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nsaids.pptx
1. NON STEROIDAL ANTI INFLAMMATORY
DRUGS AND ANTIPYRETIC-ANALGESICS
Dr.V.Balaji MD,
Assistant Professor
Department of Pharmacology
GNMC,Namakkal,TN.
2. INTRODUCTION TO NSAIDS
Chemically diverse, but most are organic acids
Grouped together as these drugs have common ANALGESIC
(pain reducing) and ANTIPYRETIC (fever-reducing) effects and
which have, in higher doses, ANTI-INFLAMMATORY effects
Do not depress CNS – no physical dependence or abuse
liability
Weaker analgesic than Morphine – except inflammatory pain
Also called non-narcotic, nonopioid and aspirin-like
analgesicsPrimarily act on peripheral pain mechanism, and
also inCNS (Raise threshold)
3. History of NSAIDs
• Salixalba or White Willowbark
• Sodiumsalicylate–1875
• Acetylsalicylicacid–1899
– Alsophenacetin andantipyrine
• Phenylbutazone–1949
• Indomethacin -1963
4. CLASSIFICATION
Traditional – Nonselective COX inhibitors
Group Drugs
Salicylic acids Aspirin
Propionic acids Naproxen, Ibuprofen, Ketoprofen,
Oxaprozin and Flurbiprofen
Anthranilic acid Mefenamic acid
Aryl-acetic acid derivative Diclofenac and Aceclofenac
Oxicam derivatives Piroxicam and Tenoxicam
Pyrrolo-pyrrole derivative Ketorolac, Indomethacin,
Nabumetone
Indole derivatives Sulindac and Indomethacin
Pyrazolone derivative Phenylbutazone, Oxyphenbutazone
5. CLASSIFICATION – contd.
Nimesulide,Diclofenac,
Aceclofenac, Meloxicam
and Nabumetone
Celecoxib, Etoricoxib
and Parecoxib
Preferential COX-2inhibitors
SelectiveCOX-2inhibitors
Analgesic-antipyretic with
poorantiinflammatory
action:
Paraaminophenol derivative
Pyrazolone derivative
Benzoxazocine derivative
PARACETAMOL
(ACETAMINOPHEN)
METAMIZOLE AND
PROPIPHENAZONE
NEFOPAM
6. NSAIDs and Pr ostaglandins
•All NSAIDs inhibit PG synthesis
•Prostaglandins, prostacyclines (PGI 2 ) and
Tromboxane A2 (TXA2 ) are produced from
Arachidonic acid
•The enzyme responsible is prostaglandin synthase,
also known as cycloxygenase or COX
•COX in 2 isoforms: constitutive - COX-1 and inducible
COX-2
•COX-1 serves house keeping functions
•COX-2 is generated by cytokines and others during
inflammation (constitutive in brain and JG cells) – PG
synthesis
•Most NSAIDs inhibit COX-1 and COX-2 non-
selectively and inhibit PG synthesis
•Aspirin inhibits COX irreversibly – acetylation
Other NSAIDs are competitive reversible
inhibitors
7. Proposed Mechanism: COX-1,COX-2,& COX-3
Arachidonicacid
COX-2
(inducibl
e)
Bodyhomeostasis
• S
t
o
mach
• Intestine
• Kidney
• Platelet
Inflammatory Site
• Macrophages
• Synoviocytes
• Endothelialcells
X X
Selective
COX-2inhibitor
COX-1
(normal
constituent)
X
Normal Constituent
• CNS
• Kidney
• FemaleU/G tract
Glucocorticoids
(blockmRNAexpression)
X
X
Acetaminophen
COX-3
(normal
constituent)
Pain
Fever
?HTN
?GI
• CNS,Heart, Aorta
Nonselective
NSAID
9. Major effects of PGsynthesis
inhibition
1. Analgesia:Prevention of pain nerveending
sensitization
2. Antipyresis:Reduction of Body temperature in
hyperthermia
3. Anti-inflammatory action: reduction in signsof
inflammation (pain, tenderness, swelling and
vasodilatation)
4. Antithrombotic action: Inhibition of platelet
aggregation
5. Closureof Ductusarteriosusin Newborn
10. 1. Analgesia
What isPain ?
“An unpleasant sensory and emotional
experience associated with actual or
potential tissue damage, or described
in terms of such damage.”
