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4
Which are the features of
inflammation… ?
1. Heat/fever
2. Swelling
3. Pain
4. Redness
5. Loss of function
Fever develops
Pain nerve endings are stimulated
6
• But when these reflexes are EXAGGERATED it is
required to be suppressed because ……
• RAISED TEMPERATURE ….
– May make a person incapable for doing his job.
– May inactivate several enzymes required to
maintain normal metabolism.
– In extreme cases…interfere with the state of
consciousness.
• EXCESSIVE PAIN …
– May interfere with the quality of life.
– May frighten the patient.
– In extreme cases …may produce shock …
7
Injury/infection/trauma
LTA4
PGH2
LTB4 LTC4
ISOMERASE THROMBOXANE PROSTACYCLINE
SYNTHEASE SYNTHEASE LTD4
TXA2 PGI2
PGD2 PGE2 PGF2α LTF4 LTE4
10
TXB2
• Was it frightening…. ?
• DEFINATETLY NEED A REVISION…….. RIGHT ?
11
MEMBRANE PHOSPHOLIPID
PHOSPHOLIPASE
LTA4
PGH2
LTB4 LTC4
ISOMERASE THROMBOXANE PROSTACYCLINE
SYNTHEASE SYNTHEASE LTD4
TXA2 PGI2
PGD2 PGE2 PGF2α LTF4 LTE4
12
TXB2
Summary of the chart…
• Cycloxygenase pathway generates …
– TXA2.
– PGD2
– PGE2
– PGF2α
– PGI2.
• How to remember it ?
• Alphabetical order is … DEFGH
• Here first … G & H and then D E F.
14
• vasodilatation
PGD2
• Bronchoconstriction
LTC4 AND • Increased capillary permeability
LTD4
15
OTHER CHEMICAL
MEDIATORS
PAF Histamine Bradykinin 5-HT Others
• VD • Contraction • Stimulates • Vascular • Kaillidine
• Platelet of venules nociceptors response • Lactic acid
aggregation • Relaxation of • H release • Pain • ATP
• Leucocyte arterioles • Platelet • ADP
infiltration • Increased aggregation
• Degranulation capillary
of leuco. permeability
It is not possible
to remember
everything !!
Don’t worry !!
16
• Its not possible to remember ALL THE EFFECTS
of ALL THE MEDIATORS.
• Just try to remember the NAMES OF
MEDIATORS and
• MAJOR EFFECT produced by it.
17
PAIN
• Unpleasant experience
• Protective reflex
– Warning bell of tissue damage !!
• Interferes with Quality Of Life.
• Two components
– Sensations peripheral component
– Perception central component
18
CLASSIFICATION
• Superficial or coetaneous pain
• Deep pain from muscle, joints, ligaments and
bones.
• Visceral pain-(spasm, infla., ischemia, stim. Of
nerve endings)
• Defferentiation pain /neuropathic pain-
(damage to axons or nerve membranes)
• Psychological/Functional
19
• Now move ahead for “PAIN PATHWAY”
• 1ST Slide shows afferent pathway. ( periphery to
centre).
• 2nd Slide shows efferent pathway.(centre to
periphery).
• Again you are not expected to remember it, but you
should have an idea about nuts and bolts of pain
circuits.
20
Physical/chemical stimuli
Relays fibres to
21
Sensory cortex Frontal lobes Hypothalamus Limbic system
SOMATIC SENSORY
CORTEX
`
Amygdala Hypothalamus
Anterolateral
Midbrain periaqueductal gray matter
System
Parabrachial Medullary
nucleus Locus
Reticular Raphe nuclei
cerulous
formation
22
• Prostaglandins (PGS) sensitize the nerve
endings….
• To the nociceptive stimuli …….
• Caused by …….
• Histamine…… and
• Bradykinin.
23
Pharmacological/Physiological Effects
I. Cardiovascular System
TXA2:
vasoconstrictor.
24
II. PLATELETS
TXA2 stimulates
platelet
aggregation
PGI2 inhibits
platelet
aggregation
25
NORMALLY IN GIT… So PGS have
PROTECTIVE
NSAIDS effect on GIT
blocks this
PGI2 & PGE2
So interaction of
Protease and oxygen
leucocyte with
radicles
endothelial cells
Ischemic injury
Mucosal
ulceration
26
RESPIRATORY SYSTEM
LTC4 AND LTD4 produces
bronchoconstriction +
increased mucus secretion
+Increased vascular
permeability
27
GI TRACT
PGE2 + LT’s
contract
smooth
muscle
28
V. Reproductive Organs
PGE2: and
PGF2:
Both
contract
pregnant
uterus.
