Opioids Flashcards
What causes drug to be classified as an opioid?
All substances, natural and synthetic, that bind to opioid receptors and produce agonist effect
2 chemical structures of opioids?
Phenanthrenes
Benzylisoquinolines
What is a naturally occurring opioid?
Morphine
Semisynthetic opioids (analogs of morphine)?
Heroin
Hydromorphone
Codeine
Types of of synthetic opioids?
Morphine derivatives
Diphenyl derivatives
Benzomorphans
Phenylpiperidines
Which drugs are morphinan derivatives?
Levorphenol
Butorphenol
- now becoming popular for people in withdraw, since discovering people can also become additcted to methadone
What opioids are diphenyl derivatives
Methadone
What drugs are benzomorphans?
Phenazocine
Pentazocine
Which drugs are phenylpiperidines?
Meperedine,
Fentanyl,
Alfentanil,
Sufentanil,
Remifentanil
-Most useful to us. Will ask on boards
What is another way to classify opioids?
- Agonist
- Partial agonist
- Mixed/agonist/antagonist
- Antagonist
What is an example of partial agonist?
- Buprenorphine
- regardless of dose, the drug cannot produce a full mu receptor effect like morphine
What is an example of mixed agonist/antagonist?
Nalubphine is agonist on one receptor, (kappa), and antagonist at mu reversing respiratory depression
What is example of antagonist opioid?
Naloxone
What are 3 endogenous agonists for opiate receptors?
Enkephalins
Endorphins
Dynorphins
Which receptors are opioid receptors?
Mu
Kappa
Delta
How do synthetic opioids work?
- Mimic action of endogenous opioids by binding to opioid receptors
- Activating pain modulating systems
- antinociceptive, inhibint gexcitatory neurotransmitters (ie substance P)
What are subtypes of Mu receptors?
Mu1 Mu2<<- main receptors we’re concerned with
Mu3–> immune modulation
Where are Mu receptors typically?
CNS- brain, spinal cord
All endogenous and exogenous agonists act on ___ receptors.
Mu
What are effects of activation of Mu-1 Receptors?
- Analgesia (supraspinal, spinal)
- Euphoria
- Supraspinal analgesia
- Miosis
- Bradycardia
- Urinary retention
- Low abuse potential
All endogenous and exogenous agonists act on these receptors
What are effects of action on Mu-2 recepots?
- Hypoventilation
- Physical dependence
- Spinal analgesia
- Constipation (marked)
All endogenous and exogenous agonists act on these receptors
What does activation of Kappa receptor cause?
- Supraspinal and spinal analgesia
- Dysphoria (state of unease)
- Sedation
- Miosis (pupillary constriction)
- Diuresis
- Low abuse potential (per table)
- Only dynorphins act on these receptors
What are effects of activation of delta receptors?
- Supraspinal and spinal analgesia
- Hypoventilation
- Physical dependence
- Constipation
- Urinary retention
Only enkephalins act on these receptors!
Do opioids we give interact with delta, kappa?
No
Except demerol acts on kappa
What substances are agonists to Mu1 receptors?
- Endorphins (all endogenous opioids)
- Morphine
- Synthetic opioids
What substances are agonists at Mu2 receptors?
- All endogenous opioids (endorphin, dynorphin, enkephalin)
- Morphine
- Synthetic opioids
What substance is agonist for kappa recepotrs?
Dynorphin only
What substance is agonist for delta receptors?
Enkephalin only
What substances are antagonists for all 4 opioid receptors?
- Naloxone
- Naltrexone
- Nalmefene
What is mechanism of action of opioids on cell membrane?
- Increase K conductance
-
Increase MAP kinase cascade
- this pathway leads to phospholipase A and production of prostagalndins and leukotrienes (immune modulation)
-
Inhibit Calcium channel (crux of how opioids work)
- suppression of neurotransmitter release (sub P)
- Inhibit adenylate cyclase (decrease cAMP)
Activation of opioid receptors causes either:
- Directly decrease neurotransmission (can’t make neurotransmitters)
- Inhibits release of excitatory neurotransmitters (i.e. substance P) via inhibiting Calcium channels
For pKa, all opioids all act as ____ ____
Weak bases
What characteristics of opioids allow substance to diffuse from blood to target tissue?
Only unioninized and unbound opioids can diffuse from blood to target tissue
How does % ionization and protein binding affect onset?