International Association for the Study of Pain
(IASP)
.
12. Acute PainvsChronic Pain
Acute Chronic
Usually accompanied by
obvious tissue damage
Increased autonomic
nervous activity
Pain resolves with healing
of the underlying injury
Serves a protective
function
Pain that extends 3 or 6
months beyond onset or
beyond the expected
period of healing1
Ceases to serve a
protective function2
Degrades health and
functional capability2
3
vs.
1
13. Nociceptive Neuropathic
Classification of Pain
•
•
•
Pain that arises from a
stimulus that is outside of
the nervous system –
receptors stimulated
Proportionate to the
stimulation of the
receptor
When acute serves a
protective function
Musculoskeletal
disorders are a very
common cause
•
Pain initiated or caused by
a primary lesion or
dysfunction in the nervous
system
No nociceptive stimulation
required
Disproportionate to the
stimulation of receptor
•
•
vs
15. NSAIDs induced Analgesia
•
Peripheral component:
– PGs (especially E2 and I2) sensitize afferent nerve endings to
pain
– induces chemical and mechanical stimuli
– Induce hyperalgesia – by affecting transducing property of free
nerve endings – normal stimuli may become painful
– NSAIDs do not block direct PG application related pain and
tenderness
– But, block the pain sensitizing mechanism induced by –
Bradykinin, TNF and Interleukins (IL) and others – by inhibiting
COX-2
– More effective against pain due to inflammation
Central Component: Antihyperalgesic (analgesic)
effects through inhibition of PGs release in spinal
dorsal horn and CNS
•
17. 2. ANTIPYRESIS
•
.
Against pyrexia (fever)
Reduction in body temperature in case of hyperthermia -
not in normothermic individuals
MOA: during infection and tissue injury
Fever – by generation of pyrogens - interleukins, tnf-alpha
and interferones – induce production of PGE2 in
hypothalamus – raise its temperature set point
COX-2 and COX-3 (?) isoforms
NSAIDS block the action of PG production
in hypothalumus and reduce temperature
•
•
18. 3. ANTIINFLAMMATORY
•
At the site of injury – enhanced COX-2 mediated
PG synthesis
NSAIDS inhibit PG synthesis at the site of
injury – antiiflammatory response of
different nsaids depend on capacity to
inhibit COX (potency)
Also inhibit other mechanisms: PGs are not sole
mediators of inflammation - other mediators - lts, PAF
and cytokines etc. –
Also, adhesion molecules – elam-1 & icam-1 –
chemotaxis inflammatory cell express selectins and
integrins
Some NSAIDS also act – inhibition of generation
of superoxide/free radicals - also GM-CSF, IL-6
19. 4. Antiplatelet aggregator
•
•
•
•
TXA2 is pro-aggregator (COX-1)
PGI2 is anti-aggregator
Most NSAIDs - effects on TXA2 predominates and
inhibits aggregation – prolonged bleeding time
Aspirin is highly active and acetylates COX in
circulation – before hepatic 1st pass metabolism
• Even small dose
Antithrombotic effect – Myocardial Infarction and other
cardiac conditions
20. 5. Ductus arteriosus
• It is a shunt connecting the pulmonary artery to the
aortic arch
Maintained by local PGE2andPGI2
Closesat birth
Failure to close – small dosesof NSAIDs(aspirinor
indomethacin) –closes
•
•
•
(No NSAIDs in late pregnancy– premature closure)
21. Dysmenorrhoea
• Severe pain during menstruation – may
precede menstruation or during
menstruation
• Caused by increased release of PGs
(PGF2α) due to increased destruction of
endometrial cells and release of their
contents
• Intermittent ischaemia of myometrium –
cramps
• NSAIDs - decrease PG release
22. Gastric Mucosa
All NSAIDs produce gastric mucosal
damage, ulceration and blood loss –
varying extentA
Due to inhibition of COX-1 mediated
synthesis of gastro protective PG
(PGE2 and PGI2 )
– Also back diffusion of H+ in gastric mucosa
Deficiency of PGs reduces mucus and
HCO 3 secretion – promote mucosal
ischaemia
Enhance aggressive factors over defensive
factors - Ulcerogeic
Paracetamol – free of gastrictoxicities Selective COX-2inhibitors
Misoprostol
23. Renaleffects
•
•
During hypovolemia, decreased renalperfusion
