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 are**highly 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 a**fter 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 conjugate**d 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 ****barrier**and**probably 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 i**n 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 esterase**s. **\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_)** is hydrolyzed to **monoacetylmorphine** and **finally to morphin**e, 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)**and**eventually 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 effect**or an**exaggerated response based on differences in metabolic conversion**. For this reason, routine use of codeine, especially in pediatric age groups, is being reconsidered.