L17 & L18

Question 1

Name three 1st generation anti-histamines

Answer 1

1. Chlorpheniramine
2. Diphenhydramine
3. Promethazine

Question 2

Name three 2nd generation anti-histamines

Answer 2

1. Cetirizine
2. Fexofenadine
3. Loratadine

Question 3

What type of drugs are antihistamines?

Answer 3

Inverse agonists

Question 4

Histamine stabilizes H1-receptors in _____ form
Antihistamines stabilize H1-receptors in _____ form

Answer 4

Active
Inactive

Question 5

Clinical use of 2nd Gen Antihistamines

Answer 5

Preferred for mild-moderate allergy disorders

Question 6

Clinical use of 1st Gen Antihistamines

Answer 6

Commonly used for non-allergic conditions

Question 7

Main advantages of 2nd gen antihistamines

Answer 7

Non-sedating or Less-sedating antihistamines
High H1-receptor specificity

Question 8

5 cardinal signs of inflammation

Answer 8

heating, redness, swelling, pain, loss of function

Question 9

Describe the Arachidonic Acid Cascade

Answer 9

1. Arachidonic acid is a polyunsaturated fatty acid present in cell membranes.
2. When cells are stimulated by various factors (e.g., hormones, inflammatory mediators), arachidonic acid is released from cell membranes by the action of phospholipase A2 (PKC can also activate PLA2)
3. Released arachidonic acid is then metabolized by different enzyme pathways, primarily the cyclooxygenase (COX) and lipoxygenase (LOX) pathways, leading to the formation of various eicosanoids

Question 10

Describe the Synthesis of Prostanoids

Answer 10

1. COX-1 or COX-2 cyclooxygenase action: AA → PGG2
2. COX-1 or COX-2 peroxidase action: PGG2 → PGH2
3. PGH2 converted into prostanoids

Question 11

Name 5 main prostanoids

Answer 11

classical prostaglandins (PGE2, PGF2a, PGD2), PGI2 (prostacyclin), TXA2 (thromboxane)

Question 12

What type of receptors are prostanoid receptors

Answer 12

GPCRs

Question 13

PGI2 biological function

Answer 13

Vasodilatation
Inhibition of platelet aggregation
Renin release
Natriuresis

Question 14

PGD2 biological function

Answer 14

Vasodilatation
Inhibition of platelet aggregation
Bronchoconstriction

Question 15

PGF2α biological function

Answer 15

Vasoconstriction
Bronchoconstriction
Uterine contraction

Question 15

PGE2 biological function

Answer 15

Vasodilatation
Inhibition of gastric acid secretion
Promotion of gastric cytoprotection
Bronchodilation / bronchoconstriction

Question 16

TXA2 biological function

Answer 16

Vasoconstriction
Promotion of platelet aggregation
Bronchoconstriction

Question 17

Mechanism of action of traditional NSAIDs

Answer 17

Inhibits cyclooxygenase (COX-1/2) and blocks prostanoid production

Question 18

Which NSAID irreversibly acetylates (COX-1/2) by forming covalent bonds with serine residue

Answer 18

Aspirin

Question 19

Describe the MOA of aspirin

Answer 19

Irreversibly acetylates (COX-1/2) by forming covalent bonds with serine residue → AA access obstructed by acetyl grp in aspirin-modified COX → block prostanoid production

Question 20

Describe the MOA of other NSAIDs besides aspirin

Answer 20

Inhibit COX by reversible steric hindrance, blocking the hydrophobic tunnel via hydrogen bonding

Question 21

Three Main actions of NSAIDs in inflammation

Answer 21

Anti-inflammatory, Analgesic, Antipyretic

Question 22

MAO of NSAIDs As Anti-inflammatory Drugs

Answer 22

Block formation of PGI2, PGE2, PGD2

Question 23

Effect of NSAIDs As Anti-inflammatory Drugs

Answer 23

→ Vasodilatation, which contributes to redness, heating and edema
→ Increased vascular permeability, which contributes to swelling (edema)
→ Pain associated with inflammation

