Anti-inflammatory drugs Flashcards
What 4 things occur during an inflammatory response?
- Acute microvascular changes
- Release of inflammatory mediators
- Accumulation of inflammatory cells
- Repair and healing
Name 5 inflammatory mediators (out of 8ish)
- Histamine
- Bradykinin (peptide)
- Nitric oxide
- Eicosanoid (lipid): prostaglandins, leukotrienes
- Neuropeptides (e.g. substance P)
- Cytokines (e.g. IL-1)
- Complement, PAF
What are the names of the vessels involved in the microcirculation?
Arteriole
Capillaries
Venule
What is the arteriole involved in within the microcirculation?
Blood flow changes
What is the venule involved in within the microcirculation?
Oedema formation and cell accumulation
From what substance is histamine formed from?
Histidine (Amino acid)
What 2 cells are major sources of histamine?
Mast cells (in bone marrow) Basophils (WBC in bone marrow)
When would histamine be released?
Released in allergic/hypersensitivity (IgE) responses
What is mediated by H1 receptors?
Increased blood flow
Increased microvascular permeability
Itch
Where are H1 receptors expressed?
Smooth muscles
Vascular endothelial cells
Heart
CNS
What inhibits the action of H1 receptors (antagonists)? (2)
Mepyramine
Chlorpheniramine (drowsiness is side effect)
[Non-sedating ones preferred today]
What are the other names for urticaria?
Hives, welts, nettle rash
Name 3 conditions that involve histamine
Allergy Allergic rhinitis Urticaria Hay fever Skin irritations
What are the roles of sensory nerves? (C and delta) (3)
- Transmit sensory information to CNS/initiate reflexes
- Nociception - pain and itch (processing noxious substances)
- Release neuropeptides: including substance P, CGRP and VIP
What stimulant types are there for sensory nerves? (3)
- Mechanical (pressure)
- Temperature (cold and heat)
- Chemical (mediators & capsaicin(found in chilli peppers))
What subset of sensory nerves mediate itchiness?
5% of afferent C-fibres in skin
What is the conducting velocities of skin itch?
0.5 m/s
1/2 that of normal C-fibres
What can be used to reduce itch?
Anti-histamines
Local anaesthetics
What breaks down Arachidonic acid to make prostaglandins and thromboxanes?
Cyclo-oxygenase
What is produced if arachidonic acid is broken down by lipoxygenase?
Leukotrienes
What are eicosanoids?
They are signalling molecules made by the enzymatic or non-enzymatic oxidation of arachidonic acid
(e.g. prostaglandins)
Leukotrienes are synthesised by which enzyme?
5-lipoxygenase
When may LT antagonists/inhibitors be used?
Asthma
Where are PGE2 and PGI2 released from (2)?
And what do these mediate? (2)
Released from endothelial cells and white blood cells.
They mediate increased blood flow and hyperalgesia (increased sens to pain)
What less potent eicosanoid is released from mast cells?
PGD2 (prostaglandin D2)
What does LTC4 and LTD4 do? (2)
Increase microvascular permeability
Bronchoconstrictors
What is LTB4 and what does it do?
It is a chemotaxin and recruits neutrophils to inflammatory sites (leukotriene B4)
What intermediary is produced by arachidonic acid when it is broken down by cyclo-oxygenase?
PGG2 first (Prostaglandin G2)
then PGH2 (prostaglandin H2)
What 3 substances are produced by PGH2 in the cyclo-oxygenase pathway?
Prostacyclin (PGI2)
Prostaglandins (PGE2, PGD2, PGF2alpha)
Thromboxanes (TxA2 -> TxB2)
What type of drug inhibits prostaglandin generation?
NSAIDs
What are the effects of NSAIDs?
Analgesic
Anti-inflammatory
Reduces fever
Can enhance bleeding
Name 3 examples of NSAIDs
- Salicylates (aspirin)
- Acetic acids (indomethacin, diclofenac)
- Proprionic acids (ibuprofen, naproxen)
- Oxicoms (piroxicam, phenylbutazone)
- Fenamates (meclofenamate)
In acute allergic reactions and acute inflammatory conditions- what plays a major role?
Also, what is the drug of choice?
Histamine plays a major role in inflammation and itch.
Non-sedating anti-histamines are the drug of choice
What do NSAIDs inhibit?
PG production
What 3 other treatments are used to treat an acute injury?
- Ice - suppress vasoactive components e.g. swelling
- Local anaesthetic creams (suppress sensory nerve activity)
- Noradrenaline (reduce blood flow)
What could be a potential down side to using NSAIDs?
