Opioids Flashcards
What are the 3 major classes of opioid receptors?
- Mu
- Kappa
- Delta
What are opioids?
- All drugs (both natural and synthetic) with morphine-like properties
Opioids used as analgesics are predominately ________ receptor agonists.
Mu
Mu agonists act selectively on …?
- neurons that transmit and modulate nociception; they leave other sensory modalities and motor function intact.
What is the myenteric plexus?
- group of neurons in the gut
What are the 4 factors that affect the ability of opioids to cross the blood-brain barrier?
- Molecular size (small drugs pass more readily)
- Lipid solubility (lipid soluble drugs pass more readily)
- Ionization (non-ionized get across the BBB easier)
- Protein binding (highly protein bound drugs have less free drug available for transfer)
_________ is not highly protein bound and has a moderate fraction of free base. It’s very low lipid solubility limits rate of blood-brain transfer.
Morphine
________ has high lipid solubility that enhances blood-brain transfer. It also has high protein binding and a low free fraction that partially offset this effect.
- Fentanyl
- Fentanyl is faster than morphine because it is about 600x more lipid soluble
_________ : although highly protein bound, it has a very high fraction of free base and moderate lipid solubility. The latter two features make fro rapid blood-brain transfer.
- Alfentanil (faster than fentanyl)
__________: Moderate protein binding, a moderate fraction of free base, and low-moderate lipid solubility collectively result in rapid blood-brain transfer.
Remifentanil (equivalent to alfentanil)
Analgesia is mediated _________ and ____________.
- centrally
- and directly at the spinal cord level
Analgesia is mediated centrally by what receptor and in what 3 areas?
- Mu-1 receptor
- Periaqueductal gray, locus ceruleus, and medullary nuclei
- Central effects result in descending inhibition; sends signals down from the brain saying “I don’t want to hear about it”
How is analgesia mediated directly at the spinal cord level?
- Mu-2 receptors
- Presynaptically through inhibition of primary afferent (nociceptive) nerves by decreasing release of substance P
- Postsynaptically through hyper-polarization of interneurons in substantia gelatinosa to decrease afferent transmission of nociceptive impulses
Describe gender differences in analgesia?
- INTER-INDIVIDUAL DIFFERENCES ARE LARGER than inter-gender differences
- Response to opioids is so unpredictable
- Women have slower onset & slower resolution of analgesia at same blood morphine level; women also experience greater analgesic effect at same blood level
What is tolerance?
- it takes larger and larger doses to get the same effect
- With sustained opioid exposure, patients develop tolerance - requiring increasing dose to produce the same degree of analgesia
What is the one effect of opioids that is not affected by tolerance?
Constipation
What is hyperalgesia?
- more sensitive to pain
What are the systemic withdrawal symptoms of opioids?
- restlessness
- lacrimation
- nausea
- myalgia
- diarrhea
- tachycardia
- hypertension
What is the classic sign of respiratory depression?
- tidal volume maintained, respiratory rate decreases (slow venitlatory rate, big tidal volumes)
Opioids cause a shift to the right. What does this mean?
- An increase in the apneic threshold & resting PaCO2
Opioids decrease the body’s response to __________ and __________.
- Hypercarbia and Hypoxemia
Can you get analgesia without respiratory depression?
No, you cant separate the two!
Where do we titrate the effects of opioids to?
- About a 50% reduction in pain and about a 50% reduction in ventilation
When is the peak effect of Morphine?
- 2-3 Hours ; NOT 15-20 min.
What is the more variable effect of opioids: analgesia or respiratory effects?
- Analgesia
How do opioids cause nausea and vomiting?
- Direct stimulation of the chemotactic trigger zone
- Increase vestibular sensitivity (nausea with motion)
There are ______ _________ among opioids in incidence of nausea and vomiting when given at equianalgesic doses. However, some people may have more/less nausea with one opioid than another.
- No differences
- Relates to individual pharmacogenomic profiles
What is the effect of opioids on the cough reflex?
- They decrease the cough reflex through direct effect on medullary cough center
- Doses to suppress cough usually smaller than that needed for analgesia
What is the classic sign of opioids on the central nervous system?
- Dose dependent pupillary constriction that occurs via Edinger-Westphal nucleus of oculomotor nerve (CN-III).
- If pt presents with extremely small pupils you can suspect large amounts of opioids on board
- One exception to this rule: MEPERIDINE
What are some other effects of opioids on the CNS except for pupillary constriction?
- Euphoria - activates “reward” zones
- Vivid dreams with routine doses used for pain management
- Reduced rapid-eye movement and slow-wave sleep
- Pruritis - produced at the level of the medullary dorsal horn, NOT histamine related
- Anti-pyretic
- Synergistic interactions between opioids and benzodiazepines
What are the GI effects of opioids?
- Slow gastric emptying
- Decreases lower esophageal sphincter tone
- Propulsive activity is decreased —constipation
How do opioids affect the biliary tract?
- Increase phasic wave frequency of the sphincter of Oddi, which increases biliary pressure
- Meperidine has a lesser effect on sphincter of Oddi and biliary pressure
What effect do opioids have on the urinary bladder?
- Inhibit micturition through inhibition of sphincter relaxation & decreased detrusor contraction (The bladder doesn’t squeeze as hard and the sphincter stays even tighter)
How do opioids trigger release of histamine?
- trigger release of histamine from circulating basophils and tissue mast cells in skin and lung
- Not prevented by naloxone
What are the cardiovascular effects of opioids?
- Peripheral vasodilation - caused by central reduction of sympathetic NS activity
- Dose-dependent bradycardia
- At clinically relevant doses, morphine does not suppress myocardial contractility
How is morphine metabolized?
- Liver
- Hepatic extraction is 70% (only 30% of the morphine in the blood leaves the liver)
- Reduction of hepatic blood flow decreases morphine clearance
What are the major morphine metabolites?
- Morphine-3-glucuronide: inactive, excreted by kidney
2. Morphine-6-glucuronide: ACTIVE, excreted by kidney; approx. 5-10% as potent as morphine
You can give any drug as a constant infusion if you know 3 numbers: _____?
- Effective plasma concentration
- Volume of distribution
- Clearance
Codeine
- 10% of codeine is demethylated to form morphine (only 10% of the drug causes analgesia
- Low affinity for opioid receptors
- Analgesic effect of codeine is d/t its conversion to morphine
- Commonly used as a cough suppressant
What is Tylenol # 3?
30 mg codeine & 300 mg acetaminophen
What is Tylenol # 4?
60 mg codeine & 300 mg acetaminophen
Hydromorphone
- When given IV:
* 5x more potent than morphine
* Analgesia onset: 5 min, peak: 10-20min - When given PO:
* Analgesia onset: 20-40 min, peak: 1.5 hrs
* Typical adult dose: 2-4 mg Q4-6hrs
Hydrocodone
- Only available PO
- Often used as a cough suppressant
- Typical adult dose: 5-10 mg Q4-6hrs
- Typical child dose: 0.15-0.20 mg/kg Q3-4hrs
Oxycodone
- Only available PO; effective orally b/c of less first pass metabolism than morphine
- Percoset: 5mg oxycodone & 325 mg acetaminophen
- Oxycontin: sustained release tablet, pill to be taken whole - Bolus of drug if pill is chewed or crushed, drug of abuse
Naloxone (Narcan)
- Competitive antagonist of Mu, Kappa, and Delta opioid receptors
- Administered IV, IM, or SC
- Peak effect within 1-2 min after IV admin.
- Metabolized in the liver
What does a standard ampule (“amp”) of Naloxone contain?
400 ug in 1 mL
What are we trying to achieve with naloxone (narcan)?
- Partial antagonism of excessive opioid-induced respiratory depression and/or sedation
- Small titrated doses (0.5 ug/kg) totaling 0.5-1.5 ug/kg
- Want to go slow because we only want a partial reversal
Why is rapid antagonism of opioids with naloxone (narcan) not a good idea?
- May precipitate acute severe withdrawal symptoms in patients with opioid dependency and/or tolerance
- Even small doses of naloxone (0.8-1.2 ug/kg) have been reported to precipitate immediate hypertension, tachycardia, and overt pulmonary edema.
Why was Meperidine initially developed?
