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Non – Steroidal Anti – Inflammatory Drugs

NSAIDs
Dr: MANZOOR AHMED UNAR
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NSAIDs
Inflammation

 A localized protective or immune response,


elicited by injury or destruction of tissues.

 It may occur in response to foreign organism or


antigenic substances liberated during the
acute or chronic inflammatory response.

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NSAIDs
Inflammation

 Inflammation may be beneficial for the host,


when it causes invading organisms.

 Or may be deleterious if it leads to chronic inflammation


without resolution of the underlying injurious processes.

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NSAIDs
Inflammation

 Inflammation is triggered by the release of


chemical mediators from injured tissues. e.g.

 Histamine (vasodilator, ↑↑↑ vascular permeability)


 Serotonin (vasodilator, ↑vascular permeability)
 Bradykinin (vasodilator, ↑vascular permeability, ↑ pain)
 Prostaglandins (vasodilator, ↑ vascular permeability, ↑chemotaxis)
 Leukotrienes (↑↑↑ vascular permeability, ↑chemotaxis)
 Pollens (asthma) ,
 Autoimmune response (rheumatoid arthritis).

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NSAIDs
Inflammation

 Dilatation of Arterioles, Capillaries, and Venules ,


 Increase Permeability and Blood flow,
 Exudation of Fluids, Plasma Protein,
 Leukocytic migration into inflammatory focus.

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NSAIDs
Inflammation

 Inflammation is characterized
(acute form ) by classical signs :

 Pain (Dolor)
 Heat ( Calor)
 Redness (Rubor)
 Swelling (Tumor) and
 loss of function (Functio Leasa).
NSAIDs
Inflammation

In response to various stimuli


the Arachidonic acid (20 carbon fatty acid )
released from phospholipids of cell membrane.

Arachidonic acid metabolized through two pathways:

Cyclooxygenase pathway = products are called Prostanoids.


e.g. Prostaglandin, Prostocyclines, Thromboxanes.

Lipooxygenase pathway = products are called Eicosonoids


e.g. Leukotrienes.

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Metabolism of Arachidonic Acid

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NSAIDs
Inflammation

 Kinins, Neutrophils and Histamine are also released


at the site of tissue injury.

 Stimulation of the neutrophil membranes produces


oxygen derived free radicals, Super oxide.

 Which may stimulate production of other reactive molecules


such as hydrogen peroxide and hydroxyl radicals.

 The interaction of these substances with arachidonic acid


results in the generation of chemotactive substances,
thus precipitating the inflammatory response.

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NSAIDs
Inflammation

Mechanism of Prostaglandin:

Activates Phosphatidylinositol (IP3) → increase


intracellular Ca++ → Vasodilatation → Increase
Vascular permeability → Chemotaxis.

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NSAIDs
Treatment of Inflammation

Treatment has two primary goals:


 The relief of pain,
 The slowing or arresting the tissue damaging process.

Drugs:
 Non Steroidal Anti Inflammatory Drugs (NSAIDs).
 Glucocorticoids.
 Slow Acting Anti Rheumatic Drugs.
 Disease Modifying Anti Rheumatic drugs. (methotrexate, gold
salts, salfasalazine).

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NSAIDs
Inflammation

Cyclooxygenase (Cox) Enzymes:

 Cox – 1 isofrom has homeostatic function ,


 Cox – 2 isofrom facilitate the inflammatory response.

 So the highly selective Cox-2 inhibitors, are safer


than nonselective Cox- inhibitors.

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NSAIDs
Non – Selective Cox Inhibitors

 Aspirin ( Acetyl Salicylic Acid ) ( 1200-1500 mg tid).


 Ibuprofen (Propionic Acid Derivative) ( 600 mg qid).
 Diclofenac (Phenyl Acetic Acid derivative) ( 50-75 mg qid).
 Flurbiprofen (Phenyl Alkanoic Acid Derivative) ( 300 mg tid).
 Indomethacin (Indole Derivative) ( 50-70 mg tid).
 Tolmetin (Pyrroleallkanoic Acid Derivative) ( 400mg qid).
 Phenylbutazone (Pyrazolone Derivative)
 Oxaprozin ( 1200-1800mg qid)
 Naproxin(oxicam) ( 375mg bid ).
 Fenprofen ( 600 mg qid).
 Ketoprofen ( 70 mg tid).
 Sulinadac ( 200mg bid).
 Diflunisal ( 500mg bid).
 Paracetamol

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NSAIDs
Selective Cox - 2 Inhibitors

 Celecoxib, (100-200 mg bid).


