Non-opioids

Question 1

What is an NSAID?

Answer 1

NSAIDs are drugs that act to relieve inflammation but are not structurally related to the corticosteroids.

Question 2

3 effects of NSAID

Answer 2

• Analgesic
• Antipyretic
• Anti-inflammatory (at higher doses)

Question 3

How do NSAID’s work?

Answer 3

Dampens the body’s inflammatory response by inhibiting COX-2 enzyme (COX-1 is inhibited as well)

Question 4

Possible side effects of NSAID’s

Answer 4

Ulcers because of COX-1 inhibition, gastric haemorrhage, Reye’s syndrome in children (aspirin), ARF

Question 5

How does paracetamol/acetaminophen work?

Answer 5

Activates cannabinoid receptors

Question 6

What is COX?

Answer 6

An enzyme that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin.

Question 7

Where is COX-1 found?

Answer 7

Exists in the tissue as constitutive isoform

Question 8

Where is COX-2 found?

Answer 8

At site of inflammation, cytokines stimulate the induction of the 2nd isoform

Question 9

How is COX-2 inhibited

Answer 9

Anti-inflammatory actions of NSAIDs.

Question 10

Prostaglandin synthesis pathway

Answer 10

Membrane phospholipid -> arachnoidid acid

Then Physiological regulation by COX-1 and Inflammatory response by newly expressed COX-2.

Question 11

NSAID Analgesic effects

Answer 11

(CNS and peripheral effect) may involve non-
PG related effects
Not very strong

Question 12

NSAID Antipyretic effects

Answer 12

(CNS effect) Reduce/increase body temperature

Question 13

NSAID Anti-inflammatory effects

Answer 13

(except acetaminophen) due mainly to 
 PG inhibition (particularly COX-2 inhibitors)

Question 14

Uricosuric

Answer 14

Drugs that promote the excretion of uric acid

Question 15

COX-2 central cytokine release

Answer 15

1. COX-2 upregulation in dorsal horn neurones and supporting cells
2. Prostogalndin production (also via COX-1)
3. Action on PGE2 receptors on dorsal horn neurones
4. Enhanced depolarisation of secondary neurones.

Question 16

COX-2 peripheral inflammation

Answer 16

1. COX-2 upregulation in inflammatory cells
2. Prosogladin production
3. Action of peripheral terminal PGE2 receptors
4. Peripehral sensitization

Question 17

NSAIDs effect on peripheral inflammation?

Answer 17

Inhibit COX 2 so prostaglandins cannot be produced. Preventing development of peripheral sensitization

Question 18

NSAIDs effect on central cytokine release?

Answer 18

Inhibit COX 2 (and COX-1) so prostaglandins cannot be produced. Preventing enhanced depolarisation of secondary sensory neurones.

Question 19

Inhibition of COX-1 is responsible for their GIT toxicity.

Answer 19

Gastritis and peptic ulceration with bleeding and perforation (inhibition of PG + other effects).

Question 20

Effect on Respiration: triphasic (Aspirin)

Answer 20

1. Low doses: uncoupling phosphorylation → ↑ CO2 → stimulates
   respiration.
2. Direct stimulation of respiratory center → Hyperventilation → resp.
   alkalosis → renal compensation.
3. Depression of respiratory center and cardiovascular center → ↓ BP,
   respiratory acidosis, no compensation + metabolic acidosis also.

Question 21

GI system (Aspirin)

Answer 21

1. Dose dependent hepatitis.

2. Reye’s syndrome (liver and brain damage in children 9-12).

Question 22

Metabolic (Aspirin)

Answer 22

1. Uncoupling of Oxidative Phosphorylation.

2. Hyperglycemia and depletion of muscle and hepatic glycogen.

Question 23

Endocrine: (Aspirin)

Answer 23

corticosteroids, thyroid.

Question 24

Cardiovascular (Aspirin)

Answer 24

1. Platelets: Inhibition of platelet COX-1-derived TxA2with the net effect of
   increasing bleeding time (inhibition of platelet aggregation).
2. Endothelial COX-2 derived PGI2can inhibit platelet aggregation (inhibition
   augments aggregation by TxA2).
3. Aspirin (acetylsalicylic acid) covalently modifies and, irreversibly inhibits
   platelet COX. The enzyme is inhibited for the lifetime of the platelet (~8 -11
   days). Effect achieved at very low dose.
4. Basis of therapeutic efficacy in stroke and MI (reduces mortality and
   prevents recurrent events).

Question 25

Additional Cardiovascular Considerations (Aspirin)

Answer 25

1. Blood vessels/smooth muscle: COX-2 derived PGI2can antagonize catecholamine- and angiotensin II-induced vasoconstriction (NSAIDs can elevate bp). 2. Atherosclerosis: Inhibition of COX-2 can destabilize atherosclerotic plaques (due to its anti-inflammatory actions).

Question 26

Renal (Aspirin)

Answer 26

1. COX-1 and COX-2 – generated PGs (TxA2, PGF2, PGI2(glom), PGE2 (medulla), powerful vasodilators) can both increase and decrease Na+ retention (natriuresis predominates), usually in response to changes in tubular Cl-, extracellular tonicity or low bp. 2. NSAIDs tend to promote Na+retention and can therefore increase bp. Can counteract effects of many anti-hypertensives (diuretics, ACE inhibitors and -AR antagonists). 3. PGs have minimal impact on normal renal blood flow but become important in the compromised kidney. Patients (particularly elderly and volume depleted) are at risk of renal ischemia with NSAIDs.

Question 27

Gastrointestinal (Aspirin)

Answer 27

-PGs (generated via COX-1) 1) inhibit stomach acid secretion, 2) stimulate mucus and HCO3-secretion, vasodilation and therefore, 3) are cytoprotective for the gastric mucosa. -Therefore, NSAIDs with COX-1 inhibitory activity will produce opposite effects, leading to gastric distress, gastric bleeding, sudden acute hemorrhage (effects are dose-dependent).

Question 28

Gestation (Aspirin)

Answer 28

-PGs (generated from COX-2) are involved in the initiation and progression of labor and delivery. Therefore, inhibition of their production by NSAIDs can prolong gestation.

Question 29

Analgesia (Paracetamol mechanism of action)

Answer 29

both centrally and peripherally -associated with moderate anti-inflammatory actions. -results from inhibition of PG synthesis in inflamed tissues. -[PGs àlittle pain relief themselves, but potentiate the pain caused by other mediators of inflammation (e.g., histamine, bradykinin).

Question 30

Anti-inflammatory action (Paracetamol mechanism of action)

Answer 30

PGs in inflammation àvasodilation and increase vascular permeability. -Inhibition of PGs by NSAIDs attenuates, not abolish, inflammation (NSAIDs do not inhibit mediators of inflammation). -Very modest relief from pain, stiffness, swelling for RA àoften prescribed for their anti-inflammatory actions.

Question 31

Antipyretic actions (Paracetamol mechanism of action)

Answer 31

Fever, heat stroke, increase T°are hypothalamic problems. So, NSAIDs do not decrease body T°. -Fever àrelease of endogenous pyrogens (e.g., interleukin-1) released from leucocytes àacts directly on the thermoregulatory centers in hypothalamus àincrease body temperature. -This is associated with increase in brain PGs (pyrogenic). -Prevents the T°-rising effects of interleukin-1 by preventing the increase in brain PGs.