Download 11/12/2014 Opioids

11/12/2014
Opioids
Natural or semi‐synthetic compounds derived from the seedpod of poppy plants
Papaver somniferum, Papaver
somniferum, Papaver orientale, Papaver
orientale, Papaver bracteatum
as well as synthetic drugs that:
• bind to an opiate receptor
• produce analgesia
• can be blocked by an opioid antagonist.
Opioids
Opioids have been used as analgesics for >3,500 years (potentially 10,000 years)
‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐‐
To date, the analgesic and addictive (euphoric) properties of opioids have not yet been
completely separated.
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Components of Opium – Dried Latex from Poppy Seed Pod
Morphine
Main psychoactive component (10‐15%)
Codeine
Second most predominant alkaloid (up to 3%)
Thebaine
Minor constituent, precursor for other opioids
other opioids
Papaverine
Antispasmodic, separate mech‐
anism of action
Other Opium Alkaloids Include Cryptopine, Narceine, Noscapine (Narcotine)
Paper chromatography of opium alkaloids, pH 3.5 (separation based on polarity)
http://www.unodc.org/unodc/en/data‐and‐analysis/bulletin/bulletin_1960‐01‐01_2_page005.html
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Isolation and Purification of Opioids from Opium – Multistep Process
General schematic for heroin production
purified heroin
crude opium extract
black tar heroin
Basic amine renders alkaloids more water soluble at low pH (acidic)
Synthesis of Diacetylmorphine (Diamorphine, Heroin)
Nucleophilic alcohols react with electrophilic reagent acetic anhydride
Alcohols in morphine converted to esters in heroin – is heroin more or less hydrophobic?
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Heroin Metabolism
HO
O
O
H
N
O
heroin
6‐monoacetylheroin
morphine
detection in urine distinguishes between heroin and other opioid use
Heroin is a pro‐drug for morphine with 2‐4 x greater potency
Heroin crosses BBB more readily (hydrolysis can occur in brain or periphery)
Undergoes extensive first‐pass metabolism when taken orally – hence, injected or snorted
Opioid Receptors
Three types of opioid receptors
1. Mu (, MOP)
2. Kappa (, KOP)
3. Delta (, DOP)
Each receptor is a protein built from ca. 400 amino acids / 60% sequence identity between types
Opiod analgesia attributed to activation of mu receptors.
All clinically used opiods produce effects at least partly by acting on mu receptors.
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Opioid Receptors
Existence of receptors on which opium acted lead to search for endogenous ligands.
Endogenous opiods are peptide chains derived via hydrolytic cleavage of longer peptide
Endogenous opiods
are peptide chains derived via hydrolytic cleavage of longer peptide
precursors. delta
pp
kappa
mu
* Nociceptin (NOP) receptor does not respond to opiod antagonist naloxone
Pharmacology of Opioids
Opiate receptors are located at multiple points along the pain signaling pathway
Site of injury ‐> primary afferent axons ‐> spinal cord ‐> thalamus ‐> brainstem, midbrain, cortex
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Pharmacology of Opioids
Downstream effects of opioid binding
1. G‐protein dissociates into  and  components
2.  and  components activate K+ channels, inhibit Ca2+ channels, reduce cAMP
3. Neuron is hyperpolarized / inhibited (K + leaves cell, becomes more negative)
Opioid receptors are G‐protein coupled receptors (GPCRs)
Pharmacology of Opioids
Downstream effects of opioid binding mu‐opioid receptor, continued:
Release of pain‐producing substances is blocked
• Glutamate
• Substance P
• Calcitonin gene‐related peptide (CGRP)
Reduction in ascending pain signals to the brain
Indirect activation of pathways leading to release of serotonin, norepinephrine, enkephalin.
Hence, SSRIs can also lead to reduction in pain
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Agonist versus Antagonist Activity at Opioid Receptors
Agonist
Drug binds receptor and simulates natural (endogenous) neurotransmitter
Morphine
‐opioid agonist
Analgesia, sedation, euphoria
Antagonist
Drug binds receptor and blocks action of endogenous neurotransmitter or agonist drug.
Naloxone
‐opioid antagonist
Blocks morphine effects
Agonist, Partial Agonist, Antagonist, Inverse Agonist Reponses
morphine
buprenorphine
(Suboxone®)
naloxone
naloxone in opioid‐dependent patients is a partial inverse agonist
elicits withdrawal
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Pharmacological Effects of Opiods
• Analgesia and indifference to pain, without loss of consciousness
• Euphoria –
E h i feeling of contentment, well‐being, lack of concern
f li
f
ll b i l k f
• Depression of respiration
• Suppression of cough center in brain stem (antitussive)
• Sedation and anxiolysis
• Nausea and vomiting Nausea and vomiting
• Increased intestinal tone, decreased motility, constipation
• Pupil constriction
Opioid Induced Euphoria Opioids act indirectly in the ventral tegmental area by inhibiting GABA neurons
via mu opioid receptors. GABA neurons inhibit dopamine releasing neurons.
Opioids inhibit the inhibitors, increasing dopamine input in the nucleus accumbens
and other areas of the brain’s reward pathway.
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Pharmacokinetics of Opioids
Primary metabolism of opiates is via CYP2D6 and CYP3A4 isoenzymes (>90%).
Estimated 20‐30% of patients have a genetic opioid metabolic defect in one of these enzymes.
• Over‐active enzyme ‐> require higher dosage for pain relief
• Inactive enzyme ‐> results in high levels of opioid
Potential allergic reactions and respiratory depression
Some opioids bypass CYP450 metabolism and undergo glucuronidation instead
Oxymorphone (Opana®, Numorphone®), hydromorphone (Dilaudid®), tapentadol (Nucynta®, Palexia®) Opioid Tolerance Can Occur In As Short of a Time Period As 10 Days
Endogenous opioids
g
p
((e.g. ‐endorphin) released intermittently and metabolized rapidly.
g 
p )
y
p y
Exogenous opioids (e.g. morphine) chronically remain attached to receptors, leading to receptor
desensitization due to interference with normal receptor recycling and re‐sensitization.
Receptor recycling / re‐sensitization involves uncoupling of receptors from G‐protein,
cellular uptake, then return to membrane.
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Opioid Overdose
Tolerance to euphoric effects builds more quickly than tolerance to respiratory depression.
Depression of breathing – most important acute side effect and cause of overdose death. Janis Joplin
John Belushi
Kurt Cobain
Opiod Dependence – Altered Physiological State Induced By Drug Whereby
Withdrawal of Drug Elicits Biological Reactions Typical for Drug Class
Withdrawal symptoms generally opposite of pharmacological effects.
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Opioid Drug Testing – Differentiating Heroin From Codeine and/or Morphine
HO
O
O
H
N
O
heroin
6‐monoacetylheroin
morphine
Detection of 6‐monoacetyl heroin and its downstream metabolites indicates heroin use
codeine
Opioid Drug Testing – False Positives Due to Poppy Seed Consumption
1 g poppy seeds contains up to 33 mcg morphine, 14 mcg codeine
Positive drug tests can result from moderate consumption (e g 2 poppy seed rolls 1 5 g)
Positive drug tests can result from moderate consumption (e.g. 2 poppy seed rolls, 1.5 g)
Standard cutoff now increased to 2 mcg / mL
GC‐MS verification to distinguish between legal consumption and illicit drug use:
• Examine morphine : codeine ratio
• Look for presence of 6‐monoacetylmorpine, a heroin metabolite
p
y
p
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