 Rofecoxib, (12.5-50 mg qid).
 Meloxicam, (7.5-15 mg qid).
 Valdecoxib, (10mg qid).

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NSAIDs
General Properties:

 Well absorbed and food does not change their bioavailability.

 Highly metabolized by liver.

 All under go biliary excretion and reabsorption


(i.e. entero heptic circulation), final elimination is renal excretion.

 Highly protein binding ( ≥ 98% ) usually to albumin.

 All NSAIDs can be found in synovial fluid after repeated dosing.

 Causes Gastric irritation, Nephrotoxicity and Hepatotoxicity.


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NSAIDs

Mechanism of action:

 Inhibit the biosynthesis of Prostaglandins by


inhibiting the enzyme Cyclooxygenase

 They also inhibit Peroxidase

Do not block the formation of Leukotreines,


So these are not an Ideal Anti-inflammatory Drugs

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Mechanism of action of NSAIDs

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NSAIDs
Various NSAIDs have additional possible mechanism of action as

 Inhibition of Chemotaxis,

 Down – regulation of Interleukin -1 production,

 Interference with Ca++ mediated intracellular events

 Decreased production of Free – Radicals and Super Oxides,

 Benoxaprofen inhibit Leukotriene synthesis,


but with drawn due to toxicity.

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ASPIRIN

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NSAIDs
ASPIRIN

 They are simple organic acids.


 Rapidly absorbed from stomach and upper small intestine.
 Plasma peak level within 1-2 hrs.
 Serum half - life 15 minutes.
 Metabolized in liver .
 Rapidly hydrolyzed to acetic acid and salicylate,
by esterase in tissue and blood.
 Bind to albumin 70% (saturable).
 Excreted by kidney.

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NSAIDs
ASPIRIN

 Aspirin is Acetyl Salicylic Acid (ASA), synthetically prepared.


 Salicylates first documented in 1763.
 Aspirin become popular as anti – inflammatory in 1899.
 Aspirin was standard, against which all anti-inflammatory
agents were measured.
 Aspirin now, less often used as anti – inflammatory.
 It is very irritant.

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NSAIDs
ACTIONS OF ASPIRIN

Aspirin is a non- selective inhibitor of both Cox isoforms

 Anti-inflammatory.
 Analgesic.
 Antipyretic.
 Anti-rheumatic.
 Anti-thrombotic.
 Uricosuric.

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NSAIDs
ACTIONS OF ASPIRIN

(1) Anti – inflammatory effects :-

 Inhibits Prostaglandin (PGE2) synthesis.

 Stabilizes lysosomes,
 Interferes chemical mediators,
 Inhibit granulocytes adherence to damage vasculature,
 Inhibit the migration of polymorpho-nuclear leucocytes
and macrophages into site of inflammation.
 Inhibit antigen induced release of histamine.

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NSAIDs
ACTIONS OF ASPIRIN

(2) Analgesic effects :-


 Peripherally inhibits the synthesis of prostaglandin (PGE2),
which is responsible for sensitization of nerve endings
to the action of Bradykinin, Histamine, and Chemical mediators.

 Centrally rises the pain threshold and


blocking impulses between thalamus and cortex.

 Reduces the headache, toothache, muscular and joint pain.


( no effect on visceral pain ).

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NSAIDs
ACTIONS OF ASPIRIN

(3) Anti – Pyretic effects :-

 Reduce elevated temperature back to normal,


by inhibition of Cox 1 & 2 in the CNS,
( no effect on normal body temperature ).
.
 In the pre-optic nucleus of hypothalamus, inhibits PGE1 synthesis
 acts on heat regulating center setting the thermostat at lower level.

 Dilatation of the coetaneous blood vessels to loose heat.

 Increases sweating.

