Non-Steroidal Inflammatory Drugs Flashcards
Give some background on non-inflammatory drugs.
Very widely used
About 50 drugs - significant structural heterogeneity
Principle action - targets key enzymes in prostaglandin synthesis
Three primary therapeutic effects
- Analgesia
- Anti-inflammatory
- Antipyretic
Tell me about the inflammatory response.
Fundamental response of the body to injurious stimuli
- Includes a wide variety of noxious agents
Normally a protective response to reduce risk of further damage to organism
Alerts body through signalling pain
- Reduces further risk of damage through continued
use/activity
Tell me about autacoids.
Diverse range of local molecular mediators and signalling agents employed
Examples:
Bradykinins, Histamine, Cytokines, Leukotrienes, Nitric oxide, Neuropeptides
Eicosanoids - includes prostaglandins
Signalling overlap ensures robust inflammatory response
Key feature is localised release + short half lives allow fine control of the signalling response
What are eicosanoids ?
They are 20 carbon long phospholipid derivatives used as signalling molecules
Variation in synthetic routes give rise to different classes
All Eicosanoid classes derived from Arachidonic acid which is cleaved from cell membrane phospholipids
What are prostanoids?`
A class of Eicosanoids
Examples:
Prostaglandins (PGs)
Prostacyclins
Thromboxanes
Tell me about Cyclo-Oxygenase (COX) enzymes.
Enzymes involved in synthesis of PGs
Cell membrane phospholipids \/ (Phospholipase A2 removes phosphate group) Arachidonic acid \/ (COX-1/COX-2) PG 'G' \/ (COX-1/COX-2) PG 'H' \/ (Specific PG enzymes) PGs 'D, E, F, I'
Tell me about PG ‘E’
Most important in mediating inflammatory response
Vasodilation
Hyperalgesia
Fever
Immunodilation
What is special about COX-1?
It is constitutively expressed (always there)
It is expressed in a wide range of tissues
PG synthesis by COX-1 has major cytoprotective role
- Gastric mucosa
- Myocardium
- Renal parenchyma
- Ensures local perfusion - reduces ischemia
Due to this most ADRs caused by NSAIDS are due to COX-1 inhibition
What is special about COX-2?
COX-2 expression is induced by inflammatory mediators such as bradykinin
COX-2 seems to be constitutively expressed in parts of the brain and kidney
Main therapeutic effects of NSAIDS therefore occur through COX-2 inhibition
What is the difference between COX-1 and COX-2?
COX-1 is ‘tight’
It has a smaller hydrophobic tunnel where the active site is.
Small, sharp, aspirin-like drugs fit in both mouths
COX-2 is ‘baggy’
Bigger hydrophobic tunnel
Easier for things to get in
Big, Blunt drugs only fit into COX-2 mouth
Gibe some general pharmacology of prostaglandins.
Especially PG ‘E’
Prostaglandins bind at GPCRs
Specific action depends on PG receptor type
Often action includes synergising effects of other autacoids - e.g. Bradykinin/Histamine
PG ‘E’ has at least 4 main types: EP 1-4
How are prostaglandins involved in inflammatory response.
A range of autacoids and prostanoids released post injury
Especially PGE2 and PGD2
Released from local tissues and blood vessels
Autacoid release also induces expression of COX-2
Synergise with other autacoids - Bradykinin/Histamine
PGs act as potent vasodilators
- But they don’t increase vascular permeability
What are some of the effects of PG ‘E’ in terms of inflammatory response.
EP2 receptor Gs
Increase vasodilation
EP1 receptor Gq (on C fibres) Increase peripheral nociception Increased neuronal to Bradykinin Inhibition of K+ channels Increased Na+ channels sensitivity
In combination these act to increase ‘C’ fibre activity
(PGs may also activate previously silent ‘C’ fibres)
How do PGs lead to increased peripheral sensitisation?
EP 1 binding leads to increased ‘C’ fibre activity
EP 1 is a Gq GPCR, activation leads to increased intracellular Ca2+
Increased Neurotransmitter release
Other autacoids involved increase sensitivity
How do PGs lead to increase central nociception?
