pharmacology -opiods
Terms
undefined, object
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- Opiod analgesic action
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act on opiod receptors
SELECTIVE pain block - no change in consciousness or other sensations -
Opium vs. opiates vs. opiods
Narcotics -
Opium - dried resin from seed
Opiates - alkaloids found in some opium and synthetic derivatives
opiods - any agent with morphine-like activity
Narcotics
- any drug making you sleep (rarely used this way anymore)
- opiod analgesics
-legal term for abused substances - Endogenous opiods
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made in body --> NTs/neuromodulators
mostly peptides, but also morpheine and codeine - families of endogenous opiods
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enkephalins - preproenkephalin
endorphins - prepro-opiomelanocortin
endomorphins - don't know precursor
dynorphins - preprodynorphin - Opiod receptors
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mu - most important
delta
kappa
most are full agonists, but there are also partial agonist, mixed agonist/antagonist (by receptor type), and antagonists -
Preferred ligands for:
mu
Delta
Kappa -
not totally specific
Mu: beta-endorphin, endomorphins
Delta: enkephalins
Kappa: dynorphins - Cellular effects of opiods
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g-pro linked
opens K channel --> hyperpolarization
close some Ca channels --> down NT release
May alter adenylyl cyclase -
receptors involved in some opiod fx
analgesia
down resp
down GI motility
psychotomimetic (LSD-like)
sedation
euphoria
miosis
increased sphincter tones -
analgesia - mu (and some k)
down resp - mu
down GI motility - mu, k
psychotomimetic (LSD-like) - kappa
sedation - mu, k
euphoria - mu
miosis - mu, kappa
increased sphincter tones - mu - pharmacological effects of opiods
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analgesia
euphoria/psychological dependence
sedation
resp depression
N&V
antitussive
miosis
pruitis
GI effects
blilary/ureter and bladder
CV effects
neuro endocrine - pharmacological effects of Opiod - anlgesia
-
affects both the psychological and emotional components
- raise pain threshold, decrease interpretation of remainign pain
selective block of pain
given enough opiods, you can block almost any pain (no ceiling effect) -- except neuropathic pain - Mech of analgesia for opiods
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action in both brain and spinal cord
augment the effects of endogenous antinociceptive systems - Memorize that one diagram
- yeah, that's right. Memorize it
- pharmacological effects of Opiod - euphoria/psych depend
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high abuse - only in people with abuse, not with medical use
mechanism - at least partly due to opiod activation of VTA/NA pleasure pathway - pharmacological effects of Opiod - sedation
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drowsiness/impaired thinking
additive with EtOH
mainly at high doses
still don't cause loss of consciousness
no ataxia
usually can get analgesia w/o sedation - pharmacological effects of Opiod - respiratory depression
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can be lethal, but can be useful
decreased rate and depth of breath
usual cause of death in OD
direct depression of brainstem resp centers (reduced responsiveness to CO2 - Should I give passive O2 to someone with opiod OD?
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NO!!! need to be pos pressure
if passive, the O2 will decrease the intrinsic drive to breathe even more - pharmacological effects of Opiod - N&V
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partly due to chemorecepor trigger zone (CTZ)
better if person lays down (vestibular contribution) - pharmacological effects of Opiod - antitussive
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depress cough reflex by action in 'cough center' of medulla
happens at low dose
receptors aren't well known - pharmacological effects of Opiod - miosis
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pupil constriction - poor night vision
abuser don't like it b/c it points them out
don't get tolerance to it
stimulates Edinger-Westphal nuclues (increases parasympathetic tone) - pharmacological effects of Opiod - pruritis
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ITCHING
more common with IJ than PO
histidine release from mast cells
can come with flushing/sweating
spinal mechanism? - pharmacological effects of Opiod - GI effects
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down acid production
increased constipation from decreased intestinal, pancreatic secretions
partially due to local fx, partially CNS
Useful for diarrhea, often bad for SEs
Doesn't tolerate out - pharmacological effects of Opiod - biliary sphincter, ureter, bladder
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increased tone in all
bilary stone/spasm = pain
enough opiod = mask pain, low dose = feel pain - pharmacological effects of Opiod - CV effects
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not much CV effects
postural hypotension - pharmacological effects of Opiod - neuroendocrine effects
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decreased gonadotropin-releasing hormone (GnRH)and corticotropin-releasing (CRH)hormone
--> erratic menstruation, decreased libio/impotence in men - Tolerance to opioids
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inevitable with prolonged/frequent use
10x-100x is common
rate/magnitude varies by drug/dose/freq/duration
rate/magnitude also vary by effect (miosis/constipation don't tolerate out)
lots of cross-tolerance among MU agonists -> drug changing is common - Basis of tolerance to opioids
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don't know exact mech
internalization of receptors
desensitization -- PO4 the receptor
uncouple receptor from g pro - Physical dependence to opiods
-
inevitable with prolonged/frequent use of MOST
morphine generally takes 10-14 days at tid/qid
-- differs per person per drug - opioid withdrawal
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provoked with sudden decrease in dose or opioid receptor antagonist
symptoms - opioid craving, psych/physical effects (opposite of opioid effects)
unpleasant, but rarely lethal
onset/duration varies by agent half-life - opioid withdrawal symptoms
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insomnia,
anxiety
irritability
dysphoria
sesitivity to pain
abdominal cramps
N&V
diarrhea
muscle aches
mydriasis
sweating
piloerection
tachycardia
hypertension
fever - Opioid detoxification
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only prevents PHYSICAL dependence
1. switch to long acting opioid (methadone)
2. gradually change dose to wean off
3. eventually stop - Toxic OD of opioids
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common cause of death in abuse
Triad of symptoms - resp depression, miosis (dilate with enough hypoxia) and coma
pulmonary edema = cause of death for 50% of cases
- initiated by mu receptors
- not reversible by antagonist
therapy is vital fcn support, opiod (MU) antagonist
- don't give too much
- very fast action (~5min) - Therapeutic effects of opioids
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analgesia
cough supression
antidiarrheal - Adverse effects of opioids
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Psych dependence
physical dependence
resp depression
N&V
dizziness
sedation
constipation
miosis
pruritis
biliary spasm
urinary retention
hypotension - Opioid kinetics (general rules)
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well-absorbed
low F due to 1st pass
highly lipid soluble
- lots of routes available (nasal, buccal, skin, IM, SC, IV, intrathecal, epidural) - Morphine
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full MU agonist
most common, inexpensive
terminal cancer use!
