Pharmacology L6: Pain and Inflammation NSAIDs Flashcards
What is local inflammation?
the sum of the host’s defences to infectious or noxious stimuli as well as the beginning of many disease processes (“-itis”)
How does local inflammation provide early protection?
Provides early protection by restricting tissue damage to the site of infection
What are 5 key features of local inflammation?
- swelling- caused by increased vascular permeability fluid leaks into tissue: (oedema), accompanied by migration of leukocytes to infection site
- redness- caused by increased blood volume, vasodilation
- heat- caused by increased blood volume and endogenous pyrogens (TNF-α, IL-1β, IL-6)
- pain- caused by stimulation of neuronal pathways
- loss of function- pain and tissue damage combined (eg rheumatoid arthritis)
How is swelling caused by local inflammation?
caused by increased vascular permeability fluid leaks into tissue: (oedema), accompanied by migration of leukocytes to infection site
How is redness caused by local inflammation?
caused by increased blood volume, vasodilation
How is heat caused by local inflammation?
caused by increased blood volume and endogenous pyrogens (TNF-α, IL-1β, IL-6)
How is pain caused by local inflammation?
caused by stimulation of neuronal pathways
How is loss of function caused by local inflammation?
pain and tissue damage combined (eg rheumatoid arthritis)
What does local inflammation look like?
What controls inflammation?
Inflammatory mediators are intercellular chemical messengers released by inflammatory cells such as macrophages, monocytes, neutrophils, platelets, eosinophils, mast cells and endothelial cells.
What are 2 major mediators which control inflammation?
- eicosanoids-oxygenated derivatives of arachidonic acid, including prostaglandins and leukotrienes
- histamine- stored in mast cells (the major role of histamine in inflammation is to mediate allergic reactions)
What are eicosanoids?
oxygenated derivatives of arachidonic acid, including prostaglandins and leukotrienes
What are histamine?
stored in mast cells (the major role of histamine in inflammation is to mediate allergic reactions)
With the exception of histamine, inflammatory mediators are not ____. What happens instead?
stored They are synthesized and released in response to inflammatory stimuli
What happens with inflammation? EXAM QUESTION
How do Steroidal Anti-Inflammatory Drugs (SAIDS) work in inflammatory?
- Corticosteroids indirectly inhibit PLA2- via a protein call annexin-1.
- This reduces PLA2 activity and prevents the production of all subsequent steps; leading to reduced inflammation.
How do SAIDS creams work?
Cream = penetrate/cross membrane –> cause transcription of DNA in key proteins
SAIDS are _____ (hydrophilic/lipophilic)
lipophilic
What are 5 ways that corticosteroids work?
Powerful = turning off inflammatory process from the beginning (affects all consecutive steps)
- they are hydrophobic so they easily pass through cell membrane
- once inside cell, they bind to glucocorticoid receptors, and this complex moves into nucleus
- Induction of mRNA expression for annexin
- Inhibition of prostaglandin and leukotriene synthesis
- Corticosteroids have many and major adverse side effects so long-term use is not encouraged.
_____ have many and major adverse side effects so long-term use is not encouraged.
Corticosteroids
What are 3 side effects of glucocorticoids?
- cataracts-in rheumatoid arthritic patients receiving 20 mg of prednisone/day for 4 years, >50% will develop cataracts
- Inhibits tissue growth, especially in children
- Patients may become immunosuppressed with chronic use.
For glucocorticoids, ____ (single/multiple) ______ (large/small) doses given systemically not a problem
single; large
What are NSAIDS: Non-Steroidal Anti-Inflammatory Drugs?
NSAIDS inhibit cyclo-oxygenase (COX) enzymes,
- thus inhibiting prostaglandin syntheses, and thereby reducing inflammation.
For anti-inflammatory actions, the NSAIDs that preferentially block the production of COX-____ (1/2)-related prostaglandins may be clinically superior to those which preferentially block COX-___(1/2).
2; 1
What are the 2 forms of COX enzymes?