Particularly important in conditionsof
– CHF
,hypovolaemia, cirrhosis and renal impairment (Na+retention
and edema)
– Patent under antihypertensives anddiuretics
PGscause: (Intrarenal regulator)
– Renalvasodilatation and inhibition of tubularreabsorption
– Frusemide like effect – inhibition of Cl-reabsorption
– Increased excretion of Na+,K+andwater
NSAIDsblock these renal effects by inhibition PGs
– Impairment of renal bloodflow
– Na+and water retention
– Papillary necrosison prolongeduse
•
•
•
25. Salicylates
•ASPIRIN is acetylsalicylic acid, the Prototype - converted in the
Body to Salicylic acid – Oldest analgesic
•Other important salicylates – Sulfasalazine, Diflunisal
•Natural Sources - fruits, vegetables, herbs, spices, nuts, and tea
26. Pharmacological – analgesic,
antipyretic andantiinflammatory
•
•
•
Weaker analgesic than Morphine – 600 mg VsCodeine 60 mg
Aspirin irreversibly inhibits COX-1& COX-2activity
Inhibits COXirreversibly by acetylation – fresh enzyme
synthesis requires for return
– Mainly effective in pains related toinflammation, tissue injury,
connective tissue and integument pain
– Not much effective in visceral and ischemicpain
Mechanism – prevention of PG-mediated sensitizationof
nerve endings
Other mechanisms:
– Raisingof pain threshold by acting centrally – morphine like – butno
sedation, subjective effects, tolerance or physicaldependence
– Resetting of hypothalamic thermostat – feverreduction
Anti-inflammatory dosesare higher than analgesicdoses
•
•
•
27. Pharmacological actions –contd.
• Metabolic effects: Increased cellular metabolism
• Uncoupling of oxydative phosphorylation →increased heat
production
Increased utilization of glucose – decreasedblood sugar and
glycogen depletion
Negative Nitrogen balance (increased protein to carbohydrate)
Toxic doses: Hyperglycaemia
•
•
•
• Respiration:
•
•
•
Low doses:↑ CO2→stimulates respiration
Increased sensitivity of Respiratory centre to CO2
In Poisoning - Direct stimulation of respiratory center→
Hyperventilation
Higher doses- depression of respiratory center →Death dueto
Respiratory Failure
•
28. Aspirin – acid-baseBalance
•
•
Analgesic doses(0.3 – 1.0 gm /day) – no effects
Anti-inflammatory doses(4 - 5 gm/day) – veryimportant
changes in acid-basebalance
– Initially Respiratorystimulation – due to stimulation ofrespiration
and hyperventilation - Increased expelling of CO2in spite of increased
production – Respiratoryalkalosis
• Increased excretion of HCO3-with Na+,K+and water – Compensated
RespiratoryAlkalosis
– Still Higher doses: Respiratory depression – retention of CO2–
Respiratory acidosis
• Added acids – pyruvic acid, lactic acid and dissociated salicylic acid Net
result is – UncompensatedMetabolic acidosis
29. Aspirin –contd.
GIT:
Salicylic acid – irritant to mucosa causing nausea and
vomiting
Unionized in stomach and absorbed but upon
absorption – ionizesand indiffusible (Ion trapping)
Locally – back diffusion of acid – necrosis of mucosa and
arteries – ulceration, erosive gastritis etc.
Occult blood loss – haematemesis
Salicylate-induced gastric bleeding is painless
and may lead to an iron deficiency anemia
•
CVS:
–
–
Therapeutic doses have no significant cardiovascular
effect
High doses- increased BP- increased COand
peripheral vasodilation by exerting a direct effect
on smooth muscle
Toxic doses - depress circulation directly and by
central vasomotor paralysis CCF– low cardiac reserve
patients
–
–
30. Aspirin –contd.
•
Hematologic effects:
–
–
– Itinhibits the platelet aggregation by decreasing
the production of TXA2– lasts for aweek
In doses greater than 6 gm/day, aspirin may
reduce plasma prothrombin levels
Prolonged use – decrease in synthesis of clotting
factors
•
Urate Excretion:
–
–
–
Doselessthan 2 gm/day – urate retention
2-5 gm/day – variable effects
More than 5 gm/day – increased urateexcretion
31. Aspirin Pharmacokinetics
•
•
Absorbed from stomach and SI
Poorly water soluble –
limitation
– Solubility c an be inc r eas ed by alk aliz ations – but ???