- Higher % unionized= higher diffusible fraction and faster onset
- Higher % unbound= faster onset
What are factors affecting pharmacokinetics and phacaodynamics of opioids?
- Age
- neonates show decrease of rate of elimination d/t immature cyp 450
- elderly show greater brain sensitivity to the drug
- Weight- dose based on lean body mass not actual weight in kg
- Renal failure
- Hepatic failure
What is spinal analgesia effect by opioids?
- Produced by receptor activation in spinal cord and dorsal root ganglian
- specifically in substantia gelatenosa (lamina II, III): direct stimulation of these receptors produces intense analgesia from inhibition of substance P release
What is supraspinal analgesia effect by opioids?
- Produced by receptor activation in periaquaductal/periventricular gray matter (most effect)
- Hypothalamus, amygdala. Stimulation of these receptors reduce tranmission of nociceptive info from peripheral nerves into the spinal cord and up neuoraxis
What are some perioperative central nervous system effects of opioids?
- Analgesia
- Euphoria
- Drowsiness
- Repsiratory depression
- miosis
- Nause- chemoreceptor trigger zone
- Does not produce amnesia or anesthesia
- except at big whopping doses, get anesthesia but NO amensia
- Modest decrease ICP
- Decrease CBF
- Advantages in neuro-anesthesia
- hemodynamic stability
- CV stability
What are some perioperative cardiovascular effects of opioids?
- No impairment in CV function?
- Dose dependent bradycardia from vagal stimulation
- Tachycardia with demerol(meperedine) (close relationship to atropine and has antimuscarinic effects)
- myocardial depression with demerol
- Decrease CO and BP?
- Vasodilation
- from histamine relase with morphine and demerol
Other than demerol, very cardiac stable
What are cardiovascular affect of morphine (MSO4) when combines with N2O versus alone?
When combined with N2O, CV depression noted
Morphine alone does nto cause CV depression
What are perioperative ventialtory effects?
- Dose dependent respiratory depression
- dropping RR but increase TV
- Decrease compliance chest wall
- “chest wall rigidity”
- Constriction of pharyngeal and laryngeal muscles
- Hypercarbia, hypoxia
What are nontherapeutic respiratory effects of opioids
- Decrease RR with increased Vt (low doses)
- Decrease RR and Vt (high doses)
- Decrease hypoxic ventilatory drive (issue in COPD)
- Ventilatory respone curve reduced and shifted to right
- takes more CO2 to get brain to breath
Respiratory depression difference of morphine vs fentanyl?
- Peak onset of respiratory depression is slower for morphine than fentanyl
- Respiratory depression produced by morphine lasts longer than fentanyl
What increases magnitude/duration of opioid induced respriatory depression?
- Increased dose
- intermitten bolus vs continuous
- speed of injection
- never give drugs fast!!!
- Concurrent admin with other anesthetics
- synergistic effects
- Decreased clearance
- Age
- extremes of age
All opioids have a ____ ___ in plasma levels from reuptake of opioid from muscle, far, lung and intestine.
Secondary peak
What would you do to your dose in patient with alkalosis?
Decrease dose. Opioid weak base and more unionized in alkalotic patient.
How do opioids affect skeletal muscle?
- Laryngeal muscles spasm causing resistance to ventilation
- Inhibition GABA (GABA is inhibitory NT. therefore more excitatory in place= more spasm)
- Increase in dopamine
- Can make ventilation difficult or impossible
- treat by giving muscle relaxant
Perioperative Renal/GI/liver effects?
- Increase pristaltic and tone of ureters
- urgency
- Blocked catecholamine release and cortisol
- decrease stress response in OR
- Spasm of sphincter of oddi with increase in biliary pressure
- give glucagon to help ease spasm
- Constipation- decrease GI motility
- Prolonged gastric emptying
- can lead to nausea vomiting
What is relationship between opioids and pruritis?
- Cause is unknown
- Histamine release most probably and causes some of itching
- Occurs primarily on face and in nose
- fentanyl nose itch
What are the neuroaxial effect of opioids?
- Opioids placed in epdiural space may undergo uptake into
- fat
- systemic absorption
- diffusion into CSF
- Penetration into CSF depends on lipid solubility
- more lipid soluble, quicker peak CSF concentration
- Vascular absoprtion of opioid from epidural space depends on lipid solubility
- more lipid soluble, quicker peak concentration of opioid
- in fact, effect may be due to systemic absorption rather than CSF absorption
____ movement of opioid in CSF depends on lipid solubility. Describ
Cephalad
- Highly lipid soluble substance will be limited in migration because of uptake into spinal cord
- ie fentanyl
-
LESS lipid soluble opioid will remain in CSF for transfer to cephalid location
- ie morphine
morphine will move cephalad. Fentanyl will not
Side effects of neuraxial opioids?
