NON-OPIOID

ANALGESICS
KILEMI MITHEU
 NON STEROIDAL
ANTI-INFLAMMATORY DRUGS
OUTLINE

• Review inflammation and immune response

• Discuss mode of action of NSAIDS
• Differentiate the specific classes of NSAIDS including
nonselective and selective cyclooxygenase inhibitors
• Discuss the indication and contraindication of different
NSAIDS
• Discuss drug interaction and the adverse effects of NSAIDS
and their specific management
 INFLAMMATION

• Inflammation is a normal, protective response to tissue injury caused by several

factors:
✓ Physical trauma
✓ Noxious chemicals or
✓ Microbiologic agents
IMMUNE RESPONSE
• Occurs when immunologically competent cells are activated in response to
foreign organisms or antigenic substances
• The body tries to inactivate or destroy invading organisms, remove irritants,
and set the stage for tissue repair
• When healing is complete, the inflammatory process usually subsides
• However, inappropriate activation of the immune system can result in
inflammation, leading to immune-mediated diseases such as rheumatoid
arthritis
Inflammation
• Inflammatory response include:
• Warmth
• Pain
• Redness and
• Swelling

Phases of inflammation:
• Acute
Transient local vasodilatation and increased capillary permeability
• Delayed/ Sub acute
Infiltration of leukocytes and phagocytic cells
• Chronic proliferative
Tissue degeneration and fibrosis occurs
CYCLOOXYGENASE (PROSTAGLANDIN-
ENDOPEROXIDE SYNTHASE)
• An enzyme responsible for formation of prostanoids (thromboxane,
prostaglandins and prostacyclin)
• Catalyses the conversion of arachidonic acid (a polyunsaturated omega -6 fatty
acid) to prostaglandins which contribute to inflammation
• Has two isoforms; COX 1 and COX 2
COX-1
• Expressed constitutively in most cells and tissues including blood
platelets
• The source of prostanoids which has homeostatic functions such as
cytoprotection of gastric epithelium and platelet aggregation
• Generation of autoregulatory and homeostatic prostanoids
• Helps to protect the stomach and kidneys
• The reason why non-selective NSAIDs have serious adverse effects on
these organs
 COX -2

• Induced during inflammation and inflammatory process

• Up-regulated by cytokines, stress and growth factors

• The principle source of prostanoid formation in inflammation and cancer

• There is a considerable pool of COX-2 in CNS

- Most traditional NSAIDS inhibits both COX-1 and COX-2 but vary in degree to
which they inhibit each isoform
NON STEROIDAL ANTI INFLAMMATORY
DRUGS
• NSAIDS have Analgesic, antipyretic and anti-inflammatory actions
• Non-narcotic, non- opioid, do not depress CNS, do not produce physical
dependence, no abuse
• The anti-inflammatory and antipyretic actions are related to inhibition of
COX-2
• The adverse effects particularly those affecting the GIT are as a result of
COX-1 inhibition (effect of old NSAIDS)
• Compounds with selective inhibitory action on COX-2 available
 THERAPEUTIC STRATEGIES

• Treatment of inflammation involves two primary goals:

✓ Relief of symptoms and maintenance of function

✓ Slowing or arrest of tissue damaging process

• Inflammation is reduced by use of:

➢ Nonsteroidal anti-inflammatory drugs
➢ Glucocorticoids (Steroids)
➢ Disease modifying antirheumatic drugs (DMARDS)
CLASSIFICATION OF NSAIDS

• NSAIDs can be classified based on:

• Their chemical structure or Mode of action
• Selectivity of COX inhibition
• Plasma half life
 NSAIDS: CLASSIFICATION BASED ON
CHEMICAL STRUCTURE
SALICYLATE ACIDS Aspirin, Diflunisal

