8/30 Opiates - Welsh Flashcards
opium
mixture of alkaloids from opium poppy (papaver somniferum)
alkaloids
class of naturally occurring organic N-containing bases
ex. morphine, cocaine, caffeine, nicotine, vincristine, atropine, quinine
opiate
naturally occuring opium-derived alkaloid (morphine or codeine)
opioid
ANY natural, synthetic, or semi-synthetic compound with morphine-like props
classification of opioids
1. interaction with GPCR (mu, kappa, or delta)
- most opioid analgesics are relatively selective mu opioid agonists
- some kappa agonists (pentazocine, nambuphine, butorphanol), but not highly selective
- selective delta agonists are mainly peptides (none currently used clinically)
2. intrinsic activity
-
pure agonists:
- full agonists (morphine, fentanyl)
- partial agonists (buprenorphine)
-
pure antagonists:
- naloxone, naltrexone (used for detox, overdose, maint therapy for addicts)
-
mixed agonist-antagonists__:
- pentazocine, nalbuphine, butorphanol
- kappa agonists that produce analgesia but also act as mu antagonists (interfere with morphine, heroin, etc)
endogenous opioid peptides
endorphins, enkephalins, dynorphins
- located primarily in brain → fx as neurotransmitters or neuromodulators
- modulate pain transmission in spinal cord
- alter acetylcholine release in GI myenteric plexus
- beta endorphins are the cleavage product of pro-opiomelanocortin (POMC; precursor hormone for ACTH)
action of opioids in analgesia
- cellular mech of action
morphine has a mostly inhibitory effect on neuron
at presyn terminal
1. inhibits formation of cAMP (catalyzed by adenylyl cyclase)
2. inhibits uptake of Ca
- binding of morphine to mu receptor suppresses Ca influx → inhibits release of nts that convey pain perception (ex. glutamate, Substance P)
at postsyn terminal
1. opens K channel
- leads to hyperpolarization of cell → dampened neuron firing, reduced neuron excitability and pain
general clinical properties of opioid analgesics
both acute and chronic effects
- all mu opioid agonists produce these effects
- EXCEPTION: histamine release varies from one mu opioid to another
- EXCEPTION: meperidine (Demerol) productes mydriasis (pupil dilation)
clinical selection is usually based on PK considerations (speed of onset o action, duration, halflife, CNS permeability)
major clinical uses of opioids
6 with examples
1. analgesia for ACUTE moderate to severe pain (morphine, heroin)
- myocardial infarction (most imp use of morphine)
- severe injuries (exception: head injury)
- post-op
- renal colid, kidney stones
- severe bone/jt pain
- cancer patients (fentanyl IM or IV if pt becomes morphine-tolerant)
2. analgesia for moderate lon-term, chronic pain (oxycodone, hydrocodone)
3. anesthesia (fentanyl) : regional anesthesia such as spinal/epidural
4. cough suppressant (codeine, dextromethorphan)
5. relief from diarrhea (diphenoxylate, loperamide preferred due to lower BBB penetration)
6. acute PE (morphine) : vasodilatory effects to reduce dyspnea, resp distress, pain, anxiety
- use is controversial
- CNS effects of opioids
a. analgesia and mood
mechanisms:
- act centrally (brainstem, dorsal horn) to inhibit transmission and processing of pain signals
* emotional response to pain is altered by opioid actions on limbic cortex - act peripherally on sensory neurons
* sometimes useful for pain caused by tissue infl and nerve ending damage (ex. herpes zoster aka shingles)
clinical chars of opioids
- type of anagesia
- why addition?
- what types of pain respond?
- dosage?
- produce selective analgesia without hypnosis, sedation, impaired sensation
- potential for addiction bc can cause mood elevation/euphoria
- greater effect in chronic, burning pain than in sharp, temporary pain (ex. incision) → neuropathic pain (infl nerve pain) can be very resistant
- dosage can vary greatly from patient to patient
euphoria
opioids elicit euphoria by suppressing release of GABA → stimulating release of dopamine in a neighboring neuron
CNS effects of opioids
b. sedation
- drowsiness, feelings of heaviness, difficulty concentrating
- sleep may occur with relief of pain (but opioids are not hypnotics)
- most likely to occur in elderly/debilitated pts, those taking other CNS depressants (ex. alcohol, anesthetics, benzodiazepines)
CNS effects of opioids
CNS toxicity
contraindicated in cases of head injury!!!
