Opioids Flashcards
Opiate
a compound that is structurally related to products found in opium
-morphine, codeine etc
Opioid and endogenous opioid
any agent regardless of structure, that has the functional and pharmacological properties of an opiate
-endogenous opioids: naturally occurring ligands for opioid receptors
Narcotic
a drug that produces a stuporous sleep-like state, may or may not be analgesic. Includes opioid and some other abused drugs
Pain
A subjective symptom or unpleasant sensory or emotional experience that is typically associated with actual or potential tissue damage from mechanical or thermal causes or disease
Analgesia
a state in which no pain is felt despite the presence of normally painful stimuli
Analgesics
drugs that alleviate pain without impairing other sensory modalities, in contrast to anesthetics
Endorphins
- Endogenous opioid peptide
- precursor is POMC
- beta-endorphin in hypothalamus and nucleus tractus solitarius
- also in anterior pituitary: co-released with aCTH during stress
Enkephalins
- endogenous opioid peptide
- precursor proenkephalin
- leucine and methionin enkephalins have wide CNS distribution
- *especially in interneurons, including those in pain pathways
- peripheral site include adrenal medulla, nerve plexuses and exocrine glands of stomach and intestine
Dynorphins
- endogenous opioid peptide
- precursor prodynorphin
- Dynorphin A, co-localized with vasopressin in magnocellular cells of hypothalamus and posterior pituitary
- shorter dynorphins have wide CNS distribution; some are associated with pain pathways, especially in spinal cord
What receptors is beta endorphin effective on
Mu and Delta
What receptors is Met-enkephalin effective on
Mu and Delta
Leu- enkephalin effective on which receptors
Mu and Delta
what receptors is Dynorphin A effective on
Mu and Kappa
What receptors is Dynorphin B effective on
Mu an Delta and Kappa (mostly Kappa)
What receptors is alpha-Neoendorphin effective on
Mu, Delta, Kappa ( mostly kappa)
What receptors is Endorphin-1/2 effective on
Mu
What do plasma opioid peptide amount refelct
-plasma opioid peptides reflect release from secretory systems such as the pituitary and the adrenals; plasma levels do not reflect neuraxial release
WHat do brain/spinal cord/CSF levels of opioids reflect
levels of pepties in brain/spinal cord and in CSF arise from neuraxial systems NOT from peripheral systems. so it does reflect neuraxial release
Mu receptor
- supraspinal and spinal analgesia
- slowed GI transit
- modulation of hormone release
Delta Receptor
- supraspinal and spinal analgesia
- modulation of hormone and neurotransmitter release
Kappa Receptor
- supraspinal and spinal analgesia
- Psychotomimetic effects
- Slowed GI transit
Describe the distribution of opioid receptors in the body
- wide distribution in brain and periphery
- neuronal cell soma and axon terminals
- macrophage cell types (ex: microglia)
- astrocytes
- enteric nervous system
What are opioid drugs used for
- analgesi
- cough suppression
- antidiarrheal/constipation
- respiratory depression
- peripheral vasodilation, reduced peripheral resistance, inhibition of baroreceptor reflexes
- nausea
- pupillary constriction: miosis
- sedation
- euphoria
- increased biliary pressure
general information on the ascending pain pathways (fibers involved)
- noxious stimuli activate nociceptors-pain receptors
- A-delta fibers ( myelinated) mediate sharp localized pain to dorsal horn of spinal cord (somatic pain and lamina I-glutamate)
- C fibers (unmyelinated) mediate dull diffuse, aching, or burning pain (visceral or neuropathic pain, Lamina II: glutamate and substance P)
Ascending pain pathway
- 2nd order neurons in spinothalamic tract
- thalamus, limbic system, somatosensory and association cortex (emotional cortex)
descending pain pathways
- periaqueductal gray (midbrain) and rostro-ventral medulla to dorsal horn
- via dorsolateral funiculus
- release NE, 5-HT, enkephalin
- inhibit activity of ascending pain pathways
Mechanisms of Mu Opioid receptor (MOR) Induced Analgesia
- suprspinal
- sinal cord
- peripheral
- supraspinal
- disinhibition of periaqueductal gray output neruons
- spinal cord
- pre and post synaptic effects on ascending pathway
- peripheral
- specific to inflammatory pain
- normalizes hyperalgesia
Opioid and cough suppression
- direct actions on medullary cough center
- may not be mediated by opioid receptors
- codeine and hydrocodeine
