Non-Steroidal Anti-Inflammatory Drugs Flashcards
How many drugs are there in the NSAID class?
About 50
Do the drugs in the NSAID class show structural homogenity?
No, there is significant heterogeneity, and the drugs have different potencies and different efficacies
What is the principle action of NSAIDs?
They act on key enzymes in prostaglandin synthesis
What are the primary therapeutic effects of NSAIDs?
- Analgesia
- Anti-inflammatory
- Antipyretic
What does local injury result in?
A signalling response provided by many autocoids
What are the features of the local response to injury?
- Rapid
- Focused
Integrated
What is the inflammatory response?
A fundamental response of the body to injurous stimuli
What injuries can cause an inflammatory response?
- Physical/chemical injury
- Structural strain
- Infections
- Many diseases
- Autoimmune conditions
What is the advantage of the inflammatory response?
It is normally a protective response to reduce the risk of further damage to the organism
How does the inflammatory response alert the body to damage?
Through signalling pain
What is the importance of the inflammatory response signalling damage through pain?
It reduces the risk of further damage through continued use/activity
What are autocoids?
A diverse range of local molecular mediators and signalling agents employed
Give 7 examples of autocoids
- Bradykinins
- Histamine
- Cytokines
- Leukotrienes
- Nitric oxide
- Neuropeptides
- Eicosanoids
What class of molecules do eicosanoids include?
Prostaglandins
What does signalling overlap with autocoids ensure?
A robust inflammatory response
What are the key features of autocoids?
- Localised release
- Short half life
What does the localised release and short half life of autocoids allow for?
Fine control of the signalling response
What are eicosanoids? C
20C phospholipid derivatives used as signalling molecules
What gives rise to different classes of eicosanoids?
Variation in synthetic routes
What are prostanoids?
A subclass of eicosanoids
Give 3 examples of prostanoids
- Prostaglandins
- Prostacyclins
- Thromboxanes
What are eicosanoids derived from?
Arachidonic acid
Where does arachidonic acid come from?
It is cleaved from cell membrane phospholipids
What enzyme cleaves arachidonic acid from cell membrane phospholipase?
Phospholipase A2
What happens to arachidonic acid in the synthesis of prostaglandins?
COX-1/COX-2 enzymes convert it to prostaglandin G
What happens to PG G in the synthesis of prostaglandins?
COX-1/COX-2 enzymes convert it to prostaglandin H
What happens to PG H in the synthesis of prostaglandins?
It is converted to specific PG enzymes - PGs D, E, F, I
What is the most important prostaglandins in mediating the inflammatory response?
E
What is prostaglandin E responsible for?
- Vasodilation
- Hyperalgesia
- Fever
- Immunomodulation
Where is COX-1 expressed?
In a wide range of tissue types
Describe the expression of COX-I
Constituitive - expressed all the time
What is the importance of PG synthesis by COX-I?
It has a major cytoprotective role in;
- The gastric mucosa
- The myocardium
- The renal parenchyma
It also ensures optimised local perfusion
How do prostaglandins ensure optimised local perfusion?
It ensures vasodilation, and so ensures delivery of nutrients
What is the clinical relevance of the cytoprotective role of prostaglandins in the GI tract?
A major ADR of long term NSAIDs is a reduction in mucus and therefore damage to underlying tissue
What is the half life of prostaglandins?
10 minutes
What is the result of the short half life of prostaglandins?
It needs constant synthesis
Why are most ADRs of NSAIDs due to COX-1 inhibition?
Due to its constitutive expression
What is COX-2 expression induced by?
Inflammatory mediators, such as bradykinin
Where is COX-2 consitutively expressed?
In parts of brain and kidney
How do the main therapeutic effects of NSAIDs occur?
Via COX-2 inhibition
Do COX-1 and 2 work independantly?
No
What is PG synthesis with COX-1 and -2 depedant on?
Tissue and organ type
How does prostaglandin synthesis occur with COX-1?
It has a hydrophpobic channel, where arachinodic acid enters and gets catalysed to prostaglandins
What kind of drugs fit into the mouth of COX-1?
Small, sharp, aspirin-like drugs
What kind of drugs can fit in the mouth of COX-2?
- Small, sharp, aspirin-like drugs
- Big, blunt drugs
What receptors do prostaglandins bind with?
GPCRs
What do the specific actions of prostaglandins depend on?
The receptor types
What are the main types of receptors for PG E?
EP1-4
What does the action of prostaglandins often include?
Synergising effects of other autocoids, e.g. bradykinin and histamine
Which prostanoid in particular is released post-injury?
PGE2
Where are autocoids and prostanoids released from post injury?
Local tissues and blood vessels
What does autocoid release induce?
Expression of COX-2
What do autocoids synergise with?
Other autocoids, e.g. bradykinin and histamine
Do prostaglandins act as vasoconstrictors or vasodilators?
They are potent vasodilators
Do prostaglandins increase the capillary permeability?
Not directly, but they synergise permeating effects of bradykinin/histamine
Which prostaglandin receptors are responsible for vasodilation?
EP2 (Gs)
Which prostaglandin receptors are responsible for increased peripheral nociception?
EP1 (Gq)
What are painful stimuli carried by?
Afferent C fibres
What happens to the surrounding tissue following trauma/injury?
