MOD 6- OPIOD Flashcards
_________, the prototypical opioid agonist, has long been known to
relieve severe pain with remarkable efficacy
Morphine
What is the source of morphine?
Source
Opium, the source of morphine, is obtained from the poppy,
Papaver somniferum and P album.
After incision, the poppy seed
pod exudes a white substance that turns into a brown gum that is
crude opium.
Opium contains many alkaloids, the principal one
being morphine, which is present in a concentration of about
10%.
“So morphine is alkaloid”
_____________is synthesized commercially from morphine.
Codeine
Classification and Chemistry
Opioid drugs include__________, ______ and_________
- ** full** agonists,
- partial agonists,
- and antagonists.
Morphine is a full agonist at the___________
the major analgesic opioid receptor
µ (mu)-opioid receptor,
major analgesic opioid receptor
Morphine
TABLE 31–1 Opioid receptor subtypes, their
functions, and their endogenous
peptide affinities.
µ ( mu ) functions
- Supraspinal and spinal analgesia;
- sedation
- ; inhibition of respiration;
- slowed gastrointestinal transit; (same with kappa)
- modulation of hormone and neurotransmitter release (Same with delta )
μ (mu)
Endogenous
Opioid Peptide
Affinity
Endorphins >** enkephalins > dyno**rphins
**ENDo( ending the pain) > enKep( keep the pain) > DYNo (DYing) **
δ (delta)
Functions
- Supraspinal and spinal analgesia; ( same to all)
- modulation of hormone and neurotransmitter release ( same to mu)
κ (kappa)
FUNCTIONS
- Supraspinal and spinal analgesia; (same mu)
- psychotomimetic
- effects; slowed gastrointestinal transit ( same mu)
δ (delta)
Endogenous
Opioid Peptide
Affinity
Enkephalins >endorphins and dynorphins
“DELTA( DEaLT by KEpt) EnKEP
κ (kappa)
Endogenous
Opioid Peptide
Affinity
Dynorphins > >
endorphins and
enkephalins
Kappa ng DYNOsaur
In contrast,
codeine functions as a_____________
partial (or “weak”) μ-receptor agonist
Simple substitution of an allyl group on the nitrogen of
the full agonist morphine plus addition of a single hydroxyl group
results in___________a strong μ-receptor antagonist
naloxone,
Some
- *opioids**, eg, __________are capable of producing an agonist (or
- *partial agonist)** effect at one opioid receptor subtype and an
- *antagonist effect at another.**
nalbuphine,
The receptor activating properties and
affinities of opioid analgesics can be manipulated by pharmaceutical
chemistry;in addition, certain opioid analgesics are modified in the
__________, resulting in compounds with greater analgesic action.
in the liver
- *Opioid alkaloids (eg, morphine**) produce analgesia through
- *actions at receptors in the central nervous system (CNS)** that
- *respond to certain endogenous peptides** with **opioid-like pharmacologic
properties. **
Endogenous Opioid Peptides
The general term currently used for these
endogenous substances is _______________
endogenous opioid peptides.
Three families of endogenous opioid peptides have been
described in detail: the_________, __________ and ___________
The three
families of opioid receptors have overlapping affinities for these
endogenous peptides
- endorphins,
- the pentapeptide enkephalins methionine-enkephalin (met-enkephalin) and leucineenkephalin(leu-enkephalin)
- ** dynorphins.**
The endogenous opioid peptides are derived from **three precursor **proteins: ____________, _________ and _____________
- prepro-opiomelanocortin (POMC),
- preproenkephalin (proenkephalin A),
- and preprodynorphin (proenkephalin B).
The endogenous peptides
_________ and ___________ also possess many of the
properties of opioid peptides, notably analgesia and high-affinity
binding to the μ receptor.
endomorphin-1 and endomorphin-2
Note : Endomorphin-1 and -2 selectively activate
central and peripheral μ-opioid receptors but much about them
remains unknown, including the identity of their preproendomorphin
gene.
Both the endogenous opioid precursor molecules and the
endomorphins are present at CNS sites that have been implicated in
_____________
pain modulation.
Evidence suggests that they can be released during
stressful conditions such as pain or the anticipation of pain and
diminish the sensation of noxious stimuli
Evidence suggests that they can be released during
stressful conditions such as pain or the anticipation of pain and
diminish the sensation of noxious stimuli
This elevated dynorphin level is
proposed to increase pain and induce a state of long-lasting hyperalgesia.
Most opioid analgesics are well absorbed when given by subcutaneous,
intramuscular, and oral routes.
subcutaneous,
intramuscular, and oral routes.
However, because of the
______________ the oral dose of the opioid (eg, morphine) may
need to be much higher than the parenteral dose to elicit a therapeutic
effect.
