opiates Flashcards
what is the difference between opium and opiate and opiod?
opium: dried powdered mixture containing 20 alkaloids obtained from the unripe seed capsules of the poppy
opiate: alkaloids extracted from the opium poppy
opioid: substances that mimic the effects of morphine
Can be endogenous OR exogenous
what is a narcotic?
- to make numb
- Federal government uses the term narcotic synonymously with illicit drugs
what are the different types of opiates?
- natural: Harvested from the opium plant (ex. thebaine, morphine, codeine)
- semisynthetic: created from natural opioids (ex. heroin)
- synthetic: completely created in lab (ex. fentanyl, methadone)
why is fentanyl a dangerous fully synthetic opiod?
it is 50 times more potent than heroin and 100 times more potent than morphine.
what schedule drugs are most opiate drugs?
schedule 2 but varies substantially in abuse liability and medical uses
what type of schedule drug is heroin?
schedule 1
what was the opioid epidemics?
when some pharmaceutical companies made a push to reduce opioid stigma & increase prescriptions - opioid overdoses quadruples
what is the route of admin of opiates?
- orally (as pills or liquids - vicodine, oxycodone low bioavialbility)
- “skin-popping”: Subcutaneous injection (heroin)
- “mainlining”: IV injection (heroin)
- intra-muscular injection for medical use of morphine
- Nasal, inhalation (smoking- “chasing the dragon”), & rectal use also occur
- Transdermal patches for sustained pain relief used in medical settings (Lower risk for abuse)
what is the absorption of opioids?
Opioids have lower bioavailability if taken orally due to first-pass metabolism
Rapid absorption when injected/ snorted!
what is distribution of opiods?
Heroin is 10x more lipid soluble than morphine
Readily passes BBB, 3x more potent than morphine!
Peak concentration in ~5 min vs. morphine ~20 min, oxycodone (oral) peak concentrations ~ 1 hr
Plasma protein binding for most opiates
Fentanyl (~80%)
Morphine (~30%)
Oxycodone (~45%)
where are heroine, codeine, and morphine metabolized? what are they metabolized into?
liver
Heroin: metabolized into morphine & morphine-6-glucuronide (M6G)
active metabolites!
M6G produces powerful pain-relieving effects
Codeine: metabolized into M6G & morphine
~10% of Caucasian individuals lack CYP2D6 enzyme experience little analgesia from codeine.
~3% of Caucasian individuals have duplicate CYP2D6 gene expression & are ultra-metabolizers more susceptible to benefits & adverse effects of codeine
Morphine: ~90% converted into inactive metabolites, 10% MG6
how are opiates removed from the body? which form of kinetics?
by urine and feces
first order kinetics
know chart on slide 17 (fentanyl, morphine, heroine, codine)
what are the dangers of fentanyl?
the more fentanyl a person ingests, the more they risk death
what are the 3 major families of endogenous opioid neuropeptides?
- endorphins
- enkephalins
- dynorphins
where are endorphins synthesized and what responses do we see with these?
synthesized: hypothalamus and pituitary gland
responses: analgesia, euphoria/ reinforcing aspects of opioid use, constipation, respiratory depression
where are enkephalins synthesized and what responses do we see with these?
synthesized: CNS and adrenal medulla in PNS
responses: analgesia, euphoria
where are dynorphins synthesized and what responses do we see with these?
synthesized: hypothalamus, striatum, hippocampus, spinal cord
responses: DEPRESSED, pain/stress, learning, and memory
what are the 3 major classes of opioid receptors?
- mu receptors
- delta receptors
- kappa receptors
what are the endogenous opioid peptide that comes to mu receptors? what effects do they produce and what part of the brain?
Endogenous peptides: Endorphin
Analgesia— thalamus, periaqueductal gray, raphe, spinal cord
Reinforcement—nucleus accumbens
Mood —amygdala
Cardiovascular and respiratory depression, cough control, nausea and vomiting—brainstem
Sensorimotor integration—thalamus, striatum
what are the endogenous opioid peptide that comes to delta receptors? what effects do they produce and what part of the brain? where are these receptors found?
Endogenous peptides: endorphin & enkephalin
δ-receptors found in cerebral cortex, thalamus, striatum, spinal cord
Role for δ-receptors in olfaction, motor integration, reinforcement, and cognitive function.
