Professional Documents
Culture Documents
Chapter - 31 - Opioid - Analgesics - Antagonist - PDF Filename UTF-8''Chapter 31 Opioid Analgesics & Antagonist
Chapter - 31 - Opioid - Analgesics - Antagonist - PDF Filename UTF-8''Chapter 31 Opioid Analgesics & Antagonist
Maribojo, Jr Morphine
Chapter 31 Opioid Analgesics & Antagonists Full agonist at the opioid receptor
Simple substitution of an allyl group on the nitrogen
INTRODUCTION Codeine
What are analgesics? Partial (or "weak") receptor agonist.
Substances employed for their ability to reduce the perception of Naloxone
pain impulses by the CNS Strong antagonist at receptor
Simple substitution of an allyl group on the nitrogen plus addition
Terminology: of a single OH group
Opioid Nalbuphine
All compounds related to opium Capable of producing an agonist (or partial agonist) effect at one
Opiates opioid receptor subtype and an antagonist effect at another
Drugs derived from opium
Narcotic III Endogenous Opioid Peptides
“Stupor”, substance with abuse or addictive potentials Naturally occuring ligands for opioid receptors
Three families of endogenous opioid peptides with their precursor proteins
Opioid analgesics have been described in detail:
Natural and semisynthetic alkaloid derivatives from opium Endorphins
Synthetic surrogates o Prepro-opiomelanocortin (POMC)
Opiod like drugs whose actions are blocked by naloxone Enkephalins
Endogenous peptides that interact with opioid receptors o Preproenkephalin (proenkephalin A)
methionine-enkephalin (met-enkephalin)
Morphine leucine-enkephalin (leu-enkephalin)
Prototypical opioid agonist Dynorphins
Standard against which all drugs with strong analgesic action are o Preprodynorphin (proenkephalin B)
compared
Relieve severe pain with remarkable efficacy POMC
Pure alkaloid, naming it after Morpheus, the Greek god of dreams Contains the met-enkephalin sequence, β-endorphin, and several
nonopioid peptides, including adrenocorticotropic hormone
Opium poppy (ACTH), β-lipotropin, and melanocyte-stimulating hormone
Source of crude opium from which isolated morphine
Preproenkephalin
Naloxone Contains six copies of met-enkephalin and one copy of leu-
Nonselective antagonist enkephalin
Blocked the action opioid analgesic and other opioid-like drugs Leu- and met-enkephalin have slightly higher affinity for the
(delta) than for the opioid receptor
BASIC PHARMACOLOGY OF THE OPIOID ANALGESICS
I Source of Morphine Preprodynorphin
Opium is obtained from the poppy Yields several active opioid peptides that contain the leu-
o Papaver somniferum and P album enkephalin sequence:
Crude opium o Dynorphin A
o After incision, the poppy seed pod exudes a white o Dynorphin B
substance that turns into a brown gum o α and β neoendorphins
Opium contains many alkaloids, the principle one being
morphine, which is present in a 10 % concentration Additional family: Endomorphin-1 and endomorphin-2
Codeine is synthesized commercially from morphine Unknown mechanism
Possess many of the properties of opioid peptides, notably
II Classification & Chemistry analgesia and high-affinity binding to the receptor.
A. Spectrum of clinical use Selectively activate central and peripheral -opioid receptors
o Analgesics
o Antitussives “Both the endogenous opioid precursor molecules and the endomorphins
o Antidiarrheal are present at CNS sites that have been implicated in pain modulation. “
B. Strength of analgesia Suggests that they can be released during stressful conditions
o Strong such as pain or the anticipation of pain and diminish the sensation
o Moderate of noxious stimuli
o Weak
C. Ratio of agonist to antagonist Dynorphin A
o Agonists An analgesic action through its binding to (kappa) opioid receptors
o Antagonist “controversial”
o Mixed agonist-antagonis Found in the dorsal horn of the spinal cord
o Role in the sensitization of nociceptive
neurotransmission.