- may exacerbate damage caused to respiratory center in brain
- opioid induced miosis, nausea, and general CNS clouding can confuse neuro eval
CNS effects of opioids
respiratory depression
- clinical chars
mechanisms:
- direct effects on resp centers in medulla
- decreased sensitivity to incr blood levels of CO2 in resp center of brainstem
- increased arterial CO2 retention → cerebral vasodil → increased ICP
clinical characteristics:
- abnormal drive to breathe (despite normal resp rate)
- dose-related effects
- v large doses can cause irreg breathing or apnea
- SLEEP depresses response to CO2 further → can potentiate opioid effect
resp depression is the major toxicity of opioids and nearly always cause of death from OD
- resp depression is directly correlated with analgesic effect
- difficult to reverse resp depression without losing some analgesic effects
CNS effects of opioids
cough suppression (antitussive)
- depression of cough center in medulla (and possibly periphery)
- diff molecular mechanism from analgesia or resp depression
- cough suppressed by d-isomers of opioids (ex. dextromethorphan), which have no analgesic activity
- codeine or dextromethorphan is the preferred agent (vs. morphine)
CNS effects of opioids
pupillary constriction
aka miosis
- caused by stimulation of Edinger-Westphal nucleus (PSNS) of CN III
- VISIBLE SIGN of opioid OD
- reversed by naloxone, atropine, or ganglionic blockers (ex. mecamylamine)
CNS effects of opioids
nausea and vomiting
direct stimulation of chemoreceptor trigger zone (CTZ) in area posrema (floor of 4th ventricle) → activates vomiting center!
- markedly potentiated by stimulation of vestibular apparatus → ambulatory patients are much more likely to vomit than those who are lying still!
CNS effects
muscle rigidity (skeletal tonus)
large IV doses can cause generalize stiffness of sk muscle
- believed to be due to mu-mediated incr in striatal dopamine synth AND inhibition of striatal GABA release
- happens most commonly with fentanyl and congeners
- may play a role in some OD fatalities
CV effects of opioids
- bradycardia due to stim of central vagal nerve
- vasodilation and orthostatic hypotension due to decreased central sympathetic tone
opioid effect on histamine release
morphine, fentanyl, meperidine cause non-immunological release of histamine → vasodilation, hypotension
occasionally causes redness of skin, urticaria (hives/rash), pruritis (itchy skin) near injection site
NOT an allergy (true allergic responses are v rare)
opioid smooth muscle effects
1. intestine and stomach
-
constipation : sm muscle spasm, diminished peristalsis, delayed gastric emptying
- chronic opioid use req admin of laxatives
- application: diphenoxylate and loperamide are poorly CNS-absorbed → used in tx of diarrhea!
2. biliary system
- contraction of sm muscle along biliary tree
-
spasm of sphincter of Oddi
- both can precipitate biliary coli (gallstones)
- effect anatonized by naloxone and partially reversed by glucagon, nitroglycerin, atropine
3. urinary tract
- anti-diuretic effect → urinary retention
- prob both central and peripheral mechs involved!
opioid effects on pregnancy and neonate
sometimes used (sparingly) to relieve labor pain (fentanyl, butorphanol, meperidine)
- all cross the placenta → if given during labor, can cause resp depression in baby
chronic use may cause physical dependence in utero and life-threatening neonatal withdrawal after delivery
opioid tolerance
repeated dosing → reduction in effect of opioid
- end up needing higher dose to produce same effect
mechanism MAY involve adaptive response of adenylyl cyclase and/or G protein coupling (i.e. it is NOT a pharmacokinetic effect)
develops rapidly to depressant effects: analgesia, resp depression, euphoria
develops much less to stimulatory effects: miosis, constipation
ex. heroin addicts/methadone maintenance pts may have little euphoria from high doses BUT still experience constipation and miosis
ex2. terminal cancer patients are tolerant to resp depression BUT require laxatives for constipation
physical dependence
(vs. psychological dependence)
withdrawal syndrome
produces withdrawal sx when drug stopped
- small dose of opioid can stop sx
giving antagonist (naloxone) to a physically dependent person → rapid onset of more severe withdrawal syndrome
symptoms: sweating, rhinorrhea, vomiting, diarrhea, piloerection, mydriasis, shaking chills, drug seeking behavior
physical dependence
vs
psychological dependence
physical: natural need for higher doses for analgesia
psych: addiction, craving for the “high”
methadone for opioid addiction
long-lasting opioid (24-35hr halflife vs 2-3hr morphine) used for detoxification to wean addicited individual off of morphine, heroin, etc.