- independent of respiratory suppression
- stimulation of mechano-or chemoreceptors (throat/respiratory passages)
- cough center in medulla
- efferent transmission to diaphragm, intercostal muscles and lungs
Opioids and antidiarrheal/constipation
opioid receptors are densely distributed in enteric neurons in the myenteric and submucosal plexi and on a variety of secretory cells
-opioids decrease gastric emptying
Opioids and respiratory depression
- Most serious side effect
- mechanism:
- decreased sensitivity of brainstem chemoreceptors to CO2
- direct depressant effect on rhythm generation
- increase chest wall rigidity (with higher doses, such as those used in anesthetic induction)
- can have interactions with other CNS depressants
Opioids and peripheral vasodilation, reduced peripheral resistance, inhibition of baroreceptor reflexes
- cardiovascular effects may be minimal when patient is supine
- when supine patients assume heads up position, orthostatic hypotention and fainting may occur
- mechanism: release of histamine from mast cells
- fentanyl and sufentanil have much less effect on histamine
- blunting of reflex vasoconstriction by increased PCO2
Opioids and Nausea
direct stimulation of chemoreceptor trigger zone (CTZ) in area postrema
Opioids and Miosis (pupil constriction)
- disinhibition of edinger-westphal output neurons
* inhibition of local GABAergic interneurons disinhibits output neurons
Opioids and sedations
- drowsiness and cognitive impairment
- can augment respiratory depression
- likely due to general CNS inhibition
Opioids and Euphoria
- primarily mediated by mesolimbic circuit
- Mu opioid receptors (MORs) on GABA interneurons in ventral tegmental area (VTA) disinhibit dopamine (DA) neurons
- Mu opioid receptors on GABA medium spiny neurons in nucleus accumbens (NAc)
Opioids and endocrine effects Anterior Pituitary
Males: reduction of cortisol, testosterone and gonadotropins
Females: same as males, also reduction of leutenizing hormone (LH) and follicle stimulating hormone
- mechanism thought to involve both hypothalamic effects (reduced GnRH and CRF) and pituitary effects (direct inhibition of pituicytes)
- minimal effects on thyrotropin
Opioids and anterior pituitary prolactin
- plasma prolactin elevated by opioids
- dopamine released from tuberoinfundibular neurons inhibits prolactin release from pituitary lactotrope cells
- opioids inhibit dopamine release by presynaptic mu opioid receptors
Opioids and endocrine effects: posterior pituitary antidiuretic hormone and oxytocin
- ADH reduced by kappa receptor agonists
- oxytocin reduced by kappa receptor agonists
- note that agents such as morphine may yield a hypotension secondary to histamine release, this would, by itself, promote ADH release
Opioids and increased biliary presure
- opioids suppress inhibitory innervation of the sphincter of oddi
- morphine may increase pressure of common bile duct more than 10 fold in 15 minutes
- this effect may exacerbate pain in patients with biliary colic. so don’t give opioids as an analgesic to patients with this
Describe absorption of opioids
- oral absoprtion and bioavilability varies by compound
- poor for morphine and naloxone (extensive first pass metabolism)
- oral potency approx. 1/3 that of parenteral
- good for methadone
- rectal absorption is adequeate
- morphine and hydromorphone available as suppositories
- transdermal absorption for some highly lipophillic opioids
- fentanyl
- onset of action related to lipophillicty
- heroin vs morphine
distribution of opioids
- all opioids bind to plasma proteins with varying affinity
- rapidly leave the blood compartment and localize in highest concentrations in highly perfused tissues such as the brain, lungs, liver, kidneys, and spleen
- Adipose tissue: important consideration especially with frequent high-dose administration or continuous infusion of highly lipophillic opioids that are slowly metabolized (ex: fentanyl)
Metabolism of opioids (morphine like compounds)
-mainly converted to polar metabolites
- Mostly glucuronides
- E.g., Morphine-3-glucuronide (M3G), Morphine-6-glucuronide
- Can undergo other modification
- ex: N-dealkyla=on, hydrolysis, conjugation
- metabolites may be active
- codeine converted to orphineconverted to M3G (CNS excitatory) and M6G (opioid agonist
- hydrocodone converted to hydromorphone converted to H3G (CNS excitatory)
- Heroin (inactive) converted to mono-acetyl morphine converted to morphine etc.
