Do prostaglandins produce pain?
NO, but they potentiate the pain caused by other mediators of inflammation (e.g. histamine, bradykinin).
Prostaglandins sensitize sensory nerve endings to nociceptive stimuli.
Do NSAIDs have an antipyretic action?
Fever - endogenous pyrogen (interleukin I) released from leucocytes - these act on thermoregulatory centre in hypothalamus.
This effect also causes a rise in hypothalmus prostaglandins which are pyogenic.
Can you use aspirin for gout?
No because they raise plasma urate levels at low doses by inhibiting uric acid secretion in the renal tubules.
Do prostaglandins cause inflammation?
they are released from cells in response to chemical/ physical trauma.
they stimulate inflammatory cell chemotaxis (vasodilation, >> permeability >> oedema
- they sensitize sensory nerve endings to nociceptive stimuli.
Relationship of COX (cyclooxygenase Isozymes)
NSAIDS are non-selective inhibitors of COX-1 and COX-2.
COX-1 has a protective effect on GI tract. COX1 is involved with synthesis of prostaglandins that are cytoprotective.
COX-2 - normally levels are low, it is up-regulated in the inflammatory process by substances such as cytokines, endotoxins.
Relationship between NSAIDs and lithium
NSAIDs inhibit the renal excretion of lithium and can increase lithium levels and toxicity.
Can you combine Spironolactone with NSAIDs?
Not advisable due to increased risk of hyperkalaemia.
Why is it advisable for children not to have salicylates?
Increase risk of Reye's syndrome
(salicylates; aspirin - salicyclic acid)
Relationship of aspirin levels to pharmological and toxic effects
Adverse effects of aspirin
>> does; tinnitus, hyperventilation, fever, dehydration, metabolic acidosis, organ failure, death
hypoprothrombinaemia - impairment of haemostasis.
Tx of salicylate overdose
IV Sodium bicarbonate
Celecoxib - what's special about this NSAID?
Is the first selective COX-2 inhibitor (therefore doesn't affect cytoprotective effects of COX-1).
Less risk of GI bleeding.
>>> risk of cardiovascular events
NSAIDs has two unusual indications, what are they?
(neurogeneration is accomopanied by inflammatory COX mechanisms)
(angiogensis of tumour growth requires COX-2 activity)
antidote to acetaminophen overdose
what is >>>> acetaminophen toxic?
due to depletion of hepatic glutathione that converts the hepatotoxic quinone intermediate.
Adverse effects of acetaminophen?
long term use is associated with an increased risk of renal dysfunction.
What is COX?
an enzyme that catalyzes the first step in the synthesis of prostaglandins from arachidonic acid
Found in endoplasmic reticulum
How do NSAIDS work?
decrease COX activity by competitive inhibition.
(non-selective, therefore affects the cytoprotective GI aspect of COX-1)
Except aspirin; forms a covalent, irreversible inhibition of COX.
Net effect << prostaglandin production
Why does APAP (acetaminophen) only have a WEAK anti-inflammatory effect?
Because it inhibits COX-3 only.
Can you give NSAIDs in pregnancy?
NO, especially in the second half of pregnancy.
Acetaminophen can be safely given for analgesia and antipyresis.
What are the two groups of analgesics?
- nonopiods (also called NSAIDs because of significant anti-inflammatory effect)
MOA of opioids?
Act primarily in the spinal cord and brain to inhibit the neurotransmission of pain.
MOA of nonopioids?
Act primarily on peripheral tissues to inhibit the formation of algogenic or pain-producing substances such as prostaglandins?
Three origins of pain, what are they?
Why are drugs like codeine (moderate opiod agonist) best combined with acetaminophen or a NSAID?
Moderate opioid agonists cause intolerable adverse effects if given in high doses for severe pain.
Therefore best given submaximally with another drug for best clinical effectiveness.
(NB. strong opioid are better tolerated, therefore use for severe pain)
Strong Opioid Agonists include:
CNS effects of Morphine (7)
- euphoria/ dyphoria
- nausea/ vomiting
- respiratory depression
- inhibition of cough reflex
What is the importance of miosis if a patient has taken opioids?
It's a diagnositic sign of opioid overdose because little/ no tolerance developes to miosis
What is the cardiovascular effect of morphine (and other opioids)?
- orthostatic hypotension (careful with this)
- it would helps patients with coronary artery disease due to << peripheral resistance
Therefore: << Cardiac work, << myocardial oxygen demand.
How do opioids depress respiratory function?
Reduce hypercapnic drive
Reduce tidal volume and rate
IMP. cerebral circulation is very sensitive to CO2 levels and responds with incrase in cerebral blood flow, therefore >> pressure.
DON'T use opioids with closed-head injuries.
What's the antidote to opioid overdose?
Other effects of opioids (except CV and cns):
nausea and vomiting (opiods stimulate chemoreceptor trigger zone in the medulla)
Pruritus (due to release of histamine)
Flushing and warmth of upper torso (due to histamine)