FAR 381: NSAIDs CARDINAL SIGNS OF INFLAMMATION:

INFLAMMATION:

? WHAT ?

a protective response of the body to tissue injury that may be caused by; noxious
chemical stimuli, physical trauma, or micro-organisms

? PURPOSE ?

- Destroy invading organisms

- Remove irritants
- Restore tissue structure & function

PROSTAGLANDINS:

NOTE: Inflammation can be over exaggerated, become harmful to the body, &
ROLE AS LOCAL MEDIATORS:
uncomfortable
- Prostaglandins are produced in small amount in virtually all tissues
- They act locally in the tissues with which they are synthesized, & are rapidly

CAUSES: degraded
- Actions are mediated through binding to G-protein coupled receptors
- Infective agents → bacteria, fungi viruses & their toxins
- Prostaglandins are involved in constitutive functions & mediate pain, fever &
- Immunological agents → cell-mediated & antigen-antibody reactions
inflammatory processes
- Physical agents → heat, cold, radiation, mechanical trauma
- Thromboxane’s & leukotrienes related chemicals that are synthesized form
- Chemical agents → organic or inorganic poisons, acids
the same precursor as prostaglandins
- Inert materials → foreign bodies

SYNTHESIS:

- Arachidonic acid is the primary precursor of all prostaglandins

o Present as a component of the phospholipids of cell membranes
- Arachidonic acid is released from the membranes via the action of
phospholipase A2
o Controlled by hormones & other stimuli
 - There are two major pathways for synthesis COX-2:
o Cyclooxygenase pathway
- COX-2 is not normally present (at least in most tissues) but is strongly
o Lipoxygenase pathway
induced by inflammatory stimuli
- Normally present at the site of inflammation – produced by cell involved in
inflammation
- Also found in other tissues & organs
o Kidneys, brain, uterus, bone, joints & vascular endothelium
- Induced by cytokines (tumour necrosis factor alpha & interleukin 1&2)
- Expressed in CNS & plays a role in central mediation of pain & fever

NSAIDs:

- Drug class that reduces pain, decreases fever, prevents blood clots & reduces
inflammation
- Available as tablets, capsules, suppositories, creams, gels & injections
- Provide symptomatic relief in chronic joint disease such as that occurs in
arthritis, as well as in more acute inflammatory conditions such as fractures,

CYCLOOXYGENASES: sprains & sports injury

- Are also useful in the treatment of postoperative, dental & menstrual pain, &
COX-1: of headaches & migraines

- Constitutive enzyme that synthesizes prostaglandins involved in normal house - Many are available over the counter – used for a variety of ailments

keeping functions
- Present in almost all tissues & organs (blood vessels, platelets, stomach,
intestine, kidneys) MECHANISM OF ACTION:

- Physiological effects - Block the synthesis of prostanoids (prostaglandins, thromboxane A2,

o Gastric protection prostacyclin)
o Platelet aggregation - Inhibition alleviates pathologic effects associated with inflammation
o Vascular homeostasis o However, physiologic functions can be inhibited, leading to side effects
o Maintenance of blood pressure - Long term therapy use of NSAIDs is limited by side effects, most importantly –
gastrointestinal side effects
 - Inhibit the COX-1 & COX-2 isoforms through competitive inhibition at the Antipyretic:
enzyme active sites
- Normal body temperature is regulated by the hypothalamus that controls
- Although both COXs exist as homodimers, only one partner is used at a time
balance between heat loss & heat production
for substrate binding
- NSAIDs Inhibit the effects of prostaglandins on the thermoregulatory centre in
- NSAIDs bind to & inactivate the COX site at only one of the monomers of the
the hypothalamus & restores normal body temperature
COX dimer & this is sufficient to shut down prostanoid formation
- Lack of prostanoid formation alleviates pain & inflammation

THERAPEUTIC EFFECTS:

Analgesia:

- Reduction of pain arising from inflammation or tissue damage

- Decrease production of prostaglandins that sensitize nociceptors to bradykinin
- Combined with opioids for post-operative pain

INDICATIONS:

- Chronic joint diseases (osteoarthritis, rheumatoid arthritis)

- Acute inflammatory injuries (sport injuries, fractures, sprains, soft tissue
injuries)
- Post-operative pain e.g. dental procedures
Anti-inflammation: - Menstrual pain
- Headaches
- Inhibits the release of prostaglandins, histamine, thromboxane & leukotrienes
in the area of tissue injury
- Suppress pain, swelling & increased blood flow associated with inflammation
ADVERSE EFFECTS:

GIT:

- Most common adverse effect

- Inhibition of COX-1 leads to a decrease in prostaglandins that inhibit acid
secretion & protect the mucosa
 - Abdominal pain, ulcerations, bleeding, anaemia, diarrhoea, nausea & vomiting Salicylic acids Aspirin
NS AID
Propionic acids Naproxen, Ibuprofen, Ketoprofen,
- Proton pump inhibitors (PPIs) used for patients at high risk for ulcers or
Oxaprozin & Flurbiprofen
history of peptic ulcer disease
Anthranilic acid Mefenamic acid

Aryl-acetic acid derivative Diclofenac & Aceclofenac

KIDNEYS:
Oxicam derivatives Piroxicam & Tenoxicam
- No adverse effects at therapeutic doses in healthy individuals
- Renal insufficiency in susceptible patients Pyrrolo-pyrrole derivatives Ketorolac, Indomethacin & Nabumetone
o Inhibition of prostaglandins responsible for maintenance of renal blood
Indole derivatives Sulindac & Indomethacin
flow
o Haematuria & renal necrosis Pyrazolone derivatives Phenylbutazone & Oxyphenbutazone

SKIN CONDITIONS – Stevens Johnson syndrome – very rare, fatal PREFERENTIAL INHIBITORS:

CENTRAL NERVOUS SYSTEM – headaches, vertigo, depression Preferential COX-2 inhibitors Nimesulide, Diclofenac, Aceclofenac,
Meloxicam & Nabumetone
HEMATOPOIETIC EFFECTS – thrombocytopenia, prolonged bleeding due to poor
clotting, leukopenia Selective COX-2 inhibitors Celecoxib, Etoricoxib & Parecoxib

Analgesic-antipyretic with poor anti-

CLASSIFICATION: inflammatory action:

Traditional non-selective NSAIDs – Stevens Johnson syndrome – very rare, fatal Para-aminophenol derivatives Paracetamol (Acetaminophen)

More COX-1 selective Pyrazolone derivatives Metamizole & Propiphenazone

More COX-2 selective Benzoxazocine derivatives Nefopam

TRADITIONAL NON-SELECTIVE NSAIDs:

Traditional – Nonselective COX inhibitors:

GROUP DRUGS
 Celecoxib Celebrex

TRADITIONAL NSAIDs: Etoricoxib Arcoxia

ACTIVE INGREDIENT TRADE NAMES

Ketorolac Toradol INDICATIONS MECHANISM OF ACTION ADVERSE EFFECTS

Flurbiprofen Transact, Strepsils intensive - Mild pain - Inhibits COX-2 - Abdominal pain
- Inflammation enzyme → Inhibits - Dyspepsia
- Fever formation of - Diarrhoea
INDICATIONS MECHANISM OF ACTION ADVERSE EFFECTS - Rheumatoid inflammatory
arthritis mediator
- Mild pain - Inhibits COX-2 - Anticoagulatory
- Osteoarthritis (prostagl&in)
- Inflammation enzyme → Inhibits effect
CONTRAINDICATIONS DRUG-DRUG COMMENTS
- Fever formation of - Abdominal pain
INTERACTIONS
inflammatory - Dyspepsia
mediator - Diarrhoea - Allergy (drug - Alcohol - Less inhibition of
(prostagl&in) specific) - Anticoagulants platelet
CONTRAINDICATIONS DRUG-DRUG COMMENTS - Chronic renal (Warfarin) aggregation
INTERACTIONS insufficiency compared to COX-
- Hepatic failure 1 (approved drugs)
- Allergy (drug - Inhibitors of liver - Inhibition of platelet
- Prone to gastric - Increase platelet
specific) enzymes aggregation
ulcers aggregation
- Chronic renal - Alcohol - Gastric ulcer
(removed drugs)
insufficiency - Anticoagulants formation
- Hepatic failure
- Prone to gastric
ulcers

COX-2 SELECTIVE INHIBITORS:

ACTIVE INGREDIENT TRADE NAMES

Meloxicam -meloxicam
ASPIRIN: Antipyretic

INDICATIONS PHARMACOKINETICS ADVERSE EFFECTS - Fever occurs when set point of hypothalamic thermoregulatory centre is
elevated
- Mild pain - Oral & rectal - Anticoagulatory
- Reduce fever via inhibition of prostaglandin synthesis
- Inflammation formulations effects
- Peripheral vasodilation & sweating
- Fever - Absorption delayed - Gastric ulcers
- Rheumatic fever
- Cardiovascular by food intake - Allergic reactions
disorders - Rapidly hydrolysed Analgesic
in plasma & tissue
- Synthesis of prostaglandin inhibited
yielding salicylate
- Less sensitizing of nerve endings to action of
(anti-inflammatory
o Bradykinin
properties)
o histamine
- Metabolized in liver
o other chemical mediators
- Eliminated via
- Mild pain relief
kidneys
CONTRAINDICATIONS DRUG-DRUG COMMENTS Antiplatelet activity
INTERACTIONS
- Inhibits COX-1 enzyme & prevents formation of thromboxane A2
- Children with viral - Anticoagulants - MoA – irreversible - Prevent blood clotting
infection (Warfarin) acetylation of - Cardiovascular conditions & used to prevent strokes
- Pregnancy - Probenecid & COX-1 & COX-2
- Allergic to Aspirin sulfinpyrazone → - Can cause Reye’s
interferes with syndrome ADVERSE EFFECTS:
uricosuric agents & Increased risk of bleeding
reduces urate
- Inhibition of platelet activation causing decreased blood clotting
secretion
- Exacerbates bleeding gastric ulcers

Reye’s syndrome
THERAPEUTIC EFFECTS:
- Children more affected than adults (approximately 30% fatality in children)
Anti-inflammatory
- Results in liver & brain damage
- Inhibits cyclooxygenase activity –diminishes prostaglandin formation - Symptoms: rash, vomiting, fever, convulsions & death
- Rheumatoid arthritis–symptomatic relief - Associated with viral infection & aspirin use
- Reduce swelling & redness
TOXICITY & OVERDOSE - Inhibit COX-3

- Chronic overdose is fatal in 25% of cases

o Nausea, vomiting, headaches, dizziness, impaired vision, hyperthermia
- Known as acetaminophen in the USA
- Administer activated charcoal to reduce absorption of drug, followed by
- Weak anti-inflammatory activity ,does not have gastric & platelet effects
gastric emptying
o Not usually classified as an NSAID but combined with aspirin & various
PARACETAMOL: Acetaminophen NSAIDs to treat pain, inflammation & fever
- Analgesic & antipyretic activity
INDICATIONS PHARMACOKINETICS ADVERSE EFFECTS
o Inhibits prostaglandin synthesis in the CNS
- Mild pain - Oral, rectal & IV - Fatal hepatotoxicity - Weak anti-inflammatory activity
- Fever formulations @ toxic doses o Poor effect on cyclooxygenase in peripheral tissues
- When aspirin is - Rapidly absorbed - Renal tubular - No effect on platelet function or blood clotting
contraindicated from GIT & exert necrosis
(pregnancy, effect within 30min (prolonged use)
children, gastric - Inactivated in liver MECHANISIM OF ACTION:
ulcers) – conjugated with
- Inhibit prostaglandin synthesis (central)
sulphate &
o Very weak COX-1, weak COX-2 inhibitor
glucuronide
o COX-3 inhibitor (found in CNS)
- N-acetyl-p-
benzoquinone
imine accumulation
ADVERSE EFFECTS:
leads to liver &
kidney necrosis - No significant adverse effects at normal therapeutic doses
CONTRAINDICATIONS DRUG-DRUG COMMENTS o Fatal hepatotoxicity at toxic doses
INTERACTIONS o Renal tubular necrosis rare complication of prolonged, large dose
therapy
- Renal & hepatic - Alcohol - Weak anti-
o Skin rash & minor allergic reactions occur infrequently
impairment - Drugs altering liver inflammatory
o Contra-indicated in patients with hepatic & renal impairment
- Allergic to enzymes activity → not have
paracetamol gastric & platelet
effects
PARACETAMOL: Overdose
- Exert effects in
CNS ADVERSE EFFECTS

- Leading cause of acute liver failure – potentially fatal

- Early symptoms – nausea & vomiting
- Later symptoms – lactic acidosis, comma, right upper quadrant tenderness
(liver failure)
- Treatment – N-Acetylcysteine – intravenous infusions