Anda di halaman 1dari 18

NSAIDs means..

Non Steroidal Anti Inflammatory Drugs

If you want to study ANTI INFLAMMATORY drugs , you should


know

What is inflammation ?...

Response of the body to injurious stimuli

So it is beneficial.

Than why it is required to be suppressed ?

Because at times it can be in EXAGGERATED form and


can be.

Harmful to body

Extremely disturbing to the patient

Which are the features of inflammation ?

1. Heat/fever

2. Swelling

3. Pain

4. Redness

5. Loss of function

NSAIDS addresses mainly fever, pain and swelling.


Redness is not a problem from functional point of view.
Loss of function is usually restored when FEVER , PAIN and
SWELLING are taken care of if it is due to those features..
Loss of function because of permanent fibrosis cannot be
reversed.
IN ONE WAY, fever and pain are beneficial .. HOW ?
Infection occursFever develops.. Raised
temperature kills microbes.. INFECTION CLEARS !!!!.
Tissue damage occur .Pain nerve endings are stimulated
Person feels pain. Gets idea about tissue damage and tries to remove
the source of injury which would have otherwise ignored.
But when these(Pain& Fever) 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 casesinterfere with the state of consciousness.
EXCESSIVE PAIN
May interfere with the quality of life.
May frighten the patient.
In extreme cases may produce shock.

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 .

A. Cycloxygenase pathway generates


1. TXA2-Vasodilatation and inhibition of platelet
aggregation
2. PGD2 -vasodilatation
3. PGE2 Affect the hypothalamus temperature
regulating system produces fever .
Increases water electrolytes and mucus secretion
in GIT.
4. PGF2-Produces contraction of uterine smooth
muscles.
5. PGI2- Vasodilatation and inhibition of platelet
aggregation
How to remember it ?
Alphabetical order is DEFGH
Here first G & H and then D E F.
B. Lipo-oxygensae pathway generates
1. 12 HPETE through 12-lipoxygenase
2. 15 HPETE through 15-lipoxygenase
3. 5-HETE through 5-Lipoxygenase
4. 5-HETE subsequently produces
a. LTA4 LTB4
b. LTA4 LTC4 LTD4 LTE4. Bronchoconstriction
Increased capillary permeability

OTHER CHEMICAL MEDIATORS

1- PAF

VD

Platelet aggregation

Leucocyte infiltration

Degranulation of leuco.

2- Histamine

Contraction of venules

Relaxation of arterioles

Increased capillary permeability

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

Warning bell of tissue damage !!

Interferes with Quality Of Life.

Two components

Sensations peripheral component

Perception central component

CLASSIFICATION of Pain

A. Superficial or cutaneous pain

B. Deep pain from muscle, joints, ligaments and bones.

C. Visceral pain-(spasm,infla.,ischemia, stim. Of nerve endings)

D. Differentiation pain /neuropathic pain- (damage to axons or


nerve membranes)

E. Psychological/Functional

Mechanism of action :

Prostaglandins (PGS) sensitize the nerve endings.


To the nociceptive stimuli .

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.

PG synthesis in peripheral tissueaction of


inflammatory mediators e.g. histamine, Kinins, IL
&INFCOXIIPG,PGI2&TXA2
Inhibition of neutrophil aggregation and activation
kallikrein synthesis synthesis of kinins pain, VD
& edema.
Stabilization of lysosome enzyme release of
proteolytic enzymes cell death
Hyaluronidase enzyme capillary permeability
edema.
salicylate in large dose may be lead to hyperthermia due
to uncoupling of oxidative phosphorylationATP
3- C.V.S
At therapeutic dose no effect
Toxic dose peripheral V.D& V.M.C hypotension.
In patient with active rheumatic carditis with heart
failure(edema) Aspirin is preferred than Na salicylate
edema.
4- Respiration& acid/base balance
Ordinary dose up to 1 g little effect
Large dose> 5 g in adult: respiratory rate washing of
CO2respiratory alkalosis. renal excretion of bicarbonate
compensated respiratory alkalosis(this well lower plasma
bicarbonate so impairs protection against acidosis)
Large dose especially in children lead to metabolism acidosis
due to impaired carbohydrate metabolism.
May precipitate bronchial asthmaCOX shift to LOX pathway
LT.
5- GIT
ACIDIC pH keeps Aspirin nonionized insoluble particles +Local
COX inhibition and decreased PGs +Reduces motility of
stomach Increases the contact of salicylates with gastric
mucosa and GI irritation So Use aspirin with Plenty of water or
after food, Milk, Alkali, Soluble of buffered aspirin.
Epigastric distress, nausea, vomiting due to central
action on C.T.Z. and peripheral irritation action.
Ulceration and bleeding due to inhibition of
prostaglandin synthesis(E2&I2) which have
cytoprotective action.
6- Liver
Large dose transaminase activity
Hepatotoxic (Reyes syndrome)
7- Kidney
Aspirin PGRenal V.D. renal vasoconstrictionrenal
blood flow Na retention
Large dose Nephropathy.
8- Uric acid
Is normally filtered through glomeruli, reabsorbed in
proximal tubules and secreted by distal part of proximal
tubules.
Small dose of aspirin (1-2g) uric acid excretion
hyperuricemia Worsen gout.
Large dose of aspirin (>5g) uric acid reabsorption
uricosuric effect treat gout(alkalinize the urine).
9- Uterus: PG uterine relaxation Delays labour.
10- Blood
Aspirin in small dose (75-150mg) irreversibly inhibits TXA2
synthesis by platelets platelet aggregation bleeding time
is prolonged to nearly twice the normal value. This effect lasts
for about a week (turnover time of platelets). In other word,
acetylates platelet COX irreversibly in the portal circulation
before it is deacetylated by first pass metabolism in liver.
Large dose due to dicumarol like action they compete with vit k
synthesis of activated prothrombin & factor vii, ix & x
hyoprothrombinemia
In patient with G-6PD deficiency they produce haemolytic
anaemia(idiosyncrasy).
11- Endocrine
Hypothalamus ACTH adrenal cortex Cortisol
Adrenal medulla adrenaline
Displace T3&T4 from plasma protein their free form
T.S.H.
12- Immune response: cortisol AG/Abs reaction.
13- Metabolic action
Uncoupling of oxidative phosphorylation.
Moderate dose insulin like hypoglycemia
Hyperglycemia in large dose due to cortisone & adrenaline
large dose negative nitrogen balance, increase amino acid
loss in urine, increase glutamic ?GABA ratio convulsion.
USES
1. As analgesic For headache (including mild migraine),
backache, myalgia, joint pain, pulled muscle, toothache,
neuralgias and dysmenorrhea; it is effective in low doses
(0.30.6 g 68 hourly). Analgesic effect is maximal at ~
1000 mg (single dose).
2. As antipyretic dose (0.30.6 g 68 hourly). It is effective in
fever of any origin; dose is same as for analgesia Antipyretics
are not useful in fever due to heat stroke; only external
cooling lowers body temperature.
3. Acute rheumatic fever Aspirin is the first drug to be used in
all cases; other drugs are added or substituted only when it
fails or in severe cases (corticosteroids act faster). In a dose of
45 g or 75100 mg/kg/day .Dose reduction may be started
after 47 days and maintenance doses (50 mg/kg/day) are
continued for 23 weeks or till signs of active disease (raised
ESR) persist. Withdrawal should be gradual over the next 2
weeks.
4. Rheumatoid arthritis Aspirin in a dose of 35 g/day is
effective in most cases; produces relief of pain, swelling and
morning stiffness, but progress of the disease process is not
affected. Since large doses of aspirin are poorly tolerated for
long periods it is rarely used now; other NSAIDs are preferred.
5. Osteoarthritis It affords symptomatic relief only; may be
used on as and when required basis, but paracetamol is the
first choice analgesic for most cases.
6. Chronic gout 5-6g/day
7. Post myocardial infarction and post stroke patients By
inhibiting platelet aggregation at low doses. It has been
argued that high doses can reverse the beneficial effects by
concurrently inhibiting PGI2 (antiaggregatory and
vasodilatory) synthesis in vessel wall.
8. Prophylaxis against myocardial infarction, cancer rectum
&colon, Alzheimer disease, radiation induce diarrhea &
cataract.
9. Other less well established uses of aspirin are:
a. Pregnancy-induced hypertension and pre-eclampsia:
imbalance between TXA2 and PGI2 is believed to be
involved: aspirin 80100 mg/day benefits many cases by
selectively suppressing TXA2 production.
b. Patent ductus arteriosus: aspirin can bring about closure
and avoid surgery.
c. Familial colonic polyposis: aspirin and other NSAIDs
suppress polyp formation and afford symptomatic relief in
this rare disorder.
d. Prevention of colon cancer: incidence of colon cancer
among regular aspirin users is much lower. Colonic tumours
express large quantities of COX-2. However, the rofecoxib
trial (APPROVE) was prematurely terminated and the drug
withdrawn due to increased incidence of cardiovascular
events. The Adenoma Prevention with Celecoxib (APC) trial
has also been terminated due to 2.5 fold increase in risk of
major fatal/nonfatal cardiovascular events.
e. To prevent flushing attending nicotinic acid ingestion, which
is due to PGD2 release in the skin.
10. Local application

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.

Propionic acid derivatives


Ibuprofen was the first member of this class to be introduced in
1969 as a better tolerated alternative to aspirin.
Dosage and preparations of propionic acid derivatives
Drug Plasma Dosage Preparations
t
1. Ibuprofen 2 hr 400600 mg(510 Tab, cap, susp,
mg/kg) TDS gel
2. Naproxen 1216 hr 250 mg BDTDS Tab, gel
3. Ketoprofen 23 hr 50100 mg BD Tab, Cap, Amp,
TDS Gel
4. Flurbiprofen 46 hr 50 mg BDQID Tab

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.

Adverse effects A high incidence (up to 50%) of gastrointestinal


and CNS side.
effects is produced.
1. GIT: Gastric irritation, nausea, anorexia, gastric bleeding and
diarrhoea .
2. CNS: Frontal headache (very common), dizziness, ataxia,
mental confusion, hallucination, depression and psychosis .
3. Leukopenia, rashes.
4. Increased risk of bleeding.
5. Teratogenicity
Contraindication
1. Machinery operators, drivers.
2. Psychiatric patients.
3. Epileptics, kidney & liver disease.
4. Peptic ulcer
5. Allergy & asthma.
6. Pregnant women and in children
Sulindac 150-200mg
Similar to indomethacin but less potent & less toxic .
Less effect on renal PGallowed in patient with renal insufficiency
Uses: arthritis, acute gout &cataract.

PARA-AMINO PHENOL DERIVATIVES

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.

ARYL-ACETIC ACID DERIVATIVES

Diclofenac sodium or potassium.

It is well absorbed orally, 99% protein bound, metabolized and

excreted both in urine and bile. The plasma t is ~2 hours.

However, it has good tissue penetrability and concentration in

synovial fluid is maintained for 3-4 times longer period than in

plasma, exerting extended therapeutic action in joints.

Pharmacodynamics

Inhibit COX both central & peripheral both COX-1&COX-2.

Increase incorporation of arachidonic acid into triglycerides both

PG& LT synthesis

Clinical uses :Dose 12.5-25-50-75-100mg Tab, Cap, Supp, I.M, Skin

gel& eye drops.


Rheumatoid , Osteoarthritis, Bursitis, Ankylosing Spondylitis

Toothache, Headache , Dysmenorrhea Post-Traumatic And

Postoperative Inflammatory Condition.

Adverse effects

1. Gastric irritation (Mild epigastric pain, nausea, dizziness,


rashes).
2. Reversible elevation of serum aminotransferases
3. Kidney injury is rare

Preferential COX-2 inhibitors


Nimesulide 100mg tab, 50 mg/5 ml susp, Meloxicam Dose: 7.515 mg OD tab,
Supp , amp , Nabumetone. 500 mg tab; 1 tab OD.

Selective COX-2 inhibitors (Coxibs)

Effective anti-inflammatory and anti-rheumatic with less


gastric and renal toxicity.
Currently, 3 selective COX-2 inhibitors : Celecoxib, Etoricoxib
and Parecoxib are available in India; Lumiracoxib is marketed
in Europe, while Rofecoxib and Valdecoxib have been
withdrawn for increasing cardiovascular (CV) risk.
Paracoxib only selective COX-2 inhibitor for parental use.

Disadvantage of (Coxibs)

Increases cardio vascular mortality because of inhibition of


endothelial PGI2 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 precipitated .

Advantages of (Coxibs)
No ADR like

GI ulceration

Bleeding tendency

Topical NSAIDs

1. Diclofenac 1% gel : VOVERAN EMULGEL, RELAXYL GEL, DICLONAC GEL.


2. Ibuprofen 10% gel : RIBUFEN GEL.
3. Naproxen 10% gel : NAPROSYN GEL.
4. Ketoprofen 2.5% gel : RHOFENID GEL.
5. Flurbiprofen 5% gel : FROBEN GEL.
6. Nimesulide 1% gel : NIMULID TRANS GEL, ZOLANDIN GEL, NIMEGESIC-T
GEL
7. Piroxicam 0.5% gel : DOLONEX GEL, MOVON GEL, PIROX GEL, MINICAM
GEL.

Selection of NSAID

Mild/moderate pain .Paracetamol Low dose ibuprofen

Anda mungkin juga menyukai