MOD 6- OPIOD

Question 1

_________, the prototypical opioid agonist, has long been known to
relieve severe pain with remarkable efficacy

Answer 1

Morphine

Question 2

What is the source of morphine?

Answer 2

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”

Question 3

_____________is synthesized commercially from morphine.

Answer 3

Codeine

Question 4

Classification and Chemistry

Opioid drugs include__________, ______ and_________

Answer 4

• ** full** agonists,
• partial agonists,
• and antagonists.

Question 5

Morphine is a full agonist at the___________
the major analgesic opioid receptor

Answer 5

µ (mu)-opioid receptor,

Question 6

major analgesic opioid receptor

Answer 6

Morphine

Question 7

TABLE 31–1 Opioid receptor subtypes, their
functions, and their endogenous
peptide affinities.

µ ( mu ) functions

Answer 7

• Supraspinal and spinal analgesia;
• sedation
• ; inhibition of respiration;
• slowed gastrointestinal transit; (same with kappa)
• modulation of hormone and neurotransmitter release (Same with delta )

Question 8

μ (mu)

Endogenous
Opioid Peptide
Affinity

Answer 8

Endorphins >** enkephalins > dyno**rphins

**ENDo( ending the pain) > enKep( keep the pain) > DYNo (DYing) **

Question 9

δ (delta)

Functions

Answer 9

• Supraspinal and spinal analgesia; ( same to all)
• modulation of hormone and neurotransmitter release ( same to mu)

Question 10

κ (kappa)

FUNCTIONS

Answer 10

• Supraspinal and spinal analgesia; (same mu)
• psychotomimetic
• effects; slowed gastrointestinal transit ( same mu)

Question 11

δ (delta)

Endogenous
Opioid Peptide
Affinity

Answer 11

Enkephalins >endorphins and dynorphins

“DELTA( DEaLT by KEpt) EnKEP

Question 12

κ (kappa)

Endogenous
Opioid Peptide
Affinity

Answer 12

Dynorphins > >
endorphins and
enkephalins

Kappa ng DYNOsaur

Question 13

In contrast,
codeine functions as a_____________

Answer 13

partial (or “weak”) μ-receptor agonist

Question 14

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

Answer 14

naloxone,

Question 15

Some

• *opioids**, eg, __________are capable of producing an agonist (or
• *partial agonist)** effect at one opioid receptor subtype and an
• *antagonist effect at another.**

Answer 15

nalbuphine,

Question 16

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.

Answer 16

in the liver

Question 17

• *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. **

Answer 17

Endogenous Opioid Peptides

Question 18

The general term currently used for these
endogenous substances is _______________

Answer 18

endogenous opioid peptides.

Question 19

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

Answer 19

1. endorphins,
2. the pentapeptide enkephalins methionine-enkephalin (met-enkephalin) and leucineenkephalin(leu-enkephalin)
3. ** dynorphins.**

Question 20

The endogenous opioid peptides are derived from **three precursor **proteins: ____________, _________ and _____________

Answer 20

1. prepro-opiomelanocortin (POMC),
2. preproenkephalin (proenkephalin A),
3. and preprodynorphin (proenkephalin B).

Question 21

The endogenous peptides
_________ and ___________ also possess many of the
properties of opioid peptides, notably analgesia and high-affinity
binding to the μ receptor.

Answer 21

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.

Question 22

Both the endogenous opioid precursor molecules and the
endomorphins are present at CNS sites that have been implicated in
_____________

Answer 22

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

Question 23

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

Question 24

This elevated dynorphin level is
proposed to increase pain and induce a state of long-lasting hyperalgesia.

Question 25

Most opioid analgesics are well absorbed when given by subcutaneous,
intramuscular, and oral routes.

Answer 25

subcutaneous,
intramuscular, and oral routes.

Question 26

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.

Answer 26

first-pass effect,

Question 27

Certain analgesics such as _______________
are effective orally because they have reduced first-pass metabolism.

Answer 27

codeine and oxycodone

Question 28

Nasal insufflation of certain opioids can result in rapid
therapeutic blood levels by _________________________

Answer 28

avoiding first-pass metabolism.

Question 29

Other
routes of opioid administration include oral mucosa via__________
and transdermal via transdermal patches.

Answer 29

lozenges,

Question 30

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.

Answer 30

transdermal patch

Question 31

The uptake of opioids by various organs and tissues is a function
of both _______ and ____________

Answer 31

physiologic and chemical factors.

Question 32

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 __________.

Answer 32

brain, lungs,liver, kidneys, and spleen

Question 33

Drug concentrations in ___________
may be much lower, but this tissue serves as the main reservoir
because of its greater bulk.

Answer 33

skeletal muscle

Question 34

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_______________

Answer 34

, fentanyl.

Question 35

The opioids are converted in large part to polar metabolites
(mostly glucuronides), which are then readily excreted by the
kidneys.

Question 36

The opioids are converted in large part to polar metabolites

• *(mostly ____________)**, which are then **readily excreted by the
  kidneys. **

Answer 36

glucuronides)

Question 37

For example, morphine, which contains free hydroxyl
groups, is primarily conjugated to____________, a compound with neuroexcitatory properties.

Answer 37

morphine-3-glucuronide

(M3G)

Question 38

The neuroexcitatory
effects of M3G do not appear to be mediated by
μ receptors but rather by the _______________

Answer 38

GABA/glycinergic system

Question 39

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.**

Answer 39

** morphine-
6-glucuronide (M6G)**

Question 40

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 ____________

Answer 40

1. M3G-induced CNS excitation(seizures) or
2. enhanced and prolonged opioid action produced by M6G

Question 41

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

Answer 41

probenecid

Question 42

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.

Question 43

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.

Question 44

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.

Answer 44

Heroin (diacetylmorphine

Question 45

______________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

Answer 45

Hepatic oxidative metabolism

Question 46

. In high concentrations,
____________________ may cause seizures

Answer 46

normeperidine

Question 47

The P450 isozyme CYP3A4 metabolizes____________l by N -dealkylation in the liver.

Answer 47

fentany

Question 48

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.

Question 49

_________________ undergo metabolism in
the liver by P450 isozyme CYP2D6, resulting in the production
of metabolites of greater potency.

Answer 49

Codeine, oxycodone, and hydrocodone

Question 50

Genetic polymorphism of CYP2D6 has
been documented and linked to the variation in analgesic response
seen among patients.

Question 51

However, oxycodone and its
metabolites can accumulate under conditions of renal failure and
have been associated with prolonged action and sedation

Question 52

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.