Increased sustained nociceptive signalling peripherally result in increase in cytokine levels in dorsal horn cell body
This causes increase in COX-2 synthesis and increase PGE2 synthesis
PGE2 then acts via local GPCR EP2 receptor (Gs type)
(This increases sensitivity + discharge rate of secondary interneurons)
Increase in cAMP
Increase in PKA
Decrease in Glycine receptor binding affinity
Increase in pain perception
How do PGs and other Eicosanoids induce pyrexia?
In infected/inflammatory states bacterial endotoxins stimulate macrophage release IL-1
IL-1 within the hypothalamus (via induction of COX-2?) stimulates PGE2 synthesis
PGE2 via EP3 receptor - Gi type GPCR
Results in both increased heat production and decreased heat loss
What are the main therapeutic effects of NSAIDs?
Anti-inflammatory
Antipyretic
Analgesic
Main therapeutic effects achieved via competitive COX-2 inhibition
Tell me about some of the pharmacokinetics of NSAIDs.
Typically given orally but many topical preparations for soft tissue injury
Linear pharmacokinetics within therapeutic dose range
T1/2 has two groups:
- T1/2 10 hrs
Many heavily bound to plasma protein 90-99%
What are the ADRs of NSAIDs?
Inhibition of COX-1 leads to many side-effects
Most ADRs seen in GI
GI - Stomach pain - Nausea - Heart burn - Gastric bleeding - Ulceration (Can offset GI ADRs with PPI or misoprostol)
Renal/Renovascular ADRs
In patients with compromised hepatic/renal/heart function
PGE2 and PGI2 maintain renal blood flow
- Reduced GFR
- Further risk of renal compromise
- Na+/K+/Cl- and H2O retention follow with increased likelihood of hypertension
Vascular
- Risk increase bleeding time, increase bruising
Hypersensitivity
- Skin rashes usually mild
- Rare but very serious - Stevens Johnson syndrome
- Bronchial asthma be careful
Reyes syndrome (paediatric)
- Rare but serious brain/liver injury - usually in viral
infections treated with aspirin risk of damage
How can NSAIDs be used in conjunction with opiates?
In combination with low dose opiates
- Extends therapeutic range for treating pain
Acts by different mechanisms to extend range
Reduces ADRs seen with opiates alone
What is the significance of using NSAIDs in combination?
Often occurs due to self medicating with NSAIDs
NSAIDs given together increases risk of ADRs
Given together they can affect each others PK/PDs due to competition for plasma protein binding sites
(Many NSAIDS heavily bound)
NSAIDs + low dose Aspirin - compete for COX-1 binding sites - may interfere with cardio protective action of aspirin
What is the significance of using NSAIDs and other drugs?
NSAID protein binding can affect PK/PDs
Highly protein bound drugs affected by NSAID:
Sulphonylurea (Hypoglycaemia)
Warfarin (Increased bleeding)
Methotrexate (Wide ranging serious ADRs)
What is special about aspirin?
The first NSAID
Relatively higher long term risk of ADRs
The only NSAID to irreversibly inhibit COX enzymes by acetylation
T1/2 less then 30 minutes Hydrolysed in plasma to salicylate Salicylate PKs dose dependent At lower doses, first order, T1/2=4 hours Higher doses - zero order kinetics Salicylate is a standard NSAID
Tell me about Paracetamol.
It is a unique ‘non NSAID’ non opiate analgesic
Known as a NOAD
Very effective for mild/moderate analgesia and fever
Unknown mechanism
(Might work in CNS on a COX-3 isoform)
At therapeutic doses has much better ADR profile than other NSAIDs
(Long term use can lead to higher risk of toxicity)
Small therapeutic window
Caution in those with compromised hepatic function or alcoholics
At higher doses it becomes zero order
Toxicity caused by increase in NAPQI
Which is highly reactive nucleophilic and binds with cellular macromolecules / mitochondria
Leads to necrotic hepatic cell death
Can also lead to renal failure