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NSAIDs
ACTIONS OF ASPIRIN

(4) Anti – platelet aggregation :-


 Bleeding time increased because it inhibit platelet aggregation, by
diminishing the formation of Thromboxane A2.
(Thromboxane A2 is power full stimulator of platelet aggregation)

 It also increases prothrombin time by inhibition of its synthesis.


( at large doses aspirin causes hypo prothrombinemia,
by antagonizing vitamin K).

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NSAIDs
ACTIONS OF ASPIRIN

(5) Anti gout :-

 In larger doses (over 5g /day) Aspirin


inhibits reabsorption of
uric acid and acts as uricosuric agent.

 Also inhibit the enzyme xanthine oxidase,


which catlyze the conversion of xanthine
and hypoxanthine to uric acid.

 While at lower doses 1-2 g / day) may


decreases urate excreation ).

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NSAIDs
ACTIONS OF ASPIRIN

(6) Actions on respiratory system:


 At ordinary doses no effect on respiratory system.

 Larger doses stimulate the respiratory center,


( leading to hyperventilation, with respiratory alkalosis )

 Toxic doses depress respiratory center,


( leads to increase PCO2 in the blood, result in respiratory acidosis).

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NSAIDs
ACTIONS OF ASPIRIN

(7) Action on C.V.S:


Large doses produce peripheral vasodilatation,
congestive cardiac failure, acute pulmonary edema.

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NSAIDs
ACTIONS OF ASPIRIN

(8) Actions on G.I.T:


Nausea, vomiting by local irritation and
stimulation of chemoreceptor trigger zone

At higher doses may cause peptic ulcer, dyspepsia,


gastric bleeding.

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NSAIDs
Uses of ASPIRIN

1. Analgesic : relieves mild to moderate pain (not visceral pain).


2. Anti – inflammation : in high doses for rheumatoid arthritis.
3. Anti – pyretic :
4. Deceases the Transient Ischemic Attacks : e.g.
unstable angina, coronary artery thrombosis,
myocardial infarction and thrombosis after coronary artery bypass.
5. Dysmennorrhoea (inhibiting Prostaglandin F2)
6. Useful in neonatal period to close the ductus arteriosus
7. Topical application of salicylic acid used as keratolytic agent for
warts

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NSAIDs
ASPIRIN

Side Effects
Gastritis
Gastric ulcers.
Duodenal ulcers.
Upper GIT bleeding.
Fecal blood loss.

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NSAIDs
ASPIRIN ( Adverse Effects )

(At high doses)


 Salicylism (reversible ) vomiting, tinnitis, decrease hearing, vertigo.
 Respiratory alkalosis/Respiratory and Metaboilc acidosis.
(At toxic doses)
 Elevate liver enzymes, fatty infiltration of liver
 Hepatitis (rare).
 Decrease renal function, chronic interstitial nephritis
 Bleeding.
 Rashes.
 Asthma.
 Reye's syndrome ( when used during viral infection ).
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NSAIDs
ASPIRIN

Contraindications

 Hemophilia.
 Peptic ulcer.
 Chronic renal failure
 Asthma.

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NSAIDs
DOSES OF ASPIRIN

 Minor pains 600 mg QID


 Acute rheumatic fever 5-8 g
 Rheumatic arthritis 600 mg QID

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Humanity has but three great enemies;
Fever, Famine and War.
Of these by far the most terrible , is
“ fever.”

( Sir William Osler )

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ASPIRIN INTOXICATION

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NSAIDs
ASPIRIN INTOXICATION

1. Acid - Base Balance:

Higher doses simulates respiration Respiratory alkalosis

Toxic doses respiration depressed ,


with accumulation of CO2 in plasma Respiratory acidosis.

Toxic doses interfere carbohydrate metabolism


accumulation of metabolites e.g.
Pyruvic acids , Lactic acids, Aceto acetic acid.

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NSAIDs
ASPIRIN INTOXICATION

2. Water metabolism :
Toxic doses causes dehydration, due to
 Increased renal excretion of water.
 Hyper ventilation.
 Sweating.

3. Electrolyte metabolism:
Aspirin intoxication causes increased renal excretion of
Sodium, Potassium and Bicarbonate, result in hypokalemia,
Hypernatremia due to dehydration
Hyperkalemia due to9 renal impairment

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NSAIDs
ASPIRIN INTOXICATION

4. Carbohydrate metabolism: Hyperglycemia due to:


Decrease synthesis of glycogen, and
Glycogenolysis due to release of adrenaline.

