OPIOD ANALGESICS Flashcards
ANALGESICS
pain relief
what is pain
- unpleasant sensation accompanying tissue damage that is detected and transmitted to the CNS by SOMATIC NOCICEPTIVE AFFERENT NEURONS
. alpha delta - sharp pain
. C - aches (muscle strain) - sensation that persists long after an injury // not associated with any injury NEURALGIA / PHANTOM LIMB SYNDROME
- as a result of spontaneous activation of pain mediators in CNS
how is pain sensed by the body
primary pain receptor = CALCIUM - triggers A.P
.ATP facilitates DEP entering P2X R / VG Na+ channels
. NGF - survival/health of neurons in CNS
affect expression for Trk R / upregulate expression of TRPV
(more TRPV - neuron more sensitive to pain stimuli
.GPCR - facilitate opening of TRPV//Na+
. VG K+ inhibit DEP/HYPER = limit pain sensation
. opioids/cannabinoids/NE = inhibitory effects
explain pain perception
.excitatory pathways enter DORSAL HORN of SC (both alpha delta + C afferent neurons)
. ascending tract of pain sensory network = glutamate NT
.descending tract - pain suppressor sites feeds down to gate control system
- Serotonin/ Enkephalin/ GABA = block activity of alpha delta + C afferent neurons
opioids
agonists
group of analgesic (pain relief) drugs - bind to opioid receptors
what blocks the effects of opioids
opioid antagonists
NALOXONE / NALTREXONE
opioids target neurons in both PNS + CNS
periaqueductal grey matter (midbrain)
nucleus reticularis (medulla)
= enhance pain suppressive effects of descending pathway
blocks transmission of nociceptive afferent neurons
block upward pathway of pain sensation - Dorsal horn
what kind of molecules are opioids
amphipathic
.benzene ring
. bind to GPCR (no need to get inside cells like LA)
.transmembrane receptors - external domain that binds to ligands
= get pass BBB -> CNS
(need to be hydrophobic to pass endothelial cells)
what is naloxone
competitive antagonist
similar to heroin/morphine (drugs of abuse)
3 opioid receptors
- mu (u) binds agonist MORPHINE
natural ligands: met-enkephalin, B-endorphin, dynorphin - kappa (k) bind KETOCYCLOZAINE
natural ligands: B-endorphin, dynorphin - delta (D) in VAS DEFERNS of mouse
natural ligands: met-enkephalin, leu-enkephalin B-endorphin (no clinically used drugs bind to this R)
= no serious side effects
opioids mimics the structure of naturally occurring opioid peptides
Tyr-Gly-Gly-Phe
amino acid sequence shared by leu-enkephalin, met-enkephalin, B-endorphin and dynorphin
others pain enhancing peptides fall into the class of tachykinins
opioid mechanism of action
- opioid receptors are coupled to Gi
- activation of Gi = inhibits adenylate cyclase = decreased levels of cAMP
- MAP kinase pathway also activated
immediate result = increased K+ efflux and inactivation of VG Ca2+ channels
net result: HYPERPOLARISATION of neuron + INHIBITION of NT release
pharmacokinetics
absorption, distribution, metabolism, and elimination of drugs
opioid pharmacokinetics
- rate of anesthetic effect onset is dependant on LIPID SOLUBILITY of drug *passing BBB
- most opioids metabolized > more polar + water-soluble compounds = LESS ACTIVE than original drugs
- some opioids metabolized to compounds with GREATER ACTIVITY:
CODEINE»_space; Morphine = higher affinity of (u) receptors
uses of opioids
analgesic/euphoric :
MORPHINE
FENTANYL - very potent = used with GE
OXYCODONE - post surgery/chronic moderate-severe pain
CODEINE (cough suppressant) - slowly converted to morphine (20% potency)
LOPERAMIDE - antidiarrheal activity (R on GI tract)
what is nalbuphine
antagonist of (u) receptors agonist of (D) receptors partial agonist of (k) receptors
side effect of opioids
- respiratory depression
- sedation
- constipation
- nausea
- irregular menstrual cyles/male impotence
- myosis (constriction of pupil)
- immunosuppression
- increase pain associated with gall bladder
- dysphoria (state of discomfort/unease)
what do opioid antagonists do
reduce opioid side effects
. methylnaltrexone
. used to treat constipation associated with (u) agonists
. cannot cross BBB - does not alter CNS effect of agonists
explain side effects of all the receptors
mu - affects everything except dysphoria/hallucinations
D - decrease GI movement/respiratory depression
K - causes dysphoria/hallucinations
tolerance
increasing doses of drug to produce same effect (habituation)
cross-tolerance
tolerance to one opioid often accompanied by tolerance to others
physical dependence
sudden end of long-term opioid use . increased irritability . fever .sweating .nausea . diarrhea . piloerection . hyperalgesia (increased sensitivity to pain)
what is used to treat physical addiction to morphine or heroin
METHADONE - opioid agonist - no physical dependance
psychological dependence
strong cravings for the drug for months after physical symptoms have ended
(rarely in patients who use morphine to control pain)
what receptors are key to hyperalgesia (increased sensitivity to pain)
NMDA glutamate receptors
what normally happens with opioid withdrawal and how can you prevent this
normally opioid agonist decreases pain, then when stopped = increases pain further
give antagonist = pain decreases (less) but no rebound effect when stop taking drug
how can you repackage old drugs to reduce abuse
extended-release opioids reduce maximum dose:
OxyContin - extended-release form of oycodone
crush-resistant DETERx extended-release oxycodone
= less likely to be snorted
OXN Naloxene-treated hydrocodone prevents IV administration of the crushed compound
explain the mechanism of physical dependence
.(mu) receptor expression is regulated by CREB (activator gene)
. CREB activated by cAMP
. (mu) receptor agonists bind to (mu) receptors activating Galpha i = inhibits adenylate cyclase
.decreased expression of (mu) receptors = make cells less sensitive to (mu) agonists
= need higher dose to achieve same effects
what drug prevents opioid addiction
AT-121
how does AT-121 work
bifunctional agonist = binds to both (mu) and NOP R
100x more EFFICACY than morphine
without respiratory/cardiovascular depression, sedation, inhibition of motor activity, or dependance
(pretreatment with AT-121 - prevented dependence associated with oxycodone)
