2. 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.
4. The classic signs and symptoms of acute
inflammation
English
Redness
Swelling
Heat
Pain
Loss of function
Latin
Rubor*
Tumor/Turgor*
Calor*
Dolor*
Functio laesa**
5. 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.
7. NSAIDs
• 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
8. NSAIDs
• Analgesic
• Antipyretic
• Anti-inflammatory actions
• Compared to Morphine:
–
–
–
–
Weaker analgesics
Do not depress CNS
Do not produce physical dependence
No abuse liability
Cont..
9. 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.
10. Common characteristics of all 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
14. 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
15. Mechanism of action
Cont..
• 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
18. Beneficial actions due to PG synthesis
inhibition
•
•
•
•
•
Analgesia
Antipyresis
Antiinflammatory
Antithrombotic
Closure of ductus arteriosus
19. 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
20. Salicylates - Aspirin
• Prototype
• Acetylsalicylic acid
• It was obtained from „willow bark‟ (Salicaceae) but
is now synthesized
• Methyl salicylate is a volatile liqiud derivate.
• Irreversible inhibitor of COX
• Nonselective inhibitor of COX
(Counter irritant)
21. 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
22. Aspirin – Pharmacological actions
2. Analgesic action:
•
•
•
Mild analgesic effect
≤ codeine
Effective in non visceral pain
Inhibition of
peripheral PG
synthesis
23. 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
24. Aspirin – Pharmacological actions
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(400µg500µgstimulation 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).
25. Aspirin – Pharmacological actions
5. CVS:
•
•
•
No direct effect in therapeutic doses
Larger doses increase Cardiac Output (3g)
Toxic doses depress VMC
6. GIT:
•
Acid
•
•
•
Irritate gastric mucosa and cause epigastric distress,
nausea and vomiting
pH 7.1
Gastric
pH 1.5
Also stimulates CTZ
A
mucosal cell
s
“Ion trapping”
Asp
p
Heart burn, dyspepsia, gers.astritis, erosion,
Gastric ulcers.
26. Aspirin – Pharmacological actions
7. Effect on platelets/coagulation:
•
•
•
TXA2 enhances platelet aggregation
PGI2 decreases it
Low doses(80-100mg/day) An anticoagulant effect with
a prolonged BT
27. Aspirin – Pharmacological actions
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
28. Aspirin – Pharmacological actions
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.
29. 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
• Vd=0.17L/kg
• Slowly enters the brain but freely crosses placenta
30. 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
31. Aspirin – Adverse effects
a) Gastrointestinal:
•
•
•
•
b)
•
•
•
•
Most common
Epigastric distress, Nausea, Vomiting
Increased occult blood loss in stools
Gastric mucosal damage and peptic ulcer
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
32. 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
34. 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
35. 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
38. Uses
Aspirin – Uses
1. As analgesic
2. As antipyretic
3. Antiinflammatory
i. Acute rheumatic fever
ii. Rheumatoid arthritis
iii. Osteoarthritis
4. Cardio protective
39. 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
40. Other clinically used Salicylates
a)
•
•
b)
•
Sodium salicylate:
Aspirin alternative in rheumatic fever
But now is obsolete
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
41. 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
42. Pyrazolone Derivatives
Cont…
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
43. 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
• 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.
44. Indole Derivatives
Cont..
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
45. 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
46. 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
47. 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
48. 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
• Has no advantages except a longer duration of action
49. 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
50. 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
1hour
51. Para aminophenol Derivatives
Cont..
• 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
52. 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
53. Para aminophenol Derivatives
Cont..
paracetamol
Glutathione
N-acetyl benzoquinone imine
For normal
therapeutic doses
In toxic doses
Treatment
Oxidation of SH group
Of hepatic and renal
Cell proteins
Glutathione
Glutathione conjugate
of toxic metabolite
(non toxic, excreted)
Methionine or
N-acetylcysteine
Conjugates of toxic
metabolite
Cell proteins get covalently
Bound to toxic metabolite
→cell death
54. Para aminophenol Derivatives
Cont..
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
55. 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
56. 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
57. 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
58. Selective COX-2 Inhibitors
Cont..
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
59. 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”
