Non-Steroidal
Antiinflammatory
Drugs
by
Dr. Sherif Ahmed Shaltout
Analgesics
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Drugs which relieve pain .They are classified into:
Narcotic
Non narcotic
-Relieve all types of pain -Relieve pain of moderate
except itching and colic
to low intensity
-It is accompanied with
- NO
Changes in mood
-Addiction liability
-No
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ANTIPYRETIC ANALGESICS
Group of drugs which lower high body
temperature, relieve pain (without narcosis)
and some have anti inflammatory action
Mechanism; inhibition of prostaglandin synthesis by inhibition
of their synthetizing enzyme namely cyclooxgenase enzyme.
Cyclooxgenase enzyme (COX)
1- COX-1: constitutive (its inhibition……..> S/E)
2- COX-2: Inducible (its inhibition……> Therapeutic)
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Classification:
I-Non selective COX inhibitors:
1-Salicylates: Acetyl salicylic acid, Na salicylates, Salicylamide.
2- Pyrazolone derivatives: Dipyrome, phenylbutazone.
3- Indol derivates: Indomethacin, sulindac.
4- Fenamates: Mefenamic acid, flufenamic acid.
5-Pro ionic acid derivatives: Ibuprofen, ketoprofen naproxene.
6- Aryl acetic acid derivatives: Diclofenac.
7- Oxicams: Piroxicarn, Meloxicam.
8-Aniline derivatives: Phenacetin, paracetamol .
II-Selective COX2 inhibitors:
 Rofecoxib, celecoxib, etodolac, nimesulide
(1)- Salicylates
Salicylic acid derivatives.
Classification:
1- Locally acting (Irritant): salicylic acid and methyl salicylate.
2- For systemic use: Acetylsalicylic acid (Aspirin) and Na
salicylates.
Pharmacokinetics:
1- Absorption : orally from upper GIT, WHY??
2- Distribution : All over the body.50-80% bound to pl.albumin.
3- Metabolism : Main: is conjugated in liver with glucuronic acid
and glycine .1 % is oxidized into gentesic acid which is also
active.
4- Excretion is renal and is increased by ???.
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Pharmacodynamics:
Local actions:
1- Salicylic acid:
 Keratolytic (20% in colloid).
 Anti fungal and antiseptic
2- Methyl salicylate (oil of winter green) irritant, used as counter
irritant for painful muscles or joints.
 Systemic actions
1- CNS:
1- Analgesic : Relieve somatic pain rather than deep visceral pain
. Salicylates analgesia induced centrally by elevating pain
threshold in subcortical area (thalamus) and peripherally  PGs
released during inflammation & sensitize nerve endings to
kinins.
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2- Antipyretic in fevers, no effect on normal body temp.
 pyrogen-induced PGE2 in fever*  resetting of
hypothalamic thermostat to normal   temperatureregulating mechanisms  VD & sweating
Toxic dose ---> hyperpyrexia due to uncoupled
oxidative phosphorylation
3- Anti-inflammatorv action: (Large dose> 5 g/day) :
Inhibition of :
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PGs.
Bradykinines
Protease and Hydrolase enzymes
Hyaluronidase and Fibrinolysin
Hyaluronic acid the "ground substance
(Inhibit antigen antibody reaction through increased ACTH ---> increase cortisone
release)
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2- CVS : decreases blood pressure
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-Small therapeutic dose due to vasodilatation by inhibition of rho dependent
tyrosine kinase.
- large dose due to inhibition of VMC and direct action on the walls.
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3- Blood
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Inhibit platelet aggregation with small dose due to
inhibition of thromboxane A2
Hypoprothrombinemia : (Large dose 5 g/day)
competes with vit K. leading to decrease synthesis of
prothrombin and factor VII IX and X
In patients with G-6-PD deficiency ---> haemolysis
(idiosyncracy)
(Reduction of ESR and leucocytosis)
4- Respiration and acid base balance:
 Large dose ---> respiratory alkalosis due to stimulation of
respiratory center (directly and through Co2 production from
uncoupling of oxidative phosphorylation)….> hyperventilation
---> loss of Co2
- then compensated respiratory alkalosis due to excretion of
bicarbonate, sodium and potassium by the kidney
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- Toxic dose causes metaboilc acidosis in children.
precipitate acute bronchial asthma in susciptable patients
by inhibition of cycloxygenase enzyme, therefore arachidonic acid
will be acted upon by lipoxygenase (LOX) enzyme ---> excess
leukotrienes.
5- GIT:
a- Nausea and vomiting centrally due to stimulation of CTZ
peripherally due to local irritation.
b- Gastric irritation and hyperacidity locally release of
acetylsalicylic acid and systemically by decrease synthesis of PG E1
and PGI
c-ulceration ---> bleeding
6- Kidney (blood uric acid)
a- Small dose (<5 g/day): decrease uric acid excretion by
distal convoluted tubules ---> hyperuricaemia ---> worsen gout.
b- Large dose (> 5 g/day): decrease uric acid reabsorption
from proximal convoluted
7- Endocrine actions:
a- Stimulate adrenaline release from adrenal medulla.
b- Stimulate hypothalamus ---> anterior pituitary ---> increase ACTH
secretion ---> adrenal cortex ---> increase adrenal cortical hormone levels.
c- Displaces T3 and T4 from plasma proteins ---> decrease TSH ---> decrease
radioactive iodine uptake by thyroid.