COX-2 is largely expressed in inflammatory cells, in which it produces inflammatory PGs (pain, swelling, vasodilation); COX-1 produces homeostatic (physiological) PGs, which assist with regulation of kidney blood flow, gastric acid secretion, etc.
What is COX-2?
largely expressed in inflammatory cells, in which it produces inflammatory PGs (pain, swelling, vasodilation)
What is COX-1?
produces homeostatic (physiological) PGs, which assist with regulation of kidney blood flow, gastric acid secretion, etc. Housekeeping (we have it all the time)
How can reduced inflammation lead to pain relief?
What are the 3 actions of NSAIDS as a drug class?
- anti-inflammatory
- anti-pyretic (lower elevated body temperature)
- analgesic (anti-pain)
What is fever?
Fever is not inflammatory response, rather body response to pyrogen (as a defensive)
What are the anti-inflammatory actions of NSAIDS?
- By reducing COX-2 activity, NSAIDs reduce aspects of inflammation to varying degrees.
- This is accomplished by reducing synthesis of PGs involved in vasodilation and indirectly by reducing the access of histamine which would increase permeability of post-capillary venules.
What are the analgesic effects of NSAIDS?
- NSAIDs reduce pain caused by tissue damage or by inflammatory mediators that act on nerve endings- Indirect link –> reduce PG impacting nerve endings
- This action is indirect in that the NSAIDs decrease the production of PGs, which normally would sensitise the nerve endings to pain-producing mediators; effective in arthritis, bursitis, dysmenorrhea, postpartum pain, etc.
NSAIDs reduce pain caused by ____ damage or by inflammatory mediators that act on ______
tissue; nerve endings
The analgesic effects is NSAIDS are _____ (direct/indirect) in that the NSAIDs decrease the production of _____, which normally would sensitise the nerve endings to _____-producing mediators; effective in arthritis, bursitis, dysmenorrhea, postpartum pain, etc.
indirect; PGs; pain
What are the 5 anti-pyretic effects of NSAIDS?
- NSAIDS reduce fever.
- Body temperature is controlled by a hypothalamic “thermostat” which ensures that heat production and heat loss are in balance around a set-point.
- Fever occurs when hypothalamic interleukin-1, an inflammatory mediator, generates E-type PGs that elevate the setpoint.- Allow temp to increase this set point
- NSAIDs act by interrupting this synthesis of PGE and resetting the setpoint; the body then adjusts dilation of blood vessels, sweating, etc. to restore normal body temperature.- “breaking the fever”
- In children, febrile convulsions may require anti-pyretic agents, such as ibuprofen, to be used.
Fever occurs when hypothalamic interleukin-1, an inflammatory mediator, generates E-type PGs that elevate the _____.
setpoint
NSAIDs act by interrupting this synthesis of PGE and resetting the _____; the body then adjusts ____ (dilation/constriction) of blood vessels, sweating, etc. to restore normal body temperature.
setpoint; dilation “breaking the fever”
What happens when someone is very sick (high fever)
If very sick –> fever might drop and then go back up = meds have worn off (time for next dose)
What are the 2 mechanims of action for Aspirin (acetylsalicylic acid)?
- Aspirin inhibits both COX-1 and COX-2 enzymes, thus reducing production of prostaglandins.
- Because aspirin also inhibits thromboxane formation, it is a potent anticoagulant.
What are the 3 adverse effects of Aspirin (acetylsalicylic acid)?
- Gastrointestinal- increased risk of gastrointestinal bleeding By inhibiting COX-1, it inhibits production of PG’s in the stomach which maintain the mucous lining and also allows histamine to produce more gastric acid (ulcerogenic).
- Need some PG to maintain the muscosa in the stomach lining (if taking med to inhibit PG = decrease lining and increase histamine to produce acid)
- COX1/COX2 >10, meaning that aspirin is a more potent inhibitor of COX-1 than COX-2
- Need some PG to maintain the muscosa in the stomach lining (if taking med to inhibit PG = decrease lining and increase histamine to produce acid)
- means higher doses of aspirin must be ingested to inhibit COX-2, i.e. to have an anti-inflammatory effect, which may make the stomach is prone to damage when used for e.g. rheumatoid arthritis.