Surrounding tissue and neurones synthesis prostaglandins - PGE2 in particular. Other autcoids are also released, notably bradykinin
What happens to the PGE2 released in response to trauma/injury?
It binds with C fibre neuronal EP1 GPCR
What does GPCR activation by PGE2 in pain cause?
- Increased neuronal sensitivity to bradykinin
- Inhibition of K+ channels
- Increased Na+ channel sensitivity
What is the result of inhibition of K+ channels by PGE2?
Neurone tends to be more polarised
What is the result of increased Na+ channel activity caused by PGE2 in pain?
It increases the likelihood of C fibres firing in response to moderate stimulation
What do the actions of GPCR activation by PGE2 in pain do in combination?
Act to increase C fibre activity
What might prostaglandins do to previously silent C fibres?
Activate them
How does peripheral sensitisation occur?
EP I binding leads to increased C fibre activity
Other autocoids are involved in increasing sensivity
What is EP1?
A Gq GPCR
What does activation of EP I lead to?
Increase in intracellular calcium, therefore increased neurotransmitter release
What is allodynia?
The sensitisation of receptors to cause pain signalling In response to normally non-stimulating stimulus intensity i.e. non-painful things are painful
What does increased sustained nociceptive signalling peripherally result in?
Increased cytokines levels in the dorsal horn cell body
What does increased cytokine levels in the dorsal horn cell body lead to?
Increased COX-2 synthesis and therefore increased PGE2 synthesis
What is the effect of the increased PGE2 produced due to increased sustained nociceptive signalling peripherally?
It acts via a local GPCR EP2 (GS type) to increase the sensitivity and discharge rate of secondary interneurones by incresaing cAMP and PKA
im not 100% sure on this lol
What is one aspect of the increase in sensitivity and discharge rate of secondary interneurones?
Removal of glycinergic inhibition
What do bacterial endotoxins do in infected/inflammatory states?
They stimulate macrophage release of IL-I
What happen as a result of IL-I release in infected/inflammatory states?
It acts within the hypothalanus to stimulate PGE2 synthesis via the induction of COX-2
What receptor is involved in pyrexia due to PGE2?
EP3
What kind of receptor is EP3?
Gi type GPCR
What is the result of PGE2 stimulation of EP3 receptors?
Results in increased heat production and decreased heat loss
Why does pyrexia even happen in infection like what is the point
it makes the body less pleasant for bacterial infection
transition to no caps for speed cus literally cba with this
ok
how are the main therapeutic effects of nsaids acheived
cox-2 inhibition
how is the pharmaclogical action of nsaids achieved
competitive inhibition of cox-1 and 2
nearly all not all
how do nsaids competitively inhibit cox1/2
occupation of cox 1/2 hydrophobic channel by nsaid competes with AA site occupation
how many diff types of nsaids are there
about 50
what is different about the diff types of nsaids
affinity
efficacy
cox1/2 selectivity
what do nearly all nsaids have therapeutic efficacy as
analgesics
anti inflammatories
antipyreics
what determines the choice of nsaid
dominant disease state
patients level of pain
individual patient response
how are nsaids administered
typically orally, but many topical preperations for soft tissue injuries
what is good about topical nsaids
can get very high penetration, and therefore safer than oral for given amount of pain relief as lots of drugs gets only to the site you want to treat
what kind of pharmacokinetics do nsaids have
linear, but only within therapeutic dose ranges
what is the half life of nsaids
nsaids can be divided into 2 groups based on their half life - <6 hours and >10 hours
what are nsaids that have a half life of <6 hours good for
acute pain
what are nsaids that have a half life of >10 hours good for
chronic pain - only need one tablet a day
are nsaids protein bound?
many are heavily protein bound, 90-99%
what are the main therapeutic uses of nsaisds
anti inflammatories
analgesia
describe the use of nsaids as anti-inflammatories
very wide use in msk disorders, e.g. ra and osteoarthritis
what are nsaids used for in analgesia
mild to moderate pain
how do nsaids compare to opiates
they are less effective, but have a better adr proflie
what leads to the side effects of nsaids
inhibition of cox-1 constitutive pg synthesis
what is long term use of nsaids in the elderly associated with
iatrogenic morbiditiy and mortality
where are the major adrs of nsaids seen
in the stomach/gi tract
When do renal ADRs occur with nsaids
in compromised individuals with HRH or hypovolaemia
what % of nsaid users have gi adrs
35%
are gi adrs in nsaid users always symptomatic?
no, often asymptomatic
what are the gi adrs of nsaids
varying degrees of stomach pain, nausea, heartburn, gastric bleeding, and ulceration
how do nsaids cause gi adrs
gastric cox-1 pge2;
- stimulates cytoprotective mucus secretion throughout the gi tract
- reduces acid secretion
- promotes mucosal blood flow
how can the adrs of nsaids be offset?
PPIs or misoprostol
why can nsaids lead to renal adrs
because pge2 and pgi2 maintain renal blood flow. if reduced by nsaids, then gfr decreases, and therefore risk of renal compromise
what follows renal compromise caused by nsaids
na k cl and water retention with increaed likelihood of hypertension
What is the difference between allodynia and spontaneous pain?
Spontaenous pain occurs without a stimulus
What do allodynia and spontaneous pain have in commmon?
They both cause hyperalgesis - pain at a normally non-stimulating level of stimulus intensity
