Week 12 - Opiates Flashcards
What are opiates
- opium
- opiates/opioids
- morphine & codeine
- heroin
- synthetic opiates
- endogenous ‘opiates’
what are opiates also known as?
narcotics or narcotic analgesics
nacrcotic analgesics
decrease sensitivity to pain and induce sleep
what criteria must opiates meet
- sedative-hynotic & analgesic properties
- acts on endorphin/enkephalin receptors
- actions antagonized by naloxone
Opium
- extracted from poppies
- active ingredients in seedpod sap
- 2 main ingredients: morphine & codeine
heroin
- derived from morphine
- semi-synthetic opiate
- 10 x more lipid soluble vs morphine = faster absoprtion in increased concentrations
synthetic opiods
- opiate-like effects (stimulate opiod receptors) but different chemical structure
- egs: meperidine, gentanyl, dextromethorphan & LAAM
Morphine
- base, pKa 8.0
- less effective when taken orally (vs injection)
- oral administration undergos significant first pass metabolism in liver, absorbed slowly (desirable for analgesic properties)
administration of heroin
- usually injected
- can be taken intranasally (snuff)
- inhaled (chasing the dragon)
distribution
- concentrated in heart, lungs, kidney, liver, spleen & bound to proteins in blood
- pass through placental more readily than BBB (low lipid solubility) heroin is highly lipid soluble
- within brain, opiates are concentrated in basal ganglia, amygdala & periaquaductal gray matter
active ingredients of opiates
- morphine itself
- heroin: molecules are inactive in the brain but it’s metabolites are active
- codeine: primary action through metabolites
2 phases of metabolism in liver
- digestive system enzymes (CP450)
- metabolic interference - conjugation btwn metabolite/drug molecule & water loving substance
excretion of morphine
- active transport mechanism from brain
- 10% excreted unchanged (in urine)
- 1/2 life = 2-4.5hrs
- 90% eliminated <24 hrs
excretion rates of other opiates
- varies
- codeine: 1/2 life = 1.4-3.5 hrs
- methadone has a very long half-life (25-40 hrs)
opiate receptors & endogenous opiates
- 4 types in the brain, also exist outside CNS - classical and non-classical
- endorphines are an endogenous morphine
endogenous opioids
- enkephalins
- endorphins
- endomorphins
- dynophins
- nociceptin
thought to function as NTs, NMs or hormones
3 classical opiate receptors
Mu (MOR) - limbic system, hippocampus, amygdala, thalamus, nucleus accumbens, VTA, hypthalamus
Kappa (KOR) - hypothalamus, thalamus, nucleus accumbens, amygdala, VTA
Delta (DOR) - limbic system, pfc, hypothalamus, nucleus acucmbens, medulla
non-classical opiate receptor
opiod receptor-like or nociceptin (ORL): non-typical, different pharmacological profile
neurophysiology of opiates
- receptors do not always act independently
- some opiates act on more than one receptor
all opiod receptors are metbotropic and work on
- second messengers (inhibitory effects on postsynaptic cell & inhibitory neuromodulator of NTs from presynaptic membrane or)
- kinases directly from inside the cell
opiate receptors on pre-synaptic and post-synaptic cells
presynaptic: inhibit Ca+ influx - inhibitory neuromodulator
post-synaptic: enhance K+ flow out of neurons causing hyperpolarization - inhibitory NT
neurophysiology of synthetic opiates
- similar action to morphine
- act as antagonists to opiates - block the action of any other opiate
- known as mixed agonist-antagonists: have some opiate like activity of their own but block other opiates
neurophysiology of naloxone
- opiate antagonist
- block Mu receptors but has no opiate effects
- used to treat opiate overdoses
neurophysiology of pain effects
- blunt sensory information to areas of spinal cord responsible for pain (inhibits transmission dull/burning pain)
- stimulates receptors in periaqueductal gray & thalamus (physical pain)
- stimulates receptors in limbic system (emotional pain)
what opiate receptors are associated with different pain types
Mu - most pain types except phantom limb
kappa - visceral pain
delta - thermal or mechanical pain
other CNS effects of opiates
- VTA contains Mu receptors and opiates stimulate the mesolimbic DA system (reinforcing properties)
- repeated injection of morphine into PV gray area results in physical dependence
- 3 vital life functions mediated by brain stem areas are depressed (respiration, vomiting, coughing)
effects of opiates on body
- nausea and vomiting after 1st dose
- constricted pupils
- dilated peripheral blood vessels - decrease BP, flushed face, sweating
- constipation (GI tract mu receptors) & decreased urine flow
- decreased sex hormones, sex drive, fertility
effects on sleep
regular users:
- doesn’t increase sleep but induces drowsiness and lethargy
- indirect sleep benefits (alleviation of pain)
- alters nature of slepe (increase muscle tension and decrease slow wave & REM)
- acute admin causes insomnia
subjective effects of opiates
- euphoria
- creativity/dream states
- rush
effects on mood
- initially decreases anxiety and depression; after tolerance - unpleasant mood
- depends on prior opiate experience
- when in pain no experience of sleepiness & other subjective effects
effects of performance
- slows performance in non-users
- tolerance develops to these effects
unconditioned behaviour
rodents: morphine has a biphasic effect on SMA (low doses increase movement, high doses decrease movement)
primates: no excitatory phase (just decrease SMA)
conditioned behaviour
low doses: increased response rate for positive reinforcers and increased avoidance of shock
high doses: decrease response rates and decreased avoidance behaviour but not escape
self-administration in animals
- responding for food not affected by morphine unless withdrawing
- can continue normal activities with little effect for some time
- self administration increases with deprivation and cocaine
self-administration in humans
In lab studies
- opiates are reinforcing by various routes of admin
- morphine > codeine > propoxyphine
- only reinforcing in non users if they experience pain
out of lab data
- chipping (using sporadically or socially)
- addiction & maturing out (5-10 yrs of use once adults reach 40s decrease of use)
discrimination
- discriminated from saline
- morphine generalizes to all other mu opiates, but only partly to mixed agonist-antagonists
- can discriminate between morphine & mixed agonist-antagonists
- tolerance to discriminative effects in 1-3 days (increase with dose)
tolerance
- rapid tolerance to most effects
- tolerance develops at different rates for different effects
tolerance due to
- metabolism
- receptors
- learning (context-dependent effects)
opiates and cross tolerance
- occurs with other opiates
- not with depressants, stimulants or hallucinogens
- partially occurs with alcohol
withdrawal
- never fatal
- starts 6-12 hours after last dose; peak 1-3 days usually over <1 week
- resembles the flu
- dose dependent
withdrawal stages
restlessness, agitation, yawning, chills, hot flashes, short breathing, goose bumps, drowsiness, sleep, cramps in stomach back and legs, vomiting, diarrhea, twitching/kicking & sweating
acute effects
at high doses
- comatose state
- decreased breathing
- convulsions
- accidental overdose
- death
overdose
- potentiated effect with alcohol, barbituates
- cut heroin with quinine (can be lethal when admin IV)
- conditioned tolerance
chronic use
Medical problems:
- constipation
- cancer
- possibly increased AIDS and Hep B risk (sharing needles)
other
- socio-cultural effects (addiction)
reproduction: males
- lowers testosterone
- lowers sex drive
- lowers fertility
reproduction: females
- menstrual irregularities
- amenorrhea
- lowers fertility
- pregnancy (increases need for opiates and effects lifestyle)
fetal development
- mothers opiate withdrawal decreased blood oxygen levels
- decreases birth weight, premature, illness & complications
- withdrawal: starts <72 hours of birth and lasts 6-8 week and includes irritability, yawning, tremors, difficulty sucking, seizures
maintenance therapies
- methadone
- buprenorphine
- trial therapies: ultra-rapid detox using naltrexone
