Analgesic Drugs Flashcards
How do analgesic drugs act at sites of injury to reduce nociception and pain?
Decrease nociceptor sensitisation in inflammation primarily by blocking synthesis of prostaglandins
What do analgesic drugs suppress to reduce nociception and pain?
Suppress nerve conduction by blocking voltage gated Na+ channels
Suppress synaptic transmission of nociceptive signals in the dorsal horn of the spinal cord
How do analgesic drugs act to reduce nociception and pain?
Activate descending inhibitory controls
Target ion channels upregulated in nerve damage
What is the definition of an opiate?
Any substance extracted from opium or of similar structure to those in opium
What is the definition of an opioid?
Any agent that acts upon opioid receptors
What mediates supraspinal anti-nociception?
Descending pathways from the brainstem
What do brain regions involved in pain project to?
Specific brainstem nuclei
What do the neurons of the brainstem nuclei give rise to?
Efferent pathways that project to the spinal cord afferent input
What are the regions of the brain involved in supraspinal anti-nociception?
Periaqueductal grey = midbrain
Locus ceruleus = pons
Nucleus raphe magnus = medulla
What excites the periaqueductal grey?
Electrical stimulation = produces profound analgesia
Endogenous or morphine and related compounds also cause excitation
What is the function of the activated periaqueductal grey neurons?
Project to the neucleus raphe magnus and excite serotonergic and enkephalinergic neurons
Where do serotonergic and enkephalinergic neurons project to?
The dorsal horn = results in suppression of nociceptive transmission
What is the function of locus ceruleus neurons?
Project to dorsal horn and inhibit nociceptive transmission once excited
What mediates opioid action?
G protein coupled opioid receptors
Where do G protein coupled opioid receptors signal to?
Preferentially signal to Gi/o
What does preferential signalling of opioid receptors to Gi/o produce?
Inhibition of opening of voltage activated Ca2+ channels and opening of K+ channels = Gi/o betagamma subunit
Inhibition of adenylate cyclase = Gi/o alpha subunit
What are the different classes of opioid receptors?
mu, delta and kappa
Which opioid receptor is responsible for most of the analgesic action of opioids?
mu
What are some features of delta opioid receptors?
Contributes to analgesia
Activation can be proconvulsant
What are some features of kappa opioid receptors?
Contributes to analgesia at the spinal cord and peripheral level
Activation associated with sedation, dysphoria and hallucinations
What are the major adverse side effects of opioids?
Addictive, apnoea, orthostatic hypotension
What are some GI side effects of opioids?
Nausea, vomiting, constipation and increased intrabiliary pressure
What are some CNS side effects of opioids?
Confusion, euphroia, dysphoria, hallucinations, dizziness, myoclonus and hyperalgesia
How do opioids cause apnoea?
Blunt the medullary respiratory centre to CO2
Involves mu and delta receptors
How do opioids cause orthostatic hypotension?
Reduce sympathetic tone and bradycardia
Cause histamine-evoked vasodilation
How does morphine cause bronchospasm in asthmatics?
It causes mast cell degranulation
How do opioids cause GI side effects?
Have action on CTZ
Increase smooth muscle tone
Decrease motility via enteric neurons
Involves mu and delta receptors
How do opioid agonists cause analgesia?
Mainly through prolonged activation of mu receptors
In what setting is morphine used?
Acute severe pain and chronic pain
Where is morphine metabolised?
In the liver by glucuronidation at the 3 and 6 positions = yields M3G (inactive) and M6G (retains analgesic activity and excreted by kidney)
What do sustained release preparations of morphine contain?
High doses of drugs designed to be released over 12-24hrs
What are some features of diamorphine?
More lipophilic than morphine
Enters CNS rapidly when given via IV
Can be used for severe post operative pain
What is codeine?
Naturally occurring weaker opioid for mild/moderate pain
How is codeine metabolised?
Hepatic metabolism = demythylation to morphine by CYP2D6 and CYP3A4 accounts mainly for analgesia
What are the more potent semi-synthetic derivatives of codeine?
Oxycodone and hydrocodone
What are some features of codeine?
Given orally
Additional anti-diarrhoeal and antitussive effects
What are some features of fentanyl?
75-100x more potent than morphine
Given IV to provide maintenance anaesthesia
Suitable for transdermal delivery in chronic pain
When is pethidine indicated?
In acute pain = especially labour
Has rapid onset
What are some draw backs of pethidine?
Short duration so not suitable for chronic pain
Contraindicated when used with MAO inhibitors
Norpethidine is neurotoxic metabolite = causes seizures
What are some examples of opioid agonists?
