Lecture 9: Anti-Inflammatories I

Comprehensive practice flashcards covering NSAIDs, COX isoforms, prostaglandin pathways, and specific drug mechanisms like Aspirin and Paracetamol based on the lecture transcript.

According to the lecture, what are the three main categories of anti-inflammatory and immunosuppressant drugs?

1. NSAIDs and Coxibs, 2. Antirheumatoid drugs, and 3. Biologicals.

What is the primary enzyme targeted and inhibited by NSAIDs in the production of lipid inflammatory mediators?

Cyclo-oxygenase ($COX$).

By what mechanism do Glucocorticoids inhibit the production of arachidonate from phospholipids?

They induce lipocortin, which inhibits the enzyme Phospholipase $A_2$ ($PLA_2$).

Which specific prostaglandin is responsible for bronchoconstriction and myometrial contraction during labour?

$PGF_{2\text{α}}$.

What are the two primary physiological effects of Thromboxane $A_2$ ($TXA_2$)?

It is thrombotic (promotes platelet aggregation) and a vasoconstrictor.

How do NSAIDs exert their analgesic effect on damaged and inflamed tissue?

They decrease the production of prostaglandins ($PGs$), which prevents the sensitisation of nociceptors to inflammatory mediators like bradykinin and $5$-HT.

Which mediator is responsible for activating the thermostat in the hypothalamus to raise body temperature during a fever, and how is its production induced?

$PGE_2$; its production is induced via $IL-1$ activating $COX-2$.

Each subunit of the Cyclo-oxygenase ($COX$) enzyme contains which two catalytic sites?

The Cyclooxygenase site and the Peroxidase site.

What characterizes the expression and location of the $COX-1$ isoform?

It is constitutively expressed in most tissues, specifically in platelets, the stomach, the kidney, and the colon.

What characterizes the expression of the $COX-2$ isoform?

It is an inducible expression, primarily found in inflammatory cells after stimulation by cytokines, growth factors, or tumor promoters.

What structural difference in the binding channel allows $COX-2$ specific drugs to avoid binding to $COX-1$?

$COX-2$ has a wider channel and an extra side pocket due to a Valine residue, whereas $COX-1$ has a bulkier Isoleucine residue.

How does Aspirin interact with the Cyclo-oxygenase enzyme to inhibit its activity?

It binds covalently to a Serine ($Ser$) residue in $COX$, preventing arachidonic acid from reaching the catalytic site.

Which two specific drugs are identified as being more than $50$-fold $COX-2$ selective?

Celecoxib and Rofecoxib.

Why does the inhibition of prostaglandins by NSAIDs often lead to gastric side effects like dyspepsia and ulceration?

Prostaglandins normally inhibit acid secretion and protect the gastric mucosa.

What medication can be co-administered with NSAIDs to provide protection against gastric bleeding and ulceration?

Misoprostol (a prostaglandin analogue).

Unlike Aspirin, which site or function of the $COX$ enzyme does Paracetamol specifically inhibit?

The peroxidase function of $COX$.

Under what conditions is the activity of Paracetamol reduced?

It is reduced in conditions of severe inflammation where there are high levels of arachidonic acids and peroxides.

What is the name of the hepatotoxic metabolite of Paracetamol that is dangerous in its unconjugated form?

$N$-acetyl-p-benzoquinone imine.

Which NSAID is categorized as a 'suicide inhibitor' due to its irreversible binding to its target?

Aspirin.

What is a clinical use for Aspirin other than analgesia and anti-inflammation, particularly for high-risk patients?

Anti-thrombotic action for patients at high risk of arterial thrombosis.

Which leukotrienes are characterized as bronchoconstrictors that also increase vascular permeability?

$LTC_4$, $LTD_4$, and $LTE_4$.

What is the primary role of Leukotriene $B_4$ ($LTB_4$) in the inflammatory process?

It acts as a chemotaxin.

Which prostaglandin inhibits platelet aggregation and acts as a vasodilator causing hyperalgesia?

$PGE_2$ (additionally, $PGI_2$ and $PGD_2$ inhibit aggregation).

According to the transcript, why might Naproxen be chosen over Aspirin for chronic pain conditions?

Because it is a longer-lasting and more potent drug.

What is $COX-3$ and where is it primarily found according to the lecture notes?

It is a splice variant of $COX-1$ found in the CNS of dogs (not humans).