29
Pharmacological/Physiological Effects
30
PGS produce PAIN… how ?
PERIPHERALLY :
PGS sensitize the nerve
endings to bradykinin and
histamine
PAIN
CENTRALLY :
PGs Lower the threshold
for central pain circuits
31
PGS produces FEVER….. How ?
• Maintains balance
between heat
production and heat loss
• It regulates heat dissipating
mechanisms
32
Hypothalamus
Normally
When temperatures activates heat losing
hypothalamus is So temperature is This set point it
is elevated beyond mechanisms like
adjusted to a set normalized elevated in FEVER
level sweating and
point
vasodilatation
33
PGs PRODUCES INFLAMMATION …
HOW ?
Increased
capillary
perameabilit
y
INFLAMMATION
34
Mechanism Of Action : NSAIDS
MOST
IMPORTANT
Inhibits the cycloxygenase MECHANISM
36
• Aspirin Diflunisal
Salicylates • Na.salicylate salicylamide
• Acetaminophen
Para-aminophenol
• Diclofenac
Phenyl Acetic acid • Ketorolac
• Piroxicam
Oxicams
• Phenylbutazone Oxyphenbutazone
Pyrazolone derivatives • Analgin Azapropazone
Propionic acid • Ibuprofen Ketoprofen Flurbiprofen
derivatives • Naproxen
• Mafenamic acid
Fenamates • Flufenamic acid
Preferential COX-2 • Nimesulide
inhibitors • Meloxicam Nebumatone
Selective COX-2 • Celecoxib Rofecoxib
37
inhibitors • Paracoxib Lumiracoxib Valdecoxib
38
SALICYLATES
LOCAL ACTIONS
39
Analgesic activity
NSAIDS
blocks..
PAIN
CENTRALLY :
PGs Lower the
threshold for
central pain
circuits
41
ANTIPYRETIC ACTIVITY
• Hypothalamus contains thermoregulatory centre
• Maintains balance between heat production and heat
loss
• It regulates heat dissipating mechanisms
PGE2 has two
mechanisms :
When there is
Increased 1. Increases
tissue Raised body
Neutrophil Stimulates PGE2 synthesis heat
damage/inflamati temperature
releases IL-1 COX-2 enzymes in production.
on/AG:AB FEVER
hypothalamus 2.shuts down
reaction/infection
HEAT LOSING
MECHANISM
47
PHARMACOKINETICS
• Metabolism
Aspirin Deacetylation
Salicylate
Salicylic acid
48
PHARMACOKINETICS
• EXCRETION :
Salicylate
Glycine Oxidized to
Glucuronic acid
conjugation Gentisic acid
conjugation
49
ADVERSE REACTION
• INTOLERANCE :
» HS reaction.
» Angioedema & anaphylactic symptoms adrenalin
» G6PD deficiency hemolytic anaemia
»
Cell Membrane Phospholipids
• Phospholipase A2
NSAIDS
Arachidonic Acid
Cyclooxygenase I&II
Leucotriens
Prostaglandin H2
Inflammation Bronchospasm 50
So increased
So AA
AA is production of SO… NSAIDS
metabolism is
metabolized NSAIDS blocks LTs which PRODUCES/AGG
channelized
by COX and LO COX pathway produces RAVATES
towards LO
pathways bronchoconstri BRONCHOSPASM
pathway
ction
51
GIT
Hypopro
Local thrombi
mucosal nemia
irritation
Antiplate
let
action
GI BLEEDING
52
KIDNEY
Impairment
of RBF and
Na & GFR
H2Oretention
Papillary
necrosis on
long term use
NEPHROTOXICITY
53
REYE’S SYNDROME
Children < 12 years develops viral infection (influenza & vericella)
Administered aspirin
54
Aspirin Toxicity - Salicylism
CV
&
H D RS
Headache
y r e
- timmitus
Confusion Sweating Marked p e h
t Collapse
- dizziness
and and Nausea, acid-base i
– hearing e x y Convulsio
drowzines hyperventi vomiting disturbanc o
impairmen r i d
s lation es
t – dim n ns
vision p a r
y a Coma &
Death
55
MANAGEMENT OF SALICYLISM
• Hospitalization
• Gastric lavage
• Rx of
– Hyperthermia
– Dehydration
– Hypokalamia
– Acid base disturbances
– Ketosis
• Alkalization
• Vit,K, BLOOD TRANSFUSION 56
USES
• LOCAL APPLICATION
– Keratolytic
– Fungistatic
– Antiseptic
– Counter irritant
– IBS
57
• ANALGESIC
– Musculoskeletal pain
– Dysmenorrhea
• ANTIPYRETIC
– Remember, it reduces fever due to inflammation
but not due to ….?????