Converted to salicylic acid in gut, liver and
plasma
80-85% bound to plasma protein - can cross
placenta and CSF
Metabolized in liver by conjugation with glycine –
salicyluric acid
Excreted as glomerular filtration and tubular
secretion T1/2 life is 15-20 minutes
– 8 – 12 H r s due to metabolic pr oc es s s atur ation
– H igh dos es have long t1/2
32. Aspirin - ADRs
•
Gastrointestinal disturbances
– Nausea, vomiting, epigastric distress and gastric mucosaldamage
•
Hypersensitivity and Idiosyncrasy: FDE,rash, urticaria, asthma
(bronchospasm – aspirin sensitive asthmatics)
Salicylism: on repeated administration (3-5gm/day)
•
–
–
–
headache, mental confusion, lassitude, anddrowsiness
tinnitus and difficulty inhearing
hyperthermia, sweating, thirst, hyperventilation, vomiting, anddiarrhea
•
Hepatotoxicity:
–
–
Risein serum transaminases – hepatotoxic
Reye`sSyndrome– rare diseaseof hepatic encephalopathy when given in
viral conditions of influenza andvaricella
•
•
•
Nephrotoxicity: Na+and water retention, ch. Renalfailure
Prolongation of bleed time or reduce prothrombin level
Respiratory:Asthma, rhinitis
33. Treatment of acute Poisoning- Aspirin
•
•
•
Fatal dose: 15 – 30 gm Low in
caseof children
Features: Vomiting, dehydration, acidosis, petechial
haemorrhage, hyperglycaemia, hyperpyrexia, confusion and
coma etc.
Management:
•
–
–
Inducing emesis or administering gastric lavage
Appropriate infusion measures to correct abnormal
electrolyte balance and dehydration – Na+, K+,HCO3etc.
asper need
Alkalinization of theurine
Dialysis as required
Vit.K injection
–
–
–
34. Aspirin –
Therapeutic uses
1. Analgesic: Headache, migraine, backache, tothache,
dysmenorrhea etc (300 to 600 mg 8Hrly)
2. Rheumatoid arthritis: (3-5gm/day)
Usedto be standard first line ofdrug
Poorly tolerated – newerNSAIDS
1. Acute Rheumatic Fever: (4-5gm/day)
First drug of choice – other drugsare added when itfails
Doseis reduced after 1 weektherapy
Continued for 3-4weeks
gradual withdrawal for over 2weeks
1. Osteoarthritis
2. Antipyrretic
35. Aspirin and Myocardial infarction
•
Routinely prescribed forpost myocardial infarction
patients – prophylaxis purpose to preventre-
infarction
MOA- TXA2(pro-aggregator)
inhibition Doseis very low (60 –
100mg/day)
High doses inhibit PGI2(anti-aggregator)
Primary prophylaxis (100 to 150 mg –
moreuseful) ReducesTIAand lowers
incidence of stroke
•
•
•
•
•
Aspirin preparations: Tablets of various strength – 75 mg,100
mg, 325 mg, 650 mg etc. Aspirin, Disprin, Loprin, Ecospirin
etc.