ACETIC ACIDS INDOLEACETIC ACIDS

• Indomethacin
• Etodolac
• Sulindac
CARBOXYLIC ACIDS PYRROLIZINE CARBOXYLATE
• Ketorolac
PHENYLACETIC ACIDS
• Diclofenac
HETEROARYLACETIC ACID
• Tolmentin
PROPANOIC ACIDS Iboprofen
Fenoprofen
Naproxen
ENOLOIC ACIDS OXICAMS Meloxicam
Piroxicam
 CLASSIFICATION

• Based on COX Inhibition

• Non-Selective COX inhibitors
• Selective COX inhibitors
 NON-SELECTIVE NSAIDS

• Salicylic acid derivatives:Aspirin, Sodium salicylate, Salacylate, diflunisal,

sulfasalazine, Olsalazin
• Indole & indene acetic acid derivatives: Indomethacin, Sulindac
• Heteroaryl acetic acid derivatives:Tolmetin, Diclofenac, ketorolac
• Arylpropionic acids: Ibuprofen, Naproxen, Flubiprofen, Ketoprofen,
fenoprofen, oxaprosin
• Anthranilic acids (fenamates): Mefenamic acid, Meclofenamic acid
• Alkanones: Nebumetone
SELECTIVE COX 2 INHIBITORS
• Enolic acids :Oxicams (Piroxicam, meloxicam)

• Diaryl-substituted furanones – Rofecoxib

• Diaryl-substituted pyrazoles – Celecoxib, parecoxib,etoricoxib

NB:The selective COX-2 inhibitors do not affect platelet function at their usual
doses. The efficacy of COX-2-selective drugs equals that of the older NSAIDs, while
GI safety may be improved
 PHARMACODYNAMICS

• NSAID anti-inflammatory activity is mediated chiefly through inhibition of

prostaglandin biosynthesis
• Various NSAIDs have additional possible mechanisms of action:
✓ Inhibition of chemotaxis
✓ Down-regulation of IL-1 production
✓ Decreased production of free radicals and superoxide
✓ Interference with calcium-mediated intracellular events

NB: Aspirin irreversibly acetylates and blocks platelet COX, while the COX-
selective NSAIDs are reversible inhibitors
NSAIDS: MOA

• They act primarily by inhibiting the cyclooxygenase enzymes that

catalyze the first step in prostanoid biosynthesis
• This leads to decreased prostaglandin(PGs) synthesis with both
beneficial and unwanted effects
• PGs are synthesized in various tissues and have several physiological
actions which include their role in inflammation
• Inhibition of COX-2 is leads to anti- inflammatory and analgesic
actions of NSAIDs
• Simultaneous inhibition of COX-1 accounts for adverse effects in the
GI tract
OTHER MECHANISM OF ACTION OF NSAIDS

• Inhibition of phosphodiesterase which reduces production of superoxide

that damage tissues
• Inhibition of leukocyte migration
• Removal of toxic hydroxyl residues
• Inhibition of platelet aggregation
NB: Traditional NSAIDS (tNSAIDS)-Inhibit both COX-1 and COX-2 e.g.
Aspirin
- The inhibition decreases prostaglandin and thromboxane synthesis
throughout the body
- Release of prostaglandins necessary for homeostatic function is
disrupted as is the prostaglandins involved in inflammation
- Aspirin but not its active metabolite (acetylates) irreversibly inhibits
cyclooxygenase unlike other NSAIDS whose inhibition is reversible
COX INHIBITORS THERAPEUTIC ACTIONS

