Pharmacology

Question 1

Can endogenous cannabinoids act as anti-inflammatory compounds?

Answer 1

Yes

Endogenous canabinoids include **anandamide **and **2-arachidonyl glycerol **which act on canbinoid receptors CB1 and CB2

CB1 is a central receptor, while CB2 is a peripheral receptor

Activation of these receptors results in:

• anti-inflammatory responses
• **analgesia **
• appetite stimulation
• anti-nauseant
• sedation
• psychoactivity (may contribute to schitzophrenia)

Question 2

In what ways are prostaglandin molecules used as drug treatments?

Answer 2

Prostaglandins are not widely used as drug treatments because they are generally too unstable and expensive to produce.

Esoprostenol / Prostacyclin (PGI₂ analogue)

A vasodilator and platelet activation inhibitor administered in pulmonary hypertension

Misoprostol (PGE₁analogue)

An adjuvant to mifepristone as an abortifacient

Question 3

Describe the effects of NSAIDs and their indications

Answer 3

Anti-inflammatory

• acute and chronic nflammatory conditions including rheumatoid arthritis and gout (but not aspirin-competes with urea in kidney tubules)

Analgesia

• removes and inhibits hyperalgesic factors that potentiate pain in the inflammatory response
• headaches, menstrual pain, musculoskeletal pain and more

**Antipyretic **

• paracetamol is usually prefered than NSAIDs

**Anti-aggregatory **

• are vasoprotective by preventing the aggregation and activation of platelets

Question 4

List the four main adverse effects of NSAIDs

Answer 4

1. Loss of GIT protection
2. Increased bleeding time
3. Compromised renal blood flow
4. Pulmonary bronchoconstriction

Question 5

Describe the adverse effects of NSAIDs on GIT protection

Answer 5

NSAIDs inhibit the muscosal synthesis of PGE₂

In addition to its inflammatory actions, PGE₂ also has a gastro-protective role inducing:

• increased mucus secretion
• reduced gastric acid secretion
• promotes blood flow
• promotes angiogenesis

NSAID inhibition of COX enzymes prevents the formation of PGE₂and thus its protective effects on the GIT are lost

Question 6

Describe the adverse effects of NSAIDs on bleeding times

Answer 6

Given the absence of a nucleus in platelets compared to endothelial cells, there is a relative decrease in the synthesis of platelet COX products

The reduced synthesis of Thromboxane A₂(TxA₂) leads to impaired platelet aggregation -> in the event of any bleeding, the ability to form a clot is impaired and bleeding times are increased.

Question 7

Describe the adverse effects of NSAIDs on the renal system

Answer 7

NSAIDs compromise renal blood flow as a result of decreased prostacyclin-mediated dilation of the renal vessels

NSAIDs can also increase systemic blood pressure as a result of decreasing the level of PGE₂ which is involved in PGE₂-mediated naturesis

These adverse effects may cause renal failure if the following comorbidities are present:

• hypovolumetric
• underlying renal diseases
• heart failure

As these are comorbidities associated elder patients, care must be taken in prescribing NSAIDs to the elderly

Question 8

Describe the adverse effects of NSAIDs on the pulmonary system

Answer 8

NSAIDs may cause bronchoconstriction in ~ 10% of asthmatics.

This is thought to be a result of the overproduction of leukotrienes given that the COX-mediated prostanoid pathway of arachadonic acid (AA) is inhibited - shunting AA into the leukotriene pathway

Question 9

What is the pharmacological basis of low dose aspirin regimes for cardioprotection?

A daily dose of aspirin (80mg compared to normal 300mg) allows consistant cardioprotection to prevent the development of athersclerosis but not be at high concentration levels to cause constant anti-inflammatory effects that would, over time, produce significant side effects.

Answer 9

The balance between **prostacyclin (PGI₂) **and **Thromboxane A₂ (TXA₂​) **is a significant factor in the likelihood and progression of atherosclerosis.

Acetylation and inhibition of COX enzymes by aspirin irreversibly occurs in both endothelial cells and platelets; but has a greater affect in platelets because they lack a nucleus to replace the COX enzymes over the remaining 8-day life span of the platelet. Endothelial cells can produce new COZ enzymes within hours.

This tips the balance towards PGI₂> TXA₂

A daily dose of aspirin (80mg compared to normal 300mg) allows consistent cardioprotection to prevent the development of athersclerosis but not be at high enough concentration levels to cause constant anti-inflammatory effects that would, over time, produce significant side effects.

The low dosage would be concentrated enough in the hepatic portal to irreversibly inhibit circulating platelets before aspirin was severely diluted in systemic circulation or cleared

Question 10

What are aspirin-triggered lipoxins?

Answer 10

**Aspirin triggered lipoxins **are formed from acetylated COX-2 following NSAID acetylation

It acts on the same FPR-2 receptor as endogenous lipoxins LXA₄and LXB₄.

Both the endogenous and aspirin triggered lipoxins are implicated in inflammation resolution

This is a target mechanism for the development of new anti-inflammatory drugs.

Question 11

Is paracetamol an NSAID?

Answer 11

No, paracetamol is it’s own special class of therapeutic drug

• analgesic
• antipyretic

Note: no anti-inflammatory effects

It is especially used in children as aspirin is contraindicated in children < 12 y.o

The mechanism is still unknown…but thought to indfluence canabinoid receptors

Has a very wide therapeutic window but is hepatotoxic in overdose

Question 12

Discuss COX selectivity to organ systems and the differing effects of selective COX inhibitors

Answer 12

It is thought that COX-1 is preferentially expressed by platelets and the stomach; while COX-2 is preferentially expressed by the CNS and macrophages

Example: Celecoxib

• COX-2 inhibition > COX-1
• Less adverse GIT effects
• Less anti-platelet activity

Question 13

What are the indications for glucocorticoid treatment?

Answer 13

Physiological Replacement for Addison’s Disease

Anti-Inflammatory Use:

• Asthma (commonly beclomethasone)
• Topical conditions
  
  • skin, eye, etc.
• Hypersensitivity states
  
  • severe allergic reactions
• Rheumatoid arthritis

Question 14

List the three methods of glucocorticoid action

Answer 14

Glucocorticoids engage a wide range of targets in the nucleus and genome to alter gene transcription.

Up to 30% of the genome is affected by glucocorticoid actions

There are three mechanisms of GC action:

_Direct Transactivation _

• Transcriptional machinery already operating at a low level. The liganded glucocorticoid receptor (GR) dimer binds to one or more ‘positive’ glucocorticoid response elements (GREs) within the promoter sequence and upregulates transcription

Direct Transrepression

• Transcriptional machinery is constitutively driven by transcription factors. In binding to the ‘negative’ GRE, the receptor complex displaces these factors and expression is inhibited.

Tethered Transrepression

• The transcription factors P65 and P50 bind to the NFκβ site, promoting gene expression. This is prevented by the presence of the GR, which binds the transcription factors, preventing their action

Question 15

What effects could a TNFa based therapy have in inflammatory diseases

Answer 15

TNFa activates leukocytes and endothelial cells to ellicit:

• Nitric oxide / prostaglandin production
• Cytokine production

which results in:

• inflammation
• angiogenesis
• impacts cell survival