Analgesia Flashcards
Define analgesics
the objective tratment in all types of pain, irrespective of origin, is to achieve symptom control and improve the patient’s quality of life
-a drug that relieves or reduces pain
What does NSAIDS stand for?
non-steroid anti-inflammatory drugs
What is the arachidonic acid cascade?
1-arachidonic acid (phospholipase A2)
2-cyclooxygenase (COX) -converts AA to intermediates
3-other cell/ tissue specific enzymes intermediates converted to prostanoids
4-prostanoids (prostaglandins,thromboxane)
What are the types of COX enzymes?
COX 1,2, 3
Where are COX 1 enzymes found and what is their function?
found- most tissues/cells mainly endoplasmic reticulum
function- gastric protection
blood flow
platelet aggregation
Where are COX 2 enzymes found and what is their function?
found- mast cells, fibroblast, macrophages, endothelial cells, more in nuclear membrane
function- inflammation, pain, fever
Where are COX 3 enzymes found and what is their function?
Found- mainly in CNS (animal models)
function- poorly understood, may not be active in humans
Name some NSAID examples
-aspirin
-ketoprofen
-fenoprofen
-celecoxib
What are 4 main therapeutic effects of NSAIDS?
-anti inflammatory
-analgesic
-antipyretic
-platelet aggregation
Describe the anti inflammatory effects of NSAIDS
-inhibition of COX 2 derived prostaglandins
-which are powerfil vasodilators
-promote the release of other vasodilators
-e.g substance p and histamine
COX2 - reduces vasodilation, oedema, swelling, redness,neurogenic inflammation
Describe the analgesic effects of NSAIDS
-inhibition of COX-2 derived prostaglandins, reduce sensitisation of free nerve endings
-COX inhibition in the dorsal horn of 2nd order neuron
-reduction of prostaglandin production
-reduced transmitter release
-reduced 2nd order neuron sensitivity
NSAIDS help to reduce peripheral and central sensitisation
Describe the antipyretic effects
pyrogens- stimulate PGE2 in hypothalamus
PGE2- inhibits temp sensitive neurons
NSAIDS- reduce PGE2 production by binding to COX-2
Describe platelet aggregation as an effect of NSAIDS
cox-1 inhibition reduces thromboxane A2 production
-reduces the ability of platelet aggregation and blood clotting
-new platelet production required as platelets never recover the ability to aggregate
-good cox-1 selectivity- covalent binding
What are the side effects of NSAIDS?
-gastrointestinal
-respiratory
-renal
-liver
Describe the gastrointestinal side effects of NSAIDS
-prostaglandins promote production of alkali mucus
-blocks prostaglandin production
-asprin induced gastriris
-ulceration
Describe cox-2 selective NSAIDS
-fewer gastric complications
-reduced effects on platelet aggregation
-some evidence of reduced analgesia
-increased thrombic/ CV risks
Describe the respiratory side effects of aspirin
-aspirin induced asthma
-tissue injury, arachoidonic acid,
pathway 1- cox1, thomboxane, prostaglandin
pathway 2- lipoxygenase, leukotriene (bronchoconstrictors)
NSAIDS increase the production of leukotrienes
Describe the renal side effects of NSAIDS
prostaglandins- promote vasodilation therfore glomerular filtration
taking NSAIDS- block prostaglandin production, reduce renal filtration, sodium retention
Describe liver damage as a side effect of NSAIDS
-retention of bile ( cholestasis)
-mitochondrial damage
-inhibition of prostaglandin E2 production ( cytoprotection)
-reactive metabolites ( autoimmune)
-endoplasmic recticulum stress
Describe paracetamol structure and function
-non opiod- not strictly NSAID
-Poor peripheral cox1/2 inhibition
-targets COX2 mabye COX3 in CNS
-doesn’t inhibit platelet aggregation
-doesn’t damage gut mucosa
-activation of descending inhibitory pathways-central effect
-may reduce prostaglandin production or activate cannabinoid receptors
Paracetamol pharmacokinetics
paracetamol is metabolised in the liver to NAPQI (toxic) by CYP3A4, CYP2E1
NAPQI is conjugated to glutathione forming glutathione conjugate
define opioid
a compound resembling opium in it physiological effects
How do opioids work?
1-bind to specific opioid receptors
2-mimic the action of endogenous peptide neurotransmitters for example endorphins, enkephalins and dynorphins
(we have natural, semisynthetic and synthetic opioids)
natural-morphine, codine
semisynthetic-oxycodone, hydromorphome
synthetic-fentynal
What are the different type of opiod receptor?
delta- supraspinal/spinal peripheral
k-spinal
all G protein coupled receptors- down regultation of nerve cell excitability
Describe the mechanisms of the spinal cord opiod receptors
1-voltage gated ca channels -activity decreased
voltage gated k channels-activity increased
2-overall effect- decreasing neuronal excitability, sensitivty of synapses
-first order afferents, second order neurons
reduction in noiception leading to analgesia
Describe the general peripheral mechanisms of analgesia
-u-opioid receptors located on free nerve endings
-activation- reduces 1st order noiceptor sensitivity
Describe the central analgesia mechanism
-spinal-inhibition of noiception
-supraspinal effects- limbic system
-supraspianl effevts- brain stem
-noiceptin receptors-descending control
widespread effects of noiception and pain perception
Give some examples of mild opioids
-morphine analogues-codeine
-synthetic derivatives-tramadol
-mainly work by weakly activating opioid receptors
-lower efficacy at the receptor
Describe how codeine is converted
codeine is converted into morphine in the liver
-people have different metabolism speed
-respiratory depression
-GI motility
Give some examples of strong opioids
-morphine analogues-morphine
-synthetic derivatives-fentanyl
-strong agonists of opiod receptors
-high potency/good efficacy
short term side effects of opioids
-constipation, depression of cough reflex, respiratory depression, nausea, tolerance effects- adaptation of 2nd messenger cascade, europhoria, physical dependence
Long term side effects of opioids
-immune suppression
-decreased sex hormone production
-opiate induce hyperalgesia
how do local anaesthetics work?
MOA- block voltage gated NA + ion channels
LA partition into cytoplasm
binds to intracellular face of v-gated NA+ channel
-results in channel inactivation