Can increase bleeding
What is an example of a common chronic condition where anti-inflammatory drugs are used?
Arthritis
Name the mediators involved in arthritis?
TNF alpha IL-1 IL-6 IL-8 IL-10 IL-17
PGE2
What 2 forms does cyclo-oxygenase exist in?
COX-1
COX-2
From a clinical point of view, which cyclo-oxygenase is important to inhibit?
COX-2
Where are COX-1 mostly found and what are they involved in?
Found in most cells,
Involved in normal physiology to maintain homeostasis
Give 2 examples where COX-1 is important
- GI tract - PG important in maintaining good blood flow
- In vasculature - TxA2 stimulates platelets to aggregate (thrombus)
[PGI2 inhibits this]
What does COX-2 release, and when is it induced?
Releases high levels of prostaglandins at inflammatory sites
Induced in inflammatory cells by inflammatory stimuli
What COX inhibitor is used in patients with cardiovascular risk?
With oral NSAIDs: associated use of proton pump inhibitors (inhibit GI reflux due to excess acid e.g. esomeprazole)
Can alternatively use prostaglandin analogues (e.g. misoprostol)
Also gradual increase in NSAID use via topical application (e.g. agents such as diclofenac)
What does DMARDs stand for?
Disease modifying anti-rheumatic drugs
Give 3 examples of slow-acting anti-rheumatic drugs
- methotrexate (first choice)
- Gold salts (sodium aurothiomalate & auranofin)
- Anti-malarials (chloroquine)
- Sulphasalasine (may prevent oxygen radical damage)
- Penicillamine (can work well, decreases cytokines)
What are the advantages of using corticosteroids or glucocorticoids when treating RA?
Many anti-inflammatory activities:
- Inhibit AA release
- cytokine inhibition
- Down regulation of adhesion molecules
- Inhibition of enzyme induction (COX, NOS)
Many effects on immune response:
- Inhibition of lymphocyte t-cell proliferation
- Induces apoptosis
What are the potential side effects from using corticosteroids or glucocorticoids? (5)
Osteoporosis Increased risk of infection Adrenal atrophy Diabetes Infection
What is the benefit of giving corticosteroids/glucocorticoids locally?
where would these be given?
Potentially decreases side effects
Given intra-articular i.e. directly into the joint
What is methotrexate, and in what scenarios may it be used?
It is a folate antagonist.
Cancer chemotherapy, rheumatic arthritis
May be best mixed with NSAID
What is an established therapy for RA?
Inhibition of TNF-alpha
What are the 2 modes of action with anti-TNF drugs?
Monoclonal antibody (infliximab, adalimumab)
Soluble TNF receptor fusion protein (etanercept)
What are the 2 modes of action with anti-TNF drugs?
Monoclonal antibody (infliximab, adalimumab)
Soluble TNF receptor fusion protein (etanercept)
Give 2 examples of anti-TNF antibody drugs
- Infliximab (Brand name: Remicade)
- Adalimumab (Brand name: Humira)
Name an example of a drug that is soluble TNF receptor construct
Etanercept (Enbrel)
Why/when would anti-TNF drugs be used?
When other DMARDs have failed - can be well tolerated compared to other anti-inflam drugs.
Disadv: expensivee, also may suffer opportunistic infections (e.g. tb)
What 3 cytokines have been investigated as emerging drug approaches when treating RA?
IL-1: antibodies/receptor antagonist
IL-6 blocker: used on people who dont respond to anti-TNF or methotrexate
IL-17 receptor antagonist: in development
How does the new drug Rituximab (MabThera) work?
Removes antibody-producing white blood cells called B-cells
How does the drug Abatacept (Orencia) work?
Inhibits action of T cells and reduces damaging effects
Outline the characteristics of the traditional methods of treatment for rheumatoid arthritis (3)
Treat symptoms (pain, swelling)
Less aggressive
Maybe less toxic (NSAID) used, unlike methotrexate/steroids
Outline the characteristics of modern treatments of rheumatoid arthritis (5)
Limit joint destruction
Early aggressive treatment
Methotrexate used early (in both elderly and young)
Combination therapy
Increasing use of biologics and biosimilars
Which disease is a chronic inflammatory disease, that is associated with inflammation and pain and joint remodelling?
Arthritis
Why does a DMARD need to be used?
Because although may not be first line drug (such NSAIDs), NSAIDs don’t affect the course of disease so disease modifying drug may be necessary
Of the new therapies, which is the most successful?
Biologics that block TNF-a.
