Opioid Agonists (2) Flashcards
Where do opiates originate from?
Papaver somniferum (opion /poppy juice)
When was morphine, codeine, and papaverine first discovered?
Morphine: 1803
Codeine: 1832
Papaverine: 1848
Opioids are all _________ substances
Exogenous
How did the term narcotic come about?
Greek for stupor, which has the potential to produce physical dependence
What is the purpose of the agonists-antagonists group?
Used to transition from pure agonist
List pure opioid agonists:
- Morphine
- Meperidine
- Sufentanil
- Fentanyl
- Alfentanil
- Remifentanil
- Codeine
- Hydromorphone
- Oxymorphone
- Oxycodone
- Hydrocodone
- Propoxyphene
- Methadone
- Tramadol
- Heroin
List opioid Agonists-antagonists:
- Pentazocine
- Butorphanol
- Nalbuphine
- Nalorphine
- Bremazocine
- Dezocine
- Meptazinol
List opioid antagonists:
- Naloxone
- Naltrexone
- Nalmefene
What chemical structure does morphine, codeine, and thebaine have?
Phenanthrenes
What chemical structure does Papaverine and Noscapine have?
Benzylisoquinoline
Where are agonist receptor sites for opioids located?
Pre and postsynaptic sites in CNS
Same receptors activated by endogenous ligands
What are the endogenous ligands that bind to opioid receptors?
- Enkephalin
- Endorphins
- Dynorphins
What is the MOA of presynaptic opioid receptors?
Inhibition of Ach, dopamine, norepinephrine, and substance P
Increased K+ conductance, Ca2+ channel inactivation, decreased neurotransmission,
Where are opioid receptors found in the brain?
- Periaqueductal grey
- Locus Ceruleus
- Rostral Ventral Medulla
- Hypothalamus
Where are opioid receptors located in the SC?
Interneurons and primary afferent neurons in the dorsal horn (substantia gelatinosa)
Intense analgesia
Are there opioid receptors outside the CNS?
Yes, Sensory neurons and immune cells
(Intra-articular morphine after knee surgery)
Label:
A) Hypothalamus
B) Periaqueductal grey
C) Rostroventral Medulla
What are the main effects from M1 opioid receptor?
- Analgesia (supraspinal/spinal)
- Euphoria
- Low abuse potential
- Miosis
- Bradycardia
- Hypothermia
- Urinary retention
What are the main effects from M2 opioid receptor?
- Analgesia (spinal)
- Depression of ventilation
- Physical dependence
- Constipation (marked)
What are agonists for Mu1 and Mu2 receptors?
- Endorphins
- Morphine
- Synthetic opioids
What are antagonists for Mu1, Mu2, Kappa, and Delta receptors?
- Naloxone
- Naltrexone
- Nalmefene
What is the main effects of Kappa opioid receptor?
- Analgesia (supraspinal/spinal)
- Dysphoria, sedation
- Low abuse potential
- Miosis
- Diuresis
What are agonists of Kappa opioid receptors?
Dysnorphins
What are the main effects of Delta opioid receptors?
- Analgesia
- Depression of ventilation
- Physical dependence
- Constipation (minimal)
- Urinary retention
What are agonists of Delta opioid receptors?
Enkephalins
Which receptor produces physical dependence?
Mu2 and Delta
What is a CV system benefit of opioids?
Cardioprotective from myocardial ischemia
What are CV side effects of opioids?
↓ SNS tone in peripheral veins
* Decrease venous return, CO, BP
* orthostatic hypotension and syncope
↓HR/ Histamine release leading to ↓BP
Further CV depression (↓CO/BP) when giving opioids with _____ or _______.
N2O, Benzos
What are respiratory side effects of opioids?
- Increase in resting PaCO2
- Respiratory depression (Mu2)→ decreased rate with compensatory increase in VT
- Cough suppression
*
What happens with opioid OD?
Apnea, Miosis, hypoventilation, and coma
What med can antagonize ventilatory depression of opioids but doesnt antagonize analgesia?
Physostigmine: increases CNS levels of Ach
Which opioids is used for cough suppression?
*Codeine
*Dextromethorphan (no analgesia)
What can cause PaCO2 shift to the left/decreasing the level?
Metabolic acidosis
What can cause paCO2 shift to the right/increase?
- Sleep (slightly)
- Opiates
- Anesthesia
What are CNS side effects of opioids?
- Decrease CBF and maybe ICP
- Myoclonus with large doses
- Skeletal thoracic (chest wall)/ abd muscle rigidity
- Sedation
Why do we need to be cautious when giving opioids to patients with head injuries?
