1. Non-narcotic Analgesics
Course Coordinator
Jamaluddin Shaikh, Ph.D.
School of Pharmacy, University of Nizwa
Lecture-29 & 30
December 13, 2011

2. Inflammation
Inflammation: a protective response to tissue injury caused by harmful stimuli, noxious chemicals, or pathogens
Inflammation is triggered by the release of chemical mediators from injured tissues
Mediators vary with the type of inflammation
5-HT, histamine, prostaglandins (PGs), bradykinin, interleukins
PGs are produced by virtually all tissues. They act locally on the tissue, where they are synthesized and are rapidly metabolized at the site of action

3. Inflammation Vasodilatation PGE2 Inflammation Redness & warmth
Swelling
Inflammation
Pain
inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement of plasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. Prolonged inflammation, known as chronic inflammation, leads to a progressive shift in the type of cells present at the site of inflammation and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process

4. thermoregulatory centre
Thermoregulation
normal state
hypothalamic
thermoregulatory centre
PGs
heat
production
heat
lost
NORMAL TEMPERATURE

5. Fever Infection PGE2 Pyrogen Humoral signal PGE2 Inflammation
WBC
Hypothalamus
Pyrogen
Humoral
signal
A trigger of the fever, called a pyrogen, causes a release of prostaglandin E2 (PGE2). PGE2 then in turn acts on the hypothalamus, which generates a systemic response back to the rest of the body, causing heat-creating effects to match a new temperature level.
Fever occurs when the set-point of the ant hypothalamic thermoregulatory centre is elevated. This can be caused by PGE2 synthesis, stimulated when an endogenous pyrogen, such as a cytokine, is released from WBCs that are activated by infection, hypersensitivity, malignancy, or inflammation.
PGE2
Hypothalamus
Inflammation

6. thermoregulatory centre
Fever
hypothalamic
thermoregulatory centre
various pyrogens
PGs
Pyrogens are substance inducing fever
heat
lost
heat
production
FEVER

7. Membrane Phospholipid
Prostaglandin Production
Membrane Phospholipid
Arachidonic acid
Prostaglandin G2
Prostaglandin H2
Phospholipase A2
Cyclooxygenase (COX)
Prostaglandin I2
(Prostacyclin)
Prostaglandin E2, F2
(PGE2, PGF2)
Thromboxane A2
(TxA2)

8. Types of COX and Function

9. Anti-inflammatory Drugs
Anti-inflammatory drugs: The drugs which reduce inflammation
Antipyretic drugs: The drugs which decrease fever
Non-steroidal anti-inflammatory drugs (NSAIDs)
NSAIDs are a group of agents that are anti-inflammatory
Act primarily by inhibiting COX and decreased PG synthesis

10. Classification of Analgesics
Non-selective NSAIDs: aspirin, ibuprofen
Preferential COX-2 inhibitors: nimesulide
Selective NSAIDs: celecoxib, rofecoxib
Analgesic with poor anti-inflammatory activity: paracetamol

11. Non-selective NSAIDs: Aspirin
Mechanism of Action
Irreversibly acetylates COX causing inhibition of PG synthesis
Aspirin produces its analgesic and anti-inflammatory effects by inhibition of PGE2 and prostacyclin biosynthesis at the site of pain production

12. Aspirin: Actions
Antipyretic: Antipyretic effect is due to 1) inhibition of the synthesis of PGE2 in the hypothalamus, 2) resetting of the thermostat and 3) by increasing heat loss as a result of peripheral vasodilation & sweating
Anti-inflammatory: inhibits inflammation in arthritis
Analgesic: By decreasing PGE2 synthesis, NSAIDs repress the sensation of pain
Effect on platelets: Thrombaxane A2 enhances platelet aggregation. Low doses of aspirin can irreversibly inhibit TX production in platelets
GI effects: In the presence of aspirin, PGs are not synthesized, resulting in increased HCl secretion and decreased mucus production

13. Aspirin: Therapeutic Effects
Fever
Pains associated with inflammation
Anti-platelet to prevent transient ischemic attacks and myocardial infarction

14. Aspirin: Adverse Effects
Salicylism: high therapeutic doses cause deafness, nausea, vomiting and abdominal pain
Regular use of aspirin, even in low dose, frequently causes dyspepsia
Prolonged Bleeding Time because of anti-platelet activity. Should be withdrawn one week before surgery
Reye´s syndrome, a rare disease of children with high mortality, is characterized by hepatic failure and encephalopathy often occurring in the setting of a viral illness. It occurs frequently after ingestion of aspirin
Dyspepsia: stomach upset.
Encephalopathy : disorder or disease of the brain

15. physiological functions proinflammatory prostanoids
Nonselective NSAIDs
Selective
and nonselective
NSAIDs
arachidonic acid
physiological
activation
inflammation
COX-1
COX-2
(constitutive form)
(inducible form)
prostanoids ensuring
physiological functions
proinflammatory prostanoids
COX-1 inhibition
COX-2 inhibition
Unwanted effects mainly on the
GIT and kidney
Anti-inflammatory, analgesic
and antipyretic effects

16. Paracetamol: Mechanism of Action
Paracetamol is an antipyretic and mild analgesic with little anti-inflammatory properties and no antiplatelet action
No irritant effect on the gastric mucosa and can be used in place of aspirin in individuals who are intolerant of aspirin
Useful in pediatrics since, unlike aspirin, it has not been associated with Reye´s syndrome
Paracetamol: Mechanism of Action
Inhibits PG biosynthesis in the CNS

17. Paracetamol: Pharmacokinetics
Rapidly metabolized in the liver
In paracetamol overdose, the capacity of metabolizing mechanisms is increased and a reactive metabolite, N-acetyl benzoquinone imine, is formed by a cytochrome P450 - dependent metabolic pathway
N-acetyl benzoquinone imine is extremely toxic and causes hepatocellular damage