These drugs have three major therapeutic actions, stemming from the
suppression of prostanoid synthesis in inflammatory cells mainly through
inhibition of the COX-2 isoform
ANTI-INFLAMMATORY EFFECT
• Prostaglandins mainly derived from COX-2 play a significant part in
vasodilation and oedema of inflammation
• NSAIDs reduce these components of inflammation (by reducing the
synthesis of vasodilator prostaglandins)
ANTI-PYRETIC EFFECT
• A center in the hypothalamus controls the balance between heat production and
heat loss thereby regulating normal body temperature
• Fever occurs when there is a disturbance of this hypothalamic thermostat
• This disturbance is caused by Interleukin-1 which releases prostaglandins in the
central nervous system, where they elevate the hypothalamic set point for
temperature control, thus causing fever
• NSAIDs reset this thermostat thru’ dilatation of superficial blood vessels leading
to sweating and reduction of temperature
• Normal body temperature in healthy humans is not affected by NSAIDs
 ANALGESIC EFFECT
• NSAIDS are effective against mild or moderate pain from inflammation or tissue
damage
• Decreased prostaglandin generation means less sensitization of nociceptive nerve
endings to inflammatory mediators such as bradykinin and 5-hydroxytryptamine
• Are effective in arthritis, pain of muscular and vascular origin, toothaches,
dysmenorrhoea and pain related to cancer metastasis in bone
• Alone or together with opioids, NSAIDS decrease postoperative pain
 PHARMACOKINETICS

• NSAIDS have many differences in kinetics

• However, they have common general properties
• All NSAIDs are weak organic acids except Nabumetone a ketone prodrug,
that is metabolized to the acidic active drug
• Most NSAIDs are well absorbed after oral administration and circulate highly
bound to plasma proteins
• The majority are metabolized by the liver, mostly to inactivate metabolites.
Few (eg nabumetone and sulindac) have active metabolites
• Elimination of active drug and metabolites is primarily via the urine
 ADVERSE EFFECTS
Generally quite similar for all of the NSAIDs and is due to inhibition of
prostaglandin synthesis and therefore antagonizing the following roles of
prostaglandin
Gastrointestinal
➢GI related: dyspepsia; bleeding
• Normally production of prostacyclin (PGI 2) inhibits gastric acid secretion, and
PGE2 and PGF2α stimulate synthesis of protective mucus in both the stomach
and small intestine
• Inhibition of COX-1 reduce beneficial levels of these prostaglandins, resulting in
increased gastric acid secretion, diminished mucus protection, and increased
risk for GI bleeding and ulceration
 ADVERSE EFFECTS CONT..

Increased risk of bleeding (antiplatelet effect)

• TXA2 enhances platelet aggregation
• Aspirin irreversibly inhibits COX-1–mediated TXA2 formation, while other
NSAIDs reversibly inhibit the production of TXA2
• Platelets lack nuclei, they cannot synthesize new enzyme when inhibited by
aspirin, and the lack of thromboxane persists for the lifetime of the platelet
(8 to 10 days)
• Decrease in TXA2 production, reduces platelet aggregation (the first step in
thrombus formation) , producing an antiplatelet effect with a prolonged
bleeding time
 ADVERSE EFFECTS CONT..

Actions on the Kidney

• NSAIDs prevent the synthesis of PGE 2 and PGI2( prostaglandins that are
responsible for maintaining renal blood flow)
• Decreased synthesis of prostaglandins can result in retention of sodium
and water and may cause edema in some patients
• Patients with a history of heart failure or kidney disease are at
particularly high risk
• These effects can also mitigate the beneficial effects of antihypertensive
medications.
RENAL EFFECTS
OF NSAIDS
ADVERSE EFFECTS CONT..
Cardiac effects
• COX-2 selective NSAIDS have been associated with an increased risk
for cardiovascular events, by decreasing PGI 2 production mediated by
COX-2
• An increased risk for cardiovascular events, including MI and stroke, has
been associated with all NSAIDs except Aspirin
• COX 1 inhibition has cardiovascular protective effect due to a
reduction in the production of TXA2 (vasoconstrictor)
ADVERSE EFFECTS CONT..
Other adverse effects:
• CNS adverse events, such as headache, tinnitus, and dizziness, may occur
• Hypersensitivity reactions (in app. 15% of patients taking aspirin)
✓ urticaria, bronchoconstriction, and angioedema
• Fatal anaphylactic shock is rare
• Uterus: Prolongation of gestation, Inhibition of labour
• NSAIDs should be used with caution in patients with asthma
DRUG INTERACTIONS