Opiod drugs
o Increased levels can be found in the dorsal horn after
tissue injury and inflammation
Agonist Partial agonist Antagonist Proposed to increase pain and induce a
(Morphine) (Codeine) (Naloxone) state of long-lasting hyperalgesia.
Appears to be independent of the opioid receptor system but
Certain opioid analgesics are modified in the liver, resulting in dependent on the activation of the bradykinin receptor
compounds with greater analgesic action Can bind and activate the N -methyl-D-aspartate (NMDA) receptor
Opioids derived from opium are phenanthrene derivatives and complex
include four or more fused ring
Most of the synthetic opioids are simpler molecules
Receptores types Opioid motif – Tyr-Gly-Glu-Phe-(Met or Leu)
I Classic Receptor Selected Endogenous Opioid Peptides
All are members of the G protein-coupled family of receptors and Leu-enkephalin Tyr-Gly-Glu-Phe-Leu
show significant amino acid sequence homologies. Met-enkephalin Tyr-Gly-Glu-Phe-Met
Dynorphin A Tyr-Gly-Glu-Phe-Leu-Arg-Arg-Ile….
Mu receptors Dynorphin B Tyr-Gly-Glu-Phe-Leu-Arg-Arg-Gln….
Mediate supraspinal and spinal analgesia, sedation, respiratory α neoendorphins Tyr-Gly-Glu-Phe-Leu-Arg-Lys-Try-
depression and physical dependence, miosis, and reduced GI Pro-Lys
motility, modulation of hormone and neurotransmitter release β neoendorphins Tyr-Gly-Glu-Phe-Leu-Arg-Lys-Try-Pro
Subtypes μ 1 , μ 2 β3 endorphin Tyr-Gly-Glu-Phe-Met-Thr…..
o μ 1 – supraspinal and spinal analgesia Novel Endogenous Opioid related Peptides
o μ 2 – mediate respirator depression Orphanin FQ/Nociceptin Phe-Gly-Gly-Phe-Thr…..
Enkephalins and endorphins are endogenous ligands
Morphine is an exogenous ligand PHARMACOKINETICS
Endorphins > Enkephalins > Dynorphins Absorption
Most opioid are well absorbed when given by subcutaneous,
Delta receptors intramuscular, and oral routes
Mediate supraspinal and spinal analgesia, dysphoria, o Considerable interpatient variability in the first pass
psychotomimetic effects (eg hallucination), respirator and effect
vasomotor stimulation caused by drugs with antagonist activity Unable to predict effective oral dose
Subtypes δ 1 , δ 2 Oral dose of the opioid (eg, morphine) may need to be much
Enkephalins are endogenous ligands higher than the parenteral dose to elicit a therapeutic effect due
Morphine is an exogenous ligand to first pass effect.
Enkephalins>> Endorphins & Dynorphins Morphine, hydromorphone, oxymorphone undergo extensive first
pass effect
Kappa receptors Certain analgesics such as codeine and oxycodone are effective
Mediate supraspinal and spinal analgesia, psychotomimetic orally because they have reduced first-pass metabolism
effects (eg hallucination), slowed GI transits Nasal insufflation of certain opioids can result in rapid therapeutic
Subtypes κ 1 , κ 2 , and κ 3 blood levels by avoiding first-pass metabolism.
o κ 1 – mediates spinal analgesia Other routes of opioid administration include oral mucosa via
o κ 2 - unknown lozenges, and transdermal via transdermal patches
o κ 3- mediates supraspinal analgesia
Dynorphins are endogenous ligands Distribution
Morphine is an exogenous ligands All opioids bind to plasma proteins with varying affinity
Dynorphins >> Endorphins and Enkephalins o Rapidly leave the blood compartment and localize in
Propsed to mediate a sedation analgesia with reduced addiction highest concentrations in tissues that highly perfused
liability and respiratory depression Brain, lungs, liver, kidneys, and spleen
o Respiratory depression and miosis may be less severe Drug concentrations in skeletal muscle may be much lower
with κ agonists o Serves as the main reservoir because of its greater
bulk.