25% oral F, but ok due to low cost
morphine 6-glucuronide = active metabolite
- longer t1/2
- accumulates in chronic use
- lots of effects - Heroin
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full MU agonist
no legit use in US
most widely abused opioid
more lipid soluble = more crosses BBB
active metabolite (monoacetyl morphine) which also crosses BBB
metabolised to morphine in brain - codeine (3 methyl-morphine)
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low affinity MU agonist
10% metabolized by 2D6 to morphine (lots of polymorphisms = OD or no fx)
alone = not potent, but good when combined w/ NSAIDS
relatively high F
PSYCH dependence UNLIKELY but POSSIBLE
- common abuse = kids or people trying to avoid withdrawal to other opioid
PHYSICAl dependence extremely unlikely regardless of dose/duration - meperidine
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DEMEROL, pethidine
1/10th as potent, shorter action
less constipation, miosis and urineary retention
toxic CNS stimulant is metabolite (normeperidine), long t1/2
Interact with MAOI - serotonin syndrome
mainly abused by HC pro's - Fentanyl
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SUBLIMAZE
80-100x more potent
high lipid solubility
short duration (0.5-2h)
versatile - Fentanyl uses
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pre-, intra-, post-op ANALGESIA
opioid ANESTHESIA
- not unconsicous, but not aware of pain
TRT chronic pain (patch) or breakthru pain (lollypop)
animal tranquilizer (esp w/ droperidol) dart gun - methadone
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good F
long t1/2 (15-40h), strong tissue binding - methadone uses
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analgesia
facilitate detox of opioid physical dependence
methadone maintenance:
no high, but occupies receptors
no withdrawal, craving
get person out of drug scene
makes person methadone-dependent, but they aren't an addict - diphenoxylate
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LOMOTIL
exclusively for diarrhea
abuse unlikely --> added atropine = atropine poisoning b/f high - loperaminde
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IMMODIUM
poor F
exclusively for diarrhea
abuse unlikely --> F ~0 therefore, action is only in gut -
propoxyphene HCl
propoxyphene napsylate -
DARVON/DARVON N
potency about same/less than codeine
for mild/moderate pain
PSYCH dependence, but not physical -
Partial MU agonists and Mixed KAPPA agonist/ MU antagonist
Shared characteristics -
big dose can cause withdrawal
minimal cross dependence
LOW:
-resp depression
-physical dependence
Low to Mod:
-psych dependence - buprenorphine
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BUPRENEX
partial MU agonist
- bind tightly, slow dissociation = long duration
25-50x potency for analgesia
VERY low F --> only IJ or sublingual
Used as analgesic (vet med) and detox (subs for methadone) - pentazocine
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TALWIN
strong KAPPA agonist, weak MU ANTagonist
analgesia from kappa agonism
Low F --> only slightly more potent than coediene (when PO)
psychotomimetic at large doses - TALWIN NX
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petazocine + antihistimine = abuse as an IJ(similar to heroin)
add naloxone --> no effect when PO, but blocks effect when injected for abuse - butorphanol
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STADOL
mixed kappa/mu antagonist
similar to pentazocine - Opioid antagonists shared charactersists
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pure antagonist at ALL receptors
prevent/reverse all clinically active opioids
Used to treat OD and excessive Post-op effets - Examples of opioid antagonists
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naloxone/NARCAN
naltrexone/REVIA
nalmefene/REVEX - tramdol
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ULTRAM
weak MU agonist - similar to codeine/propoxyphene
inhibits 5HT/NE reuptake
moderate to severe pain
abuse potential low, but increasing - dextromethorphan
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stereoisomer of opioid
NOT an opioid b/c no action at any known opioid receptor
No opioid or high/physical dependence
Increasingly abused for hallucinogenic effects
-Binds to PCP site