Anti-Inflam Drugs Flashcards
What is the sequence of events to occur in the body after a wound?
Inflammation
Granulation tissue
Wound contraction
What type of response is the inflammatory response?
Innate, non-adaptive
Developed early in evolution
Can lead onto the adaptive immune response
What actually occurs in the inflammatory response?
Acute microvascular changes
Release of inflammatory mediators
Accumulation of inflammatory cells
Repair and healing
What are microvascular changes triggered by?
A variety of cells and plasma in and around these vessels.
These include local hormones and inflammatory mediators.
Give some examples of inflammatory mediators in the body
Histamine Bradykinin Nitric Oxide Eicosanoid lipid (prostaglandins, leukotrienes) Neuropeptides Cytokines Complement
What are the main components of the microcirculation?
Arterioles (blood flow changes)
Venule (oedema formation and cell accumulation)
Capillaries
Histamine and antihistamine:
- What are they formed from?
- What cells are the major source?
- When is it released?
- Give the name of different receptor and the hormone that binds
It is formed from histidine.
The major source is mast cells and basophils.
It is preformed and released in allergic/hypersensitivity responses.
H1 receptors mediate: increased blood flow, increased microvascular permeability, itch.
There are H1 antagonists (anti-histamine). H1 antagonists go into two categories: sedating and non sedating.
What is the role of sensory nerves?
What stimulates them?
Histamine has a link with sensory nerves.
These nerves are the pain fibres, either C and A delta.
These nerves have a dual role:
- Transmit sensory information to CNS/initiate reflexes, release neuropeptides
- Release neuropeptides including CGRP (in trigeminal nerves leads to pain and migraine. CCRP antagonists are being used to reduce headaches)
Stimulants:
- Mechanical (pressure)
- Temperature
- Chemical
How do the distinct subset of sensory nerves mediate itch?
They are C fibres.
They respond to histamine and are insensitive to mechanical stimuli.
They have slow conducting velocities of 0.5m/s.
(Anti-histamines are effective anti-itch agents)
Why do we have arachidonic acid metabolism?
Arachidonic acid is a type of eicosanoid.
This pathway: anytime you have tissue injury, inflammation is involved in healing the wound.
The signals play an important role in the regulation of signal transduction implicated in pain and inflammatory responses.
What are the two pathways that arachidonic substrate can be metabolised?
It can be metabolised via the cyclo-oxygenase pathway to make prostaglandins and thromboxanes
or by the lipoxygenase pathway to leukotrienes.
What is a eicosanoid?
Eicosanoids = name for the arachidonic acid metabolites.
They are mainly prostaglandins and leukotrienes.
Prostaglandins are synthesised via the cyclo-oxygenase pathway and they are a variety of different types of enzyme pathways here.
COX1 = present all time
COX2 - inducable and found at inflammatory sites
(PGE2 and PGI2 are released from endothelial cells and lymphocytes. They mediate increased blood flow and hyperalgesia.
PGD2 released from mast cells and less potent).
Leukotrienes are synthesised by 5-lipoxygenease. These inhibitors are used in asthma. Leukotriene C4 and D4 increase microvascualte permeability and are bronco-constrictors. Leukotriens B4 is a chemotaxis so will recruit neutrophils to inflammatory sites - most potent chemotaxin.
Explain the cycle-oxygenase pathway
Arachidonic acid is a poly-unsaturated acid as it has 4 double bonds.
Oxygen is added to mediate the cyclic endoperoxides (PPG2 and PGH2).
These are both unstable with the oxygen inserted to break up double bonds.
They are then metabolised by what every enzyme relevant to each tissue.
Endothelial cells - prostacyclin is the major product
Epithelial cell - prostaglandins E2 is major product
Mast cells - prostaglandin D2 major product
Lung and reproductive tissues - PGF2alpha (not very involved in inflammation)
Thromboxanes are produced in platelets and they have a role in cardiovascular regulation
How do non-steroidal anti-inflammatory drugs inhibit arachidonic acid?
They inhibit its metabolism by inhibiting the cyclo-oxygenase pathway.
This means no prostaglandins or thromboxanes are produced.