• Salicylate is roughly 80 to 90% plasma

protein bound and can be displaced from
protein binding sites, resulting in increased
concentration of free salicylate
• Alternatively, aspirin can displace other
highly protein-bound drugs, such as warfarin,
phenytoin, or valproic acid, resulting in higher
free concentrations of these agents
DRUG INTERACTIONS

• Antacids prescribed to patients on NSAIDS variably delay

absorption

• NSAIDs Attenuate the effectiveness of ACE inhibitors by

blocking the production of vasodilator and natriuretic PG

• NSAIDs augment the risk of bleeding in patients receiving

warfarin because almost all NSAIDs suppress normal platelet
functioning
 DRUG INTERACTION CONT..

• NSAIDs also increase warfarin levels by displacing it from protein

binding site.

• Corticosteroids and SSRIs increase the frequency and severity of GI

complications when combined with NSAIDs

• Patients receiving lithium should be monitored because certain NSAIDs

(e.g. Peroxicam) reduce renal excretion of lithium
SPECIFIC NSAIDS
ACETYSALICYLIC ACID ( ASPIRIN)
• Asprin (acetylsalicylic acid) is the prototype drug in salicylic acid derivatives

• Rarely used as an anti-inflammatory medication but used for its

antiplatelet effects at doses of 81–325 mg once daily

Dosing:
• Low dose <300mg are effective in reducing platelet aggregation
• Intermediate doses (300-2400mg/day) have antipyretic and analgesic effects

• High doses(2400-4000mg/day) are used for anti-inflammatory effect

 PHARMACOKINETICS

• Asprin is rapidly absorbed partly from the stomach and mostly from the upper
small intestines, by passive diffusion
• The drug yields a peak plasma salicylate level within 1- 2hours
• An increase in PH increases the solubility hence absorption
• Distributed throughout the body tissues and transcellular fluids,
• Highly protein bound 80-90%
PHARMACOKINETICS CONT..

• Metabolized in blood plasma, erythrocytes

and liver to Salicyluric acid, phenolic
glucuronide and acyl glucuronide
• Excreted in urine as free salicylic acid (10%),
salicyluric acid (75%), phenolic glucuronide
(10%) and acyl glucuronides (5%)
 PHARMACODYNAMICS

• Covalently modifies COX-1 and COX-2,

• Irreversably inhibits COX activity so that aspirin anti-platelet effect lasts
8-10 days(the life of the platelet)
• Mechanism of action in rheumatic disease may involve cellular and
immunological processes such as inhibition of antibody production and
antigen induced release of histamine
• Salicylates also induce nonspecific stabilization of capillary permeability
during immunological insults
 CLINICAL USES

After coronary artery bypass grafting

• Aspirin decreases the incidence of transient ischemic attacks, unstable
angina, coronary artery thrombosis with myocardial infarction, and
thrombosis after coronary artery bypass grafting
• Epidemiologic studies suggest that long-term use of aspirin at low dosage is
associated with a lower incidence of colon cancer, possibly related to its
COX-inhibiting effects
 CLINICAL USES CONT..

• Treatment of inflammatory bowel disease

• Low doses are cardioprotective
• High doses are given for treatment of acute rheumatic fever
• May be used preoperative in carotid artery stenting, carotid endarterectomy,
infrainguinal artery bypass
 ADVERSE REACTIONS

Haematologic
• Prolonged bleeding time, thrombocytopenia
• Aspirin causes hemolysis in patients deficient of glucose-6-phosphate
dehydrogenase
• Ototoxic Effects: Tinnitus, hearing loss
• GI: nausea, vomiting, GI distress, occult bleeding, dyspepsia, GI bleeding
ADVERSE REACTIONS CONT..