5. Protein metabolism : decrease synthesis and increase


breakdown of amino acid and protein.

6. Lipid metabolism :
Inhibit synthesis, depress release and enhance break down
of tissue fatty acids.
Also lower plasma cholesterol level

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NSAIDs
ASPIRIN INTOXICATION

7. Other enzymes
 Aspirin inhibit a large number of enzymes,
some of those involved in the conversion of
glutamic acid to glutamine and GABA,
result in aspirin poisoning convulsion

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NSAIDs
ASPIRIN INTOXICATION

GIT : Irritation of gastric mucosa, aggravate peptic ulcer,


gastric bleeding

CVS : Dilatation of peripheral vessels, CCF, Acute pulmonary edema.

Kidney : Diuresis Dehydration Oligurea → Acute renal failure.

Liver : Fatty infiltration of liver, non- specific hepatitis.

Endocrine effects : Release catecholamine from adrenal medulla.


Depressed activity of thyroid.

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NSAIDs
Medical Treatment Of Aspirin Intoxication

Medical Treatment of aspirin poisoning has 3 objectives:

 To prevent further absorption of aspirin, by


emesis, gastric lavage, multidose activated charcoal.

 To correct dehydration and acid-base abnormalities with


lactated Ringer or isotonic sodium chloride solution.

 To reduce the amount of salicylate within the body by


excretion, in presence of adequate serum K+ and NaHCO3
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NSAIDs
Medical Treatment Of Aspirin Intoxication

 Gastric lavage may be beneficial, unless contraindicated,


with in 60 minutes after salicylate ingestion.

 Dialysis can used for quickly eliminate aspirin from the


body.

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ASPIRIN

PARACETAMOL

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ACETAMINOPHEN / PARACETAMOL

 Acetaminophen is the active metabolite of Phenacetin


 Weak prostaglandin inhibitor in peripheral tissues

 PCM was first used clinically by Von Mering in 1893.


 Marketed in US – 1950, in UK - 1956

 Well tolerated.
 Very safe drug
 Rarely produce side effects.

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ACETAMINOPHEN / PARACETAMOL

 Well absorbed after orally and rectal administration


 Peak plasma conc: with in 30 – 60 minutes
 Slightly bound to plasma proteins
 Half-life 2-3 hours

 Lacks anti-inflammatory property


 Lacks platelets inhibiting property
 Not affect uric acid level
 Not affect platelet aggregation

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ACETAMINOPHEN / PARACETAMOL

Indications
 Analgesic and Antipyretic (equivalent to aspirin)
 Used in mild to moderate pain, headache, myalgia,
postpartum pain, alone or in combination with NSAIDs

 Suitable in all with a wide range of medical conditions


– Children
– Elderly
– Patients with mild to moderate liver disease ,
renal disease, GIT problems, Asthmatics

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ACETAMINOPHEN / PARACETAMOL

Adverse Effects
 Therapeutic doses may increases hepatic enzymes

 Larger doses causes dizziness, excitement,

 Toxic doses (15 gm) may be fatal,


death caused by severe hepatotoxicity with
centrilobular necrosis, acute renal-tubular necrosis

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ACETAMINOPHEN / PARACETAMOL
Intoxication

 At therapeutic doses, 90% is metabolized in the liver


to sulfate or glucuronide conjugates,
that excreted by the kidney

 The remaining 10% metabolized via


cytochrome (P450 2E1) to a toxic and reactive,
N-acetyl-p-benzoquinone imine (NABQI) metabolite,
which is inactivated by glutathione rapidly and no harm.

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ACETAMINOPHEN / PARACETAMOL
Intoxication

 In over doses, the liver conjugation becomes inundated


causing paracetamol metabolized by an alternative pathway
and more formation of N-acetyl-p-benzoquinone imine (NABQI).

 NABQI binds covalently with nucleophilic aspects of cell,


leading to necrosis.

 Necrosis can occur in the liver and in the kidney tubules.

