Lecture 7 - Anti-inflammatory and immunosuppressant drugs Flashcards
What are the 3 groups of anti-inflammatory and immunosuppressants drugs?
NSAIDs, Coxibs & Paracetamol
Describe the formation of Aspirin
Salicin - converted to salicylic acid. Derivatized one of the hydroxyl function groups in salicylic acid with an acetyl group- forming the acetyl ester - which reduces the negative effect. This was developed into Aspirin
What are inflammatory mediators and sites of action of NSAIDs?
Arachidonic acid is produced from membrane phospholipids by the enzyme Phospholipase A2. It acts as a second messenger AND a substrate for 2 important groups of enzymes - lipozygenases & cyclooxygenase. This ultimately leads to generation of a lot of LIPID-soluble mediators.
What does the lypooxygenase pathway lead to?
Production of leukotrienes
What does the cyclooxygenase pathway lead to?
Production of prostoglandins and thromboxanes
What are prostaglandins?
Created by cells and act on surrounding areas. Also involved in delivery and strengthening of pain signals and induce inflammation. Also involved in processes such as constriction of muscle cells around blood vessels, aggregation of platelets during blood clotting and constriction of the uterus during labour.
What are the 3 types of NSAIDs?
- Anti-inflammatory
- Analgesic
- Antipyretic
What do anti-inflammatory NSAIDs do?
Modify inflammatory reaction
- decrease vasodilation, and in turn oedema
- ineffective against mediators that contribute to tissue damage associated with chronic inflammatory conditions
What do analgesic NSAIDs do?
Reduce certain sorts of pain
- decrease production of prostaglandins in damaged and inflamed tissue with sensitives, nociceptors to inflammatory mediators - e.g. bradykinin, 5-HT
What do antipyretic NSAIDs do?
Lower raised temperature
- thermostat in hypothalamus activated via IL-1 induced COX2 production of PGE
Describe the make up of COX
- made up of 2 identical subunits - each with 2 catalytic sites
- 2/3 isoforms
What is the function of COX-1?
Constitutive expression, platelets, stomach, kidney, colon, most tissues
What is the function of COX-2?
Inducible expression - most cells, but especially inflammatory cells after stimulation with cytokines, growth factors or tumour promoters. Immediate-early response gene
What is the function of COX-3?
In CNS, target for paracetamol
Describe the 2 different active sites of COX
They are collectively termed prostaglandin synthase
- 1st site - cyclooxygenase active site
- 2nd site - entirely separate perioxidase reaction (breakdown of hydrogen peroxide by peroxidase enzymes, resulting in water being produced) - needed to activate the heme groups that participate in the cyclooxygenase reaction
What is the cyclooxygenase reaction?
The cyclooxygenase (COX) enzyme catalyzes the conversion of arachidonic acid, a fatty acid, into prostaglandin H2 (PGH2)
Describe the enzyme complex created
Enzyme complex is a dimer of identical subunits - so all together, there are 2 cyclooxygenase activate sites anf 2 peroxidase active sites in close proximately
Describe what each subunit has
Each subunit has a small carbon-rich knob, pointing downwards. These knobs anchor the complex to the membrane of the endoplasmic reticulum.
What do COX1 & COX2 inhibitors inhibit?
Inhibit cyclooxygenation reaction of arachidonic acid to prevent production of PGs.
Where is the enzyme cyclooxygenase found?
Enzyme is resident in the ER membrane. COX2 has a slightly wider structure due to small bend.
What does Aspirin bind to?
Binds covalently to a Ser residue in COX preventing arachidonic acid from reaching the cyclooxygenase site
What is the composition of aspirin?
Aspirin is composed of 2 parts:
- acetyl group attached to salicylic acid. When it attacks cyclooxygenase, it connects its acetyl group to a serine amino acid, permanently inactivating the enzyme
What are the main differences in NSAIDs?
Toxicity, duration of action and patient tolerance
What level of selectivity is seen in NSAIDs?
