L17 & L18 Flashcards
Name three 1st generation anti-histamines
- Chlorpheniramine
- Diphenhydramine
- Promethazine
Name three 2nd generation anti-histamines
- Cetirizine
- Fexofenadine
- Loratadine
What type of drugs are antihistamines?
Inverse agonists
Histamine stabilizes H1-receptors in _____ form
Antihistamines stabilize H1-receptors in _____ form
Active
Inactive
Clinical use of 2nd Gen Antihistamines
Preferred for mild-moderate allergy disorders
Clinical use of 1st Gen Antihistamines
Commonly used for non-allergic conditions
Main advantages of 2nd gen antihistamines
Non-sedating or Less-sedating antihistamines
High H1-receptor specificity
5 cardinal signs of inflammation
heating, redness, swelling, pain, loss of function
Describe the Arachidonic Acid Cascade
- Arachidonic acid is a polyunsaturated fatty acid present in cell membranes.
- 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)
- 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
Describe the Synthesis of Prostanoids
- COX-1 or COX-2 cyclooxygenase action: AA → PGG2
- COX-1 or COX-2 peroxidase action: PGG2 → PGH2
- PGH2 converted into prostanoids
Name 5 main prostanoids
classical prostaglandins (PGE2, PGF2a, PGD2), PGI2 (prostacyclin), TXA2 (thromboxane)
What type of receptors are prostanoid receptors
GPCRs
PGI2 biological function
Vasodilatation
Inhibition of platelet aggregation
Renin release
Natriuresis
PGD2 biological function
Vasodilatation
Inhibition of platelet aggregation
Bronchoconstriction
PGF2α biological function
Vasoconstriction
Bronchoconstriction
Uterine contraction
PGE2 biological function
Vasodilatation
Inhibition of gastric acid secretion
Promotion of gastric cytoprotection
Bronchodilation / bronchoconstriction
TXA2 biological function
Vasoconstriction
Promotion of platelet aggregation
Bronchoconstriction
Mechanism of action of traditional NSAIDs
Inhibits cyclooxygenase (COX-1/2) and blocks prostanoid production
Which NSAID irreversibly acetylates (COX-1/2) by forming covalent bonds with serine residue
Aspirin
Describe the MOA of aspirin
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
Describe the MOA of other NSAIDs besides aspirin
Inhibit COX by reversible steric hindrance, blocking the hydrophobic tunnel via hydrogen bonding
Three Main actions of NSAIDs in inflammation
Anti-inflammatory, Analgesic, Antipyretic
MAO of NSAIDs As Anti-inflammatory Drugs
Block formation of PGI2, PGE2, PGD2
Effect of NSAIDs As Anti-inflammatory Drugs
→ Vasodilatation, which contributes to redness, heating and edema
→ Increased vascular permeability, which contributes to swelling (edema)
→ Pain associated with inflammation
MAO of NSAIDs As Analgesic Drugs
Block PGE2 sensitization of peripheral nociceptive fibres → Reduced sensitization of pain signal transmission via the norciceptors
Why is there an “Analgesic Ceiling” for NSAIDs
NSAIDs are able to suppress mild-moderate pain because it does not directly block nociceptive activation
MAO of NSAIDs As Antipyretic
Block formation of PGE2 in the hypothalamus
Effect of NSAIDs As Antipyretic
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
Role of Aspirin beyond inflammation
As an anti-platelet drug or “blood thinner”
Why does Aspirin block more TXA2 than PGI2
- 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
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
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
Name a COX-2 Selective Inhibitor (Coxibs)
Celecoxib
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 ________
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
Name a CNS-selective COX (may be COX-3) inhibitor
Paracetamol (Acetaminophen)
Main features of Paracetamol
Good analgesic, Potent antipyretic, but weak anti-inflammatory effect