• Hepatic toxicity
• Skin: rash, bruising, urticaria
• Hypersensitivity reactions (anaphylaxis, asthma)
• Pregnancy category risk: C (D in third trimester). There is an
increase in perinatal mortality, anaemia, antepartum and postpartum
haemorrhage
• Infants born of mothers ingesting aspirin may have reduced birth weight
DRUG INTERACTION
• Acetazolamide and ammonium chloride increases blood levels of aspirin
therefore enhancing aspirin toxicity
• Antacids in high levels reduces blood levels of aspirin
• Antihypertensives: Reduced antihypertensive effect
• Corticosteroids: Enhanced salicylate elimination
• Probenecid: Decreased uricosuric effect
• Heparin: Increased risk of bleeding
• Drug- food: Caffeine may increase the absorption of aspirin
• Drug- lifestyle:Alcohol use increases risk of GI bleeding
 SALICYLATE INTOXICATION

-It often occurs in children and is fatal

-CNS effects include intense hyperpnea and hyperpyrexia

-It should be considered in any children in coma, cardiovascular collapse and

those with convulsions

Use of 10-30g of aspirin may cause death

 SALICYLATE INTOXICATION

Acid-base disturbance
• At the beginning there is Respiratory Alkalosis

• Then there is Metabolic Acidosis

✓ Depletion of HCO3, accumulation of salicylic acids derivatives, respiratory
depression

• Lastly is Mixed Acidosis (respiratory and metabolic)

✓ Gastric lavage and force alkaline diuresis- alkalinize urine

 SYMPTOMS OF SALICYLATE
INTOXICATION
• Headache, dizziness, tinnitus
• difficulty in hearing
• blurred vision
• mental confusion
• drowsiness
• Sweating, thirst
• Hyperventilation
• nausea, vomiting and occasional diarrhoea.
 CONTRAINDICATION

• Patients with haemophilia

• Children and young adults<20 years with viral illness because it is associated
with Reye’s syndrome
• REYE’S SYNDROME characterized by acute onset of encephalopathy, liver
dysfunction, fatty infiltration of the liver
• Patients with severe hepatic damage
• Hypoprothrombinaemia
• Vitamin k deficiency
✓ Note: Aspirin should be stopped 1week before surgery
NONACETYLATED SALICYLATES

These drugs include:

• Magnesium choline salicylate
• Sodium salicylate
• Salicyl salicylate
 NON-ACETYLATED
SALICYLATES CONT..

• Effective anti-infalammatory drugs

• Less effective analgesics than aspirin
• Less effective than aspirin as COX inhibitors hence no inhibition of
platelet aggregation
CLINICAL USES
Preferable when: COX inhibition is undesirable: Patients with asthma,
bleeding tendencies and renal dysfunction
COX-2 SELECTIVE INHIBITORS
(COXIBS)

• Celecoxib
• Etoricoxib
• Lumiracoxib
• Meloxicam
• Rofecoxib
• Valdecoxib : Withdrawn from the market due to
cardiovascular thrombotic events associated with them.
 PHARMACODYNAMICS

• Induced at sites of inflammation

• Selectively bind to and block the active site of the COX-2 enzyme much
more effectively than the COX-1
• Inhibit COX-2 mediated prostacyclin synthesis in the vascular
endothelium thus enhances vasoconstriction and platelet aggregation
• Have analgesic, antipyretic and anti-inflammatory effects similar to those
of non selective NSAIDS
 TOXICITY

• Renal Toxicity
• Higher incidence of cardiovascular thrombotic events associated with
rofecoxib and valdecoxib resulted in their withdrawal from the market
 CELECOXIB

PHARMACOKINETICS DRUG INTERACTIONS

• Half life of 11hours • Interacts with warfarin-

metabolised via CYP2C9
• 27% excreted unchanged in urine
• Recommended dosage of 100-200mg BD