What are adverse effects of overdose of Aspirin?
- Large doses, cause tinnitus (ringing in the ears an early sign of toxicity) and higher doses can be fatal to the CNS
- There are no antidotes to aspirin overdose
- Children under 12 should not take aspirin (use paracetamol or ibuprofen) as it can cause Reye’s syndrome in which the liver fails- can be fatal.
How does Aspirin cause Reye’s Syndrome?
- Children and youth under 19 years or age, given aspirin for the treatment of fever-causing or viral illness may lead to fatty change in the liver and acute non-inflammatory encephalopathy.
- Symptoms include vomiting, irritability, lethargy and hepatomegaly.
- Of those affected, 25% progress to severe stages.
- You can develop Reye’s syndrome without using aspirin, but this is relatively rare.
- Can have liver, brain and CNS effects
- Seizures and comas are possible
How is the low dose of aspirin for prevention of heart attacks?
Small doses (350 mg twice a week) cut heart attacks in middle aged male USA physicians (5 yr trial, 1980s) by 50%- a phenomenal result!
Aspirin did not increase stroke rates- another phenomenal result. Why?
Because of the uniqueness of aspirin’s action: preferentially acetylating COX-1 over COX-2.
Changes COX1 –> inactivates it –> prevent clots
This is selective____ inactivation of platelet COX-1 (in circulation) and reduction in clotting mechanisms (thromboxane from platelets is reduced). Platelets do not have a nucleus- so cannot make new COX-1.
PERMANENT
Aspirin thus prolongs _____ time of the blood; a single dose of aspirin doubles ____ time, and this effect last for a week- not coincidentally, the time it takes platelets to regenerate.
clotting; clotting
What are 3 characteristics of Propionic Acid Derivatives- Ibuprofen and Naproxen?
- effective competitive COX inhibitors, and better tolerated than many others
- there are several propionic acid derivatives, with same pharmacological effects-differences are potency and t1/2’s in plasma
- basically have aspirin-like effects, but GIT side effects usually less severe
COX1:COX2= ~1:2- so slightly COX- 2 selective.
COX1:COX2= ~1:2 What does that mean?
Greater affinity for antagonising COX2
so slightly COX- 2 selective = More effective for reducing inflammation (reduce fever, pain relief) and few problems with stomach (not targeting COX1)
What are the 4 Therapeutic Uses Of Naproxen & Ibuprofen?
- Therapeutic efficacy in rheumatoid arthritis similar to aspirin
- side effects of high doses fewer than high doses of aspirin -but aspirin is cheaper.
- More effective against pain from dysmenorrhoea than aspirin.
- >50 % of patients with rheumatoid arthritis will achieve adequate relief from this group of drugs, and with their lower incidence of side effects compared to aspirin, are favoured by many physicians over aspirin.
What are 5 characteristics of Celebrex - celecoxib?
- selective COX-2 inhibitor (COX-1/COX2 ~1/30)
- modern new drug treatment for rheumatoid arthritis
- important and very popular NSAID released in the last few years
- side effects on stomach usually less than conventional NSAIDS; but there is still a significant fraction of patients reporting quite severe cardiovascular side effects
- drug is not more efficacious than other NSAIDS, but has a better side effect profile
Celebrex - celecoxib is a drug that is not more efficacious than other _____, but has a better side effect profile
NSAIDS
What are new COX-2 inhibitors?
Etoricoxib FDA withdrawn; Lumiracoxib TGA cancelled registration; Parecoxib FDA withdrawn; Rofecoxib-Vioxx (withdrawn from market); Valdecoxib (withdrawn from market) ….
How is COX-2 inhibition having this effect?
- Drugs such as Rofecoxib (Vioxx, which was withdrawn from the market in 2004 after a lawsuit in which Merck was ordered to pay $253.4m to the widow of a man who died from a heart attack linked to the drug)…
- these drugs also inhibit COX-1 inside these cells that line blood vessels.