36. Aspirin –Contraindications
1. Sensitive Persons
2. Children with viraldiseases
3. Peptic ulcer diseaseand bleeding disorders
4. Chronic liver diseases
5. Diabetes, CHFand juvenile Rh.Arthritis
6. G-6-PDdeficient persons
7. Stopprior to surgery, near termpregnancy,
breast feeding mothers etc
37. Aspirin – Drug Interactions
•
Aspirin and Probenecid:
–Antagonize Uricosuric action of probenecid
–Probenecid become ineffective in Gout
Aspirin and oral anticoagulants (warfarin and
sulfonylureas)
–Toxicity (increased tendency of bleeding)
Aspirin and anti-hypertensive:
–NSAIDscause fluid retention and oedema
– antihypertensive effects are decreased
Aspirin and Diuretics: (furosemide and
thiazides)
–Blunting of Furosemideeffects
•
•
•
38. Aspirin - Uses
•
Analgesic: Backache, myalgia, toothache, joint pain, pulled muscle and
dysmenorrhoea
Antipyretic : Fever of any origin – Paracetamol safer
Acute Rheumatic fever: 75 – 100 mg/kg/day (or, 4 – 5 gm/day) –
marked symptomatic relief – all cases
– dose reduced after 4 - 7 days and maintained for 2 - 3 weeks till s/s
stops - withdrawal should begradual
RheumatoidArthritis: Reduction in pain, swelling and stiffness – large
dose
Osteoarthritis: Asand when needed – Paracetamol is the choice
Post-myocardial infarction and post stroke: Routinely used – inhibits
platelet aggregation (TXA2) at low dose (60 – 100mg/day) – but, high
dose can reverse (PGI2 inhibition)
– New onset or sudden onset angina (risk of infarction) - 75 to 150 mg/day for 12
weeks ….Also in TIA
Other uses:PIH,PDA,Familial colonic polyposis and Prevention of colonic
cancer
•
•
•
•
•
•
39. Propionic acid derivatives
•
•
Ibuprofen, Naproxen, Ketoprofen, Flurbiprofen
Analgesic, antipyretic and anti-inflammatory efficacy islower than
aspirin (low potency) – all inhibits PGsynthesis (Naproxen – most
potent)
– Antiplatelet activity – short with Ibuprofen but longer with naproxen
Adverse Effects: Better tolerated than aspirin and Indomethacin –
milder – gastric discomfort, nausea,vomiting,
– gastric erosion rarely
– CNSeffects - headache, dizziness,blurring of vision, tinnitus and depression
– Rash,itching and hypersensitivity are less
– Precipitates aspirin induced asthma
•
40. Propionic acid derivatives –contd.
•
Pharmacokinetics: All are well absorbed orally – 90-99%plasma protein
bound
–
–
–
But lesserdisplacement of otherdrugs
Inhibits platelet function – use with anticoagulants areavoided
Decreasesantihypertensive and diuretic actions of furosemide, thiazides and beta-
blockers
Uses:Not given in pregnancy and Peptic ulcer patient
Ibuprofen: Simple analgesic and antipyretic – like low dose aspirin–
dysmenorrhoea
Also in Rh.Arthritis, OAand musculoskeletal disorders – pain prominent
conditions
Also in STI,fractures, vasectomy, tooth extraction, postpartum andpost
operative pain
Naproxen – preferred in acute gout – stronger anti-inflammatoryand
inhibition of leucocyte migration – longer half-life(12-16 hours)
•
–
–
–
–
41. Fenamates - Mephenamic acid
•
Analgesic, antipyretic and weak anti-inflammatory –
inhibition of certain PGsynthesis – peripheral + central
analgesic
ADRs:Diarrhoea, epigastric distress, skin rash,
dizziness and other CNSADRs
Kinetics:Slow oral absorption, but complete,bound to
plasma protein – displacementreactions
Uses:asanalgesic in muscle, joint and soft tissue pain ---
- Dysmenorrhoea
•
•
•
42. Enolic acid derivatives - Piroxicam
•
Multiple action NSAID,Longacting, good anti-inflammatory, good analgesic-antipyretic
action
–
–
–
Reversible, non-selective COXinhibition
Synovial fluid – lowers PGsynthesis and inhibits platelet aggregation DecreasesIgM
rheumatoid factor and leucocyte chemotaxis
•
•
ADRs: Contrast COX-1 blocking action - More GI effects than Ibuprofen - but less
than Indomethacin, lesser ulcerogenic – lesser occult blood than aspirin - also rash,
pruritus and serious skinreactions
• Kinetics: Rapid complete absorption, 99% plasma bound, t1/2– 2 days (ss – 1 week);
excreted in bile and urine – EHcirculation
Uses:Longterm anti-inflammatory – rheumatoid arthritis, osteo-arthritis,
ankylosing spondylosis, acute gout etc. – Not first choice for any conditions …
Relative higher toxicity thanOthers
43. Acetic acid - Indomethacin
• Indole acetic acid derivative - Potent anti-inflammatory andprompt
antipyretic
–
–
Relieves only inflammatory and injury related pain
Highly potent inhibitor of PGand neutrophil motility
• Use:Reservedrug - ankylosing spondylitis, destructive arthropathies,
psoriatic arthritis, postoperative pain, malignancy associated fever,
medical closure of PDA
Kinetics:well absorbed orally, 90%PPbound and t1/22 – 5 Hours
ADRs:High incidence of gastric and CNSside effects (COX-1related) –
gastric, irritation, nausea,anorexia, bleeding anddiarrhoea
•
•
– CNS:Frontal headache, dizziness, ataxia, mental confusion, hallucination,
depression and psychosis
– Leucopenia, hypersensitivity, rashetc.