PHARMACODYNAMICS
• Is a selective COX-2 Inhibitor
• Because it is a sulfonamide. it may cause rashes.
• Dose not affect platelet aggregation at usual doses
NON-SELECTIVE COX
INHIBITORS
• Diclofenac • Ketorolac
• Diflunisal • Nabumetone
• Etodolac • Naproxen
• Flurbiprofen • Oxaprozin
• Ibuprofen • Piroxicam
• Indomethacin • Sulindac
• Ketoprofen • Tolmetin
 DICLOFENAC

• Phenylacetic acid derivative

• Adverse effects in approx. 20% of patients:
• gastrointestinal distress
• occult gastrointestinal bleeding
• gastric ulceration which is less frequently than with some other NSAIDs
• Dosage of 150 mg/d impair renal blood flow and glomerular filtration
rate
• Elevation of serum aminotransferases may occur more commonly with
this drug
 TOLMENTIN

• Acetic acid derivative

• short half-life (1–2 hours); not often used
• It is ineffective (for unknown reasons) in the treatment of
gout
• May cause (rarely)thrombocytopenic purpura
KETOROLAC
• For systemic use as an analgesic, not anti-inflammatory drug; inhibits platelet
aggregation and promotes gastric ulceration
• Used successfully to replace morphine, mild to moderate postsurgical pain
• Given im/iv, oral dose formulation is available
• Treatment of seasonal allergic conjunctivitis and postoperative ocular
inflammation after cataract extraction
• Toxicities; renal toxicity with chronic use
 DIFLUNISAL
• Difluorophenyl derivative of salicylic acid. It is not converted to salicylic acid in
vivo
• Completely absorbed after oral administration
• Peak plasma levels within: 2-3hr
• Bound to plasma albumin( 99%)
• 90% is excreted as glucuronide conjugates, and its elimination is dose-
dependent
• Appears in the breast milk
• Used primarily as an analgesic in the treatment of osteoarthritis and
musculoskeletal strains or sprains
ETODOLAC
• GIT irritation is less than with other NSAIDs
• Well absorbed orally, highly bound to plasma protein
• Undergoes hepatic metabolism and renal excretion
• Undergo enterohepatic circulation and half-life is 7 hrs
• Single dose 200 to 400 mg provides analgesia that lasts
for 6- 8 hrs
• Rx of osteoarthritis and rheumatoid arthritis and the
drug appears to be uricosuric
 INDOMETHACIN
• A potent nonselective COX inhibitor
• Inhibit phospholipase A and C, reduce neutrophil migration, and T cell and B
cell proliferation
• Probenecid prolongs indomethacin's half-life
Uses:
• Gout and ankylosing spondylitis, gingivitis, conjuctivitis and epidural injection in
post-laminectomy
Adverse effects
• Gastrointestinal effects -abdominal pain, diarrhea, Gastrointestinal
hemorrhage, and pancreatitis
• Headache 15-25% of patients, associated with Dizziness, confusion, and
depression, aplastic anemia.
SULINDAC
• Sulfoxide prodrug and non selective inhibitor
• Reversibly metabolized to the active sulfide
• Metabolite, excreted in bile and then reabsorbed from the intestine.The
enterohepatic cycling action prolonged to 12-16 hours.
Indications
• Rheumatic disease, suppresses intestinal polyposis
• Inhibit the development of colon, breast, and prostate cancer
Adverse effects:
• Stevens-Johnson syndrome
• Thrombocytopenia, agranulocytosis; Nephrotic syndrome
FENEMATES: MEFENAMIC, MECLOFENAMIC,AND
FLUFENAMIC ACIDS

• N-phenylanthranilic acid derivatives

• Strong analgesic and low anti-inflammatory
• Mefenamic acid (PONSTAN) and meclofenamate sodium are
used in the short-term Rx of pain in soft-tissue injuries,
dysmenorrhea, and in rheumatoid and osteoarthritis.
• Not recommended for use in children or pregnant women.
 FENEMATES; PK