Summary Tables Blood flow to fatty tissue is much lower than to the highly
Receptor Functions Endogenous Opioid Peptide perfused tissues
Subtype Affinity o very important of accumulation after frequent high-
(Mu) Sedation Endorphins > enkephalins > dynorphins dose administration or continuous infusion of highly
Inhibition of respiration lipophilic opioids that are slowly metabolized, eg,
Modulation of hormone fentanyl
Neurotransmitter release Cross the placental barrier
(Delta) Modulation of hormone Enkephalins > endorphins and dynorphins
Neurotransmitter release Metabolism
(Kappa) Psychotomimetic effects Dynorphins > > endorphins and enkephalins The opioids are converted in large part to polar metabolites
All Receptor subtypes functions as supraspinal and spinal analgesia (mostly glucuronides), which are then readily excreted by the
Mu & Kappa subtypes also functions as slowed gastrointestinal transit kidneys
A. Conjugation in the liver by UDP-glucuranosyltransfereases
II Non Classic Receptors B. Hydrolysis by common tissue esterases
C. Hepatic oxidative metabolis by CYP3A4, CYP2D6
ORL1 (orphanin opiod like subtype 1), also known as NOP
Conjugation in the liver by UDP-glucuranosyltransfereases
Orphanin FQ/Nociceptin
Novel receptor-ligand system homologous to the opioid peptides
o Receptors: G protein-coupled orphanin opioid-receptor-
like subtype 1 (ORL1)
o Ligand: Nociceptin/Orphanin FQ
Widely expressed in the CNS and Periphery
Implicated in both pro- and anti-nociceptive activity as well as in
the modulation of drug reward, learning, mood, anxiety, cough,
and of parkisonism
Nociceptin
Structurally similar to dynorphin except for the absence of an N-
terminal tyrosine
Acts only at the ORL1 receptor, now known as NOP
Metabolism of morphine Excretion
Urinary tract/Enterohepatic circulation
Polar metabolites, including glucuronide conjugates of opioid
Conjugation of analgesics, are excreted mainly in the urine
Morphine
Small amounts of unchanged drug may also be found in the urine
Glucuronide conjugates are found in the bile, but enterohepatic
circulation represents only a small portion of the excretory
~10%: morphine-
process.
Morphine-3-
6-glucuronide
glucuronide (M3G)
(M6G)
Common opioid analgesics
Generic name Brand Approx O:P Duration Intrinsic
equiv. Potency of activity
Active metabolite Act as dose ratio analgesia
Limited ability to Produce
with analgesic
cross the blood- unexpected
neuroexcitatory to (mg) (hr)
potency four to six GABA/glycinergic
times
brain barrier adverse effects
system
Morphine -- 10 Low 4-5 High
Hydromorphone Dilaudid 1.5 Low 4-5 High
Oxymorphone Numorphan 1.5 Low 3-4 High
CNS uptake of M3G and, to a lesser extent, M6G can be enhanced Methadone Dolophine 10 High 4-6 High
by coadministration with probenecid or with drugs that inhibit Meperidine Demerol 60-100 Med 2-4 High
the P-glycoprotein drug transporter. Fentanyl Sublimaze 0.1 Low 1-1.5 high
Sufentanil Sufenta 0.02 IV only 1-1.5 High
Metabolism of Hydromorphone
Alfentanil Alfenta Titrated IV only 0.25- High
0.75
Hydromorphone-3-
Hydromorphone Conjugation
glucuronide (H3G)
CNS excitatory Levorphanol Levodromoran 2-3 High 4-5 High
Codeine -- 30-60 High 3-4 Low
Hydrocodone -- 5-10 Med 4-6 Med
Oxycodone Percodon 4-5 Med 3-4 Med
However, hydromorphone has not been shown to form significant
Propoxyphene Darvon 60-120 Oral only 4-5 Very
amounts of a 6-glucuronide metabolite
low
The effects of the active metabolites should be considered in
Pentazocine Talwin 30-50 Medium 3-4 Med
patients with renal impairment before the administration
especially when given at high doses. Nalbuphine Nubain 10 IV only 3-6 High
Buprenorphine Buprenex 0.3 Low 4-8 High
Metabolism of Heroin and Remifentanil “Esters” undergo hydrolysis by Butorphanol Stradol 2 IV only 3-4 High
common tissue esterases
Heroin Hydrolysis PHARMADYNAMICS
A Mechanism of Action
Opioid agonists produce analgesia by binding to specific G protein-
Monoacetylmorphine
coupled receptors that are located in brain and spinal cord regions
involved in the transmission and modulation of pain.
