Analgesics Flashcards
How does the body sense pain and what are the receptors involved in pain?
Peripheral sensory nerve endings detect tissue damage through specialised nociceptor proteins
TRPV1: depolarise in response to damaging heat
P2X: respond to ATP released from damaged cells
Acid sensing ion channels: respond to acid
What do local anaesthetics target and why are they inherently toxic?
They block voltage-gated sodium channels which action potential propagation is dependent on in sensory nerves. They are not selective for V-gated sodium channels, toxicity is minimised by local administration.
Why is it important to block transmission at the synapse in the dorsal horn of the spinal cord?
- arrival of the action potential causes the release of neurotransmitter from the central nerve endings of sensory nerves in the dorsal horn of the spinal cord
- neurotransmitter release is activated by calcium entry into the nerve terminal through voltage gated calcium channels
- enhanced transmission at this synapse through strengthening of synaptic connections underlies central sensitisation leading to hyperalgesia and allodynia.
How does descending inhibition work?
- descending neurons from the RVM and the LC release serotonin and noradrenaline respectively to inhibit transmission through the synapse in the dorsal horn of the spinal cord
- RVM can be activated by nerves from the PAG region of the midbrain
- PAG is controlled by cortex and hypothalamus, which contributes to perception of pain at different times
How do anti-depressant drugs enhance descending inhibition?
They inhibit noradrenaline uptake and so increase NA concentration in the CNS (antidepressant effect) which may enhance descending inhibition produced by noradrenergic neurons in the dorsal horn
What are the key sites of action of analgesic drugs?
NSAIDS: act at the periphery
Local anaesthetics: primary afferent nerve (sensory nociceptive neuron)
Opioid analgesics: synapse at dorsal horn, PAG, cortex
Gabapentinoids, Ziconitide, antidepressants: dorsal horn
What is the definition of an opioid?
Any substance whose actions are reversed by naloxone; they act as agonists at opioid receptors
What are the cellular actions of opioids?
- all 4 receptor types are g-protein coupled
- inhibition of adenylyl cyclase and so decrease in the concentration of cyclic AMP
- activation of MAP kinase leading to changes in gene expression
- inhibition of calcium entry into nerve terminals through voltage gated channels
- activation of potassium channels and so hyper polarisation of neurons
What are the sites of actions of opioids and its effects?
- Cortex, PAG, dorsal horn
- the euphoric effects produced by opioids acting in the cortex contribute to analgesia by making the pain less troublesome
- opioids produce disinhibition within the PAG: inhibit inhibitory GABAergic neurones leading to an overall increase in excitatory output to the RVM and so enhanced descending inhibition
- opioids also produce direct inhibition of transmission through the synapse in the dorsal horn
What do opioids do in the dorsal horn of the spinal cord?
- opioids act presynaptically to inhibit the release of glutamate substance and CGRP from the sensory nerve
- act post-synaptically to hyper-polarise and therefore decrease the excitability of the projection neuron in the spinothalamic tract
What are the clinically important actions of morphine?
- analgesia: used to treat moderate to severe pain, less effective against neuropathic pain, paradoxical in some patients and cause hyperalgesia
- euphoria: state of optimism, cheerfulness and well-being, contributes to overall analgesic effect
- respiratory depression: respiratory centre in the medulla becomes less sensitive to pCO2, cause of death in overdose
- nausea and vomiting: often administered with anti-emetic
- inhibition of GI motility leading to constipation: kaolin and morphine used as treatment for diarrhoea
- contraction of gall bladder and constriction of biliary sphincter
- centrally mediated pupil
- tolerance and dependence
What are the two forms of dependence from opioid use?
Psychological: takes drug to experience its pleasurable, rewarding side effects- powerful craving
Physical: takes drug to avoid withdrawal symptoms
What is the relationship between tolerance and physical dependence?
- tolerance arises because of adaptive changes occurring to counteract the effects of prolonged exposure to opioids such as desensitisation of receptors and changes in intracellular signalling pathways
- removal of opioid leads to excessive activity seen as a withdrawal response
- symptoms of withdrawal are opposite to effects seen on administration of the drugs
What is the pharmacokinetics of morphine?
- administered orally or by injection
- glucuronidation occurs at 3- and 6-OH
- morphine-6-glucuroinide is a potent analgesic
- glucuronides excreted in urine
- plasma half-life in adults is 3-6 hours
- risk of neonatal respiratory depression if administered during childbirth
What are the main properties of NSAIDs?
they inhibit COX which produce prostanoids
- analgesic
- anti-inflammatory
- antipyretic