- Pruritis- most common
- nausea/vomiting
- urinary retention
- ventilatory depression
- more rapid with lipophilic agents
- delayed with less lipophilic (6-12 hrs)
Pharmacokinetics of Morphine?
pka, %non-ion, protein binding, Vd, partiion coeff, elim half time
- pKa: 7.9
- Percent non ionized: 23%
- Protein binding: 35%
- Vd: 224 L (mod)
- Partition coeff: 1
- Elimination half time 1.7-3.3 h
General characteristics morphine?
- Poor lipid solubility, highly protein bound, highly ionized
- Produces analgesia, euphoria, sedation, nausea, pruritis, dry mouth
- produces vent depression
- histamine release!
- IM peak effect 45 min, IV 15-30 min
- DOA 4 hours
- Can cause bradycardia d/t direct stimulation vagus nerve
How does morphine cause bradycardia?
Direct simulation of vagus nerve, inhibits SA node
How is morphine metabolized?
- Metabolized by liver
- active metabolite: morphine-6-glucouronide (M6G)
- more potent than morphine!
- active metabolite: morphine-6-glucouronide (M6G)
- Kidney also plays role in extrahepatic metabolism
- renail failure has effects due to M6G (active metabolite)
- if kidney patient appears on exam, avoid morphine
Pharmacokinetics of meperedine?
pka, percent nonionized, protein binding, Vd, elim 1/2 time
- pKa= 8.5
- Percent non ionized= 7%
- Protein bound= 70%
- Vd = 305
- Elim 1/2 time= 3-5 hours
- part coeff= 32
Characteristics meperedine?
- Structurally similar to atropine, exhibits muscarinic effects
- Direct cardiac depressant
- Also similar to local anesthetics-blocks Na channels
- Potent alpha 2 receptor agonist effects
- DOA 2-5 hours
- Same amount of euphoria, sedation and analgesia as morphine at equianalgesic dosages
- 1/10th as potent as morphine
- Used to treat post op shivering-kappa and alpha 2 receptor activity
- avoid in pt with hx seizures, can cause seizures
What is active metabolite of meperidine?
Normeperidine
- Active metabolite lasting 3 days, 1/2 as potent- CNS stimulating
- This is what may cause seizures in patients
Characteristics hydromorphone?
- 5x more potent than MSO4
- Derivative of MSO4
- Rapid elimination and redistribution
- Q4H dosing needed
- more sedation but less euphoria than MSO4
Pharmacokinetics Fentanyl?
- pKa= 8.4
- Percent non ionized= 8.5%
- Protein binding= 84%
- Vd= 335 L
- Elim 1/2 time= 3.1-6.6
Characteristics fentanyl?
- More lipid soluble than morphine with shorter DOA- 75% of initial dose undergoing first pass pulmonary uptake
- rapid redistribution to inactive tissue sites such as fat, skeletal, and lungs
- multiple IV doses or con. infusion produces progressive saturation of inactive tissue
- Plasma [] does not decrease rapidly and DOA is prolonged- 2nd peak in plasma levels (due to drug sequestration in tissues)
- Has large volume of distribution secondary to more lipid soluble than MSO4 and plasma conc maintained by slow reuptake form inactive tissue sites
Fentanyl clinical significance?
- analgesic adjunct for sx
- blunts stimulation of incision, larngoscopy
- As sole anesthetic in large doses due to hemodynamic stability
- 100 times more potent than morphine
- wide range of doses 1-20 mcg/kg
- Lozenges 5-20 mcg/kg 45 min prior to induction
- Transdermal patch 75-100mcg/hr peak 18-24 hr left on for 72 horus
Pharmacokinetics of sufentanil?
- pKa= 8.0
- %union= 20%
- protein binding= 93%
- Vd= 123 L
- part coef= 1727<– what makes it quicker onset/off
- Elim 1/2 time= 2.2-4.6 hours
- outlier!!!
Characteristics of sufentanil?
- Analogue of fentanyl
- twice as lipid soluble as fentanyl
- highly protein bound (93%)
- undergoes first pass pulmonary uptake
- rapidly metabolized in liver
- weak active metabolite
- desmethysufentanil
- 10 times more potent than fentanyl
- 1000 times more potent than morphine
- rapid on/off, no histamine release, most potent opioid we have!
