Pharmacology 3 (PHL423)

Inflammation
❑ Inflammation is a complex protective response of the organism to
injury caused by damaging agents.
❑ It is aimed at inactivation or removal of these agents and promoting
healing.
❑ Mediators of inflammation:

❖ Prostaglandins

❖ Bradykinin
❖ Histamine
❖ Interleukins: IL-1β, IL-6, IL-17

❖ Tumor Necrosis Factor-α

❖ Platelet activating factor

Prostaglandins
❑ Potent cell signaling molecules.
❑ Multiple effects, including pain and inflammation associated with
arthritis
 Role of Prostaglandins
❑ GIT :-
❖ Normally, prostacyclin (PGI2) → (-) gastric acid secretion
❖ PGE2 & PGF2α → (+) synthesis of protective mucus layer & production of
bicarbonate
❑ Kidney :-
❖ PG → vasodilatation of afferent artery
→ increase blood flow in kidneys → increase
intraglomerular pressure → increase glomerular
filtration
❑ Uterus :-
❖ ↑uterine contractions by interacting with
PG receptors in the uterus → Facilitate labor.

❑ Platelets :-
❖ PGI2 → Potent vasodilation & inhibition of platelet aggregation,
❖ TXA2 → produced by platelets, vasoconstriction & induction of platelet
aggregation
 Role of Prostaglandins
❑ Inflammation:-
❖ PGs are natural mediators of inflammation
❖ PGE2 & PGE1 induce signs of inflammation, redness, heat, swelling &
edema
❑ Pain:
❖ PG sensitize nerve endings to the action of chemical mediators released
❖ PGE2 enhances the intensity & duration of pain caused by bradykinin &
histamine.
❑ Fever:
❖ Pyrogens (fever induced agents) released from WBCs activated by
infection, inflammation →(+) PGE2 synthesis
❖ PGE2→↑ the set-point of the hypothalamic thermoregulatory center→
fever.
 Role of Prostaglandins

Cyclooxygenase-1 Cyclooxygenase-2
(COX-1) (COX-2)
❖ Constitutive, expressed in ❖ Inducible, following
most tissues inflammation, trauma

❖ Physiological and homeostatic ❖ Pathophysiological role,

role, cell signalling maintains inflammation
Non Steroidal Anti-Inflammatory Drugs (NSAIDs)
❑ The NSAIDs are a group of chemically dissimilar agents that share in
common the capacity to induce:
❖ Analgesic
❖ Antipyretic
❖ Anti-inflammatory

Acetaminophen
• Acetyl salicylic acid (Irreversibly
Aspirin inhibits COX-1 & COX-2)
(paracetamol)
is an analgesic, antipyretic
with
Other • Piroxicam (Reversibly inhibits
COX-1 & COX-2)
Weak anti-inflammatory
NSAIDs
action
It is NOT considered to be a
Celecoxib • Selective COX-2 Inhibitors NSAID
 Aspirin
❑ Mechanism of action:
❖ Act primarily by inhibiting the COX enzymes (COX-1 & COX-2) →↓ PG
synthesis with both good and adverse effects
❑ Pharmacological actions:

1. Anti-inflammatory action:
❖ Aspirin (-) COX activity→↓ PGs (modulates those aspects of
inflammation in which PGs act as mediators).
2. Analgesic actions:
❖ Aspirin → ↓ the sensation of nerve ending to pain mediators → ↓ pain.
The salicylates are used mainly for low to moderate pain
3. Antipyretic actions:
❖ Aspirin → (-) PGE2 synthesis → resetting of hypothalamic thermostat to
normal
 Aspirin
4. Effect on Platelets:
❖ Low dose of Aspirin (81-325 mg) → Irreversible (-) COX activity→ ↓
thromboxane production.
5. Effect on GIT:
❖ Aspirin → (-) prostanoids →↑ gastric acid secretion and decrease mucus
Production
6. Effect on Kidney:
❖ Aspirin → (-) PG synthesis (responsible for maintaining renal blood
flow) → retention of Na & H2O, edema & hyperkalemia
❖ Interstitial nephritis can also occur with all NSAIDs
7. Respiratory action
❖ Higher doses → stimulates on the respiratory center in the medulla →
hyperventilation and respiratory Alkalosis
❖ At toxic levels → Central respiratory paralysis & respiratory acidosis
ensues due to continued production of CO2
 Pharmacokinetics of Aspirin
❑ Salicylate is converted by the liver to water-soluble conjugates that are

rapidly cleared by the kidney, resulting in first-order elimination and a serum

half-life of 3.5 hours.