Morphine
Some effects may be mediated by opioid receptors on peripheral
sensory nerve endings.
Conjugation of morphine "Glucoronidation:
Normeperidine
Accumulation of a demethylated metabolite of meperidine
o May occur in patients with decreased renal function
and in those receiving multiple high doses of the drug.
In high concentrations, may cause seizures.
Fentanyl
Hepatic oxidative metabolism by the P450 isozyme CYP3A4
metabolizes by N-dealkylation in the liver.
Potential receptor mechanisms of analgesic drugs. The primary afferent neuron (cell body not shown)
o CYP3A4 is also present in the mucosa of the small
originates in the periphery and carries pain signals to the dorsal horn of the spinal cord, where it
intestine and contributes to the first-pass metabolism synapses via glutamate and neuropeptide transmitters with the secondary neuron. Pain stimuli can be
when it is taken orally. attenuated in the periphery (under inflammatory conditions) by opioids acting at μ-opioid receptors
(MOR) or blocked in the afferent axon by local anesthetics (not shown). Action potentials reaching the
dorsal horn can be attenuated at the presynaptic ending by opioids and by calcium blockers
Metabolism of Codeine, oxycodone, and hydrocodone (ziconotide), α 2 agonists, and possibly, by drugs that increase synaptic concentrations of
Undergo metabolism in the liver by P450 isozyme CYP2D6, norepinephrine by blocking reuptake (tapentadol). Opioids also inhibit the postsynaptic neuron, as do
certain neuropeptide antagonists acting at tachykinin (NK1) and other neuropeptide receptors.
resulting in the production of metabolites of greater potency.
I Receptor types
Brainstem local circuitry underlying
All are members of the G protein-coupled family of receptors and
the modulatin effect of μ-opioid
show significant amino acid sequence homologies. receptor (MOR)–mediated
Multiple receptor subtypes have been proposed based on analgesia on descending pathways.
pharmacologic criteria The pain-inhibitory neuron is
o μ1,μ2 indirectly activated by opioids
o δ1,δ2 (exogenous or endogenous), which
o κ 1 , κ 2 , and κ 3 inhibit an inhibitory (GABAergic)
interneuron. This results in
enhanced inhibition of nociceptive
II Cellular actions processing in the dorsal horn of the
The opioids have two well-established direct G protein-coupled spinal cord
actions on neurons:
o Close voltage-gated Ca 2+ channels on presynaptic
nerve terminals
Reduce transmitter release
o Hyperpolarize and thus inhibit postsynaptic neurons by
opening K + channels. Opioid analgesic action on the
descending inhibitory pathway.
III Relation of physiologic effects to receptor type Sites of action of opioids on pain-
modulating neurons in the midbrain
The majority of currently available opioid analgesics act primarily
and medulla including the midbrain
at the μ-opioid receptor periaqueductal gray area (A), rostral
Analgesia and the euphoriant, respiratory depressant, and ventral medulla (B), and the locus
physical dependence properties of morphine result principally caeruleus indirectly control pain
from actions at μ receptors. transmission pathways by
Opioid analgesic effects are complex and include interaction with enhancing descending inhibition to
the dorsal horn (C).
δ and κ receptors.
Morphine does also act at κ and δ receptor sites
κ opioid receptors have been developed for reduced incidence of
respiratory depression or propensity for addiction and
dependence
Butorphanol and nalbuphine have shown some clinical success as
analgesics
o Can cause dysphoric reactions and have limited
Organ System Effects
potency
CNS:
Butorphanol has also been shown to cause significantly greater
Analgesia (Sensory & Affective)
analgesia in women than in men.
