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)