• Absorbed slowly with peak level: 2-3hrs and have short durations of
action
• 98% plasma protein bound
• 50% of mefenamic acid is excreted in urine & 20% excreted in feaces,
Adverse effects
• Renal failure
• hemolytic anemia,Aplastic anemia, thrombocytopenia
 IBUPROFEN

• Phenylpropionic acid derivative

• In doses of about 2400 mg daily, ibuprofen is equivalent to 4g of aspirin in
anti-inflammatory effect
• Oral ibuprofen is often prescribed in lower doses (400 mg/qid), at which
it has analgesic but not anti-inflammatory efficacy
• Effective in post-op, dysmenorrhea, dental, migraine
• A topical cream preparation is absorbed into fascia and muscle
• Cream is more effective, treatment of primary knee osteoarthritis
• A liquid gel 400 mg, provides prompt relief and good overall efficacy in
postsurgical dental pain
 IBUPROFEN CONT..
Contraindications
• Individuals with nasal polyps, angioedema, and bronchospastic reactivity to aspirin,
Aseptic meningitis (particularly in patients with systemic lupus erythematosus) fluid
retention

• Interaction with anticoagulants is uncommon

• The concomitant administration with aspirin: antagonizes the irreversible platelet
inhibition induced by aspirin
• Thus, treatment with ibuprofen in patients with increased cardiovascular limit the
cardioprotective effects of aspirin, and also decrease total anti-inflammatory effect
Adverse effects
Rare hematologic effects include agranulocytosis and aplastic anaemia
 NAPROXEN
• Naphthylpropionic acid derivative
• Indicated for rheumatologic conditions
• Available in:A slow-release formulation,An oral suspension,A topical preparation
and an ophthalmic solution
• Absorbed fully orally but food delays the rate of absorption
• Absorption is accelerated by co-administration of Sodium Bicarbonate but
delayed by Mg hydroxide and Al hydroxide
• Also absorbed rectally: but slowly
• 99% bound to plasma proteins, crosses the placenta and appears in the breast
milk at approx. 1%
• Peak plasma level: 2 to 4 hours
• Excreted as the glucuronide or other conjugates in the urine
NABUMETONE
• The only non-acid NSAID ; it is converted to the active acetic
acid derivative in the body
• Given as a ketone prodrug
• Half-life of more than 24 hours , permits once-daily dosing
• Renal impairment results in a doubling of its half-life
• Less damaging to the stomach than some other NSAIDS when
given at a dosage of 1000 mg/d
• Higher dosages (eg, 1500–2000 mg/d) are often needed, and is a
very expensive NSAID
• Cause pseudoporphyria and photosensitivity in some patients
 FENOPROFEN
• 85% absorption after oral administration. Food in the stomach retards
absorption
• Peak plasma level: 2 hours
• Binds to protein, half-life: approximately 3 hours
• Extensively metabolized, and is excreted in the urine
• Ketoprofen & Flurbiprofen
Similar pharmacokinetic profile to fenoprofen
• Conjugated with glucuronic acid in the liver and excreted in the urine
• Can cause fluid retention and increased plasma of creatinine conc.
FLURBIPROFEN
• Is available in topical ophthalmic formulation for inhibition of
intraoperative miosis
• Intravenously, effective for perioperative analgesia in minor ear,
neck, and nose surgery and in lozenge form for sore throat
• Adverse effects: Similar to other NSAIDs
OXAPROZIN

• Propionic acid derivative

• Differs from the other members of this subgroup: Has a very
long half-life (50–60 hours)
• Does not undergo enterohepatic circulation
• It is mildly uricosuric, more useful in gout
PARA-AMINOPHENOL DERIVATIVES
 PARA-AMINOPHENOL
DERIVATIVES

ACETAMINOFEN (paracetamol; N-acetyl-p-aminophenol)

• A weak COX inhibitor in peripheral tissues and possesses no significant anti-

inflammatory effects
• An effective alternative to aspirin as an analgesic-antipyretic agent
• It is well tolerated and has low GI side effects
• Acute overdose can cause severe hepatic damage
 PHARMACOKINETICS

• Administered orally
• Absorption is related to the rate of gastric emptying
• Peak blood concentrations are usually reached in 30-60 minutes
• Half-life 2hours and is unaffected by renal function
• It is slightly bound to plasma proteins 20-50%
• It is uniformly distributed to most body fluids
• Partially metabolised by hepatic microsomal enzymes to acetaminophen
sulphate and glucuronide which are pharmacologically inactive
 PHARMACOKINETICS

• Less than 5%is excreted unchanged.

