Pharmacological Interventions
BBS3016
Extensive summary of case studies integrated with weekly literature notes for exam
preparation.
1
, ACCORDING TO RANG AND DALE’S PHARMACOLOGY 9th EDITION
Cases
week 1: Pharmacodynamics
Case 1: A Classical Drug Through The Ages
Week 1: Mandatory Literature Week 1
o Chapter 2: How Drugs Act: General Principles
o Chapter 3: How Drugs Act: Molecular Aspects
o Chapter 25: Anti-inflammatory and Immunosuppressant Drugs
Week 2: Methods and Measurements
Case 2: Stimulating Beta Experiments
Week 2: Mandatory Literature Week 2
o Chapter 8: Methods and Measurements In Pharmacology
o Chapter 27: Respiratory Drugs
Week 3: Pharmacokinetics I
Case 3: Dose and Dosing Interval Determine Therapeutic and Toxic Effects of Biologically Active
Compounds
Week 3: Mandatory Literature Week 3
o Chapter 9: Drug Absorption and Distribution
o Chapter 11: Pharmacokinetics
o Chater 43: The Analgesic Drugs
Week 4: Pharmacokinetics II
Case 4: Individual Differences in Hepatic Drug Metabolism with Fatal Consequences
Week 4: Mandatory Literature Week 4
o Chapter 10: Drug Elimination and Metabolism
o Chapter 49: Psychoactive Drugs
Week 5: Toxicology
Case 5: How to Prevent Doxorubicin-induced Toxicity?
Week 5: Mandatory Literature Week 5
o Chapter 21: The Heart
o Chapter 22: The Vascular System
2
, ACCORDING TO RANG AND DALE’S PHARMACOLOGY 9th EDITION
Cases
Week 6: Pharmacotherapy
Case 6: Sweet, Sweet brothers
Week 6: Mandatory Literature Week 6
o Chapter 30: The Control of Glucose and Drug Treatment of DM
o Chapter 31: Pharmacological Approaches to Obesity
Week 7: Societal Impact
Case 7: Big Pharma: Patents, Payments, and Social Responsibility
3
, week 1: Pharmacodynamics
Case I: A Classical Drug Through the Ages
LG1: What is aspirin and how does it work?
o What are the different functions?
LG2: What are prostaglandins and what do they do?
LG3: What are NSAIDS and how do they work?
o Keywords: Naproxen, Ibuprofen
LG4: What is COX-1 and COX-2 and their different isoforms?
LG5: Why do Selective COX-2 inhibitors appear as the future (featured in the case)?
PART 1: Aspirin & Its Working Mechanism
Aspirin (acetylsalicylic acid) is the acetate ester of salicylic acid. It is a non-selective, irreversible
inhibitor of COX-1 and COX-2, which acts by acetylating the cyclooxygenase enzymes, preventing
arachidonic acid from being converted into prostaglandin precursors.
COX-1 vs COX-2: Irreversibly inhibited by Aspirin
COX-1
o Constitutively expressed in many tissues.
o Mediates early or acute inflammatory responses.
o Produces prostaglandins involved in normal physiological functions, including gastric
protection, kidney function, and platelet activity.
COX-2
o Mainly induced by inflammatory stimuli such as cytokines.
o Mediates late or chronic inflammatory responses.
o Produces prostaglandins that contribute to pain, fever, and inflammation.
Physiological Roles of the Inhibited Molecules
Prostaglandins
o Contribute to pain, fever, and inflammation.
o Some prostaglandins (PGE2) also protect the stomach lining and support kidney function.
Thromboxane A2 (TXA2)
o Promotes platelet activation and aggregation.
o Causes vasoconstriction.
o Excessive TXA2 can contribute to thrombosis and cardiovascular events.
Prostacyclin (PGI2)
o Inhibits platelet aggregation.
o Promotes vasodilation.
4
,Main Effects of Aspirin
Pain, fever and inflammation
COX inhibition → ↓ PGE₂ → ↓ pain, fever and inflammation
o Reduced prostaglandin production decreases pain sensitization and fever.
o This is mainly associated with inhibition of COX-2-derived prostaglandins.
Inhibition of platelet aggregation
COX-1 inhibition in platelets → ↓ TXA₂ → ↓ platelet activation and aggregation
o This is particularly important because platelets cannot efficiently synthesize new COX-1.
o Therefore, aspirin produces a long-lasting antiplatelet effect.
Cardiovascular effects
o Reduced TXA2 decreases platelet aggregation and vasoconstriction.
o This is why low-dose aspirin can be used to reduce the risk of certain cardiovascular thrombotic
events when clinically indicated.
