Analgesia and pain management, NSAIDs Flashcards
Describe acute pain. (type of pain, structures involved, duration etc.)
Nociceptive
primary afferent neurones detect noxious stimuli and information is relayed to the supraspinal structures
pain response correlates to degree of inflammation
duration: <12 weeks
Describe chronic pain. (type of pain, structures involved, duration etc.)
duration: >12 weeks no apparent ongoing tissue damage ectopic focus of neural activity central/peripheral sensitisation response to treatment is less effective unpredictable prognosis
Define allodynia.
pain due to a non-noxious stimulus
Define hyperalgesia.
increased response to a stimulus which is normally painful
What are the clinical features of somatic pain?
Aching constant pain (can be dull or sharp)
Worsens on movement
Well localised pain
State Hilton’s law.
Nerves that supply a joint capsule also supply the muscles that move the joint capsule and the skin over the joint
What is the difference between treatment of acute and chronic pain? (WHO analgesic ladder)
Acute: go DOWN the ladder
Chronic: go UP the ladder
What are the different types of NSAIDs? Give examples of each.
- Selective COX-2 inhibitors
- celecoxib
- etoricoxib
- any -coxib - Enolic acid derivatives
- piroxicam
- meloxicam
- any -icam - Salicylates
- aspirin
- diflunisol - Fenamates
- mefenamic acid - Acetic acid derivatives
- diclofenac
- indomethacin
- any -ac - Propionic acid derviatives
- ibuprofen
- naproxen
- ketoprofen
- any -en
What is the difference between the structure of COX and COX 2?
COX 1 has a tighter hydrophobic channel
COX2 has a more flexible hydrophobic channel (creates a side pocket)
In the UK, which NSAIDs are used for main inflammation (i.e. inflammation only)?
Aceclofenac
Etoricoxib
Fenbufen
Tiaprofenic acid
In the UK, which NSAIDs are used for inflammation AND pain?
acematcin celecoxib diclofenac ibuprofen indomethacin naproxen piroxicam
In the UK, which NSAIDs are used for mainly pain (i.e. pain only)?
paracoxib
Which NSAIDs can be used for:
- eye issues
- Cancer, CV issues and Alzheimer’s disease
- Ketorolac
2. Aspirin
What is the MOA of NSAIDs?
NSAIDs inhibit COX-1 and COX-2 enzymes
this prevents the conversion of arachidonic acid into prostaglandins
What is the action of phospholipase A2?
converts phospholipids into arachidonic acid and lyso-glycerol-phosphorylcholine
What are prostaglandins?
Tissue hormones
they do not diffuse very far - act locally
What are the different classes of prostaglandins?
- PG D, E and F
- Prostacyclin (PGI2)
- Thromboxane A (TXA2)
What are the actions of PGD?
acts on mast cells, brain and airways actions: - memory - sensitisation of peripheral nerve endings - bronchoconstriction - vasodilation
What are the actions of PGE?
acts on brain, kidney, smooth muscle, platelets
actions:
- memory
- sensitising nerve endings
- vasodilation (renal artery)*
- suppress lymphocytes*
- GI smooth muscle contraction + relaxation
- inhibits gastric acid secretion*
- increases platelet response to agonists
- uterine relaxation*
- = important
What are the actions of PGF?
acts on uterus, airways, vascular smooth muscle, eye actions: - uterus contraction - bronchoconstriction - vasodilation and constriction
What are the actions of PGI2?
acts on platelets, vascular smooth muscle, airways and stomach
actions:
- prevents formation of platelet plug
- bronchodilation
- vasodilation (renal artery)
- protects lining of stomach (inhibits gastric acid secretion)
- sensitisation of afferent nerve endings
What are the actions of TXA2?
acts on vascular smooth muscle, platelets, airways, uterine smooth muscle actions: - vasoconstriction - promotes platelet aggregation - bronchoconstriction - uterine contraction
What type of receptors are the prostaglandin/prostanoid receptors?
GPCRs
Compare COX-1 and COX-2 in terms of:
- regulation
- rate of gene activation
- effects of glucocorticosteroids
- rate of arachidonic acid consumption
- effect of aspirin
COX-1:
- usually constitutive (constant low level of PG production)
- 24 hours
- Inhibits activity
- 34 mmol/min/mg
- inhibited
COX-2:
- inducible
- 0.5-4 hours
- inhibits activity
- 39 mmol/min/mg
- affected
Why are COX-2 enzymes active in OA and RA?
IL-1, TVFalpha and IL-17 stimulates iNOS
iNOS induces COX2 expression
What is the effect of the COX2 pathway and 5-LOX pathway in joints?
COX2 pathway produces prostaglandins and thromboxanes
5-LOX pathways produce leukotrienes
these contribute to joint soreness and stiffness
What is the effect of COX enzymes in the stomach?
COX2: found in low levels in superficial mucosa COX1: lots in crypts - it produces PGE2 which: 1. increases mucus secretion 2. increases cell regeneration 3. increases HCO3- releasing 4. decreases H+ secretion 5. increases blood flow
What are the effects of long-term use of NSAIDs on the stomach?
Inhibit PGE2 production resulting in:
- pyrosis
- dyspepsia
- gastric pain
- injury to mucosa
- reduced blood flow
- PMN
- irregularity
- congestion
- haemorrhage
all of these manifest as gastritis and gastric ulcers
What are the effects of COX enzymes on the cardiovascular system?
- PGI2 from endothelial cells prevents platelet aggregation
- TXA2 COX1 induced platelets promotes aggregation
increases CV risk due to potential platelet aggregation
What role(s) does COX-2 play in the spinal cord and CNS?
- peripheral and central role in pain perception and sensitisation
- inflammation evoked spinal hyperexcitability might be related to the conversino of 2-arachidonolyglycerold to PGE2 subtype G via COX-2
In the spinal cord + CNS, what is COX-2 activated/upregulated by?
- cytokines
- IL-1beta
- NMDA
- Ca2+ influx
- NOS
Why are COX enzymes important in the kidneys? What is the effect of NSAIDs on the kidneys?
COX enzymes protect the kidney and maintain a normal GFR
NSAIDs and selective COX-2 inhibitors reduce GFR (by constricting blood flow to the glomerulus)
What are the effects of COX-1 and COX-2 in the kidneys?
COX-1: produces PGE2 and PGI2
- PGE2: regulates sodium reabsorption
- PGI2: increases potassium secretion (stimulates renin and RAAS)
COX-2: in small amounts in the macula densa, but increases in slat deprivation
Give examples of COX-2 selective NSAIDs.
etoricoxib
diclofenac
celecoxib
Give examples of COX-1 selective NSAIDs.
ibuprofen
naproxen
aspirin
indomethacin
What % of COX-2 must be inhibited for NSAIDs to have a significant anti-inflammatory effect?
80%
Describe category 1 NSAIDs and give examples.
rapid competitive reversible binding of COX1/2
examples:
- ibuprofen
- piroxicam
they are good for acute pain
Describe category 2 NSAIDs and give examples.
rapid lower affinity reversible binding followed by time-dependent, high affinity slowly reversible binding of COX1/2
examples:
- diclofenac
- indomethacin
good for chronic pain
Describe category 3 NSAIDs and give examples.
rapid reversible binding followed by covalent modifcation of COX1/2 - noncompetitive and irreversible
examples:
- aspirin
Give an example of an atypical NSAID
Paracetamol
What are the side effects of opioids/morphine?
N+V Dizziness Sweating Constipation Drowsiness Pruritis (itch)