Question 24

MAO of NSAIDs As Analgesic Drugs

Answer 24

Block PGE2 sensitization of peripheral nociceptive fibres → Reduced sensitization of pain signal transmission via the norciceptors

Question 25

Why is there an “Analgesic Ceiling” for NSAIDs

Answer 25

NSAIDs are able to suppress mild-moderate pain because it does not directly block nociceptive activation

Question 26

MAO of NSAIDs As Antipyretic

Answer 26

Block formation of PGE2 in the hypothalamus

Question 27

Effect of NSAIDs As Antipyretic

Answer 27

By reducing PGE2 levels, NSAIDs lower the set point temperature in the thermoregulatory center, allowing the body to dissipate heat more effectively and reduce the elevated body temp associated with fever

Question 28

Role of Aspirin beyond inflammation

Answer 28

As an anti-platelet drug or "blood thinner"

Question 29

Why does Aspirin block more TXA2 than PGI2

Answer 29

- platelets lack a nucleus and the ability to synthesize new proteins → when aspirin irreversibly inhibits the COX1 in platelets, the platelets cannot produce new COX enzymes during their lifespan - endothelial cells have nucleus and can synthesize new proteins, including COX1 → when aspirin inhibits the COX1, they can synthesize new COX1 to replace the inactivated ones

Question 30

Adverse Effects of Traditional NSAIDs - GI Tract: N&V, gastric upset, and gastric ulceration, mainly due to ___________________ - ____________ reaction: skin rash, nasal congestion, anaphylactic shock - _________ due to blood thinning by aspirin (Type A ADR) - All non-aspirin NSAIDs have increased risks of heart attack/stroke - Aspirin-linked __________ in children with viral infection - Aspirin-induced asthma in susceptible asthmatics, associated with viral URTI -- COX inhibition increases the availability of AA to be broken down by _____________ - Kidney: __________, hypernatremia, H2O retention, edema, ________, ↓glomerular filtration rate (GFR) (Type C ADR) - ________ toxicity - High dose: __________, deafness, tinnitus

Answer 30

Adverse Effects of Traditional NSAIDs - GI Tract: N&V, gastric upset, and gastric ulceration, mainly due to COX-1 inhibition: ↓PGE2 - Pseudo-allergic reaction: skin rash, nasal congestion, anaphylactic shock - Bleeding due to blood thinning by aspirin (Type A ADR) - All non-aspirin NSAIDs have increased risks of heart attack/stroke - Aspirin-linked Reye’s Syndrome in children with viral infection - Aspirin-induced asthma in susceptible asthmatics, associated with viral URTI -- COX inhibition increases the availability of AA to be broken down by LOX into leukotrienes - Kidney: acute renal failure, hypernatremia, H2O retention, edema, hyperkalemia, ↓glomerular filtration rate (GFR) (Type C ADR) - Pregnancy toxicity - High dose: Dizziness, deafness, tinnitus

Question 31

Name a COX-2 Selective Inhibitor (Coxibs)

Answer 31

Celecoxib

Question 32

Limitations of Coxibs - Expectation of _____________ with COX-2 selective inhibitors not realized (still have GI issues, but reduced) - ____________due to constitutive expression of both COX-1 & COX-2 in the kidney - ___________ in pregnancy - Relative increase in _______ favors _________, which may increase the risk of _________ (heart attack and stroke). - impair ______and hence may exacerbate ulcers - healing requires ______and ________

Answer 32

Limitations of Coxibs - Expectation of complete GI tract sparing with COX-2 selective inhibitors not realized (still have GI issues, but reduced) - Renal toxicity due to constitutive expression of both COX-1 & COX-2 in the kidney - contraindicated in pregnancy - Relative increase in TXA2 favors platelet aggregation, which may increase the risk of thrombosis (heart attack and stroke). - impair wound healing and hence may exacerbate ulcers - healing requires COX-2 and PGE2

Question 33

Name a CNS-selective COX (may be COX-3) inhibitor

Answer 33

Paracetamol (Acetaminophen)

Question 34

Main features of Paracetamol

Answer 34

Good analgesic, Potent antipyretic, but weak anti-inflammatory effect