Week 11 - Antipyretic and Narcotic Analgesics (Opioids) Flashcards
Describe the Ascending pathway: transfer pain from peripheral to brain
SUMMARY: site of stimulus - spinal cord - thalamus - somatic sensory cortex
- if stimulus was in right hand, would synapse over to left side of brain (1st order meets 2nd order neurone)
- Damage to tissue on skin (noxious stimulus example) causes noxious factors like cytokines + prostaglandins to be released from damaged cells
- Stimulus (noxious stimuli) is detected by nocicieptors
- Signal (AP) travels down 1st order neurone (dendrites - axon - cell body - axon terminal) into dorsal horn of the spinal cord where it synapses
- substance P is the chemical neurotransmitter which stimulates 2nd order neurone
- depolarisation occurs = AP generated
- 1st order neurone synapses with the 2nd order neurone crosses over to the opposite side of spinal cord when AP generated
- AP travels up from the spinal cord to the thalamus (in the brain), thalamus knows what part of body the stimulus was activated
- In thalamus 2nd order neurone synapses with 3rd order neurone (AP travels along) to sensory cortex (part of the brain that will respond to that area triggered by stimulus)
- causes perception of noxious stimuli (perception of pain is perceived here)
Describe the Descending pathway: inhibits the ascending pathway
- 1st order neurone from brain will synapse with 2nd order neurone in brain
- Synapse with 2nd order neurone (serotonin / noradrenaline neurone) which travels down to dorsal horn of the spinal cord
- ROLE: inhibit / control the communication between 1st and 2nd order neurones in ascending pathway by releasing serotonin + noradrenaline
- neurotransmitters bind to pre-synaptic neurone = substance P NOT released
nNurotransmitter causes release of endogenous opioid:- Inhibits release of substance P from pre-synaptic neurone
- Inhibits depolarisation in post-synaptic neurone = stimuli stopped
- This controls pain signalling going up to brain
- ROLE: inhibit / control the communication between 1st and 2nd order neurones in ascending pathway by releasing serotonin + noradrenaline
What 2 fibres can transfer signals
- Ad fibres = A delta fibres
- myelinated = send signals quick = quick response / movement
- have sharp, localised pain - C-fibres
- unmyelinated = send signals slower = time delay in response
- dull, diffusing pain
What are Opioids
Can be synthetic or natural and they bind to opioid receptors to mediate an analgesic effect
Endogenous Opioids:
- Enkephalins
- Endorphins
- Endomorphins
Endogenous = substance originated / made within the body
What are the 3 opioid receptors
- MOP (Mu Opioid) Receptor
- most COMMON / MAIN receptor - DOP (Delta opioid) receptor
- KOP (Kappa opioid) receptor
All the above receptors have subtypes e.g. MOP1, MOP2, MOP3 etc.
Some opioids e.g. tramadol + methadone are MOP receptor agonists but also blocks the uptake of noradrenaline + serotonin
What is the role of MOP receptors
MAIN opioid receptor as most opioids go through MOP
- are G-protein coupled receptors
- most opioids are FULL agonsits at MOP receptors
MoA (ascending pathway)
1. ALPHA sub-unit:
- inhibit adenylate cyclase = ↓ ATP converted into cAMP = ↓ intracellular cAMP
2. BETA + GAMMA sub unit:
- inhibit voltage-gated Ca2+ channels = ↓ Ca2+ influx = pre-synaptic neurotransmitters NOT released
- causes hyperpolarisation by opening K+ channels
- LOCATED: pre-synaptically on 1st order neurone AND post-synaptically on 2nd order neurone (ascending pathway)
- Pre-synaptic:
- opioids bind + inhibit release of neurotransmitter e.g. substance P + glutamate
- ↓ Ca2+ influx (no depolarisation in 2nd order neurone) + causes hyperpolarisation - Post-synaptic:
- inhibits depolarisation
- causes hyperoplarisation (opens K+ channels) = stops AP being sent
- Pre-synaptic:
MoA (descending pathway)
- when opioids bind to MOP receptors inhibit GABA = noradrenaline + 5-HT (seretonin) can be released
- inhibits signal travelling further along ascending pathway
- GABA inihibits the 2nd order (noradrenaline / seretonin neurone)
What are common side effects of opioids
- Euphoria and Dysphoria
- Sedation and confusion
- Nausea and vomitting
- GI effects
- Respiratory depression
- CV effects
- Itching
- Convulsions
How do NSAIDs work
- Inhibit cycloxygenase (COX-1 and COX-2) = ↓ prostaglandin production
- COX1/2 is an enzyme involved in conversion of archadonic acid into prostaglandins - ↓ signalling from periphery to spinal cord (in ascending pathway)
- ↓ nociceptors sensitisation and amplifciation of pain signal
Examples:
- Aspirin
- Ibuprofen
- Naproxen
How does paracetamol work
- Inhibits COX-2 = ↓ prostaglandin formation
- Inhibits peroxidases = ↓ prostaglandin formation
- ↓ sensitisation of nociceptor to noxious stimuli
- by inihibiting TRPV channels
What is pyrexia (fever)
CAUSE: release of cytokines in response to tissue injury or infection
Endogenous Mediators:
Interleukins (IL-1b, IL-6) and Tumour Necrosis Factor (TNF)
- mediators act on hypothalamus = causing release of cytokines = fever response produced
- mediators ↑ prostaglandin (PGE2) synthesis which raises thermostat
- PGE2 binds to thermoregulatory centre in hypothalamus + tells hypothalamus to ↑ core temp.
- body tries conserving heat = fever
What are the anti-pyretic effect of analgesics
TREATMENTS:
- Paraceatamol
- NSAIDs
ALL above inhibit prostaglandin synthesis (via inhibition of COX-2 (and COX-1)
- inhibition = thermostat decreases back to normal via sweating + vasodilation
- results in core temp. being restored
How do local anaesthetics work to relieve pain
- Block Na+ channels in axon membrane = AP threshold not met
- only nlocks channels open OR inactivated - NO AP = no signal (transmission of pain signal stops)