Considerable interpatient variability exists in firstpass
opioid metabolism, making prediction of an effective oral
dose difficult.
first-pass effect,
Certain analgesics such as _______________
are effective orally because they have reduced first-pass metabolism.
codeine and oxycodone
Nasal insufflation of certain opioids can result in rapid
therapeutic blood levels by _________________________
avoiding first-pass metabolism.
Other
routes of opioid administration include oral mucosa via__________
and transdermal via transdermal patches.
lozenges,
What rou te of administration can provide
delivery of potent analgesics over days.
Recently an iontophoretic
transdermal system has been introduced, allowing needle-free
delivery of fentanyl for patient-controlled analgesia.
transdermal patch
The uptake of opioids by various organs and tissues is a function
of both _______ and ____________
physiologic and chemical factors.
Although all opioids
bind to plasma proteins with varying affinity, the drugs rapidly
leave the blood compartment and localize in highest concentrations in tissues that arehighly perfused such as the __________.
brain, lungs,liver, kidneys, and spleen
Drug concentrations in ___________
may be much lower, but this tissue serves as the main reservoir
because of its greater bulk.
skeletal muscle
Even though blood flow to fatty tissue
is much lower than to the highly perfused tissues, accumulation can be very important, particularly after frequent high-dose
administration or continuous infusion of highly lipophilic opioids
that are slowly metabolized, eg_______________
, fentanyl.
The opioids are converted in large part to polar metabolites
(mostly glucuronides), which are then readily excreted by the
kidneys.
The opioids are converted in large part to polar metabolites
- *(mostly ____________)**, which are then **readily excreted by the
kidneys. **
glucuronides)
For example, morphine, which contains free hydroxyl
groups, is primarily conjugated to____________, a compound with neuroexcitatory properties.
morphine-3-glucuronide
(M3G)
The neuroexcitatory
effects of M3G do not appear to be mediated by
μ receptors but rather by the _______________
GABA/glycinergic system
In contrast,
approximately 10% of morphine is metabolized to________________, an active metabolite with analgesic potency four to six times that of its parent compound.
However, these
relatively polar metabolites have limited ability to cross the bloodbrain **barrierandprobably do not contribute significantly to the
usual CNS effects of morphine given acutely.**
** morphine-
6-glucuronide (M6G)**
Nevertheless, accumulation of M3G or
M6G may produce unexpected adverse
effects in patients with renal failure or when exceptionally large
doses of morphine are administered or high doses are administered
over long periods.
This can result in ____________
- M3G-induced CNS excitation(seizures) or
- enhanced and prolonged opioid action produced by M6G
CNS uptake of M3G and, to a lesser extent, M6G can
be enhanced by co-administration with_____________or with drugs
that inhibit the P-glycoprotein drug transporter
probenecid
Like morphine,
hydromorphone is metabolized by conjugation, yielding hydromorphone-
3-glucuronide (H3G), which has CNS excitatory
properties. However, hydromorphone has not been shown to form
significant amounts of a 6-glucuronide metabolite.
The effects of these active metabolites should be considered in
patients with renal impairment before the administration of morphine
or hydromorphone, especially when given at high doses.
Esters (eg, heroin, remifentanil) are rapidly hydrolyzed by
common tissue esterases.
___________________) is hydrolyzed
to monoacetylmorphine and finally to morphine, which is then
conjugated with glucuronic acid.
Heroin (diacetylmorphine
______________is the primary route of degradation
of the phenylpiperidine opioids (meperidine, fentanyl, alfentanil,
sufentanil)andeventually leaves only small quantities of the
parent compound unchanged for excretion.
However, accumulation
of a demethylated metabolite of meperidine, normeperidine,
may occur in patients with decreased renal function and in those
receiving multiple high doses of the drug
Hepatic oxidative metabolism
. In high concentrations,
____________________ may cause seizures
normeperidine
The P450 isozyme CYP3A4 metabolizes____________l by N -dealkylation in the liver.
fentany
CYP3A4 is
also present in the mucosa of the small intestine and contributes
to the first-pass metabolism of fentanyl when it is taken orally.
_________________ undergo metabolism in
the liver by P450 isozyme CYP2D6, resulting in the production
of metabolites of greater potency.
Codeine, oxycodone, and hydrocodone
Genetic polymorphism of CYP2D6 has
been documented and linked to the variation in analgesic response
seen among patients.
However, oxycodone and its
metabolites can accumulate under conditions of renal failure and
have been associated with prolonged action and sedation
In the
- *case of codeine**, conversion to morphine may be of greater importance because codeine itself has relatively low affinity for opioid
- *receptors.**
As a result, patients may experience either no significant
analgesic effector anexaggerated response based on differences in
metabolic conversion.
For this reason, routine use of codeine,
especially in pediatric age groups, is being reconsidered.