Metabolism of non morphine like opioids
- heaptic oxidative metabolism is primary route
- warning for meperidine in patients with decreased renal function or those receiving high doses
- accumulation of normeperidine may cause seizures
Excretion of opioids
- polar metabolites, including glucuronide conjugates of opioid analgesics, are excreted mainly in the urine
- eg: morphine primarily eliminated as M3G
- small amounts of unchanged drug may also be found in the urine
- in patients with renal impairment the effects of active polar metabolites should be considered before the administration of potent opioids such as morphine or hydromorphone
Morphne
- mu agonist
- low oral to parental potency ratio (about 1/3) F=,3 compare to methadone F=.85
- available injectable, oral, oral sustained release and suppository forms
- duration of analgesi is 4.5 hours
Heroin
- structurally similar to morphine
- diacetyl morphine
- more lipophillic than morphine
- converted to 6-acetyl morphine and morphine
- high abuse potential
Hydromorphone
2-3X as potent as morphine
Codeine
-stucturally similar to morphine
(0-methyl morphine)
-for mild pain. morphine like efifcacy is not achievable at any dose of codeine
-some codeine is metabolized to morphine
-often used in combination with aspirin or acetaminophen
Oxycodone and Hydrocodone
- structurally similar to morphine
- for moderate to severe pain
- available as sustained release oral preparation
- major abuse problem
- often used in combination with aspirin or acetaminophen
Methadone
- structurally distinct from morphine
- equivalent efficacy to morphine
- good oral bioavilabilty
- long duration of action
- used in treatment of opioid abuse and chronic pain
Meperidine
- structurally distinct from morphine
- a phenylpiperidine
- shorter duration of analgesia than morphine
- forms of toxic metabolite, normeperidine, that can accumulate with frequent use
- interactions with MAO inhibitor
Fentanyl
- structurally distinct from morphine
- mu agonist
- 100X as potent as morphine
- short acting 1-1.5 hours
- available in injectable form transdermal patches, and buccal soluble film for breakthrough pain
Levorphanol
- affinity at the MOR, KOR, and DOR
- 5-HT/NE reuptake inhibitor (SNRI) ; NMDS receptor antagonist
- rapid onset, modest duration of analgesia
Tramadol
- weak mu agonist
- blocks NE and 5-HT uptake
- used for mild to moderate pain
Etorphine, Carfentanil
- 1000-10,000X potency of morphine
- used in large animal tranquilizer darts
- increasing prevalence in street drugs
Buprenorphine
- partial mu agonist, 25-50X greater potency than morphine
- used to treat moderate to severe pain. a transdermal patch is also available
- oral buprenorphine combined with naloxone is used to treat opioid dependency -(Suboxone*)
Nalbuphine
- similar in efficacy and potency to morphine
- little euphoria and low abuse potential
- can precipitate withdrawal in opioid dependent patients
- only available by injection
other mixed agonist/antagonists include
butorphanol and pentazocine
but effective doses often yield similar side effects as full mu agonist
Naloxone
- opioid antagonist
- high affinity for mu receptors, less for kappa and delta
- much greater activity parenterally than orally
- short duration: 1-2 hours
- used to treat opioid overdoses
- can be combined with opioids to decrease parenteral abuse liability (low oral bioavailability)
- component of newer treatment for addiction (Suboxone)
Naltrexone
- opioid antagonist
- orally active with long half life (24+ hours)