Areas of overlap with μ-receptors implicated in analgesia.
what are the endogenous opioid peptide that comes to kappa receptors? what effects do they produce and what part of the brain? where are these receptors found?
Dynorphin = major peptide
Found in the striatum, hippocampus, amygdala, hypothalamus and pituitary
hippocampus, amygdala, pituitary: dysphoria, stress, memory
hypothalamus: gut motility/ feeding
Also pain perception
what are the 3 ways opioids inhibit neuron activity?
(A) Postsynaptic inhibition—binding of opioids to postsynaptic receptors hyperpolarize the postsynaptic cells, reducing firing rate.
(B) Axoaxonic inhibition— binding to receptors close presynaptic Ca2+ channels in axon terminals, reducing the release of neurotransmitter.
(C) Presynaptic autoreceptors reduce release of a co-localized neurotransmitter from presynaptic neuron.
how do opioids alter mesolimbic dopamine?
- Activity of DA neurons in the VTA are controlled by local GABA interneurons
- β-endorphin & opioid drugs increase VTA cell firing by inhibiting the inhibitory GABA cells - INCREASING DOPAMINE (disinhibition)
how does dynorphin affect the mesolimbic dopamine if it has depressive qualities?
Dynorphin acts on κ-receptors on DA neuron terminals and can reduce release of DA, causing dysphoria.
how does most opiates act at receptors?
full agonist
how does buprenorphine (surgical anethetic) act at receptors?
partial agonists
how do interventions like narcan act at receptors?
antagonist
what are subjective effects of opiates that a person may feel?
Rush: rapid onset of euphoria seconds after injection; Sensation of heroin entering system
High: feelings of joy/ ease pleasure
Nod: feelings of calm/ disinterest ;Semi- or unconscious state
Straight: period of normalcy; Not sick
what is true about the effects of opioids on CNS?
depends on dose and rate of absorption
what are the opiate user’s desired effects?
Analgesia (pain management)
Cough suppression
Sedation
Anti-diarrhea
Euphoria
what does low moderate doses of opiates do?
analgesic, constricted pupils, sense of relaxation and drowsiness/sleep, inability to concentrate
what does high doses of opiates do?
euphoria/ elation, but… coma and death
what medication do some individuals take , not for its instrumental purpose, to get the opiate feel?
- immodium (loperamine) : anti- diahrreal
Opioid addicts sometimes take very high doses of loperamide to produce euphoria and reduce withdrawal symptoms
how do opiates work to relieve pain?
both dull and sharp pain pathways contain mu receptors.
the ascending pain pathways (spinothalamic pathways) is Nociceptors -> Spinal cord
->thalamus -> S1
Opiates will shut down pain signals from ever reaching the thalamus
how does the descending pain pathways work?
the descending pain pathway (turning pain off pathways) - originates in PAG - After pain signal reaches S1, descending pain pathway can reduce pain signals by shutting down pain signals at level of the spinal cord
why does acupuncture work?
it releases endogenous opioids that trains your body to suppress pain
where does opioids inhibit pain transmission?
spinal and supraspinal levels
- Hypothalamus, limbic structures like ACC, amygdala, and nucleus accumbens.
- emotional component of pain
showed significant negative correlation between μ-opioid activity in the NAcc, amygdala, and thalamus and physical pain scores.
what are acute effects of opiate intoxication?
Euphoria
Drowsiness/ Nodding
Heavy feeling in limbs
Decreased sexual desire
Impaired social interactions
Body warmth/ flushing but lowered core body temp
Miosis
Hypotension, bradycardia (slow heart rhythm)
what are adverse effects that are seen with opiate use?
dysphoria
restlessness and anxiety,
nausea and vomiting
morphine affects the area postrema in the brainstem that elicits vomiting.
what effects occur with taking high doses?
sedative effects may lead to unconsciousness
Respiratory failure
body temperature and blood pressure fall
what are long term effects of opiates?
Impotence
Constipation
Hypoxia
Collapsed veins
Decreased immune function
what is responsible for tolerance, sensitization, and dependence by opiates?
neuroadaptive changes from chronic use
what types of tolerance do we see?
Behavioral
Pharmacodynamic :Opioid receptor desensitization & receptor internalization with chronic use
Opioid overdose:
*Respiratory failure. Why?
Cross-tolerance among the opioids
what do opiods generally do? what do we see with withdrawal?
Opioids in general depress CNS function; opioid withdrawal is rebound hyperactivity.
when do we see withdrawal symptoms for fentanyl, morphine/heroin, methadone?
Fentanyl –withdrawal symptoms ~4-6 hrs after last use, symptoms peak ~12 hours post use, last ~5 days
Morphine/ Heroin- withdrawal symptoms ~6-18 hrs after last use, symptoms peak 36-72 hours post use, last 7-10 days
Methadone- withdrawal symptoms ~24-48 hrs after last use, peak 3-21 days, last 6-7 weeks
what is the classic triad of opiate overdose symptoms? what should we also look for?
Miosis (pinpoint pupil)
Coma (level of consciousness)
Respiratory depression
also look for Pulmonary edema
excess fluid in the lungs
what are opioid risk factors?
- using an opioid after not using it for a period of time after detox, jail, etc
- using street drugs with unknown strength and purity
- using an abusive method such as snorting or injecting
- mixing with other drugs or with alcohol
- using drugs without anyone around
what is used for opiod overdose intervention?
narcan (naloxone): Competitive antagonist for Mu receptor can be used to intervene during an active opioid overdose
Displaces opioid agonists from the opioid receptor
Higher binding affinity than the opioid drugs
Only effective for opioid related overdoses
Works for ~30 min
what is the relapse rate of opiate addiction?
high; 70-90%
what are methods for combating opioid dependence?
Reformulating opioids to make them harder to use; Ex: oxycontin reformulation makes it harder to crush/ dissolve
Psychotherapy to learn social triggers that may increase risk of relapse; Group therapy, family counseling, cognitive-behavioral therapy
Drug replacement
Administer safer opioid with weaker effects to reduce withdrawal symptoms
Methadone, suboxone, etc.
what is the most effect treatment with opiate addiction?
Rapid detoxification is most effective:
in-patient treatment; briefly anesthetized and treated with Naltrexone (antagonist)
how can we combat withdrawal with other drugs?
Methadone: Agonist for µ-opioid receptor. Generates effects. Lesser high.
- Long half-life, cross-tolerance to euphoria between heroin/ morphine & methadone
- Allows addicts to avoid uncomfortable withdrawal symptoms & prevents craving
Suboxone: Buprenorphine + Naloxone
- Buprenorphine: high affinity + low efficacy at mu receptors, antagonist at kappa receptors
Less euphoria, less respiratory depression risk
Naltrexone: Antagonist. Blocks effects.
what is methadone?
synthetic opioid analgesic with full agonist activity at the µ-opioid receptor
describe methadone in comparison to heroine/morphine
Does NOT produce the rush, drowsiness (nod) or impairment in thinking/ emotion/ sensation with prescribed use
Potential for misuse because higher doses can produce euphoria
what is the route of admin of methadone?
oral - most common
what is the absorption and distribution of methadone?
Lipid soluble & well absorbed from the GI tract
Bioavailability ~80% after oral ingestion
Initial effects appear within ~30 min, peak effects & peak plasma levels ~2-4 hours post administration
Steady state blood plasma levels generally achieved within 5-7 days
Moderate-significant depot binding
what is the metabolism of methadone?
Metabolized in the liver by CYP450 enzymes
INACTIVE metabolites!
what is the excretion, kinetics, and half life of methadone?
Excreted in the urine
Methadone is eliminated via first-order kinetics.
LONG half-life
~55 hours in non-addicted individuals
~24 hours in individuals who show opioid tolerance
what are acute effects of methadone?
Decreased reaction time & impaired motor coordination
Decreased attention span/ cognitive ability
Drowsiness
Dry mouth
Muscle weakness
Decreased body temperature
Constipation
Euphoria (only at higher doses)
what is chronic effects of methadone?
Liver damage
Loss of white matter in the brain
Cardiovascular issues
Depression
Cognitive decline
Physical dependence
what type of dependence do we see with methadone users?
Physical dependence may occur because of neuroadaptations of the opioid receptors
what withdrawal symptoms do we see with methadone?
Withdrawal symptoms include: body aches/ severe pain, loss of appetite, nausea/ stomach cramps, nervousness or restlessness, fever, palpitations, etc.
Withdrawal symptoms emerge ~24-48 hrs after last use, peak 3-21 days, & persist for ~6-7 weeks
what is still possible with methadone?
overdose; Circulatory collapse, cardiac arrest, and death may occur following administration of high doses