Wakefulness, miosis, paCO2, BBB
When is skeletal muscle rigidity S/E severe?
With mechanical ventilation
How do you treat skeletal thoracic muscle rigidity from opioids?
Muscle relaxation or naloxone
What are potential GI side effects from opioids?
- Spasm of biliary smooth muscle
- Delayed gastric emptying and constipation
- N/V: direct stimulation of chemoreceptor trigger zone, increase GI secretions and delayed emptying
Which opioids commonly cause Sphincter of Oddi spasms?
- Fentanyl (99%)
- Meperidine (61%)
- Morphine (53%)
How are opioid induced biliary spasms (sphincter or Oddi spasm) treated?
- Naloxone: 40mcg IV
- Glucagon: 2mg IV→ give incrementally
- Atropine: 0.2mg IV
- Nalbuphine: 10mg IV
- Nitroglycerin: 50mcg IV
What are potential S/E of opioids for GU, cutaneous, and placenta?
GU: urinary urgency
Cutaneous: Histamine release= flushing of face, neck, chest
Placenta: Neonate depression, dependence (chronic use)
The development of the requirement for increased drug doses (usually 2 to 3 weeks):
Tolerance
What is the time frame for tolerance development to morphine?
25 days
What happens as a result of downregulation of opioid receptors?
Need increased opioid dose to get the same effect
Why does downregulation occur?
Opioid receptors on the cell membrane surfaces become gradually desensitized by reduced transcription & subsequent decreases in numbers of opioid receptors.
_______________ can develop between all opioids.
Cross-tolerance
What is onset of Meperidine withdrawal symptoms?
Peak intensity?
Duration of withdrawal?
onset: 2-6 hours
peak: 6-12 hours
duration: 4-5 days
What is the onset of Fentanyl withdrawal?
Peak intensity?
Duration of withdrawal?
O: 2-6 hours
P: 6-12 hours
D: 4-5 days
What is the onset of Morphine withdrawal?
Peak withdrawal intensity?
Duration of withdrawal?
O: 6-18 hours
P: 36-72 hours
D: 7-10 days
What is the onset of Heroin withdrawal?
Peak withdrawal intensity?
Duration of withdrawal?
O: 6-18 hours
P: 36-72 hours
D: 7-10 days
What is the onset of Methadone withdrawal?
Peak withdrawal intensity?
Duration of withdrawal?
O: 24-48 hours
P: 3-21 days
D: 6-7 weeks
Studies have shown that higher doses of intra-op opioids cause ________ post op pain
Greater
What is the intra-op dose for morphine?
1-10mg IV
What is PostOp dose for Morphine?
5-20 mg
Onset, Peak, and duration of Morphine:
O: 10-20 min
P: IV (15-30 min) IM( 45-90 min)
D: 4-5 hours
What is the IntraOp/induction dose for Fentanyl?
1.5-3 mcg/kg IV 5 min before
What is the onset and duration of Fentanyl?
O: 30-60 seconds
D: 1-1.5 hours
What is the IntraOp dose for Sufentanil?
0.3-1 mcg/kg
What is the onset and duration of Sufentanil?
O: 30-60 sec
D: 1-1.5 hr
What is the continuous infusion rate for Sufentanil?
0.5-1 mcg/kg/hr
What is the loading/IntraOp dose for Remifentanil?
Load: 0.5-1 mcg/kg over 1 min
What is the onset and duration of Remifentanil?
O: 30-60 sec
D: 6-8min
What is the rate of continuous infusion for Remifentanil?
0.125- 0.375 mcg/kg/min
What is the postop dose for Meperidine and what is it used for?
12.5 mg (post op shivering)
What is the onset and duration of meperidine?
O: 5-15 min
D: 2-4 hrs
What is the IntraOp dose of Hydromorphone?
1-4 mg
What is the postop dose of hydromorphone?
1.5-4 mg
What is onset and duration of hydromorphone?
O: 5-15 min
D: 2-4 hrs
What is IntraOp dose of naloxone?
40-80mcg
What is PostOp dose of Naloxone?
40-80 mcg
What is onset and duration of Naloxone?
O: 1-5 min
D: 30 min
What is the gold standard for opioids?
Morphine
What are the effects of Morphine?
- Analgesia
- Euphoria
- Sedation
- Nausea
- Body warmth
- Heaviness of extremities
- Dry mouth
- Pruritis
What pain does morphine aim to eliminate?
What fibers would it be working on?
Relieves visceral, skeletal muscles, joints, and integumental dull, intermittent pain
C fibers
What is the primary means of metabolism of morphine?