• ANTIINFLAMMATORY
– Arthritis
– Fibromyositis
58
ANTIRHEUMATIC
Decrease
activation
and function
of
neutrophils
Inhibits
mucopoly
saccheride
biosynthesis
59
ANTIPLATELET ACTION
– Platelets aggregates and provides the nidus for thrombus formation.
promoted by TXA2.
60
NOW IT’S TIME TO REVISE
• What is inflammation ?
• Why it is required to be suppressed >?
• How PAIN and FEVER and beneficial and how they are harmful ?
• Following injury which chemical reactions are set off ?
• What are the effects of PGD2,PGE2,PGF2α, PGI2, TXA2, LTA4 ?
• How will you classify pain ?
• Do your remember pain pathway ? If yes … good …if no … it’s ok.
• What is the effect of different mediators on I.blood vessels, II. platelets, III. GIT, IV. respiratory
system and V. reproductive system ?
• How PGS produces PAIN, FEVER and INFLAMMATION ?
• Which are the mechanisms of action of NSAIDS ?
• Which are the local actions of NSAIDS ?
• How NSAIDS produces ANALGESIC, ANTIPYRETIC and ANTIINFLAMMATORY actions ?
• How it produces anti platelet action ?
• What is the effect of aspirin on urate levels ?
• Which are the main ADRs of NSAIDS ? What are the pharmacological basis of the same ?
• How they produces reye’ s syndrome ?
• What is salicylism ? How will you treat it ?
• Which are the uses of aspirin ? Which are the pharmacological basis of the same ?
61
Diflunisal
• Cancer pain with bone metastases
• For pain control in dental (third molar)
surgery.
• 2% diflunisal oral ointment is a clinically useful
analgesic for painful oral lesions.
62
PARACETAMOL
• Analgesic
• Antipyretic
• Central action> Peripheral action
• 10–15 mg/kg every 4 hours (maximum of 5 doses/24 hours)
• NO
– GI disturbances Acid-base imbalance Electrolyte imbalance
Impairment of clotting
• ADR :
– Extremely safe drug. But rarely produces …. Hepatic toxicity
63
Paracetamol overdose
• Ingestion of >10g of paracetamol may be fatal
• May be lower in chronic alcoholics or subjects with
underlying liver disease.
Clinical features
In severe poisoning
• Up to 24 hours - none or nausea and vomiting
• > 24 hours - nausea and vomiting, right
upper quadrant pain, jaundice,
encephalopathy
64
When normal
dose of
paracetamol is
Minor amount of
taken major
highly reactive They combine Converted to
amount is NO Tissue damage
quinones/epoxide with Glutathione harmless products
metabolized by
s are formed
glucuronid e and
sulfate
conjucation
NAC SUPPLIES MAY BE… NAC
NAC “MAY”directly GLUTATHIONES has additional
conjugates with so detoxifies antioxidant and
quinones/epoxide. toxic antiinflammato
metabolites !! ry activity
Large number of
When large amount Toxic intermediates
highly reactive Glutathione supply
of drug is are formed within Tissue damage
quinones/epoxides falls short.
taken(poisoning) tissue constituents
are formed
PARACETAMOL
(acetaminophen)
Management
• Repeat blood paracetamol estimatations.
66
• Now we will discuss all the remaining NSAIDs..
• Their
– MOA,
– ADR,
– USES
are more or less same.
So we will only discuss differentiating points.
Or something UNIQUE about that particular drug.
You are not required to remember ALL THE DETAILS of ALL THE DRUGS.
This list has been added only so that …. Presentation does not look
incomplete !!!! ????
67
• PHENYLBUTAZONE & OXYPHENBUTAZONE
– Now almost obsolated
• ANALGIN :
– Fatal blood dyscrasias
• DICLOFENAC SODIUM:
• Neutrophil chomotaxis and superoxide production is reduced
• Hepatotoxicity more common than other NSAIDS.
• Eye drops/Gel for solar keratosis (3%)/Rectal suppository for post op.
analgesia/Oral mouthwash/IM injection
• ACECLOFENAC
• More GI friendly
• Some what selective on COX-2.
• Enhancement of glycosaminoglycan synthesis chondroprotective
property.
• MELOXICAM
• Preferential COX-2 inhibitor
68
• ETODOLAC
• Postoperative pain relief after coronary artery bypass operations
• IBUPROFEN
• Oral
• Topical cream preparation -primary knee osteoarthritis
• Patent ductus arteriosus in preterm infants
• FENOPROFEN
• The NSAID most closely associated with interstitial nephritis
• FLURBIPROFEN
• Also affect TNF-a and nitric oxide synthesis??