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ACETAMINOPHEN / PARACETAMOL
Intoxication

90% Conjugation

NABQI Glutathione
NABQI

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ACETAMINOPHEN / PARACETAMOL
Intoxication

 Toxicity is increased with induction of the P- 450 through drugs


such as rifampicin, phenobarbital, isonizid, phenytoin,
carbamazipine and alcohol.

 This also occur in patients with low glutathione reserves e.g.


Genetic variations
HIV-positive
Malnutrition
Alcohol related or other liver diseases.

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ACETAMINOPHEN / PARACETAMOL
Intoxication

Clinical Features
 First hours: Nausea, Vomiting, Abdomen discomfort
 24 hours : Liver tenderness, Hepatic necrosis
 Few days : Jaundice, Hypoglycemia,
Oliguria, Renal failure
Hepatic encephalopathy,

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ACETAMINOPHEN / PARACETAMOL
Intoxication

Treatment
 Gastric lavage (with in one hour of ingestion)
if > 7.5g Paracetamol used
has unclear benefits,

 Activated charcoal (with in one hour of ingestion)


if 12g of Paracetamol used
Activated charcoal adsorbs Paracetamol,
reducing its absorption by 50 to 90%

 N-acetylcysteine (NAC) (after four hours of ingestion)

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ACETAMINOPHEN / PARACETAMOL
Intoxication

NAC is indicated in
 All patients with a serum Paracetamol concentration above the
possible hepatic toxicity line on the Rumack-Matthew nomogram

 Patients with an estimated ingestion of greater than 140 mg/kg

 Patients with an unknown time of ingestion

 Patients with a presentation more than 24 hours after ingestion with


elevated transaminases

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ACETAMINOPHEN / PARACETAMOL
Intoxication

 N-acetylcysteine is believed to work by a number of protective


mechanisms.

 It acts as a precursor for glutathione, promoting normal


congugation of any remaining paracetamol, and also supplies
thiols that as antioxidants.

 NAC inhibiting cytochrome P-448 activity


and thus inhibiting the generation of the reactive
intermediate, N-acetyl-p-benzoquinone imine (NABQI).

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ACETAMINOPHEN / PARACETAMOL
Intoxication

Dialysis
In the management of patients who present late in the course
(more than 24 hours) when NAC would be of limited value.

Liver transplantation
Liver transplantation should be considered in severe cases
which progress to stage three or four hepatic encephalopathy if the
patient is otherwise a suitable candidate

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NSAIDs
IBUPROFEN

 Phenyl propionic acid derivative.


 Potent and non – selective cyclooxygenase inhibitor
 > 99 % protein bound.
 Half – life 1-2 hrs
 2400 mg Ibuprofen equivalent to 4g of Aspirin as
anti–inflammatory.

 GIT irritation & bleeding ,skin rashes, pruritis, tinnitus,


dizziness headache, fluid retention.

 Acute renal failure, interstitial nephritis, nephrotic syndrome,


hepatitis rarely occur.
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NSAIDs
DICLOFENAC

 Phenyl acetic acid derivative.


 Potent and non – selective cyclooxygenase inhibitor.
 Has anti – inflammatory, analgesic and antipyretic
effects.
 Bioavailability 30 – 70%.
 Half - life 1--2 hrs

 GIT disturbance, occult GIT bleeding, gastric ulceration

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NSAIDs
INDOMETHACIN

 Indol derivative.
 Potent, non – selective, Cox inhibitor .
 Well absorbed orally.
 Metabolized in liver.
 Excreted by bile, kidney.

 Used in rheumatic conditions, gout , ankylosing spondylitis,


patent ductus – arteriosus.

 Abdominal pain, diarrhea, GIT hemorrhage, pancreatitis, headache,


dizziness, confusion, depression.
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NSAIDs
Selective Cox - 2 Inhibitors

 Celecoxib, (100-200 mg bid).


 Rofecoxib, (12.5-50 mg qid).
 Meloxicam, (7.5-15 mg qid).
 Valdecoxib, (10mg qid).

