Introduction

Morphine Morpheus (the Greek god of dreams)

Relieve severe pain with remarkable efficacy.
Friedrich Serturner in 1803 isolated the pure
alkaloid from opium poppy.
It remains the standard against which all drugs that
have strong analgesic action are compared.
Collectively known as "opioid analgesics" and
include not only the natural & semisynthetic alkaloid
derivatives from opium but also include synthetic
surrogates, other opioid-like drugs whose actions
are blocked by the nonselective antagonist
naloxone, plus several endogenous peptides that
interact with the several subtypes of opioid
receptors.

Source

Incision of the poppy seed pod reveals a white

substance that turns into a brown gum that is crude
opium. Opium contains many alkaloids, the principle
one being morphine which is present in a
concentration of about 10%. Codeine is synthesized
commercially from morphine.

Classification & Chemistry

Opioid drugs:
Full agonists Morphine is a full agonist at the receptor
Partial agonists Codeine (weak receptor agonists)
Antagonists Naloxone

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 receptor antagonist.

Some opioids (nalbuphine) are capable of producing

an agonist (or partial agonist) effect at one opioid
receptor subtype and an antagonist effect at another.
Not only can the activating properties of opioid
analgesics be manipulated by pharmaceutical
chemistry, certain opioid analgesics are modified in
the liver resulting in compounds with greater
analgesic action

Endogenous Opioid Peptides

Opioid alkaloids (eg, morphine) produce analgesia

through actions at regions in the brain that contain

peptides which have opioid-like pharmacologic
properties. The general term currently used for these
endogenous substances is endogenous opioid
peptides, which replaces the previous term
endorphin.

The best-characterized of the opioid peptides

possessing analgesic activity are
Pentapeptides methionine-enkephalin (metenkephalin)
Leucine-enkephalin (leu-enkephalin).

These endogenous opioid peptides are derived from

three precursor proteins:
Prepro-opiomelanocortin (POMC)
POMC contains the met-enkephalin sequence, -endorphin,

and several nonopioid peptides, including ACTH, -lipotropin,

and melanocyte-stimulating hormone
preproenkephalin (proenkephalin A)
Preproenkephalin contains six copies of met-enkephalin and

one copy of leu-enkephalin

Preprodynorphin (proenkephalin B).

Preprodynorphin yields several active opioid

peptides that contain the leu-enkephalin

sequence.
These are dynorphin A, dynorphin B and &
neoendorphins

More recently, the endogenous peptides

endomorphin-1 and endomorphin-2, have been found
to possess many of the properties of opioid peptides,
notably analgesia and high affinity binding to the
receptor.
Current research is focused on whether
endomorphins selectively activate receptor subtype

Endogenous opioid precursor molecules and the

endomorphins are present at central nervous system
(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 to diminish the sensation of noxious stimuli.

Pharmacokinetics

Absorption
Most opioid analgesics are well absorbed when
given by subcutaneous, intramuscular & oral
routes.
Because of the first-pass effect, the oral dose of
the opioid (eg, morphine) may need to be much
higher than the parenteral dose to elicit a
therapeutic effect.

Interpatient variability exists in first-pass opioid

metabolism prediction of an effective oral dose
difficult.
Certain analgesics (codeine & oxycodone) are
effective orally because they have reduced firstpass metabolism, which is primarily due to a
methyl group on their aromatic hydroxyl group.

Nasal insufflation of certain opioids can result in rapid

therapeutic blood levels by avoiding first-pass
metabolism.
Other routes of opioid administration include oral mucosal
and the application of transdermal patches, which can
provide delivery of potent analgesics over days.

Distribution
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
(brain, lungs, liver, kidneys & spleen).

Drug concentrations in skeletal muscle may be much lower,

but this tissue serves as the main reservoir because of its
greater bulk.
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.

Metabolism
The opioids are converted in large part to polar

metabolites (mostly glucuronides), which are then

readily excreted by the kidneys
Morphine (which contains free hydroxyl groups) is primarily

conjugated to morphine-3-glucuronide (M3G), a compound

with neuroexcitatory properties.
approximately 10% of morphine is metabolized to morphine-6glucuronide (M6G), an active metabolite with greater analgesic
potency than morphine

In patients with renal failure / when exceptionally large

doses of morphine are administered:
M3G-induced CNS excitation (seizures) or enhanced
and prolonged opioid action produced by M6G
Hydromorphone is metabolized to hydromorphone-3glucuronide (H3G), which has CNS excitatory
properties

Esters (eg, heroin, remifentanil) are rapidly

hydrolyzed by common tissue esterases.
Heroin (diacetylmorphine) is hydrolyzed to
monoacetylmorphine and finally to
morphine, which is then conjugated with
glucuronic acid

Phenylpiperidine opioids (fentanyl, alfentanil,

sufentanil) Hepatic oxidative metabolism
is the primary route of degradation.
Eventually leaves only small quantities of the
parent compound unchanged for excretion.

The P450 isozyme CYP3A4 metabolizes fentanyl by Ndealkylation in the liver.

CYP3A4 is also present in the mucosa of the small intestine &

contributes to the first-pass metabolism of fentanyl when it is

taken orally

Codeine, oxycodone & hydrocodone undergo metabolism

in the liver by CYP2D6, resulting in the production of
metabolites of greater potency.

Genetic polymorphism of CYP2D6 has been

documented and linked to the variation in
analgesic response seen among patients

Accumulation of a demethylated metabolite of

meperidine, normeperidine, may occur in patients
with decreased renal function or those receiving
multiple high doses of the drug. In sufficiently high
concentrations, normeperidine may cause seizures.

Excretion
Polar metabolites, including glucuronide conjugates of

opioid analgesics, are excreted mainly in the urine.

Small amounts of unchanged drug may also be found in the
urine.
Glucuronide conjugates are also found in the bile, but
enterohepatic circulation represents only a small portion of
the excretory process.

Pharmacodynamics
Mechanism of Action
Opioid agonists produce analgesia by binding
to specific G protein-coupled receptors, located
primarily in brain & spinal cord regions involved
in the transmission & modulation of pain.

Receptor Types
three major classes of opioid receptors , dan
All are members of the G protein-coupled family of
receptors and show significant amino acid sequence
homologies
Multiple receptor subtypes 1, 2, 1, 2, 1, 2,
& 3.