(FE) Drugs for Pain Management Flashcards
What is nociception?
The process of detecting and signaling the presence of noxious (potentially harmful) stimulus to the CNS
What are the main types of analgesics?
1) NSAIDs
- Non-selective COX inhibitors
~ Irreversible (ASPRIN)
~ Reversible (PAROXEN, IBUPROFEN, Mefenamic acid, Diclofenac)
- COX-2 selective inhibitors (ETORICOXIB, Celecoxib)
2) CNS-selective COX inhibitor
- Reversible COX inhibitor (PARACETAMOL)
3) Opioids / Narcotic analgesics (TRAMADOL, CODEINE, MORPHINE, OXYCODONE, FENTANYL)
How is pain felt?
1) When there is damage to the cell membrane during tissue injury or inflammation, Phospholipase A2 acts on phospholipids in membrane
2) Phospholipase A2 releases arachidonic acid (AA), which is broken down with the action of LOX and cyclooxygenase (COX) enzymes
3) Prostanoids (incl. prostalglandins), leukotrienes and lipoxins (collectively known as eicosanoids) are produced by breakdown of AA
4) Eicosanoids, potent mediators of inflammation, contribute to sensitisation of nociceptive nerve endings and become more sensitive to stimuli
Steroids vs NSAIDs MOA?
1) Steroids:
- Inhibits activity of enzymes involved in the synthesis of inflammatory mediators
- Inhibits phospholipase A2 (tf preventing its release from phospholipids)
- Decreased availability of AA to be converted into inflammatory mediators
- Broader-spectrum and not as recommended for pain/bleeding
2) NSAIDs:
- Inhibits COX enzyme (tf blocking conversion of AA into prostalglandin precursors)
What are the main functions of prostanoids?
- Vasodilation/constriction
- Inhibit PLT aggregation
- Vascular permeability
- PLT aggregation
- Pain
What are the types of NSAIDs?
1) Non-selective COX inhibitors
- Irreversible
~ ASPIRIN
- Reversible
~ NAPROXEN
~ IBUPROFEN
~ Diclofenac
~ Mefenamic acid
2) COX-2 selective inhibitors
- Reversible
~ ETORICOXIB
~ Celecoxib
~ Parecoxib
Aspirin effects?
1) Anti-inflammatory
- Prevents vasodilation -> reduces heating, redness and swelling
- Reduces vascular permeability -> reduces swelling)
- Reduces pain associated with inflammation
2) Analgesic
- Blocks the production of prostalglandins -> reduces sensitisation of nociceptive fibres to stimulation by inflammatory mediators
- Higher doses may saturate their target receptors, leading to a plateau in their analgesic effect
3) Antipyretic
- Note: NSAIDs do not alter normal body temperature, only brings down temperature if there is fever
- Inhibition of COX prevents release of prostalglandins to the hypothalamus, which would cause a fever
4) Antiplatelet
- COX results in both promotion and inhibition of PLT aggregation
- COX produces thromboxane -> promotes aggregation
~ Can only be restored by formation of new PLT in 1-2 weeks
- COX produces prostalglandins -> inhibits aggregation
~ Restored by synthesis of new COX enzyme in a few hours
~ That’s why inhibition > promotion
5) Misc
- Blood thinner at low doses
- Due to adverse effects of aspirin, paracetamol has taken over as a common painkiller
Adverse effects of aspirin?
- Due to the salicylate chemical structure
Dose-dependent effect:
1) COX inhibition
- Gastric intolerance
- Bleeding
- Hypersensitivity
- ^ uric acid in urine
2) Salicylate toxicity
- Tinnitus
- Central hyperventilation
- Respiratory alkalosis -> acidosis
- Fever
- Dehydration
- Metabolic acidosis
- Hypoprothrombinemia
- Vasomotor collapse
- Renal & respiratory failure
- Coma
// - Reye’s syndrome (IMPT)
~ Rare
~ Encephalitis (swelling of brain)
~ Swollen liver
~ Vomiting, personality changes, listlessness, delirium, convulsions, LOC
~ Increased risk if taken by children with viral infection
What are the reversible non-selective COX inhibitors?
1) Naproxen
- More effective in women
- Often used in dysmenorrhea
- Half-life of 12-14 hours
2) Indometacin
- Strongly anti-inflammatory
- Reports of CNS adverse effects (confusion, depression, psychosis, hallucinations)
3) Diclofenac
- Low GI risk due to short plasma half-life (<2 hrs)
- Longer half-life in synovial fluid
~ Useful in inflammatory joint disease
What are the adverse effects of reversible non-selective inhibitors?
- Dyspepsia, N&V
- Ulcer formation and potential hemorrhage risk in chronic users
- Risk of peptic ulcers greatly increased if used for >5 days (due to inhibition of mucus secretion and bicarbonate)
- Renal effects
~ Sodium and water retention
~ Peripheral oedema
~ Hypertension
~ Suppression of renin and aldosterone secretion
~ Hyperkalemia (as inhibition of aldosterone resulted in ^ Na reabsorption and decreased K excretion)
~ Acute renal failure - Psuedo-allergic reaction
~ Rashes, itching, swelling
~ Nasal congestion
~ Anaphylactic shock - Asthma
~ Can trigger bronchospasms in susceptible asthmatics - Bleeding and bruising
~ Caution for surgical procedures when px is already on NSAIDs
What is the “triple whammy” effect?
- Occurs when NSAIDs, Diuretics and ACE-inhibitors are used together, which greatly increases risk for kidney injury
- NSAIDs inhibit COX-1/2 which results in vasoconstriction of afferent arterioles
- Diuretics reduces renal blood flow
- ACE-inhibitors result in vasodilation of the efferent arteriole
What are the risk factors and effects for NSAID-induced AKI?
1) Increased age, chronic HTN, atherosclerosis
- Narrowed renal arterioles -> reduces capacity for afferent dilation
2) Pre-existing glomerular disease or renal insufficiency
- Renal afferent dilation required to maintain GFR
3) Volume depletion (True or effective/functional)
- Lowers afferent glomerular arteriolar pressure and stimulates secretion of angiotensin II
4) Use of ACE-I
- Prevents efferent arteriole vasoconstriction to maintain GFR
5) Use of “triple whammy”
COX-1 vs COX-2 inhibition?
- COX-1 usually plays a role in maintaining normal physiologic function
- ^^ Inhibition can lead to GI ulcers & bleeding due to suppression of gastric mucosal prostalglandin
- COX-2 is usually induced at sites of inflammation and primarily responsible for prod. of prostalglandins to mediate pain and inflammation
- COX-2 inhibitors provide anti-inflammatory and analgesic effects without affecting COX-1 mediated physiological functions
What are the COX-2 selective NSAIDs?
- ETORICOXIB
- CELECOXIB
Rank the GIT risk, anti-flammatory, analgesic and anti-PLT properties for NSAIDs
Aspirin (most harmful to GIT, most anti-PLT, least anti-inflammatory and analgesic)
Naproxen
Ibuprofen
Ficlofenac
Mefenamic acid
Celecoxib
Etroicoxib (least harmful to GIT, not anti-PLT, most anti-inflammatory and analgesic)