Sufentanil clinical significant?
- Used as adjunct for surgery and induction
- Compared to morphine and fentanyl produces quicker induction, earlier emergence, and earlier extubation
- used as infustion for outpatient surgery
Pharmacokinetics alfentanil?
pka, protein binding, %union, vd, elim 1/2 times
- pka= 6.5
- %nonion= 89%
- protein binding= 92%
- vd= 27 L (very small!)
- elim 1/2 time= 1.4-1.5 hours
Characteristics alfentanil?
- analogue of fentanyl
- 90% unionized state= VERY rapid CNS onset (1.4 min compared to fentanl (6.8 min) and sufentanil (6.2)
- highly protein bound
- despite intense protein binding, alfentanil diffusible fraction is higher than that of fentanyl
- 1/5th potent as fentanyl 10-20 times more potent than morphine
- combo of propofol, alfentanil, ketamine, patient will not move for sedation!!
Clinical significant of alfentanil?
- Rapid onset is useful for blunting hemodynamic response to noxious stimuli
- rapid effect due to 90% drug in non-ionized form
- used as infusion for outpatient surgery
Remifentanil pharmacokinetics
pka, %nonion, protein binding, vd, elim 1/2 time
- pka= 7.3
- %nonion= 58%
- protein binding 66-93%
- vd= 30 (small)
- elim 1/2 time= 0.17-0.33<– due to esterases
Characteristics remifentanil?
- Chemically r/t fentanyl but unique d/t ester linkage
- metabolized by tissue/plasma esterases (not pseudocholinesterases)
- rapid onset and duration
- very small vd, minimal accumulation in tusseus, even with infusion
- potency similar to fentanyl, 100 x more potent than morphine
- really good for infusion, especially if post op pain not a concern
- ie fertility clinic
Clinical significant remifentanil?
- Use to blunt noxious stimulus
- infusions for intermittent/long surgeries where rapid recovery is desired such as neurosx, op sx
- good for intraop wakeup
What are opioid agonist/antagonist?
- Mu antagonist/partial agonist and partial agonist at kappa
- analgesia with limited ventilatory depression and low probability of dependence
- side effects sim to opioid agonist
- may cause dysphoria-appa receptor stimulation
Which drugs are agonist/antagonist?
- pentazocine
- butorphenol
- nalbuphine
- dezocine
What is nalbuphine (nubain)?
- Mixed agonist/antagonist
- Equianalgesic to morphine
- works at kappa
- antagnoize respiratory depression while maintaining analgesia
- no adverse cv problems
- unlike narcan
- reverses spasm of sphincter of oddi
What is butorphenol?
- Agonist/antagonist
- acts as agonist at kappa and weak antagonist or partial agonist at mu
- dose dependent
- nasal spray for migraines
What is naloxone?
- Pure opioid antagonist
- blocks receptor sites and reverses respiratory depression and analgesia
- competitive antagonist at mu, kappa and delta
- DOA less than most opioids
- titratable
- onset 1-2 min, reversal is dose dependent
-
not benign
- reversal of opioid effect you get tach, htn, vent dysrhythmias, severe pain and also pulm edema
- pulmonary edema in pt with cv dx
- can induce pulm edema in health patient d/t catecholamine release
Drug dosages for meperidint?
- 50-100 mg IV produces variable degrees of pain relief and is not always effecctive in pt with severe pain
- big dose
- 12.5-25 mg q 2-5 min dosing
Fentanyl dosing?
- 1-3 ug/kg
- 25-50 mcg
- Infusion rates 0.01-0.05 mcg/kg/min
Remifentanil dosing?
- 1-2mcg/kg
- 0.05-0.25 mcg/kg/min infusion
Alfentail dosages?
- 10-20 MCG/KG
- INFUSION: 0.25-0.75 mcg/kg/min
Sufentanil dosages?
- 0.1-0.3 mcg/kg
- Infusion: 0.0015-0.01 mcg/kg/min
Intermittent dosages for fentanl, morphine, hydromorphone, demerol?
- Fent 25-50 mcg
- Morphine 1-5 mg
- Hydromorphone 0.25-0.5 mg
- Demerol 12.5-25 mg
Order of potency for opioids we know?
Sufentanil > Remifentanil >Fentanyl > Alfentanil > Dilaudid> MSO4 > Demerol
SRFA duh MD