Little selectivity
What are most of the desired effects of NSAIDs found?
- most desired effects (anti-inflammatory) mediated by COX2, while unwanted side effects e.g. on gastrointestinal tract, mediated by COX1.
- therefore development of COX2 selective drugs have great therapeutic potential
What is constitutive COX2 found?
- found in CNS
- in kidney important for renal haemodynamics, tumours (important in malignancy found in breast and colon tumours)
- COX3 enzyme has also been found
What are side effects of NSAIDs in the gastrointestinal tract?
- Prostaglandins normally inhibit acid secretion and protect mucosa
- Dyspepsia (indigestion), diarrhoea, nausea, vomiting, gastric bleeding, ulceration
- co-administration of misoprostol (prostaglandins analogue) may be protective
What are the side effects of NSAIDs on renal function
- Prostaglandins maintain renal blood flow, so lack of prostaglandins can lead to renal failure
What are the effects of NSAIDs on the liver?
- liver damage (paracetamol)
What are the effects of NSAIDs on the lungs?
- Bronchospasm asthma attacks
What are the effects of NSAIDs on the skin?
Skin rashes
How can side effects on the gastrointestinal tract (GIT) be relieved?
Relieved by use of COX2 selective drugs. Metabolite of phase 1 reaction of paracetamol is toxic to LIVER - beware with patients where cytochrome P450 may be induced, or OVERDOSE get liver failure
Why should you be cautious when people have overactive P450 enzymes
High levels of P450 enzymes = high level of metabolism e.g. paracetamol.
- Metabolites of phase 1 reactions are toxic, therefore it can lead to liver damage
What % of users of different NSAIDs sustain a form of GI damage?
35-45% - small % lead to serious effects and hospitalisation
- oral vs systemic administration makes no difference
What are example of COX2-selective NSAIDs?
-Rofecoxib (Vioxx)
- Valdecoxib
- Parecoxib
- Celecoxib
Developed to reduce the burden of gastrointestinal toxicity
- raises concern regarding cardiovascular safety, though the mechanism isn’t known. Possibilities include increased arterial blood pressure, increased artherogenesis, or increased thrombotic tendency
What is artherogenesis?
Artherogenesis is the process of plaque formation inside the arteries.
It begins to the artery walls, leading to the buildup of cholesterol, fat and other substances that form plaque. Over time, plaque can block blood flow.
Atherosclerotic plaques build up inside the arteries.
What is increased thrombotic tendency?
Refers to a higher likelihood or increased risk of forming blood clots (thrombi) in the blood vessels.
What was the risk of Vioxx?
Cardiovascular toxicity
Explain features of Aspirin
- Anti-platelet action
- Reduced risk of colonic and rectal cancer
- Reduced risk of Alzheimer’s
- Weak acid, rapid and efficient absorption in the ileum
- Suicide inhibitor (irreversible)
Explain features of Paracetamol
- Analgesic-antipyretic due to CNS effects
- Weak anti-inflammatory
- COX3/1 selective
- well absorbed, metabolised in liver
- less side-effects than aspirin with long term use, but large doses may increase kidney damage
- N-acetyl-p-benzoquinone imine is HEPATOTOXIC (phase 1 metabolite) in unconjugated form
- competitive inhibitor
How is Ibuprofen different to Aspirin?
Ibuprofen is like aspirin, except that it is a competitive inhibitor
What drug is a competitive inhibitor?
Ibuprofen
Describe the features of COX2 selective inhibitors currently available?
- Antiarthritic
-Analgesic - Less GI disturbances
- Increased blood pressure
Summarise antithrombins?
Aspirin for patients at high risk of arterial thrombosis
Summarise analgesia?
- short term aspirin, paracetamol, ibuprofen
- chronic pain longer lasting more potent drug e.g. Naproxen (+codeine)
- reduce requirement for narcotic analgesics
What is an antipyretic?
paracetamol
