pain and analgesics Flashcards
what neruochemicals are released in the dorsal horn in response to pain?
- glutamate and substance P stimulate the pain ascending pathways
- GABA, enkephalin or endorphin block or attenuate the pain signal
what is the role of 5HT in PAG opiodergic and GABA-ergic interactions?
- hyperpolarization of afferent neurons when interacting with 5HT1 receptors
excitation in spinal GABA interneurons when interacting with 5HT3 receptors
what is the role of NA in PAG opiodergic and GABA-ergic interactions?
hyperpolarization of projection neurons when interacting with A-2A receptors and
hyperpolarization over terminals of primary afferent fibres when it interacts with a-2B/C receptors
excitation of GABA and opioid interneurons via a-1A receptors
what are the chemicals involved in pain?
glutamate- good/warning pain
substance P- intense, persistent, chronic- bad/ damage injury pain
prostaglandins- potentiate the pain of inflammation by blocking the action of glycine
what is an analgesic?
an anelgesic is any member of the group of drugs used to selectively relieve from pain without blocking the conduction of nerve impulses and markedly altering sensory perception or affecting consciousness
what does the selectively of the analgesic determine?
is an important factor in the distinction between an analgesic and a sedative or anesthetic
how does the WHO pain ladder work?
mild pain- non-opioid analgesics- acetaminophen, ibuprofen, naproxen
+- adjunctives: anticonvulsants for neuropathic pain and antidepressants or anxiolytics for coexisting mood disturbances
moderate pain:
opioid analgesics- codeine, oxycodone, hydrocodone, morphone
+- nonopioid analgesics- from prev step
+- adjunvants- from previous step
severe pain: opioid analgesics- higher doses of morphine, fentanyl, hydromorphone; OCA delivery of IV opioid
+- nonopioid analgesics- from previous steps
+- adjunvants from previous step
what does damaged tissues release?
prostaglandins, thromboxane’s and leukotrienes- potent triggers of pain
what are prostaglandins, thromboxanes and leukotrienes produced from?
arachidonic acid
what is arachidonic acid metabolised by?
COX to produce prostaglandins and thromboxanes or
by the enzyme lipozygenase to produce leukotrines
what is the role of prostaglandins?
-mediate inflammation, immune response and muscle constriction and relaxayion, as well as meyabolic activities
help regulate blood flow and play a role in the formation of blood clots
increase pain and can cause fever
what is the role of leukotrienes?
are a potent proinflammatory mediators. they are implicated in asthma and RA
what is the difference between the 3 different COX enzymes?
cox 1- constitutive enzyme, GI mucosa, kidneys and platelets
COX 2- non- constititive, induced in a limited number of tissues in response to immune and inflammatory mediators
cox 3- expressed in the brain, spinal chord and heart
associated in the mechanism of paracetamol action- controversy
how do NSAIDS work?
inhibit COX enzymes and reduce PG production
how are NSAIDS distinguished?
selective- targets COX enzyme: celecoxib, etoricoxib, rofecoxib, valdecoxib, lumiracoxib, parecocib
non- selective targets both COX 1 and 2- Ibuprofen, naproxen, diclofenac, mefenamic acid
what is acetaminophen used for?
used to treat mild- moderate pain or to reduce fever
has antipyretic and analgesic effects but no significant anti-inflammatory activity
what are endorphins?
are endogenous opioid neuropeptide and peptide hormones function as neurotransmitters, neuromodulators and in some cases as neurohormones
what are endorphins produced by?
produced by the CNS and the pituitary gland
how are endorphins divided?
enkephalins, endorphins and dynorphins
where do opioid receptors exist?
in the nervous, endocrine and immune system
what are the 4 subtypes of opioid receptors
u- MOP
d-DOP
k-KOP
nociceptin -NOP
what is morphine an agonist of?
MOP,KOP,DOP receptors- high affinity for MOP
coupled to Gi protein
what does the binding of morphine to u-opioid receptors lead to?
i) closing of voltage-sensitive calcium channels
ii) stimulation of potassium efflux leading to hyperpolarixation
iii) reduced cAMP production via inhibition of adenylyl cyclase
what is naloxone?
opioid antagonist and blocks effects of morphine]
used in OD
what two oral forms is morphine availible in?
oramorph, sevredol- normal release solution/ tablets; last 4 hours
zommorph capsules, MST tablets- last 12 hours
what are the common side effects of morphine?
confusion, nausea/ vomiting, constipation, urinary retention, euphoria, hallocination and sedatioin, pupillary constriction, hypotension, resporatory depression
how does respiratory depression occur with opioid analgesics?
benzo- produce additive CNS depressant effects
may delay the CNS depressant effect of methadone
patients can be treated with artificial ventilation or with naloxone
what is M6G and how does it work?
morphine- 6 -glucuronide is one of morphone metabolites
binds to u rec, higher affinity for d and lower for k receptors
responsible for much of pain relieving effects of morphine
can accumulate following chronic admin or in renally impaired individuals
what is M3G?
is the other morphine metabolite. it is devoid of analgesic activity
what is diamorphone?
also known as heroin- is a pro- drug which is converted to acetlymorphine and morphine
200x more lipid sol than morphine
how does the onset of diamorphine differ with route of admin?