– Increased risk of bleeding – low plateletaggregation
• Contraindications:machinery operators, drivers, psychiatric & epileptic
patients kidney disease,pregnancy & children
44. Acetic acid derivatives -Ketorolac
•
Potent analgesic – but modest anti-inflammatory – post operative pain
– equal efficacy with Morphine (butno receptor interaction)
Inhibits PGsynthesis – inhibits painperipherally
Uses:GivenIM and orally - Post-operative, dental, musculo-skeletal
pain
–also in renal colic, migraine – short term management of moderate
pain
–rated superior to aspirin and paracetamol and equivalent toibuprofen
– Concurrent use with morphine (reduce dose) – but notused with
anticoagulant – not to be used for more than 5 days
Kinetics:Well absorbed orally and IM – highly plasma protein bound; t1/2
5
–7 Hrs – 60%excretes unchanged in urine
ADRs:Nausea, abdominal pain, dyspepsia, ulceration, dizziness,
nervousness, pain in injection site, rise in serum transaminase,
•
•
•
•
45. Pyrazolones
• Metamizole (Analgin) is aderivative of
Amidopyrine. It is apotent and promptly
acting analgesic, antipyretic, andspasmolytic
- but poor antiinflammatory and noturicosuric
activity
– Analgin can be given orally, i.m. aswell asi.v.
(very slowly)
• ADRs:Agranulocytosis
• Analgin, Novalgin, Baralgan, Ultragin etc
46. Preferential COX-2
inhibitors -
Nimesulide
•
• Weak PG synthesis inhibitor, moderate COX-2 selective
– Other Mechanisms: reduced superoxide generation by
neutrophils, inhibition of PAF, TNFα release & free radical
scavenging
– Completely absorbed and 99% plasma protein bound
– Half life – 4-5 hours and excreted in urine
Uses: sports injuries, sinusitis, dental surgeries, renal
colic, arthritis, postoperative inflammatory condition,
fever, low back pain, ENT disorders– no cross
reaction of aspirin and other NSAIDS related
bronchospasm – specific usefulness
• ADRs:epigastric pain, nausea, loose motion, heart
burn, rash, pruritus, somnolence and dizziness – GIT
47. Preferential COX-2
inhibitors –
Diclofenac
•
•
Analgesic-antipyrretic and antiinflammatory – efficacy similar to
naproxen Inhibits PG synthesis – somewhat COX-2 selective
–
–
Reduced Neutrophil chemotaxis and reduced superoxide
generation No antiplatelet action (COX-1 sparing)
•
•
•
99% plasma protein boung – 2 hours
half-life Good tissue and synovial fluid
penetration
Uses: Most widely used drug – RA, OA, Bursitis, ankylosin
spondi;it is, bursitis, toothache, dysmenorrhoea, renal colic,
post trauma and post inflammatory conditions
ADRs: Mild epigastric pain, nausea, headache, dizziness and
rashes – less gastric ulceration and bleeding - Risk of heart attack
and stroke
•
48. Selective COX-2 inhibitors -
Celecoxib, Etoricoxib and
Parecoxib
•
•
•
• Inhibit COX-2 without inhibiting COX-1 - benefits
– Less peptic ulcer occurrence, less ulcer bleeds
– Do not depress TXA2 production (COX-1) of platelets
– Do not inhibit platelet aggregation, & do not prolong bleeding
time – But reduce PGI2 production
Disadvantage: Reduce PGI2 production by vascular
endothelium leading to increase prothrombotic
effect & enhance cardiovascular risks
Uses: Patients with high risks of PU, perforation at
lowest dose and shortest period
Contraindications: History of IHD, hypertension, CHF
and CVA
49. Coxibs –
contd.