❑ At anti-inflammatory dosages (more than 4 g/day), the hepatic metabolic

pathway becomes saturated, and zero-order kinetics are observed, leading

to a half-life of 15 hours or more.
 Therapeutic uses
Anti-
inflammatory
Analgesic Antipyretic Antiplatelet

Prophylactic
TIA, Stroke, Acute
Rheumatoid fever, osteoarthritis & RA MI and in patients
Headache, Myalgia & arthralgia undergoing
revascularization
procedures

Low dose Aspirin (81-325 mg) Antiplatelet

Intermediate dose aspirin:(analgesic-antipyretic)
High dose aspirin(> 4gm/d) (anti-inflammatory)
 Adverse effect Epigastric distress, dyspepsia, nausea,
and vomiting.
Misoprostol (PGE1 analogue) or a PPI
GIT disturbances (e.g. omeprazole) may be taken
concurrently

Nephrotoxicity
Aspirin given during viral infections
especially in children → ↑ risk of Reye
↑bleeding tendency syndrome (Fatal, liver damage with
cerebral edema).
Reye’s syndrome: Acetaminophen is used instead of
aspirin to reduce fever.
Ibuprofen is also appropriate
Hypersensitivity
Aspirin is category C during the 1st and
Drug interaction 2nd trimesters and category D during
the 3rd trimester.
Because salicylates are excreted in
Pregnancy breast milk, it should be avoided during
pregnancy and breastfeeding.
Acetaminophen is preferred
 Drug Interaction
1. Low dose aspirin is contraindicated in patients with gout (aspirin less than
2g/day) causes reduced clearance of uric acid as it competes with uric
acid for excretion → hyperuricemia
2. Salicylate is roughly 80 - 90 % plasma protein bound (albumin) and can
be displaced from its protein-binding sites, resulting in ↑ conc. of free
salicylate .
3. Alternatively, aspirin could displace other highly protein-bound drugs,
such as warfarin, phenytoin resulting in higher free concentrations of the
other agent
Toxicity (respiratory and metabolic effect)
Mild Form
(salicylism)
• Symptoms: N&V, marked
hyperventilation, headache,
mental confusion, dizziness,
tinnitus
• Treatment:
• symptomatic treatment is usually
sufficient.
• ↑ the urinary pH enhances the
elimination of salicylate
Severe intoxication
(Large doses)
• Symptoms: hallucinations,
convulsions, coma, respiratory
and metabolic acidosis, and
death from respiratory failure
• Treatment:
• IV administration of fluid,
dialysis (hemodialysis or
peritoneal dialysis), correction
of acid-base & electrolyte
balances
 Non selective COX-2 inhibitors
❑ These agents posses analgesic, anti-inflammatory & antipyretic effect

(used in inflammatory diseases in patients who do not respond to aspirin or

can’t tolerate it).

❑ These agents can be used in GOUTY arthritis

❖ They inhibit COX reversibly thus their antiplatelet effect is short lived →

Not effective as antiplatelet drugs.

❖ They all induce gastric side effects, nephrotoxicity, hypersensitivity

❖ e.g. ibuprofen, naproxen, diclofenac, proxicam, indomethacin

❖ Indomethacin is used in cases of patent ductus arteriosus

N.B. Celecoxib is a selective COX-2 inhibitor used in chronic inflammatory

disorders with less GIT disturbance but more risk for myocardial
Infarction & stroke.
 Acetaminophen (paracetamol)
❑ Acetaminophen inhibits PG synthesis in the CNS → antipyretic and
analgesic properties.

❑ It has less effect on COX in peripheral tissues, which accounts for its weak
anti-inflammatory activity.

❑ Acetaminophen does not affect platelet function.

❑ It is not considered to be an NSAID

❑ Therapeutic uses :
1) Patients allergic to aspirin
2) Patients with gastric complications
3) Gout
4) Viral infection in children
5) Bleeding disorders
 Acetaminophen (paracetamol)
❑ Pharmacokinetics:

❖ It is conjugated in the liver to inactive metabolites.

❖ A portion of acetaminophen is hydroxylated to form a highly reactive

(NAPQI) that causes liver damage, deactivated by conjugation with
glutathione

❖ It can be given IV in case of acute fever i.e PERFALGAN

❑ Adverse effect:

❖ Minimal adverse effects

❖ Renal tubular necrosis may occur

❖ Paracetamol hepatotoxicity

❖ Occurs with large doses of acetaminophen so the available glutathione in the

liver becomes depleted.

❖ Administration of N-acetylcysteine (glutathion precursor), can be lifesaving if

administered within 10 hours of the overdose