- used in treatment of alcoholism and opioid addiction
Naloxone for overdose treatment
- Naloxone administered (parenterally) to reverse the effects of opioids overdose
- good parenteral bioavailability
Naloxone for drug diversion
- added to oral/sublingual preparations or opioid agonists or partial agonist to prevent euphoria when injected intravenously
- poor oral bioavailability, so when taken as prescribed, has no significant effect
(contrast to naltrexone which is used to treat addiction/opioid use disorder)
Describe opioid tolerance
- rapid: nausea and vomiting
- more gradual: analgesia, euphoria, respiratory depression, endocrine
- little or none: miosis, constipation
opioid desensitization
- acute tolerance
- minutes to hours
opioid tolerance
-days to weeks
opioid dependence
-occurs during the course of tolerance
opioid addiction/substance use disorder
- behavioral pattern
* dependence does not equate addiction
Desensitization (acute tolerance) is probably mediated by receptor phosphorylation and then
1) internalization
- mu and delta show rapid agonist-induced internalization
- beta arrestin dependent endocytosis
- agonist dependent
* etorphine and enkephalins: rapid internaliation
* morphine: no significant (rapid) internalization
2) Uncoupling from G protein
Tolerance
- right shift in dose-effect curve
- surmountable with higher doses
- chronic pain patients may be taking gram amounts of morphine
- reversible with removal of drug
- incomplete cross tolerance
dependence
- state of adaptation
- revealed by drug withdrawal or antagonist treatment
- withdrawal produces opposite symptoms of acute exposure
- somatomotor and autonomic outflow increased
- hyperalgesia, hyperthermia, pupillary dilation are a few examples
- aversion
Symptoms 6-12 hours after withdrawal
Drug-seeking behavior; restlessness, lacrimation, rhinorrhea, sweating, yawning
Symptoms 12-24 hours after withdrawal
Restlessness sleep for several hours; irritability, tremor, dilated pupils,
anorexia, gooseflesh
symptoms 24-72 hours after withdrawal
Increased intensity of above, plus weakness, depression, nausea,
vomiting, intestinal cramps, diarrhea, alternating chills and flushes, aches and pains, increased heart rate and blood pressure, involuntary movements of arms and legs, dehydration, and possible electrolyte imbalance
Later symptoms of withdrawal
Above symptoms of autonomic hyperactivity alternate with brief periods of restless sleep with gradual decrease in intensity until addict recovers in 7 to 10 days, but still exhibits strong craving for drug. Some mild signs and symptoms are detectable for up to 6 months. Delayed growth and development in infants born to addicted mothers may be detected for up to 1 year.
Opioid use disorder
- not the same as dependence
- toelerance and dependence are natural consequences of chronic exposure
- mild, moderate or severe (number of criteria met)
- example criteria
- opioids are often taken in larger amounts or over a longer period than was intended
- there is a persistent desire or unsuccessful efforts to cut down or control opioid use
- a great deal of time is pent in activities necessary to obtain the opioid, use the opioid, or recover form its effects
treatment of opioid abuse/opioid use disorder
- after withdrawal (preferably medically supervised)
- Phamacological (FDA approved)
- methadone (slow acting mu agonist)
- suboxone (buprenorphine/naloxone-sublingual)
- naltrexone
- behavioral (psychosocial intervention)
- group therapy, including 12 step programs
- cognitive and behavioral therapies
- others