What are the roles of non-steroidal anti-inflam drugs to inhibit prostglandin generation?
- Analgesic (provide pain relief)
- Anti-inflam
- Reduces fever
Can however enhance bleeding (as they stop the normal vasodilation and mucus secretion associated with protection in the GI tract. They reduce thromboxain production which reduces the coagulation of blood clots)
Other ways to reduce acute inflammation is?
Ice
Local anaesthetic creams
Noradrenaline
Give a chronic example where anti-inflam drugs are used?
Arthritis
What chemical mediators cause arthritis?
TNF is in the joint as it a primary mediator. IL1 are important as they can act to increase activity and affects of other mediators.
IL6, 8 and 17 are also produced. IL10 is an anti-inflammatory cytokine.
PGE2 - produced in synovium.
What is the therapeutic pyramid in RA?
Start generalised and become localised:
Education on their condition to patient
May lead to suggestion of exercise or rest
May be offered physiotherapy to help joints
They may already by taking anti-inflammatory drugs
GP needs to make sure they are taking suitable anti-inflammatory drugs.
Patient will then have treatments reviewed and they will go on to have disease modifying anti-inflammatory drugs including steroids.
Biologics - valuable drugs are they work via other mechanism. They are being used earlier in arthritis now.
Surgery is carried out less often.
Topical agents - used in osteoarthritis as these is no inflammatory present so the anti-inflammatory drugs don’t help. These include creams.
Cytotoxic drugs can be used but they have side effects.
The cyclo-oxygenase pathway occurs via COX1 and COX2. Explain these
COX1 - found in most cells, constitutive, involved in normal physiology to maintain homeostasis. Important in maintaining good blood flow.
COX2 - induced in inflammatory cells by inflammatory stimuli. High levels of prostaglandins are released at inflammatory sites.
(important to inhibit COX2)
How do we use COX inhibitors in patients now?
Oral anti-inflammatory drugs - they should also use a proton pump to habit gi reflux.
Another way is to give NSAID (non-steroidal anti-inflame drugs) but topically. This reduces the side affects associated with GI tract.
Give some examples of disease modifying anti-rheumatic drugs
Slow acting, second line therapies:
- Methotrexate (first choice)
- Penicilliamine
Immune suppressives:
- Anti-inflammatory steroids
- Immunosuppresives
New ideas:
- Targeted rheumatic drugs
- Biologics/biosomilars antibody therapy
What are the + and - of anti-inflammatory steroids?
+ They have several activities including:
inhibit AA release
cytokine inhibition
down regulation of adhesion molecules
Inhibition of enzyme induction
+ Several effects on immune response
inhibition of lymphocyte t-cell proliferation
induces apoptosis
- Side effects Osteoporosis Increased risk of infection Adrenal atrophy Diabetes Infection
Cons are decreased if given locally:
Locally include intra-articular, aerosol and topically
Give some details on methotrexate
Folate antagonist, the widely used anti-metabolite in cancer chemotherapy
- but may act via other mechanisms for anti-inflammatory effects
Methotrexate: the most widely used disease modifying agent for RA
- better if used early
- can be toxic (blood tests)
May be best to be mixed with NSIAD
What was the first use of biologics?
Antibodies of TNF were developed.
Was highlighted that this was beneficial.
The antibodies stop the action of TNF, to cause no bind to cells and cause tissue damage.
Biologics have to be injected.
Anti-TNF antibodies can be used or soluble TNF receptor construct.
When are biologics used?
When other disease modifying anti-rheumatoid drugs have failed.
Effective for 30% of cases.
Well-tolerated due to other anti-inflammatory drugs
Patient may suffer opportunistic infection
What are some emerging drug concepts?
Cytokines:
IL1 antibodies/receptor antagonist
IL6 blocker
IL17 receptor antagonist
Cell based:
Rituximab (removes anti-body producing B cells)
Abatacept (inhibits action of T cells)
What are the modern treatments of rheumatoid arthritis?
Limit joint destruction Early aggressive treatment Methotrexate used early Combination therapy Increasing use of biologics and biosimilars.