Other Methods of Action
Uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from
the intermembrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once
again to release protons.
It induces nitric oxide (NO) radical formation, which may help reduce inflammation by reducing
leukocyte adhesion by modulation of the NF-κB signalling pathway, which is important in immune
response and inflammation.
5
, PART 2: Arachidonic Acid Metabolites
Prostaglandins and related compounds (collectively referred to as prostanoids or eicosanoids) such
as prostacyclin (PGI2), leukotrienes (LTs) and thromboxanes (TXs) are produced by many cells in the
body.
1. Arachidonic acid, a 20-carbon fatty
acid containing 4 double bonds, is
liberated in the membrane phospholipids
by phospholipase A2, which is activated
by diverse stimuli.
2. Arachidonic acid is converted by
cytosolic prostaglandin G/H synthases,
which have both cyclooxygenase (COX)
and hydroperoxidase (HOX) activity, to
the unstable intermediate prostaglandin
H2.
3. Prostaglandin H2 is converted by tissue-specific isomerases to multiple prostanoids.
4. These bioactive lipids activate specific cell-membrane receptors of the superfamily of G-
protein–coupled receptors.
Arachidonic Acid (AA) Pathway
Once free, AA can be metabolized by three major enzymatic pathways and a few minor ones:
A. Cyclooxygenase (COX) Pathway
o Enzymes: Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2)
o Pathway: AA → Prostaglandin G₂ (PGG₂) → Prostaglandin H₂ (PGH₂).
o Downstream Metabolites (Cell-type Specific):
o Prostacyclin (PGI₂): vasodilation, inhibition of platelet aggregation, increased vascular
permeability.
o Thromboxane A₂ (TXA₂): vasoconstriction, platelet aggregation, smooth muscle
contraction.
o Prostaglandin D₂ (PGD₂): bronchoconstriction, sleep regulation, allergic
inflammation.
o Prostaglandin E₂ (PGE₂): fever, pain sensitization, vasodilation, inflammation.
o Prostaglandin F₂α (PGF₂α): uterine contraction, bronchoconstriction.
6
BBS3016
Extensive summary of case studies integrated with weekly literature notes for exam
preparation.
1
, ACCORDING TO RANG AND DALE’S PHARMACOLOGY 9th EDITION
Cases
week 1: Pharmacodynamics
Case 1: A Classical Drug Through The Ages
Week 1: Mandatory Literature Week 1
o Chapter 2: How Drugs Act: General Principles
o Chapter 3: How Drugs Act: Molecular Aspects
o Chapter 25: Anti-inflammatory and Immunosuppressant Drugs
Week 2: Methods and Measurements
Case 2: Stimulating Beta Experiments
Week 2: Mandatory Literature Week 2
o Chapter 8: Methods and Measurements In Pharmacology
o Chapter 27: Respiratory Drugs
Week 3: Pharmacokinetics I
Case 3: Dose and Dosing Interval Determine Therapeutic and Toxic Effects of Biologically Active
Compounds
Week 3: Mandatory Literature Week 3
o Chapter 9: Drug Absorption and Distribution
o Chapter 11: Pharmacokinetics
o Chater 43: The Analgesic Drugs
Week 4: Pharmacokinetics II
Case 4: Individual Differences in Hepatic Drug Metabolism with Fatal Consequences
Week 4: Mandatory Literature Week 4
o Chapter 10: Drug Elimination and Metabolism
o Chapter 49: Psychoactive Drugs
Week 5: Toxicology
Case 5: How to Prevent Doxorubicin-induced Toxicity?
Week 5: Mandatory Literature Week 5
o Chapter 21: The Heart
o Chapter 22: The Vascular System
2
, ACCORDING TO RANG AND DALE’S PHARMACOLOGY 9th EDITION
Cases
Week 6: Pharmacotherapy
Case 6: Sweet, Sweet brothers
Week 6: Mandatory Literature Week 6
o Chapter 30: The Control of Glucose and Drug Treatment of DM
o Chapter 31: Pharmacological Approaches to Obesity
Week 7: Societal Impact
Case 7: Big Pharma: Patents, Payments, and Social Responsibility
3
, week 1: Pharmacodynamics
Case I: A Classical Drug Through the Ages
LG1: What is aspirin and how does it work?
o What are the different functions?
LG2: What are prostaglandins and what do they do?
LG3: What are NSAIDS and how do they work?
o Keywords: Naproxen, Ibuprofen
LG4: What is COX-1 and COX-2 and their different isoforms?
