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So it is beneficial.
Harmful to body
1. Heat/fever
2. Swelling
3. Pain
4. Redness
5. Loss of function
Injury/infection/trauma
Attacks the cell membrane of the cell
Cell membrane contains phospholipids
Activation of phospholipase occurs
It causes formation of arachidonic acid
Arachidonic acid is further metabolized by. Cyclooxygenase
pathway Lipo-oxygensae pathway.
We will study both pathways
Now get ready for a LONG CHAIN OF CHEMICAL
REACTIONS
This chemical reactions are IMPORTANT..
Products of this pathway PRODUCE NUMEROUS ACTIONS.
They are the sites of pharmacological intervention .
1- PAF
VD
Platelet aggregation
Leucocyte infiltration
Degranulation of leuco.
2- Histamine
Contraction of venules
Relaxation of arterioles
3- Bradykinin
Stimulates nociceptors
H release
4- 5-HT
Vascular response
Pain
Platelet aggregation
5- Others
Kaillidine
Lactic acid
ATP
ADP
Pain
Unpleasant experience
Protective reflex
Two components
CLASSIFICATION of Pain
E. Psychological/Functional
Mechanism of action :
Caused by .
Histamine and
Bradykinin
Figure 1.
Metabolism of arachidonic acid in inflammation. Arachidonic acid
released from phospholipids by the action of the enzyme
phospholipase A2 can be metabolized by either cyclooxygenase 1
and 2 or by 5-lipoxygenase. Cyclooxygenases generate prostanoids
like prostaglandin I2 (PGI2) and PGE2 that are involved in
physiological processes including platelet aggregation and
regulation of gastrointestinal and renal blood flow. However, both
PGI2 and PGE2 are potent vasodilator agents that contribute to the
vascular signs of the inflammatory reactions. 5-lipoxygenase forms
leukotrienes (LT) such as LTB4, a potent chemotaxin, and LTC4, LTD4,
LTDE4, which are potent bronchoconstrictor agents.
Mechanism Of Action : NSAIDS
Inhibits the cyclooxygenase
Enzyme & Reduce prostaglandin biosynthesis
COX-1
Physiologically expressed
Maintains the normal (housekeeping) function.
Expressed in ..
Platelets
GIT (So nonspecific NSAIDs produces bleeding tendency and
peptic ulcer)
COX-2
Induced in pathological states (mostly(
Physiologically expressed in kidney.
NSAIDs: Classifications based on chemistry
1- Salicylic acid derivatives(Salicylates) Aspirin sodium
salicylate salicylamide Diflunisal
2- Para-aminophenol derivatives Acetaminophen,
Phenacetin.
3- Indole and indene acetic acids derivatives:
Indomethacin, Sulindac(Prodrug)
4- Phenyl acetic acids derivatives; Diclofenac,
Aceclofenac, Etodolac, Ketorolac, Tolmetin.
5- Alkanones: Nabumetone (Ketone prodrug).
6- Propionic acids derivatives, Ibuprofen Naproxen,
Ketoprofen ,Carprofen Vedaprofen, Fenoprofen, Tiaprofenic
acid Flurbiprofen.
7- Fenamates(Anthranilic acid derivatives) Mafenamic
acid Flufenamic acid.
8- Oxicams: Piroxicam Meloxicam, Tenoxicom.
9- Pyrazolones or enolic acids derivatives:
Phenylbutazone, Oxyphenbutazone, Aprazone, analgin,
Azapropazone, Dipyrone.
10- Nicotinic acid derivatives Flunixin, meglumine
11- Hydroxamic acid derivatives: Tepoxalin
12- Coxib-class NSAIDs :Deracoxib, Firocoxib, Celecoxib,
Rofecoxib, Paracoxib, Lumiracoxib, Valdecoxib.
NSAIDs: Classifications based on Selectivity on Cox enzymes
1. Non-selective cox inhibitors (cox I, II):
diclofenac, ibuprofen, Diflunisal, aspirin piroxicam,
mefanamic acid.
2. Selective cox II inhibitors: Meloxicam, tenoxicam,
coxibs
3. Selective cox III inhibitor;
paracetamol(acetaminophen).
Sa
Salicylates
Derived from salicylic acid which itself is highly irritant. They include
Aspirin sodium salicylate salicylamide Diflunisal.
Pharmacokinetics:
Effective orally, absorbed to small extent from stomach being at low
pH in non-ionized form ,complete absorption in upper part of small
intestine, bound to plasma protein(50-80%). Excreted in urine partly
unchanged(alkaline urine increase excretion),partly conjugated with
glycine and glucuronic acid and 1% is oxidized into gentisic acid.in
low concentration first order kinetics is noticed with high
concentration saturation occurs and zero order kinetics is observed.
Action:
A- Local action;
Salicylic acid : Keratolytic , antifungal and antiseptic.
Methyl salicylate(oil of winter green: Counter-irritant.
B- Systemic action;
1- C.N.S;
- Analgesic action by inhibiting prostaglandin synthesis.
They have central action elevating pain threshold and
peripheral action due to anti-inflammatory effect. Effective
in low intensity pain without drowsiness, tolerance or
addiction.