Other concerns of selective COX-2
inhibition:
•
•
• Efficacy: COX-1 generated PGs may play
role in inflammation – broad range action
(??)
Gostroprotectivity disturbed: Injury and H. pylori
induce COX-2 – gatsroprotective PG synthesis
locally
…. Delay in ulcer healing
Concern over COX-2 Physiological Role:
Constitutive in JG renal cells – Na+ and water
retention, oedema, precipitation of CHF and
50. Para-amino phenol
derivatives - Paracetamol
(acetaminophen)
•
•
•
Phenacetin 1887 – banned now
(Nephropathy) Its deethylated active
metabolite of Phenacetin
Analgesic – Like aspirin - Antipyretic , raises pain threshold but no
PG inhibition except COX inhibition in brain – no peripheral anti-
inflammatory action
–
–
–
–
–
Good promptly acting antipyretic
Additive analgesic action with Aspirin (central +
peripheral) Negligible antiinflammatory action
Poor inhibition of PG in peripheral tissues – but high in CNS !!
Explanation:Inflammatory area – peroxide generation – cannot inhibit
COX in its presence at periphery – centrally its lacking – also COX-3
(??)
No stimulation of respiration or affect acid base balance (unlike
aspirin) …no increase in cellular metabolism
No Gastric erosion or platelet function alteration
–
–
51. Paracetamol –
contd.
• Kinetics:orally absorbed, 1/4thPP bound, t1/2: 3 – 5 hours;
Metabolism by conjugation with glucoronic acid and sulfate
ADRs:Safe and well tolerated – analgesic nephropathy (after years)
ACUTEP
ARACETAMOLPOISONING
Commonly occur in Children – low hepatic glucoronidation
conjugation capacity – also in adults
Large dose - >150 mg/kg or >10 gm in adults
Manifestations: Nausea, vomiting, abdominal pain and liver
tenderness
•
•
•
•
•
– After 12 – 18 hours – centrilobular hepatic necrosis, renal tubular
necrosis and hypoglycaemia … and coma
– Jaundice after 2 days
– High dose poisoning – fulminating hepatic failure and DEATH
52. Paracetamol
toxicity
• N-acetyl-p-benzoquinoneimine (NAQBI) – highly
reactive arylating minor metabolite – normally
detoxified by conjugation with glutathione
Large dose of Paracetamol – glucoronidation
capacity gets saturated – more NAQBI formed
Hepatic glutathione depleted – metabolites bind
covalently to proteins in liver and renal tubular cells –
necrosis
– 5-6 gm in alcoholics (CYP2E1) - dangerous
Treatment: Early cases - Induction of vomiting
(activated charcoal) and other supportive measures
– N-acetylcysteine – 150 mg/kg IV for 15 min – followed by same
dose for 20 hours … replenishes glutathione store and
prevents further binding with cellular contents
•
•
•
54. Paracetamol
Uses
•
•
Most commonly used – over the counter drug
Headache, mild migraine, musculoskeletal
pain dysmenorrhoea etc.
1stchoice in osteoarthritis, not effective in
Rheumatoid arthritis
Safest Antipyretic in children – no Reye`s syndrome
Advantages – 1) lesser gastric irritation, ulceration and
bleeding (can be given in ulceration) 2) does not
prolong bleeding time 3)
Hypersensitivity rarely 4) no metabolic
disturbances 5) can be given in all age group –
pregnancy- lactation 6) No significant
drug interactions
•
•
•
55. Topical
NSAIDS
•
•
NSAIDS are also effective topically –
gel/spray etc.
Advantages:
1. Attains higher conc. Locally in muscles and joints – low blood
levels
2. GI and other systemic ADRs are minimized
3. First pass metabolism avoided
• Kinetics:slow absorption – 10 times longer time to attain peak
plasma conc. to oral dosing
•
•
•
Highest blood level – 15% of the same oral dose,
Local conc. Upto 4 - 6mm high (dermis); 25 mm in
muscles (low) Overall efficacy depends on site
• Uses:Osteoarthritis, sprains, sports injuries, spondylitis and soft
tissue rheumatism etc. – safety no issue but efficacy (!) local
application, massaging – counter irritant - menthol and methyl
salicylate
• More efficacious in short lasting musculo-skeletal pain