Hepatic 1st pass (25%)
Glucoronic acid conjugation in hepatic and extrahepatic sites
Morphine accumulates rapidly in the __________, __________, and ___________ __________.
Kidneys, Liver, and Skeletal Muscles
What are metabolites of morphine?
- Morphine-3-glucuronide → 75-95% (inactive)
- Morphine-6-glucuronide → Active analgesic
What needs to be considered when giving morphine to patients with renal failure?
Prolonged depression of ventilation with renal failure
Which group of people tend to have increased responses to morphine and slower speed of offset?
Women
What happens to serum concentration of morphine with increased age?
Plasma concentration of morphine increases progressively with advancing age
What opioid receptors does meperidine (pethidine) activate?
Agonist at Mu and Kappa opioid receptors
potent agonist at alpha 2 receptors
What are analogues of meperidine?
- Fentanyl
- Sufentanil
- Alfentanil
- Remifentanil
What drugs is meperidine structurally similar to?
*Lidocaine: tertiary amine, ester group, & lipophilic phenyl group
*Atropine
Meperidine is ____ as potent as Morphine
1/10
What are the effects of meperidine?
- Sedation
- Euphoria
- N/V
- Depression of ventilation
How is meperidine metabolized? Metabolites?
Hepatic first pass 80%
90% hepatic metabolism
Normeperidine (metabolite)
Meperidine is ___% protein bound
60% (consideration for elderly population)
What are symptoms of meperidine toxicity?
- Delirium (confusion, hallucination)
- Myoclonus
- Seizures
How is meperidine eliminated?
Renal (acidic urine can speed elimination)
What is E1/2 time of meperidine? How does it change with renal failure?
3-5 hours
35 hours with renal failure
What routes can meperidine be given?
IV, IM, Intrathecal
What other drugs can be used for postop shivering?
Alpha 2 agonists (clonidine)
What are side effects of Meperidine?
- Tachycardia
- Mydriasis
- Dry mouth
- inotropy
- Serotonin Syndrome (MAOIs and TCAs)
- Impaired ventilation
- Crosses placenta
_______ is 75-125X more potent than Morphine
Fentanyl
What is onset for Fentanyl?
6.4 minutes
What is the primary spot for first pass metabolism for Fentanyl?
75% lung first pass
What do the lungs act as for Fentanyl?
Reservoir for fentanyl and for extraction of fentanyl
What is the metabolite of fentanyl?
Norfentanyl
How is Fentanyl metabolized and excreted?
Metabolized CYP3A
Excreted by kidneys
What is the Vd for Fentanyl?
Large Vd (High lipid solubillity)
* IV→ less than 5 min 80% is gone
Can you give fentanyl to someone with liver cirrhosis?
Yes, Not an issue because of lung first pass effect.
How does Fentanyl context-sensitive half time compare to Alfentanil, Sufentanil, and Remifentanil?
Fentanyl context sensitive half time is greater than all of these→ this is d/t saturation of inactive tissue
Other drugs do not go into tissues as much as fentanyl because the other drugs are less lipid soluble compared to fentanyl
What is the fentanyl dose for analgesia?
1-2 mcg/kg IV
What is the fentanyl dose for adjunct with inhaled anesthetics?
2- 20 mcg/kg IV
What is Fentanyl dose if giving solo for surgical anesthesia?
50-150 mcg/kg IV
What is intrathecal fentanyl dose?
25 mcg
What is oral fentanyl dose?
5-20 mcg/kg
* rapid dissolving film or lozenge (peds)
*2-8 y/o: 15-20 mcg/kg PO 45 min prior
1mg PO Fentanyl = ___ mg IV Morphine
5
What is transdermal dose of Fentanyl?
75-100 mcg (18 hours steady delivery)
What are CV side effects of Fentanyl?
Large doses→ No histamine release, Depressed carotid sinus baroreceptor relfex
No bradycardia
Decreased BP/CO
What are other general side effects of Fentanyl?
- Seizure like activity
- SSEP and EEG (> 30mcg/kg IV)
- Modest increase in ICP (6-9mmHg)
What drugs are synergistic with Fentanyl?
- Benzos
- Propofol
Decrease doses requirement
When did Sufentanil first come about? Sufentanil is _____ - ____ times more potent than Fentanyl
1974
5-12 times more potent than fent
What are pharmacokinetics of Sufentanil?
- 60% lung first pass uptake
- 92.5% protein binding
- Smaller Vd than fentanyl (larger Vd than alfentanil)
- Hepatic metabolism
- Renal and fecal excretion
- shorter context sensitive 1/2 time
What plasma protein does Sufentanil bind to?
alpha-1 acid glycoprotein
Sufentanil doses for Analgesia, Induction, IntraOp, and Infusion:
- Analgesia: 0.1 to 0.4 mcg/kg IV
- Induction: 18.9 mcg/kg IV
- Intraop: 0.3 to 1 mcg/kg IV
- Infusion: 0.5 to 1 mcg/kg/hr IV
What are side effects of Sufentanil?