- Antipyretic activity
Hypothalamus contains thermoregulatory centre
Maintains balance between heat production and heat loss
It regulates heat dissipating mechanisms
When there is tissue damage/inflammation/AG:AB
reaction/infectionNeutrophil releases IL-1Stimulates
COX-2 enzymesIncreased PGE2 synthesis in
hypothalamusPGE2 has two mechanisms :
1. Increases heat production.
2. shuts down HEAT LOSING MECHANISM
Raised body temperature FEVER
By inhibiting IL1,IL6,TNFalfainduced PGE2 synthesis so
increase heat loss by cutaneous VD, sweating and
mobilization of fluid from tissues to blood. However
,salicylate in large dose may be lead to hyperthermia due
to uncoupling of oxidative phosphorylation.
Reduces fever due to inflammation. But not due to
1. Heat stroke
2. Exercise induced/Physiological diurnal variation in
temperature.
2- Anti-inflammatory activity& anti-rheumatic.
Keratolytic
Fungistatic
Antiseptic
Counter irritant
IBS
Adverse effects
1- Acute toxicity: toxic dose >200mg
2- Salicylism at dose 3-5g ; dizziness, tinnitus, vertigo,
reversible impairment of hearing and vision, excitement and
mental confusion, hyperventilation and electrolyte imbalance.
3- Hyoprothrombinemia at small dose.
4- GIT Irritation at analgesic dose (0.31.5 g/day).
5- Allergy(Hypersensitivity and idiosyncrasy)
6- Reye,s syndrome in children with viral infection( e.g.
influenza & chicken pox) Encephalopathy& hepatotoxicity.
7- Teratogenicity cardiac septal defect.
8- Idiosyncrasy
9- Nephropathy
Precautions and contraindications
1- Allergy to salicylate
2- Bleeding tendency
3- Peptic ulcer
4- Gout
5- Children
6- Idiosyncrasy
7- Bronchial asthma
8- Pregnancy
9- Breast feeding mother
10- chronic liver disease
11- diabetics, in those with low
cardiac reserve or frank CHF
12- juvenile rheumatoid arthritis.
13- Surgery. So should be stopped 1 week
before elective surgery.
Drug Interactions
1- Aspirin displaces warfarin, naproxen, sulfonylureas, phenytoin
and methotrexate from binding sites on plasma proteins
toxicity.
2- Salicylate antagonize
Other uricosuric gents
Other anti-inflammatory agents
Antihypertensive effect of blocker, ACEIs & diuretics.
3- NSAID, Corticosteroids & alcoholulceration of Salicylate.
4- Phenobarbitone metabolism of Salicylate.
Adverse effects
1. Diarrhoea is the most important dose-related side effect.
2. Epigastric distress.
3. Gut bleeding is not significant.
4. Skin rashes
5. CNS manifestations e.g. dizziness
6. Haemolytic anaemia is a rare
INDOLE DERIVATIVE
1. Indomethacin 25,50,75mg Cap, SR, Supp, Eye drop
It is a highly potent inhibitor of PG synthesis
Pharmacokinetics it is well absorbed orally, rectal absorption is
slow but dependable. It is 90% bound to plasma proteins, partly
metabolized in liver to inactive products and excreted by kidney.
Plasma t is 25 hours.
Uses :Because of prominent adverse effects, indomethacin is used
as a reserve drug in
conditions requiring potent anti-inflammatory action like
1. Ankylosing spondylitis.
2. Acute exacerbations of destructive arthropathies.
3. Psoriatic arthritis.
4. Acute gout that are not responding to better tolerated NSAIDs.
Other uses
i. To closure patent ductus arteriosus in neonates with normal
great vessels(the most common used drug)
ii. Dysmenorrhea & premature labor.
Phenacetin nephropathy.
Paracetamol (acetaminophen) is active metabolite of phenacetin.
Pharmacokinetics
Paracetamol is well absorbed orally, only about 1/4th is protein
bound in
plasma and it is uniformly distributed in the body.
Metabolism occurs mainly by conjugation with glucuronic acid and
sulfate: conjugates are excreted rapidly in urine. Plasma t is 23
hours. Effects after an oral dose last for 35 hours.
Pharmacodynamics
Paracetamol has no anti-inflammatory action. It is a poor inhibitor of
PG synthesis in
peripheral tissues, but more active on COX3 in the brain.
its inability to inhibit COX in the presence of peroxides which are
generated at sites of inflammation, but are not present in the brain.
The ability of paracetamol to inhibit COX-3 (an isoenzyme so far
located in dog brain) could also account for its analgesic-antipyretic
action.
In contrast to aspirin, paracetamol does not stimulate respiration or
affect acid-base balance; does not increase cellular metabolism. It
has no effect on CVS. Gastric irritation is insignificant mucosal
erosion and bleeding occur rarely only in overdose. It does not affect
platelet function or clotting factors and is not uricosuric.
Adverse effects
1. Ordinary dose: paracetamol is safe and well tolerated.
1. It is not recommended in premature infants (< 2 kg) why?
2. Large dose of paracetamol depletion of Glutathione-SH..
accumulation of N-acetyl-p-benzoquinoneimine (NABQI) this
metabolite binds covalently to proteins in liver cells (and renal
tubules) causing hepatotoxicity& nephrotoxicity.
Treatment of toxicity
i. Symptomatic
ii. Gastric lavage by charcoal
iii. Specific antidote: N-acetyl cysteine.
Pharmacodynamics
PG& LT synthesis
Adverse effects
Disadvantage of (Coxibs)
Advantages of (Coxibs)
No ADR like
GI ulceration
Bleeding tendency
Topical NSAIDs
Selection of NSAID