Opioids Flashcards
Opiate
drug derived from opium, mixture of compounds from poppy, Papaver somniferum
Opioid
drug not derived from opium but interactions with opioid R
o Prototypical analgesics, antitussives, antidiarrheal drug class
Opioid R system/opiod R effects identified in:
ascarids, scallops, fish, reptiles, birds, mammals
Variants of MOR
o Alternative splicing may produce differences in structure, function of R despite R produced from same gene
o Single nucleotide polymorphism identified in dogs may also increase diversity in R structure, function –> altered drug effects
SNP identified with high prevalence in dogs experienced dysphoria with opioid admin
Different sensitivities to opioids may be due in part to individual differences in types of MOR subtypes
Nociception/ orphanin FQ receptor
Often called N/OFQ [NOP] receptor
Significant homology to other ORs
Naloxone hydrochloride does not have significant antagonistic action at R
* N/OFQ[NOP] R investigated, but details of interactions of endogenous ligand with R not well described
Antagonists of N/OFQ [NOP] produce analgesia
* May be target for future development of analgesics, analgesic adjuncts
MOR endogenous ligand
Beta-Endorphin
DOR endogenous ligand
Dynorphin A
KOR Endogenous Ligands
leucine, methionine-enkephalin
Full Agonist
dose-dependent increase in effect until maximal stimulation of R achieved
Y axis of dose response curve
Partial Agonist
dose-dependent increase in effect, plateaus at maximum effect less than maximum effect of full agonist
Can act as antagonist by partially reversing effects of full agonist
May be preferred over full antagonist if some analgesia needed
Antagonist
binds to R with high affinity, produces no effect, inhibits binding of agonists (both endogenous, exogenous) DT greater R affinity of antagonist
Also displaces previously bound agonists
Most opioid R antagonists considered competitive
* Lack of intrinsic activity, ability of agonists to overcome effect to produce maximal effect
* Shifts dose-response curve right
Potency
How much drug required for 50% Emax? (x axis on dose response curve)
Response = analgesia measured as change in latency of withdrawal or increased threshold to noxious stimulus
Fentanyl > morphine: dose of fentanyl (0.01mg/kg) needed to produce equivalent analgesia response to morphine (1mg/kg) is lower
Location of OR in Higher Centers
o Brain, brainstem: neurons, microglia, astrocytes
Periaqueductal grey
Locus coeruleus
Rostral ventral medulla
CRTZ/vomiting center
Location of OR in SC
o SC: lamina II of DH (substania gelatinosa); Adelta, C fibers synapse with projection neurons
Neurons, microglia
Conflicting evidence about astrocytes
Other Sites of ORs
o GIT
o Synovium
o UT
o Leukocytes
Immune cells can actually synthesize opioid peptides
o Uterus
o Periphery: neuronal, non-neuronal cells immune cells, periphery sensory neurons (A and C fibers)
o Others
Opioid R MOA
GPCR via Gi/o
Inhibition of AC
Decreased formation of cAMP
Inhibition of Ca2+ channels in presynaptic neurons resulting in decreased release of excitatory neurotransmitters (glutamate and substance P)
Enhanced outflow of K from postsynaptic neurons - increased activation thresholds, hyper polarization of nociceptive neurons/nociceptors
Functions Mediated by MOR
-Analgesia (+KOR, DOR)
-Antidiuresis
-Decreased biliary secretions, GI motility (+KOR), GI secretions (+KOR)
-Decreased urine voiding reflex
-Emesis/antiemesis (drug specific)
-Euphoria
-Immunomodulation (+DOR)
-Increased appetite (+KOR, DOR)
-Decreased uterine contraction
-Miosis/mydriasis (species specific) (+KOR)
-Resp Depresson
-Sedation (+KOR)
Functions Mediated by KOR
–Analgesia (+MOR, DOR)
–Decreased GI motility, GI secretions (+MOR)
–Diuresis via inhibition of ADH release
–Increased appetite (+DOR, MOR)
–Miosis, mydriasis (species specific) (+MOR)
–Sedation (+MOR)
Functions Mediated by DOR
–Analgesia (+MOR, KOR)
–Immunomodulation (+MOR)
–Increased appetite (MOR, KOR)
Absorption of Opioids
Lipophilic Compounds - typically well absorbed SC, IM; rapid absorption
Unless SR formulas used, prolonged effect vs IV not typically expected from IM or SC admin
Oral Absorption
PO: usually substantial first-pass metabolism so low PO bioavailability, may be ineffective when admin PO at standard doses
Exception: drugs that can produce active metabolites, eg codeine in humans
First Pass Metabolism
Drugs absorbed from GIT, usually following PO admin
Drugs pass through mucosa –> intestinal metabolizing enzymes (both Phase I metabolic reactions, Phase II conjugation reactions) biotransformation drug before enters intestinal capillary system
If enters intestinal capillaries intact, enters portal vein/liver site of metabolism
Any drug that makes it through the liver intact can enter systemic circulation, be distributed to elicit effect
* Despite large fraction of opioid absorbed, relatively small amt enters systemic circulation in active form where interactions with R elicit effect
Benefit of Transdermal Administration
–Bypasses first-pass metabolism
–Stratum corneum presents substantial barrier to drug absorption for some drugs
–Ex: Zobrium for cats, fentanyl patches/transdermal solution dogs
Transmucosal Opioids
bypasses first-pass metabolism
Mucosa: thinner, more vascular than stratum corneum –> less of a barrier
Buprenorphine = lipophilic, only effective if not swallowed
* Viable route of admin in cats but still somewhat variable due to conditions (eg pH) that can alter chemical properties
Absorption of TM buprenorphine in dogs small: may not be practical route of delivery DT volume, cost limitations