- Bradycardia (decreased CO)
- Rigidity (chest wall and abd muscles)
You have 250mcg/5mL vial of Sufentanil.
How many mcg in 1 mL?
How many mcg in 2mL?
If you dilute 2Ml in a 20mL syringe, what is final concentration?
- 50mcg/mL
- 100mcg/2mL
- 5mcg/mL
When did Alfentanyl come out?
Alfentanil is ____ less potent than Fentanyl
1976
1/5th
What is the onset of Alfentanil?
1.4 minutes (greater than fentanyl and sufentanil)
Pharmacokinetics of Alfentanil:
- Cirrhosis: prolongs elimination half-time
- 90% nonionized at normal pH (Lower lipid solubility
- Higher protein binding: same with sufentanil
- Metabolite: noralfentanil (hepatic P450 3A4)
What are uses and doses for Alfentanil?
- Induction laryngoscopy: 15-30mcg/kg IV
- Induction alone: 150-300 mcg/kg IV
- Maintenance: 25-150 mcg/kg/hr IV with inhaled anesthetics
When should Alfentanil be avoided?
Parkinsons disease: causes acute dystonia (muscle rigidity compartment)
Remifentanil is _____ times as potent as Alfentanil
15-20X
What is the structure of Remifentanil? What is the action/on/off set?
Ester Structure: Hydrolysis by nonspecific plasma and tissue esterases
- Brief action, rapid onset and offset (15 mins)
- Precise and rapid titratable effect
- Lack of accumulation
- Rapid recovery when discontinued
Remifentanil causes synergistic depression of ventilation when given with _________.
Propofol
What is the peak effect of Remifentanil?
30-60 second
What is the clearance of Remifentanil?
3L/min (8x more rapid than Alfentanil)
What is the primary metabolism of Remifentanil?
Non-specific tissue esterases
What is elimination 1/2 time of Remifentanil?
6.3 minutes
When is plasma steady state with infusion of remifentanil reached?
10 minutes
What is the induction and maintenance dose for Remifentanil?
Induction: 0.5- 1mcg/kg IV over 30-60 sec
Maintenance: 0.25-1mcg/kg IV OR 0.005- 2 mcg/kg/min IV
What should you do before stopping Remifentanil infusion?
Give longer acting opioid
_________ is not recommended for spinal or epidural use: probably d/t its rapid metabolism
Remifentanil
What are side effects of Remifentanil?
- Seizure like activity
- N/V
- Depression of ventilation
- Decreased BP and HR
- Hyperalgesia d/t previous acute exposure to large opioid doses
- Tolerance
What year did hydromorphone start being used?
Morphine derivative- 1926
Hydromorphone is ____ times more potent than __________.
5x more potent than morphine
What is the dose of hydromorphone? How often?
0.5 mg IV (1-4 mg total)
Re-dose every 4 hours
Does hydromorphone cause histamine release?
No
What routes can codeine be given?
PO/IM (no IV–caused histamine induced hypotension)
What is E 1/2 time for codeine?
3-3.5 hours
Where is codeine metabolized?
Liver
What is the dose of codeine for cough suppressant and analgesia?
Cough: 15mgs
Analgesia: 60mgs (120 mgs= 10mgs of morphine)
What are side effects of codeine?
- Physical dependence
- Minimal sedation
- N/V
- Constipation
- Dizziness
________ is 5-10x less potent than morphine
Tramadol
What receptors does tramadol work on? What is the dose? What are adverse interactions?
Mu with weak Kappa and delta
3 mg/kg
Interacts with Coumadin
Which opioid has the highest Vd?
Fentanyl (335)
Meperidine (305)
Morphine (224)
Sufentanil (123)
Remifentanil (30)
Alfentanil (27)
Which opioid has the shortest E1/2 time?
Remifentanil (0.17-0.33h)
Alfentanil (1.4-1.5h)
Morphine (1.7-3.3)
Sufentanil (2.2-4.6)
Meperidine (3-5)
Fentanyl (3.1-6.6)
Which opioid has the shortest effect site (from blood to brain) equilibration time?
Remifentanil (1.1 min)
Alfentanil (1.4 min)
Sufentanil (6.2 min)
Fentanyl (6.8 min)
Which opioid has the slowest clearance?
Alfentanil
Other opioid trend to know:
