
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Ibuprofen-Naproxen-Ketoprofen-Flurbiprofen
Side effects are milder and incidence is lower
Ibuprofen rated as the safest conventional NSAID
Naproxen more efficacious-better tolerated-longer lasting
Ibuprofen-200,400,600mg tab, 100mg/ml susp-400-600mg TDS
Naproxen-250,500mg tab-250-500mg BD-TDS
Ketoprofen-50,100,200mg tab, 100mg/ml amp-50-100 mg BD-TDS
Flurbiprofen-50,100,200mg tab-50-100 mg BD-QID
0.03% eye drops-1 drop 6 hourly
 ANTHRANILIC ACID DERIVATIVE
 MEPHENAMIC ACID-An analgesic, antipyretic with potent anti
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inflammatory action
Diarrhoea is the most important dose related side effect
Haemolytic anaemia is a rare but serious complication
Used primarily as analgesic in muscle, joint and soft tissue pain
where strong anti-inflammatory action is needed
125,250,500 mg tab, 250-500 mg TDS
50 mg/ml syrp, 100 mg/5 ml susp
ARYL-ACETIC ACID DERIVATIVES
 DICLOFENAC SODIUM-Similar in efficacy to Naproxen
 Most extensively used NSAID
 Used in osteoarthritis, bursitis, ankylosing spondylitis,toothache,
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dysmenorrhoea, post-traumatic and postoperative inflammatory
conditions
Affords quick relief of pain and wound edema
25,50 mg tab-50 mg TDS then BD oral,
25
mg/ml in 3ml amp given deep i.m.
1%
topical gel and 0.1% eye drops
ACECLOFENAC-Congener of Diclofenac-longer acting
100 mg tab-100 mg BD
▪ OXICAM DERIVATIVES
 PIROXICAM-long acting potent NSAID
 Antiinflammatory efficacy similar to Indomethacin
 Good analgesic-anti-inflammatory action
 Better tolerated than Indomethacin and aspirin
 Used in rheumatoid and osteo-arthritis, ankylosing spondylitis,
acute gout, musculoskeletal injuries, dentistry, episiotomy,
dysmenorrhoea, etc
 10,20 mg cap-20 mg BD for two days followed by 20 mg OD
20
mg/ml inj in 1 and 2ml amps
 TENOXICAM-a congener of Piroxicam –similar properties uses 20
mg tab-20 mg OD
 PYRROLO-PYRROLE DERIVATIVE
 KETOROLAC-A novel NSAID with potent analgesic and modest
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anti-inflammatory activity
In post operative pain it has equalled the efficacy of morphine
Does not interact with opioid receptors and is free of opioid side
effects
Used in postoperative, dental and acute musculoskeletal pain
May also be used for renal colic, migraine and pain due to metastasis
30 mg in 1 ml amp-15-30 mg im or iv every 4-6 hours (maximum
90mg/day)
10 mg tab – 10-20 mg 6 hourly
Use for more than 5 days continuously not recommended
 INDOLE DERIVATIVE
 INDOMETHACIN-It is a potent anti-inflammatory drug with
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prompt antipyretic action
A high incidence (up to 50%) of gastrointestinal and CNS side
effects is produced
Gastric irritation, nausea, anorexia, gastric bleeding and diarrhoea
are produced
Frontal headache, dizziness, ataxia, mental confusion,
hallucination, depression and psychosis can occur
Because of prominent adverse effects, Indomethacin is used as a
reserve drug in conditions requiring potent anti-inflammatory
action like ankylosing spondylitis, acute exacerbations of
destructive arthropathies, and acute gout
25,75 mg cap 25-50 mg BD-QID
1% eye drops 50 mg suppository
 PYRAZOLONES
 METAMIZOL(DIPYRONE-ANALGIN)
 It is a prompt acting analgesic and antipyretic with poor anti
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inflammatory action
It can be given orally, im as well as iv
Few cases of agranulocytosis were reported
0.5-1-5 g oral/im/iv
0.5 g tab, 0.5 g/ml in 2 ml and 5 ml amps
PROPIPHENAZONE-Claimed to be better tolerated
Agranulocytosis not reported
SARIDON-Propiphenazone 150 mg +Paracetamol 250 mg tab
DART-Propiphenazone 150 mg + Paracetamol 300 mg +
Caffeine
50 mg tab
 PREFERENTIAL COX-2 INHIBITORS
 NIMESULIDE-has relative COX-2 selectivity
 Instances of fulminant hepatic failure reported
 Withdrawn in Tanzania and many countries
 100 mg tab – 100 mg BD, 50 mg/5 ml susp
 MELOXICAM-newer congener of Piroxicam
 Long acting can be given once daily
 Gastric side effects are milder compared to Piroxicam
 Used in osteo arthritis and rheumatoid arthritis
 7.5, 15 mg tab 7.5-15 mg od
 NABUMETONE-effective in the treatment of rheumatoid arthritis,
osteo arthritis and soft tissue injury
 500 mg tab-1 tab daily
 SELECTIVE COX-2 INHIBITORS
 Cause little gastric mucosal damage
 Do not inhibit platelet aggregation-platelet TXA2 not affected
 Reduces anti aggregatory endothelial PGI2
 Rofecoxib and Valdecoxib withdrawn for increasing
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cardiovascular risk (Due to inhibit PGI2 with out effecting
TXA2)
CELECOXIB-gastric tolerability better than nonselective NSAIDs
Used in osteo arthritis and rheumatoid arthritis
100, 200 mg caps,100-200 mg BD
ETORICOXIB-newer COX-2 inhibitor - for once a day treatment
60, 90, 120 mg,60-120 mg OD
PARECOXIB-suitable for injection-efficacy similar to Ketorolac
40 mg/vial inj, 40 mg tab
40 mg oral/ im/ iv, repeated after 6-12 hours
PARA-AMINO PHENOL DERIVATIVE
 PARACETAMOL(ACETAMINOPHEN)
 Recent evidences suggests that paracetamol may act by inhibiting
cox-3 in CNS. cox-3 is involved in pain perception and fever but not
in inflammation.
 Has analgesic, antipyretic actions
 Weak anti-inflammatory action
 Does not stimulate respiration or affect acid base balance
 Does not increase cellular metabolism
 Has no effect on CVS
 Gastric irritation is insignificant
 Does not affect platelet function
 PARACETAMOL
 Well absorbed on oral administration
 1/4th is plasma protein bound
 Uniformly distributed in body
 Metabolism mainly conjugation with glucuronic acid and sulfate
 Conjugates excreted rapidly in urine
 Plasma t ½ is 2-3 hours
 Effects after an oral dose lasts 3-5 hours
 ADVERSE EFFECTS-Safe and well tolerated
 Nausea and rashes occur occasionally
 Hepatotoxicity and nephrotoxicity is seen on chronic use.
 ACUTE PARACETAMOL POISONING
 Occurs commonly in small children having low glucuronide conjugating
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capacity
15-20 g in an adult fatal
Hepatic necrosis, renal tubular necrosis, hypoglycemia –may progress to
coma and death
Minor metabolite N-acetyl-p-benzoquinoneimine is detoxified by
conjugation with glutathione
Toxicity manifests when glutathione is depleted
Specific antidote N-acetylcysteine replenishes glutathione stores of liver
and prevents binding of toxic metabolite to proteins in the liver and
kidney.
Activated charcoal is administered to decrease the absorption of
paracetamol from the GIT
Hemodialysis may be required in case with acute renal failure.
 PARACETAMOL-USES
 One of the most commonly used over the counter analgesic
 Used for headache, mild migraine, musculoskeletal pain,
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dysmenorrhoea
First choice analgesic for osteo arthritis
Is best drug to be used as antipyretic
500 mg tab 0.5-1 g TDS
125 mg/ 5 ml syrup, infants 50 mg, 1-3 years 80-160 mg, 4-9 years
240-320 mg, 9-12 years300=600 mg TDS
TOPICAL NSAIDs
 Topical formulations for application over painful muscles or joints
 Believed that drug penetrates subjacent tissues attaining high
concentrations in the affected muscles/joints, while maintaining
low blood levels
 Strong placebo effect of local application-massaging
 Presence of counter irritants like menthol, methyl salicylate, etc.
 Diclofenac 1% gel, Ibuprofen 10% gel, Naproxen 10% gel,
Ketoprofen 2.5% gel, Flurbiprofen 5% gel, Nimesulide 1% gel,
Piroxicam 0.5% gel
CHOICE - NONSTEROIDAL ANTIINFLAMMATORY DRUG
 Mild to moderate pain with little inflammation: Paracetamol or low
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dose Ibuprofen
Postoperative or similar acute but short lasting pain: Ketorolac,
Propionic acid derivative, Diclofenac, Nimesulide, Aspirin
Acute musculoskeletal, osteoarthritic, injury associated pain:
Paracetamol, propionic acid derivative, Diclofenac
Exacerbation of rheumatoid arthritis, ankylosing spondylitis, acute
gout, acute rheumatic fever: Naproxen, Piroxicam, Indomethacin, high
dose aspirin
Gastric intolerance to traditional NSAIDs or predisposed patients: a
selective COX-2 inhibitor or paracetamol
CHOICE – NONSTEROIDAL ANTIINFLAMMATORY DRUG
 Patients with history of asthma or anaphylactoid reaction to aspirin/other
NSAIDs: Nimesulide, COX-2 inhibitor
 Paediatric patients: Only Paracetamol, Aspirin, Ibuprofen, Naproxen have
been adequately evaluated in children. Due to risk of Reye’s syndrome
Aspirin should be avoided
 Pregnancy: Paracetamol is the safest; Low dose Aspirin is probably the
second best
 Hypertensive, diabetic, ischaemic heart disease, epileptic and other patients
receiving long term regular medication: possibility of drug interaction with
NSAIDs should be considered
ANALGESIC COMBINATIONS
 Additive synergism
 Aspirin + Paracetamol
 Ibuprofen + Paracetamol
 Diclofenac + Paracetamol
 Aspirin + Codeine
 Paracetamol + Codeine
THANK YOU