Euphoria; Drowsiness; Apathy; Mental confusion; alteration in
Mood
IV Receptor Distribution and Neural Mechanisms of Analgesia
Sedation – little or no amnesia
All three major receptors are present in high concentrations in the
Dysphoria (restlessness & Malaise
dorsal horn of the spinal cord.
Respiratory depression secondary to inhibition of brainstem
Receptors are present both on spinal cord pain transmission
respiratory mechanism; dose related; decreased response to CO2
neurons and on the primary afferents that relay the pain message
challenge
to them (Figure below, sites A and B).
Cough suppression
Opioid agonists inhibit the release of excitatory transmitters and
they directly inhibit the dorsal horn pain transmission neuron. Miosis
o Thus, opioids exert a powerful analgesic effect directly Truncal rigidity
on the spinal cord Nausea and vomiting – caused by direct stimulation of the emetic
chemoreceptors located in the medulla; ? vestibular component
Site of Actions of opiod analgesics
A Ascending Pain Sensory Pathway Peripheral Effects
Nociceptive nerve endings Cardiovascular
Spinal Cord Most have no significant direct effect on the heart and cardiac
Thalamus rhythm except bradycardia
B Descending Pain Modulation Pathway Medperidine tachycardia secondary to its antimuscarinic
Midbrain effects
GIT
Medulla
Stomach
“Part of the pain relieving action of exogenous pepides involves the release of o Motility is decreased
endogenous peptides” o Tone is increased
o Decreased HCL secretion
Putative sites of action of opioid Small intestines
analgesics. Sites of action on the o Increased resting tone with periodic spasm
afferent pain transmission pathway o Decreased amplitude in nonpropulsoive contraction
from the periphery to the higher Large intestines
centers are shown. o Decreased propulsive peristalsis
o Increase tone
A: Direct action of opioids on
inflamed or damaged peripheral Biliary tract
tissues o Contract biliary smooth muscles
B: Inhibition also occurs in the Renal function
spinal cord Depressed secondary to decrease renal plasma flow
C: Possible sites of action in the Mu opioids have antidiuretic effects
thalamus.
Enhance renal tubular Na reabsorption
Increas4e ureteral/bladder tone
Increase sphincter tone Benzomorphone
Uterus – prolong labor Pentazocine – a kappa agonist with weak mu anagonist or partial
Neuroendocrine – stimulate the release of ADH, prolactin, somatotropin; agonist properties
inhibit the release of LH Dezocine – highest affinity for mu receptors and less interaction
Pruritus with kappa receptors
Tolerance
Begins with the first dose, clinically manifests after 2-3 wks of
frequent exposure; develops rapidly with large doses at short
interval
No tolerance develops to the miotic, convulsant and constipating
actions
The mechanism of development of tolerance and physical
dependence is poorly understood
o Receptor recycling
Failure of morphine to induce endocytosis is
an important component of tolerance and
dependence
o Receptor uncoupling
Tolerance is due to dysfunctional of
structural interactions between the mu
receptor and G proteins, 2nd messenger
systems and their target ion channels
o NMDA receptor complex
NMDA receptor antagonist can block the
development of tolerance
o Delta opioid receptor function as an independent
component in the maintenance of tolerance
Cross Tolerance
May develop such as patient tolerant to morphine show
reduction in analgesic response to other agonist opioid but it is
usually partial or incomplete
o Opioid rotation
o Recoupling
o Use of delta antagonist with mu receptor agonist
Physical dependence
Results in a characteristic withdrawal or abstinence syndrome
S/Sx – rhinorrhea, lacrimation, yawning, chills, piloerection,
hyperventilation, hyperthermia, mydriasis, muscular aches,
vomiting, diarrhea, anxiety and hostility
The time of onset, intensity and duration of abstinence syndrome
depend on the drug used and its biologic half life
Psychologic dependence
Primary reasons for opioid abuse liability
o Euphoria, indifference to stimuli, sedation
o Abdominal effects
o Physical dependence