8- Metabolic actions:
a-Carbohydrate:
 - Small dose: hypoglycemia (increase uptake of glucose by tissues)
 - Large dose: hyperglycemia due to increase glycogenolysis
 (increase adrenaline and cortisone release) .
b- Protein:
 -Large therapeutic dose: increase protein breakdown (catabolic effect of
cortisone).
 -Large dose: accumulation of glutamine ---> convulsions.
Preparations :
1- Acetylsalicylic acid (aspirin) 325 gm tables.
2-Na Salicylate: as enteric coated tables 0.6-1.2 gm
3-Effervescent aspirin
4-Lysine acetyl salicylic acid only parentrally 500 IM or IV.
5- Ditlunisalis a salicylic acid derivative more potent analgesic and
antiinflammatory activity, longer duration of action, less gastric
bleeding, inhibit platelet aggregation and has a uricosuric effect.
250-500 mg twice daily, orally.
6-Diflunisal: is salicylate derivative, not metabolized to salicylate.
more potent anti-inflammatory effect, less side effects .It is partially
COX-2 selective. used in dental pain and cancer pain either orally or
topically 500-1000 mg twice daily.
Therapeutic uses:
1. Small dose (75-150 mg/d):prophylaxis for
transient ischemic attacks, unstable angina, acute
myocardial infarction
2. Intermediate dose (325mg 1-2tab/4hr)
Mild to moderate pain 2ry to inflammation , e.g.
arthritis, dental pain (ineffective in severe visceral
pain).
 Headache, dysmenorrhea.
 Postpartum pain, postoperative & cancer pain
(added to opioids to  their dose).
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3. Large dose (4-8 g/d)
Rheumatic fever.
Rheumatoid arthritis & other inflammatory joint
diseases.
4.Local uses:
-Salicylic acid:
- Keratolytic (removes corns and warts)
- Antifungal and antiseptic
- Remove scales (hair lotion)
- Methyl salicylates (oil of winter green) counter irrtant for
arthritis and myositis
Adverse effects:
A. Effects Common to all NSAIDs (particularly in the elderly)
1. GIT : Dyspepsia, nausea, vomiting, gastritis, ulceration with ↑ risk of
bleeding.
2. Nephrotoxicity (less with aspirin)
Analgesic nephropathy: irreversible chronic nephritis due to chronic use of
high doses of combinations of NSAIDs.
In renal insufficiency or in hypovolemic patients whose GFR depends on
vasodilator PGs (e.g. heart failure or extensive diuretic therapy),  vasodilator
PGs by NSAIDs   renal blood flow resulting in:
a. Salt & water retention (edema),  BP.
b. Hyperkalemia.
c. Acute renal insufficiency
3. Hypersensitivity reactions
Skin rash, rhinitis, asthma especially in asthmatics & patients with nasal
polyps .
4.  Bleeding tendency (stop aspirin ???)
Antiplatelet effect.
Displacement of warfarin from plasma proteins potentiating its effect.
5. Hepatotoxicity
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B. Effects Specific to Aspirin
1. Hypoprothrombinemia: bleeding risk.
2. Hyperuricemia (low-dose aspirin in gout):.
3. Reye’s syndrome: encephalopathy and liver damage in children with
fever due to viral infection (CI as antipyretic in children < 12 years).
4. Chronic toxicity (salicylism): prolonged administration of large doses
 dizziness, tinnitus, nausea & vomiting.
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5. Acute toxicity: Nausea, vomiting and bleeding
Hyperventilation, increase sweating,dehydration and
hyperthermia
- Respiratory alkalosis (adults) or metabolic acidosis (children)
- Hyperglycemia
-Delerium, convulsion, coma and death
Treatment of acute toxicity :
1-Gastric lavage with NaHC03 --> neutralizes
hyperacidity.
2- Alkalinization of urine to help excretion of salicylates
3- Correct hyperthermia by cold fomentations
4- Correction of dehydration by fluids, depending on the type
of acid base disturbance present.
5-Vit K.or blood transfusion for haemorrhagic phenomena.
6- Haemodialysis in severe cases.
Contraindications and precautions:
1- Allergy and idiosyncracy
2- Peptic ulcer
3-Bleeding tendency
4-Bronchial asthma
5-Pregnancy
6- Small dose of salicylate in gout
7- They should not be given to the "under twelve" with
influenza or chicken pox for fear of Reye's syndrome
8- They are better given after meals
9-Large doses are better avoided in presence of liver or
renal disease
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Drug interactions:
Can displace other drugs from plasma proteins
as dicoumarol and oral hypoglycemic
Compete with other uricosurics as
probenecid and phenybutazone .
Barbiturates poteniates analgesic effect of
salicylates.
2- Dipyrone (Novalgin): not antiinflammatory, not
uricosuric. not used ……..> agranulocytosis
3-Phenylbutazone: is potent. prolonged effect .not
used …..> high incidence of side effects including
peptic ulcer, renal and hepatic damage, aggranulocytosis
4- Indole derivatives
 A-Indomethacin: marked antiinflammatory , not
used as routine analgesic antipyretic due to its high
toxicity. Not used in children except for PDA
 uses:
1-rh.arthritis, pleurisy, peicarditis, Acute gout
2-closure of patent ductus arteriosus in neonates
3- Dysmenorrhea
Common side effects:
1-CNS: psychosis, confusion, headache and vertigo
2- Eye: blurred vision, corneal opacity
3- Agranulocytosis
B-Sulindac:
- Prodrug, converted in the liver to an active sulphide.
similar to indomethacin, but less potent. have renal
sparing effect.
5 –Fenamates - Mefenamic acid (ponstan)
weak and short acting. used in dysmenorrhea.
side
effects: diarrhea, hemolytic anemia
6 -Propionic acid derivatives
Short acting: Ibuprofen, ketoprofen, naproxene ,
Long acting: nabumetone and oxaprozin.
 -better tolerated due to low incidence of adverse
effects.
 -photosensitivity and skin rash (naproxene and
nabumetone).
7- Aryl acetic acid derivatives
 -Diclofenac and etidorac
 potent + allergic skin rash.
 - Ketorlac Analgesic
8- Oxicams
 Piroxicam (Feldene): potent and long acting
antiinflammatory.
Increase risk of GIT bleeding
8- Aniline derivatives
 acetaminophen (paracetamol)
Phenacetin: more toxic
 Pharmacokinetic:
- A: GIT, rapid and complete.
- M: Phenacetin (active) by HME ….> paracetamol
(more active) ….> extensively metabolized in the
liver and excreted in urine mainly as inactive
glucuronate and sulphate conjugates (94%) .
- 4% is oxidized to a toxic metabolite (N-hydroxy
derivative)…..> detoxified by conjugation with
hepatic glutathione and excreted in urine).
- 2% is excreted unchanged.
Pharmacological actions:
analgesic and antipyretic effects not antiinflammatory
– inhibits COX-3 ….> inhibit PGs only centrally.
 Dose: 500mg orally 4 times/day.
 Therapeutic uses: Analgesic antipyretic (especially
in salicylate allergy, haemostatic disturbances,
bronchial asthma, gastritis and peptic ulcer.)
 Side effects :
1- Hepatotoxicity in large dose
2- S/E mostly with Phenacetin.
Haemolytic anaemia, Allergic reaction, Nephritis
Methaemoglobinaemia
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Acute paracetamol poisoning:
-fatal hepatic necrosis
-due to accumulation of the toxic metabolites secondary to
depletion of hepatic glutathione.
-The minimal toxic dose is 10 gm.
 Treatment:
1-gastric lavage followed by activated charcoal.
2-N-acetyl cystein is a specific antidote. It increases glutathione
formation in the liver. Given orally or IV infusion in an initial
dose l40mg/kg of followed by 70 mg/kg/4hr for 72 h.
- Methionine increases the conjugation reactions. It can be given
orally in a dose of 2gm/2h for 5 doses.
 Glutathione itself is not used as it penetrates cells poorly.
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II-Specific COX-2 inhibitors (celecoxib)
(meloxicam: COX-2 > COX-1)
selectively inhibit COX2 enzymes
 effect similar to that of non steroidal anti-inflammatory drugs.
due to lack of effect on COX1
Advantages: low incidence of GIT, respiratory or renal side
effects
 little or no bleeding
Disadvant: ineffective in treatment of dysmenorrheal or
precipitate labor or prophylaxis against thrombosis or patent
ductus arteriosus
 They paradoxically increase incidence of thrombosis due to
inhibition of COX2 mediated prostacyclin. For this reason,
most of them are withdrawn from the market e.g rofecoxib
and valdecoxib
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Slowly acting disease modifying antiinflammatory drugs
-potent anti-inflammatory effect that starts after several weeks
of administration.
 -no direct analgesic effect.
 -used in combination with NSAIDS in treatment of chronic
immune mediated arthritis e.g rheumatoid arthritis.
1- Gold salts (IM)
 -uptaken by macrophages….> inhibits phagocytosis and
lysosome enzyme activity
-imapirs lymphocyte proliferation.
 Side effects:
1- Pruritus, dermatitis.
2-Thrombocytopenia, aplastic anaemia
3- Renal damage 4-Peripheral neuritis 5-Teratogenicity
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2- D-penicillamine
 It is a chelating agent which is used in
1-rheumatoid arthitis
2-Heavy metal poisoning due to formation of insoluble non toxic
complex with heavy metals except lead
3-Wilson’s disease because it chelates excess tissue cupper .
 Side effects:
 Bone marrow depression
 Nephrotic syndrome.
 Teratogenicity..
 Mystheniia gravis
3-other drugs: Methotrexate, Azathioprine, levamisole,
chloroquine