- COX-1 is responsible for the production of prostacyclin, but if COX-1 is inhibited, then blood may clot and risk of heart attack or stroke are increased.
- Ideally, a COX-2 antagonist without this effect is what is needed, especially with patients suffering from conditions like arthritis.
What is COX-1 responsible for?
COX-1 is responsible for the production of prostacyclin, but if COX-1 is inhibited, then blood may clot and risk of heart attack or stroke are increased.
What is COX-2 antagonist responsible for?
a COX-2 antagonist without this effect is what is needed, especially with patients suffering from conditions like arthritis
When should COX-2 inhibitors used?
Can use this but must be SHORT term use only
Otherwise, at risk of cardiovascular side effects
What are the 3 minimal anti-inflammatory actions for Paracetamol (acetaminophen)?
- analgesic and antipyretic = equal or better efficacy than aspirin
- lacks many of side effects of aspirin
- available over the counter (Aus?)
What is the mechanism of action for Paracetamol (acetaminophen)?
not clear, perhaps inhibits COX-3 in brain as it can cross BBB, but no actions at COX-1 or COX-2.
What are the 3 effects of Paracetamol (acetaminophen)?
- no gastric adverse effects
- No effect on COX1
- no effect on bleeding time
- well absorbed from GIT
What are the uses of of Paracetamol (acetaminophen)?
suitable substitute for aspirin for antipyretic and analgesic effects esp. in patients for whom aspirin is contraindicated (GIT problems)
Why is paracetamol (acetaminophen) not an NSAID (by definition)?
Not anti-inflammatory
What is paracetamol not helpful for?
If have oedema and swelling = paracetamol won’t help
With a Child with possible febrile convulsions, what can be done in terms of medication?
- Alternative between NSAIDS (ibuprofen) and paracetamol
- 2 hr cycles
What are 6 toxicity issues to be aware of for paracetamol?
- well tolerated at therapeutic dose levels
- useful drug in patients who demonstrate hypersensitivity to aspirin
- there is a dose-dependent, hepatic necrosis which can be fatal, as well as renal necrosis
- chronic use can lead to irreversible nephrotoxicity in some people
- hepatoxicity occurs with 10 gm dose
- fatal dose around 20-30 gms
What are 5 hepatoxicity issues to be aware of for paracetamol?
- due to formation of toxic reactive intermediary
- hepatic damage signs appear in 2-4 days
- liver enzymes and bilirubin levels in plasma rise
- 1-2 % of untreated patients will die of liver failure
- treatment give N-acetylcysteine, which replenishes glutathione
Following a therapeutic dose, it is mostly converted to _____ metabolites by the processes in blue, with a small portion (5%) being oxidized via the cytochrome P450 enzyme system in red. This highly _____ intermediary metabolite, N-acetyl-pbenzoquinoneimine (NAPQI), is normally detoxified by conjugation with to purple product. In cases of paracetamol overdose, the blue pathways become _____, and more paracetamol is shunted to the red pathway, producing NAPQI, and hepatocellular supplies of glutathione (GSH) become depleted.
nontoxic; reactive; saturated
What is the general pain management plan?
a
SAIDs mechanism of action includes blocking of both COX-1 and COX-2 enzyme function. (T/F)
T?
NSAIDs are generally antipyretic, analgesic and antiinflammatory. (T/F)
T
Paracetamol overdose is usually associated with tinnitus and development of stomach ulcers. (T/F)
F –> liver damage due to where it is metabolised
The more selective a COX inhibitor is for COX-2, the better it is for anti-inflammatory actions. (T/F)
T (eg. ibuprofen)
Side effects of chronic NSAID use include tendency for osteoporosis, possible immunosuppression, and Cushing’s syndrome. (T/F)
F –> these are for SAIDS
Using paracetamol and ibuprofen together, alternating doses, can be a good strategy for countering high fever. (T/F)
T
Aspirin is no longer used in children due to the possibility of Reye’s syndrome. (T/F)
T