Morphine, diamorphine, codeine, fentanyl, pethidine, buprenophine, tramadol, methadone
What are some features of buprenophine?
Partial agonist given by injection or sublingually
Useful in chronic pain with patient controlled injection systems
Slow onset but long duration
What are some features of tramadol?
Weak mu receptor agonist
Potentiates of descending serotonergic and adrenergic systems
Given orally
Avoid in epilepsy
What is the action of methodone?
Weak mu agonsit of phenylheptlyamine class = also acts on K+ channles, NMDA glutamate receptors and some 5-HT receptors
What is methodone used for?
Assists in withdrawl from heroin and strong opioids
What are some features of methodone?
Given orally
Long duration
Useful for chronic pain in terminal cancer
What are some examples of opioid antagonists?
Naloxone, naltrexone, alvimopan and methylnaltrexone
What is naloxone?
Competitive antagonist of mu receptor = used to reverse opioid toxicity
Why must patients on naloxone be monitored?
Naloxone has a very short half life so opioid toxicity may recur
What can naloxone trigger in addicts?
Acute withdrawl response
Why is naloxone sometimes given to newborns?
If the newborn has opioid toxicity as a result of mother being given pethidine during labour
What are some features of naltrexone?
Similar to naloxone but has advantage of oral availability and a much longer half life
What are some features of alvimopan and methylnaltrexone?
Don’t enter the CNS
Reduce GI effects of surgical and chronic opioid agonist use
What effect do NSAIDs have on nociception?
Diminish nociceptor sensitisation
What kind of pain are NSAIDs used to treat?
Mild/moderate inflammatory pain = especially ibuprofen and naproxen
What effects do non-selective NSAIDs have?
Analgesic, antipyretic and anti-inflammatory
What is the action of non-selective NSAIDs?
Largely inhibit synthesis and accumulation of prostaglandins by COX 1 and 2
What are some examples of non-selective NSAIDs?
Aspirin, ibuprofen, naproxen, diclofenac and indomethacin
What are some examples of COX 2 selective inhibitor NSAIDs?
Etoricoxib, celecoxib and lumiracoxib
What is the difference between COX 1 and COX 2?
COX 1 is constitutively active but COX 2 is induced locally at sites of inflammation by various cytokines
Inhibition of which COX by NSAIDs has the greatest therapeutic benefit?
COX 2
What effect do NSAIDs have on the activation threshold of peripheral terminals of nociceptors?
They suppress the decrease in the activation threshold that is caused by prostaglandins
What action do NSAIDs have if they cross the BBB?
Suppress the production of pain-producing prostaglandins in the dorsal horn of the spinal cord
What effect do NSAIDs have on the leukocytes that produce inflammatory mediators?
Decrease leukocyte recruitment
Why isn’t paracetamol classed as an NSAID?
It lacks anti-inflammatory activity and acts only centrally
Why do NSAIDs have limited analgesic efficacy?
Multiple pathways cause nociceptor sensitisation
Why can long term use of non-selective NSAIDs cause?
GI damage
Why can nephrotoxicity occur with NSAID use?
COX 2 inhibition is constituitively expressed by the kidney
What is a side effect of selective COX 2 inhibitors?
They are prothrombotic
What conditions cause neuropathic pain?
Trigeminal neuralgia, diabetic neuropathy, post-herpetic neuralgia and phantom limb pain
Why is neuropathic pain difficult to treat?
Doesn’t respond to NSAIDs and is relatively insensitive to opioids
What are some treatments used for neuropathic pain?
Gabapentin and pregabalin,
Amitryptyline, nortryptiline and desipramine
Carbamazepine
What are the uses of pregabalin and gabapentin?
Anti-epileptics
Gabapentin = migraine prophylaxis
Pregabalin = painful diabetic neuropathy
How do gabapentin and pregabalin treat neuropathic pain?
Reduce cell surface expression of a subunit of some voltage gated Ca2+ channels which are upregulated by damaged sensory neurons
Where do gabapentin and pregabalin decrease neurotransmitters?
The central terminals of nociceptive neurons
What class of drugs do amitryptiline, nortryptiline and despiramine belong to?
Tricyclic antidepressants
How do the tricyclic antidepressants treat neuropathic pain?
Act centrally by decreasing reuptake of noradrenaline
What effect does adding duloxetine or venlafaxine to tricyclic antidepressants have in treating neuropathic pain?
Additionally decreases reuptake of 5-HT
How does carbamazepine act?
Blocks subtypes of voltage activated Na+ channels that are upregulated in damaged nerve cells
What is carbamazepine first line for treating?
Controlling pain and intensity and frequency of attacks in trigeminal neuralgia