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NSAIDs
COX-2 Inhibitors

CELECOXIB
 Highly selective Cox-2 inhibitor (375 times more)
 Absorption decreased by food
 Half-life 11 hours
 Highly protein bound
 Dose not affect platelet aggregation
 Dose 100-200 mg BID
 Uses in rheumatoid arthritis, osteoarthritis

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Conjugation
Paracetamol Glucuronidation & 90%
Sulphation

P450

N-acetylcysteine

Toxic
Metabolite

Glutathione
(SH)

Non toxic
metabolites

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NSAIDs
ACTIONS OF ASPIRIN

(9) Acid Base Balance


 Therapeutic doses, stimulated respiration -respiratory alkalosis
(compassed by kidney by bicarbonate excretion)

 Toxic doses depress respiration with accumulation of CO2 – fall


in pH. In addition there is metabolic acidosis
 (i) aspirin ionized at blood pH – decreasing the blood Ph
 (ii) Toxic doses leads to vascular collapse – renal insufficiency
– accumulation of acids
 (iii) toxic doses interfere the carbohydrate metabolism –
accumulation of pyruvic acid
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 Large dose of paracetamol, depleted glutathione
levels
and inhibited cytosolic glutathione transferase
activity. Administration of N-acetylcysteine prevented
these effects.

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NSAIDs
IBUPROFEN

 Phenyl propionic acid derivative.


 Potent and non – selective cyclooxygenase inhibitor
 > 99 % protein bound.
 Half – life 1-2 hrs
 2400 mg Ibuprofen equivalent to 4g of Aspirin as
anti–inflammatory.

 GIT irritation & bleeding ,skin rashes, pruritis, tinnitus,


dizziness headache, fluid retention.

 Acute renal failure, interstitial nephritis, nephrotic syndrome,


hepatitis rarely occur.
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NSAIDs
DICLOFENAC

 Phenyl acetic acid derivative.


 Potent and non – selective cyclooxygenase inhibitor.
 Has anti – inflammatory, analgesic and antipyretic
effects.
 Bioavailability 30 – 70%.
 Half - life 1--2 hrs

 GIT disturbance, occult GIT bleeding, gastric ulceration

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NSAIDs
INDOMETHACIN

 Indol derivative.
 Potent, non – selective, Cox inhibitor .
 Well absorbed orally.
 Metabolized in liver.
 Excreted by bile, kidney.

 Used in rheumatic conditions, gout , ankylosing spondylitis,


patent ductus – arteriosus.

 Abdominal pain, diarrhea, GIT hemorrhage, pancreatitis, headache,


dizziness, confusion, depression.
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NSAIDs
CELECOXIB

 Highly selective Cox-2 inhibitor

 Absorption decreased 20 -30 % by food.

 Half – life 11 hr

 At dose 100 -200 mg bid, effective for rheumatoid – arthritis.

 Does not affect platelet aggregation.

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NSAIDs
ROFECOXIB

 Highly selective Cox- 2 inhibitor.


 Less protein bound.
 Half – life 17 hrs.
 Metabolized by liver, and intestinal wall.
 Does not inhibit platelet aggregation.

 Little effect on gastric mucosal prostaglandin, lower GIT


permeability.

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NSAIDs
Cox -2 – selective inhibitors

 Osteo arthritis ,
 Rheumatoid arthritis,
 Acute gouty arthritis,
 Muscular skeletal pain,
 Ankylosis spondylitis.

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The brain is
part of an
entire body.

It is not a totally
separate entity
which functions
independently.

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BUT
Are there other peptide sequences with opioid or other
biological activity?

Consider Organic Production!

Consider avoidance of “Gluten” containing feedstuffs for


cattle.

Must be seen as part of an overall strategy for individuals.

We need a quick, cheap and cheerful, pilot study


(Suggest Sunderland (UK) and Phoenix (USA))

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Paracetamol Toxicity

90% Conjugation

NAPQI Glutathione
NAPQI

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Conjugation
Paracetamol Glucuronidation & 90%
Sulphation

P450

•N-acetylcysteine
•Methonine
Toxic
Metabolite

Glutathione
(SH)

Non toxic
metabolites

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steroid

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steroids

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prostaglandin

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Arachidonic acid

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Prostaglandins:
 They are un – saturated fatty acid derivates,
contain 20 carbons with cyclic ring.
 They also inhibit Peroxidase that converts
5 – HPETE (5-hydro peroxy eicosa tetra eicoic
acid ) to
5 – HETE ( hydrooxy eicosa tetra eicoic acid ).

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