• 200-400 mg/d
• Ophthalmic formulation for inhibition of intraoperative miosis
• Flurbiprofen intravenously has been found to be effective for perioperative
analgesia in minor ear, neck, and nose surgery and in lozenge form for sore throat.
69
• PIROXICAM
• A nonselective COX inhibitor that at high concentrations also inhibits polymorphonuclear
leukocyte migration, decreases oxygen radical production, and inhibits lymphocyte function.
• Decreases the production of IgM rheumatoid factor.
• USES :
– Same
• TENOXICAM
– SAME ….
• INDOMETHACIN
• PDA – 0.1-0.2 mg/kg /12 hr X 3 times.
• Ophthalmic preparation -- conjunctival inflammation reduce pain after traumatic
corneal abrasion
• Gingival inflammation is reduced after administration of indomethacin oral rinse.
• Malignancy induced fever.
• frontal headache & other CNS side effects. C/I in psychiatric illness or epilepsy.
• HYPERKALAMIA
• KETOROLAC
• Replace morphine in some situations involving mild to moderate postsurgical pain.
• ORAL/IM/IV/EYE DROP
70
• NABUMETONE
– Pseudoporphyria and photosensitivity
• NAPROXEN
– Oral suspension/SR preperation/Eye drops
• SULINDAC :
– Suppresses familial intestinal polyposis
– It may inhibit the development of colon, breast, and prostate cancer
– Sulfa like reaction
• NIMESULIDE
• Weak PG synthesis inhibitor. Relative COX-2 inhibitor
• Other mechanisms like …
– inhibition of neutrophil activation
– Reduced generation of superoxide
– Inhibition of PAF synthesis & TNF α release.
– Free radicle scavanging
– Inhibition of metalloproteinase activity.
– possibly activation of glucocorticoid receptors???
71
SELECTIVE COX-2 INHIBITORS
• CELECOXIB
• ROFECOXIB BANNED BECAUSE OF
CARDIOVASCULAR MORATLITY
• VALDECOXIB
• ETOROCOXIB
• LUMERACOXIB
• PARACOXIB– only selective COX-2 inhibitor for
parental use.
72
Advantages Disadvantage
– Increases cardio vascular
• No ADR like mortality because of
– GI ulceration inhibition of endothelial PGI2
– Bleeding tendency production without effect on
platelet TXA2 synthesis.
– ??Incomplete suppression of
inflammation.
– COX-2 is constitutively
expressed in kidney so
nephrotoxicity can not be
avoided. Na+ and Water
retention,edema,HT,CHF may
be ppted.
73
• CELECOXIB
– GI friendly
– Sulfalike reaction
– Edema and HT
• ETOROCOXIB
– Maximum COX2: COX 1 activity ration
– OA – 60 mg OD
– RA - 90 mg OD
– Acute gouty arthritis 120 mg OD
– Acute musculoskeletal pain- 60 mg OD
– ADR :
• Dry mouth
• Aphthous ulcer
• Taste disturbnaces
• Paraesthesia
• Lumiracoxib :
– Its acidic nature allows it to penetrate well into areas of inflammation
– The half-life in synovial fluid is considerably longer than in plasma.
– Once-daily dosing.
– 900-mg dose.
– Cardiovascular safety questionable….
– Gi safety promised…
74
Traditional
NSAIDS like
aspirin produces
GI irritation
It can be
CV mortality can
prevented by
be prevented by
selective COX-2
Aspirin
inhibitors
COX-2 inhibitors
produces CV
mortality
75
TOPICAL NSAIDS
• Used for RA,OA,musculoskeletal pain,Soft Tissue Injury etc.
• Advantage (???):
– ??? High local levels????? may be better therapeutic efficacy.
– Low systemic levels GI safety.
• DILEMMA , whether the effect is ….
– Due to drug ?
– Due to placebo ?
– Due to irritant present in ointments ?
– Due to concomitant oral NSAID?
• EVIDENCES AVAILABLE SO FAR ….
– Slow topical absorption (~10 times than oral)
– Highest blood levels remains 15% below the same dose given orally.
– Upto 4-6 mm( Dermis) high concentraion.
– At 25 mm (muscle ) concentration is low and same as blood.
• MARKED INTERINDIVIDUAL VARIATION( 18-92%) 76
HIGH COST
SO AVOID
TOPICAL
NSAID
PREPERATION
DOUBTFUL
EFFICASY
77
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
Pregnancy • Paracetamol
78
79