- orally- undergoes first pass metabolism- prodrug for the systemic delivery
injected- diamorphine crosses very rapidly the BBB
how is diamorphine metabolised?
metabolised into the inactive 3MAM and the active 6-MAM and then to morphine
both morphine and 6MAM and u0opioid agonists, resullting in euphoric analgesic and anxiolytic effects
what is the effect of diamorphine on the brain?
- reduction the production of the endogenous opioids when diamorphine present
dependence on heroin
what causes the greater ‘high’ with morphine comapred to hydromorphone and oxymorphone?
produces a larger histamine release similar to morphine
instances of pruititus when used for the first time
diamorphine is associated with far more accidental overdoses and fatal positing than any other scheduled substances
what is codeine?
it is an agonist of the u and d opioid receptor with a relatively weak affinity
oral bioavailability of codeine is 50%.
about 10% of that is metabolised to morphine
what is dihydrocodeine?
is a semi-synthetic derativive of codeine with similar pharmacological effects
- selective fill agonist of MOP/ low aff for DOP and KOP receptors
what is oxycodone?
is a u-opioid receptor agonist
low affinity for the u-d- and k- opioid receptors
what are oxycodones active metabolites?
oxymorphone and noroxymorphone are active metabolites
- potent agonist of u-opioid rec
poorly cross the BBB into the CNS
both present in low conc in brain and plasma following admin
second like for moderate to severe opioid responsive pain
what is tramadol?
tramadol is synthetic analgesic agent
low affinity for opioid receptors and inhibits reuptake of NA na 5HT
what is o-desmethyltramadol
tramadol metabolite with analgesic acitivity- MOP 300x more potent
what is methadone?
synthetic opioid- used for analgesic and treatment of heroin addiction
how does methadone work?
agonist at opiid receptors- high affinity for MOP and low for others
antagonists at NMDA receptors. inhibitors of 5HT and NA reupatke
what are the methods for a transition to methadone from another opioid?
1- rapid transition- discontinuation and institution of methadone
2- slow transition- tapering previous opioid in conjection with titration of methadone dosing
what are the possibble drug interactions with methadone?
enzyme indicers
what is buprenorphine used for?
moderate-severe pain and to treat opioid dependence
what is buprenorphine an agonist/ antagonist of?
partial agonist+ hugh affinity for MOP receptor
antagonist + high affinity for DOPand KOP rec
agonist+ low affinity for the opioid- like 1 receptor
what is buprenorphine in the presence of morphine?
antagonist at MOP
what penetrates the BBB easier, buprenorphine or morphine?
buprenorphine
what receptor does buprenorphine have high affinity for?
u receptor
why is there less potential for withdrawl when buprenorphine is used for pain?
as it exhibits slower dissociation from MOP receptor
what can respiratory depression be treated with?
doxapram
what is NA?
it is an adrenoceptor
-inhibit nociceptive neurons located in the substantia gelatinosa area by activation of a2-adrenoceptors
what does NA promote?
GABA and glycine release by activation of a-1-arenoceptor located on interneurons
what does NA depress?
glutamate release by activation of a2adrenoceptors and Ad and C-fibres in the dorsal horn
what are clonidine and dexmedetomide?
a2-adrenoceptor agonists used in anesthesia and intensive care due to their sedative, ammestic, analgesic and anesthetic properties
what do a2-a -adrenoceptors serve as?
presynaptic auto-receptors and control NA release in the spinal cord
- produce analgesia when administered in LC
what do adrenoceptors do in perioperative settings?
a2 agonists are extremely valuable for the induction of anxiolysis, maintenance of sedation, management of pain and prevention of shivering
how do clonidine and dexmedetomidine work?
they limit analgesia to body regions innervated by spinal segments
they decrease anesthetic and analgesic requirements and provide sedation and anxiolysis
how do you stop clonidine?
clonidine requires tapering down from the full dosage in steps at the end of the treatment process
how are patients on dexmedetomidine withdrawed?
moved to clonidine to reduce withdrawl