LG5: Why do Selective COX-2 inhibitors appear as the future (featured in the case)?
PART 1: Aspirin & Its Working Mechanism
Aspirin (acetylsalicylic acid) is the acetate ester of salicylic acid. It is a non-selective, irreversible
inhibitor of COX-1 and COX-2, which acts by acetylating the cyclooxygenase enzymes, preventing
arachidonic acid from being converted into prostaglandin precursors.
COX-1 vs COX-2: Irreversibly inhibited by Aspirin
COX-1
o Constitutively expressed in many tissues.
o Mediates early or acute inflammatory responses.
o Produces prostaglandins involved in normal physiological functions, including gastric
protection, kidney function, and platelet activity.
COX-2
o Mainly induced by inflammatory stimuli such as cytokines.
o Mediates late or chronic inflammatory responses.
o Produces prostaglandins that contribute to pain, fever, and inflammation.
Physiological Roles of the Inhibited Molecules
Prostaglandins
o Contribute to pain, fever, and inflammation.
o Some prostaglandins (PGE2) also protect the stomach lining and support kidney function.
Thromboxane A2 (TXA2)
o Promotes platelet activation and aggregation.
o Causes vasoconstriction.
o Excessive TXA2 can contribute to thrombosis and cardiovascular events.
Prostacyclin (PGI2)
o Inhibits platelet aggregation.
o Promotes vasodilation.
4
,Main Effects of Aspirin
Pain, fever and inflammation
COX inhibition → ↓ PGE₂ → ↓ pain, fever and inflammation
o Reduced prostaglandin production decreases pain sensitization and fever.
o This is mainly associated with inhibition of COX-2-derived prostaglandins.
Inhibition of platelet aggregation
COX-1 inhibition in platelets → ↓ TXA₂ → ↓ platelet activation and aggregation
o This is particularly important because platelets cannot efficiently synthesize new COX-1.
o Therefore, aspirin produces a long-lasting antiplatelet effect.
Cardiovascular effects
o Reduced TXA2 decreases platelet aggregation and vasoconstriction.
o This is why low-dose aspirin can be used to reduce the risk of certain cardiovascular thrombotic
events when clinically indicated.
Other Methods of Action
Uncouples oxidative phosphorylation in cartilaginous (and hepatic) mitochondria, by diffusing from
the intermembrane space as a proton carrier back into the mitochondrial matrix, where it ionizes once
again to release protons.
It induces nitric oxide (NO) radical formation, which may help reduce inflammation by reducing
leukocyte adhesion by modulation of the NF-κB signalling pathway, which is important in immune
response and inflammation.
5
, PART 2: Arachidonic Acid Metabolites
Prostaglandins and related compounds (collectively referred to as prostanoids or eicosanoids) such
as prostacyclin (PGI2), leukotrienes (LTs) and thromboxanes (TXs) are produced by many cells in the
body.
1. Arachidonic acid, a 20-carbon fatty
acid containing 4 double bonds, is
liberated in the membrane phospholipids
by phospholipase A2, which is activated
by diverse stimuli.
2. Arachidonic acid is converted by
cytosolic prostaglandin G/H synthases,
which have both cyclooxygenase (COX)
and hydroperoxidase (HOX) activity, to
the unstable intermediate prostaglandin
H2.
3. Prostaglandin H2 is converted by tissue-specific isomerases to multiple prostanoids.
4. These bioactive lipids activate specific cell-membrane receptors of the superfamily of G-
protein–coupled receptors.
Arachidonic Acid (AA) Pathway
Once free, AA can be metabolized by three major enzymatic pathways and a few minor ones:
A. Cyclooxygenase (COX) Pathway
o Enzymes: Cyclooxygenase-1 (COX-1) and Cyclooxygenase-2 (COX-2)
o Pathway: AA → Prostaglandin G₂ (PGG₂) → Prostaglandin H₂ (PGH₂).
o Downstream Metabolites (Cell-type Specific):
o Prostacyclin (PGI₂): vasodilation, inhibition of platelet aggregation, increased vascular
permeability.
o Thromboxane A₂ (TXA₂): vasoconstriction, platelet aggregation, smooth muscle
contraction.
o Prostaglandin D₂ (PGD₂): bronchoconstriction, sleep regulation, allergic
inflammation.
o Prostaglandin E₂ (PGE₂): fever, pain sensitization, vasodilation, inflammation.
o Prostaglandin F₂α (PGF₂α): uterine contraction, bronchoconstriction.
6