protracted but mild withdrawal sx
- methadone must be tapered off slowly to avoid rise of acute withdrawal, craving, abuse
benefits
- intensity of withdrawal sx decreased (as well as drug seeking/illegal activity)
- develop a tolerance to opioid euphoria (so injection of heroin is non-reinforcing)
- mathadone given orally
- obtaining methadone means regular contact with caregivers/counselors
opioid overdose
resp depression is the hallmark sign of opioid intox
CLASSIC TRIAD:
- miosis
- apnea
- stupor (coma)
- pulmonary edema (late clinical manifestation)
- occasional seizures
- meperidine, pentazocine/naloxone
PK of morphine
fairly rapid absorption, wide distribution, rapid hepatic clearance from plasma
- 70% first pass metabolism
- polar metabolites cleared by kidney
morphine is hydrophilic so CNS penetration and exit are slow → slow onset and long duration
heroin is a more lipophilic prodrug of morphine w very fast CNA penetration
PK of fentanyl
80-100x more powerful than morphine
rapid absorption, wide distribution, moderately rapid hepatic clearance, short halflife (<1 hr)
- 60% first pass metabolism
extremely lipophilic → rapidly crosses bbb and other membrane barriers
multiple delivery routes: patch, intrathecal, intranasal spray, buccal mucosa
opioid agonist dosage
analgesic requirements are enormously variable!
therapeutic window is narrow and varies widely for each patient
low starting doses for:
- elderly
- hypovelemic
- debilitated
- hypothyroid
- on CNS depressants
commonly prescribed opioids
hydrocodone/acetaminophen (Vicodin)
oxycodone/acetaminophen (Percocet)
orally active opioid formulation for moderate-severe pain
dosage monitored by need to limit acetaminophen to < 8g/day (or lower if liver impaired)
two major opioid antagonists
naloxone (Narcan)
naltrexone (Vivitrol)
naloxone
Narcan
- pure, competitive antagonist at mu, kappa, and delta receptors
- highest affinity for mu
-
rapid acting: rapidly reverses opioid OD when injected IV/IM but has short duration
- immediate releif from acute resp depression, but can also induce severe withdrawal sx
- due to short half life, might need multiple/constant dosing
- not orally active
- added to many abuse-prone opioids (oxycodone, buprenorphine) to make them “abuse-resistant”
naltrexone
Vivitrol
- long-acting opioid antagonist used for maintenance therapy and relapse prevention once detox’d
- orally active
- NOT recomended for emergency OD tx
- NOT recommended for detox thx
opioid partial agonists and mixed agonist-antagonist
developed as part of effort to find analgesics with:
- lower abuse potential
- lower respiratory depression
all have analgesic props as well as ability to antagonize morphine effects
2 basic strategies:
- partial agonists at mu receptor
- mixed agonist-antagonists
partial agonists at mu receptor
ex. buprenorphine
- oral buprenorphine-naloxone combo is used for maintenance therapy in opioid and alcohol dependence
- added naloxone makes it “abuse-resistant”
mixed agonist-antagonists (nalorphine, pentazocine, nalbuphine, butorphanol)
(nalorphine, pentazocine, nalbuphine, butorphanol)
- act as kappa agonists to produce analgesia, and also act as mu antagonists
- WARNING: as mu antagonists, they can induce acute withdrawal in heroin/morphine addicts!
clinical chars of mixed agonist-antagonists
- effective analgesics (moderate-severe pain)
- relatively ltd toxicity (reduced resp depression or sm muscle effects)
- decreased abuse potential, but also decreased patient acceptance (side effects)
- can cause dysphoria, seizures, and precipitate withdrawals in addicts/OD patients