• A minor but highly reactive metabolite (N-acetyl-p-benzoquinone) Is
important in large doses because it is toxic to both the liver and kidney.
 INDICATIONS

• It is useful for analgesic or antipyretic uses

• Useful in mild to moderate pain such as headache, myalgia, postpartum pain
• It may be used concomitantly with probenecid in treatment of gout
• It is preferred to aspirin in children with viral infections
• Used in patients who are allergic to aspirin
 INDICATIONS CONT..

• Valuable in patients whom aspirin is contraindicated.

• Dosage is 325-650mg every 4-6hours
• Total daily doses should not exceed 4000mg.
 ADVERSE EFFECTS

• In therapeutic doses, a mild increase in hepatic enzymes may occur in the

absence of jaundice -Reversible when the drug is withdrawn
• With larger doses,
✓ dizziness,
✓ excitement
✓ disorientation

• Ingestion of 15g may be fatal Due to:

✓ hepatotoxicity
✓ acute renal tubular necrosis.
 ACETAMINOPHEN
INTOXICATION
• Acute ingestion of >7.5 g of acetaminophen can result in toxicity
• The most serious acute adverse effect is fatal hepatic necrosis
• Renal tubular necrosis and hypoglycaemic coma may also occur
• Hepatocellular injury and death involves conversion of acetaminophen
to N-acetyl-p-benzoquinone) which is toxic
EARLY SYMPTOMS OF
HEPATIC DAMAGE
• Nausea
• Vomiting
• Diarrhoea
• Abdominal pain
• Anorexia
• This symptoms occur the first two days
• Clinical presentations occur 2-4 days of ingestion of toxic doses with
right subcostal pain, tender hepatomegaly ,jaundice and coagulopathy.
Renal impairment may occur. Liver enzyme abnormalities peak 72-
96hours after ingestion
• Hepatic encephalopathy or worsening coagulopathy beyond this time
indicates poor prognosis
 MANAGEMENT OF ACETAMINOPHEN
OVERDOSE

• Activated charcoal if given if given within 4hours of ingestion decreases

acetaminophen absorption by 50-90%
• It is the preferred method of gastric decontamination
• Gastric lavage is generally not recommended
• N-acetylcysteine (NAC) is indicated for those at risk of hepatic injury
• It should be administered in any suspected cases of acetaminophen poisoning
• Provision of sulfhydryl groups in the form of acetylcysteine to neutralise the
toxic metabolite
 MANAGEMENT OF OVERDOSE
CONT..
• Oral loading dose of NAC is 140mg/kg followed by 70mg/kg every 4 hours
for 17 doses.
• Where available, the intravenous loading dose is 150mg/kg by intravenous
infusion in 200ml of 5% dextrose over 60 minutes.This is followed by
50mg/kg by IV infusion in 500ml of 5%dextrose over 4 hours, then
100mg/kg by IV infusion in 1000ml of 5%dextrose over 16 hours.
FURTHER READING

• Watch the video below:

https://www.youtube.com/watch?v=Mi-O8uiX0no
 REFERENCES

• H.P.Rang and Dale.et al. Pharmacology.6th edition. Churchil

Livingstone.2007.Elsever
• Katzung, basic and clinical pharmacology-11th edition
• Katzung, B.G., Masters, S.B. and Trevor,A.J., Basic and clinical
pharmacology 11th Edition. McGraw Hill Companies
• Lippincott's review - pharmacology