Opioids Flashcards
What are the three major sites of action of opioids?
- Brain (supraspinal): pre and post synaptically to activate descending inhibitory pathways
- Spinal cord: Directly on the dorsal horn of the spinal cord
- In the periphery: Peripheral terminals of nociceptive neurons
What are opioids used for in anesthesia?
- Attenuate the SNS response to noxious stimuli
- Adjunct to IA during anesthesia
- Sole anesthetic
- fentanyl/Sufentanyl/Morphine: cardiac anesthesia or critically ill patients
- Peri-op and post-op pain control
What characteristics unique to opioids set them apart from other analgesics?
- effective for moderate to severe pain
- no max dose or ceiling effect
- tolerance can develop with chronic use
- physical dependence, but not necessarily psychological dependence
- cross tolerance between drugs
- produce analgesia without loss of
- touch
- proprioception
- consciousness (in smaller doses)
What are the different opioid classifiacations?
- Naturally occuring- morphine and codeine
- Semisynthetic- analogs of morphine
- heroin, hydromorphone
- Synthetic-Exogenous
- Agonist
- partial agonist
- mixed agonist/antagonist
- antagonist
What are agonists?
Antagonists?
- Agonist- drugs that occupy receptors and activate them
- antagonist- drugs that occupy receptros but do not activate them; block receptor from agonist
What is the MOA of opioids?
- Activate stereospecific GCPR:
- Post synaptic- directly decreases neurotransmission
- increased K conductance (hyperpolarization)
- Ca channel inactivation (decreased neurotransmitter release)
- Modulation of phosphoinositide signaling cascade and phospholipase C
- inhibition of adenylate cyclase (decreased cAMP) *delayed
- Pre-synaptic- inhibits the release of excitatory neurotransmitters
- decreased ACh, dopamine, NE, substance P release
What are the opioid receptors?
What is the theory?
- MU, kappa, delta
- theory: synthetic opioids mimic action of endogenous opioids by binding to opioid receptors
- activating pain modulating systems
- The different drugs have varying affinity for the receptors?
Mu receptor
Subtypes?
Where are they?
- Subtypes Mu-1, mu-2, mu-3
- Mu-3 may be involved in immune process
- All endogenous and exogenous agonists act on mu receptors
- Mu receptors are found in the brain, periphery, and spinal cord
What are the differences between the receptors?
Supraspainal and/or spinal?
effects?
Agonists
(chart)
*Endorphins= all endogenous and exogenous agonists work on these receptors
What receptor do opioid agonist-antagonists often prinicpally interact with?
Kappa
Which CYP commonly has mutations that can alter the metabolist of opioids?
Which opioids are affected?
What opioid is least likely to be affected?
- CYP2D6
- Causes unpredictable pharmacokinetics and 1/2 lves of:
- codeine
- oxycodone
- hydrocodone
- methadone
- Fentanyl is least likely to be affected
Rate of opioid metabolism may influence ______ _______.
Ultra-rapid metabolizers are at increased risk for ______.
Side effects
PONV
What are perioperative CV effects of opioids?
- minimal CV impairment when used alone, additive when used with other anesthetics
- dose dependent bradycardia
- Central vagal stimulation
- direct SA, AV nodal depression
- Vasodilation/decreased SVR
- impairment of SNS responses and baseline tone
- pronounced w/hypovolemia
What CV effects are unique to morphine and meperidine?
- dose/infusion rate dependent histamine release.
- bronchospasm
- dramatic drops in SVR and BP
- Variable response among individual patients
- Meperidine can cause tachycardia with more prominent direct myocardial depression
What are the CNS effects of opioids?
- Analgesia
- euphoria
- drowsiness/sleep
- miosis
- nausea- chemoreceptor trigger zone (CRTZ)
- If hypoventilation prevented:
- modest decrease in ICP
- decreased CBF
- NO amnesia
What are the Renal/GI/Liver effects of opioids?
- increased tone and peristaltic activity of ureter and detrusor muscle tone = increased urgency, with decreased ability to void
- decreased catecholamine release and cortisol
- Sphinctor of oddi spasm and gallbladder contraction with increase in biliary pressure
- spasm of GI smooth muscle
- constipation- decreased GI motility
- prolonged gastric emptying
What are the GI effects of opioids?
- Decreased gastric emptying
- Direct stimulation of CRTZ on the floor of the 4th ventricle
- partial dopamine agonist?
- Morphine depresses the vomiting center in the medulla
What is the cause of pruritis?
Where does it primarily occur?
- Cause unknown
- most probably explanation is histamine release (MSO4)
- primarily on face and particularly nose
- fentanyl nose itch
What are the Skeletal muscle effects of opioids?
- Skeletal muscle rigidity in chest, abdomen, jaw, and extremeties
- esp w/large, rapid boluses
- fentanyl, sufentanil, and hydromorphone
- can make ventilation difficult or impossilbe
- high airway pressures from increased intrathoracic pressures decreases venous return
- esp w/large, rapid boluses
- Glottic rigidity and glottic closure have been reported
What are the ventilatory effects of opioids?
- Dose dependent respiratory depression
- small doses: increased TV, decreased RR; overall decrease MV
- larger doses: decreased RR and TV
- Decreased chest wall compliance
- Donstriction of pharyngeal and laryngeal muscles
- cough suppresion
- decreased response to hypercarbia and hypoxia
- Morphine and meperidine= histamine release–>bronchoconstriction
What factors can affect the magnitude and duration of opioid induced respiratory depression?
- amount of pain/surgical stimulation
- intermittent bolus vs cont. infusion
- speed of injection
- concurrent admin with other anesthetics
- decreased clearance
- age
Morphine:
use
administration
metabolism
- IM or IV for severe acute pain, PO for chronic or cancer pain
- slow release formulations available- onset delayed 3-5 hours, not used perioperatively
- Metabolism
- considerable first pass effect
- 1/2 life 3-4 hours, converted to active metabolite (morphine-6-glucuronide)
Codeine
use
administration
E1/2t
matabolism
Exception
- Use: mild pain relief, cough
- PO
- E1/2t = 3 hours
- Metabolism: prodrug, 10% is metabolized by CYP2D6 to active form and remainder is demethylated to inactive metabolite
- active form has equal analgeia to morphine
- 10% caucasians and 30% asians lack 2D6 and experience no analgesic effect
Hydrocodone:
use
route
problems
- AKA Vicodan
- PO
- Analgesia (chronic pain), antitussive
- Always combined with eithr ASA, ibuprofen, antihistamine, acetaminophen
- High abuse potential
Oxycodone
AKA
use
problems
- AKA oxycontin, percocet, percodan
- PO- available in sustained release preparation (oxycontin)
- Use: moderate to severe pain, useful for chronic and post-op pain
- in combination with ASA or acetaminophen
- No active metabolites- safer in pts with renal dysfunction
- High abuse potential
- According to Dr E: Terrible, dont give it to anyone
Methadone
route
class
plasma half life/metabolites
use
- PO, IV, SC
- synthetic
- No active metabolites; long plasma half life 8-100 hours
- Use: opioid addiction treatment (dosed q day)
- chronic pain: BID or TID
- at risk for respiratory depression d/t prolonged and unpredictable E1/2t
How long does it take to develop tolerance to opioids?
What is the progression?
- 2-3 weeks of opioid use
- Pt first shows reduction in adverse effects
- tolerance to sedative and emetic effects more rapid than constipation
- shorter duration of analgesia
- then effectivenesss of each dose decreases
Which class of opioids can cause cross tolerance?
- Cross tolerance exists among all full agonists but is not complete
- When switching to another opioid, start with half or less of the normal analgesic dose
Random stuff about opioid dependence (4)
- Physical dependence causes abstinence symptoms upon sudden D/C
- Clinically significant dependence develops only after several weeks of chronic treatment
- addiction involves psychological dependence and biologic and social factors
- Cancer pain and acute pain patients rarely experience euphoria and even more rarely develop psychological dependence or addiction
How are opioids dosed?
- Doses vary widely from one pt to another
- no minimum or max, unless combined with acetaminophen or ASA
- dose is based on how much is required to alleviate symptoms with tolerable side effects
- sustained release should be used for chronic pain
If pain is well controlled and switching opioids, calculate the equivalent dose and reduce by ____ for the dose of the new drug.
25%
What are the neuraxial effects of opioids?
- Analgesia is a result of diffusion of the drug across the dura to mu receptors in the substantia gelatinosa
- if drug is more lipophillic, will pass into the vasculature and have a systemic effect
- Opioids given epidural or spinal have a different onset, duration, and side effects as same drug given IV
- Amt of cephalad movement of opioid in the CSF depends on lipid solubility
How does lipid solubility of opioids affect neuraxial antsthesia?
- Opioids that are highly lipid soluble will have limited migration b/c of uptake into the spinal cord and vasculature
- ex. Fentanyl
- Less lipid soluble opioids will remain in CSF and will migrate
- ex. Morphine
Dose for epidural is ____ times ______ than spinal dose
5-10x
higher