- As an anticholinergic compound
- B/c of this, it is associated with lesser degrees of bradycardia & pupillary constriction than equianalgesic doses of morphine
Where does Meperidine act?
- Acts as a Mu receptor agonist (1/10th as potent as morphine)
- Also has moderate affinity for Kappa receptors
What are the Kappa agonist effects?
- Produce dysphoric, psychomimetic effect (disoriented, depersonalized feelings)
- Inhibit shivering by decreasing central shivering set point
Why can Meperidine be used as a sole agent for spinal or epidural blockade?
- B/c it has some local anesthetic activity and can produce sensory & motor blockade
In equianalgesic doses, meperidine produces respiratory depression _______ to that of morphine?
Equal
Meperidine has either a greater or lesser effect of the following than morphine.
- Contractility Depression?
- Respiratory Depression?
- Biliary pressure?
- Histamine release?
- Contractility - greater
- Respiratory Depression - equal
- Biliary pressure - less
- Histamine release - greater
What is “Serotonin Syndrome”?
- A syndrome of potentially fatal excitation, delirium, fever and convulsions in patients receiving meperidine and monoamine oxidase (MAO) inhibitors
Why would you not want to give a patient with renal failure Meperidine?
- The active metabolite Normeperidine is epileptogenic and can make you seize at high concentrations.
- It is renally excreted so if you were to give meperidine to a pt with renal failure the pt may seize due to a build up of normeperidine.
What effects does Normeperidine have?
- CNS excitation: restlessness, tremors, myoclonus, seizures
Where does Fentanyl act?
- Almost entirely a Mu receptor agonist
What is the clinical potency ratio for Fentanyl?
- 50-100 times greater than Morphine
Why does Fentanyl have a fast effect and then hang on for a while?
- Fentanyl binds tightly to opioid receptors
- Fentanyl likes fat. (Even when the fentanyl dissociates from the receptor it likes the environment, so it comes out slower than it goes in)
* Fentanyl has a Fast On, Slow Off effect!
Analgesia reduces ___________…?
- MAC (but does not make MAC zero) of volatile anesthetics and propofol
Does Fentanyl cause histamine release?
- No
Does Fentanyl have a direct effect on reducing myocardial contractility?
No
Fentanyl has a synergistic interaction with what agents?
- Benzodiazepines and propofol to produce ventilatory depression and sedation
The metabolic clearance of Fentanyl is directly proportional to _______?
- Hepatic blood flow
- Fentanyl has 100% hepatic extraction
How can Fentanyl act as a short-acting drug?
- After a bolus, central compartment concentrations decrease rapidly d/t REDISTRIBUTION of the drug from the bloodstream to fat and muscle groups
How can Fentanyl act as a long-acting drug?
- With prolonged administration, peripheral sites become saturated such that redistribution becomes a progressively less important determinant of bloodstream concentration. Bloodstream concentrations become more dependent on METABOLIC ELIMINATION of the drug, which is much slower.
What does “context-sensitive half-life” mean?
- A drug can be both long acting and short acting depending on how you give it.
Alfentanil
- Mu agonist
- Potency ratio = 10x greater than morphine, but only 1/4-1/10 as potent as fentanyl
- Rapid blood/brain equilibration - 1 min (Super Fast!)
Remifentanil
- Mu agonist
- Rapid blood/brain transfer - 1 min
- ** Rapidly metabolized by ester hydrolysis by nonspecific esterases (not pseudocholinesterase) in tissue and blood (hepatic and renal disease don’t matter) –> clearance is constant and does not change with infusion duration = 3 minutes!
Remifentanyl has much greater synergism in _______…?
- Respiratory effects than in sedative effects
- Monitoring level of consciousness underestimates effects on ventilatory status
When administering remifentanil and propofol, it is much safer to first…?
- First establish a constant remifentanil infusion rate (for analgesia) and then titrate propofol (for sedation) as needed.
Remifentanil should not be given…?
- Inline with RBCs because it will be metabolized before it gets to the patient
There is no residual analgesia with remifentanil so …?
- One must give something for pain before discontinuing remifentanil
Opioids can trigger glutamate release at the spinal cord level and mediates an increase in tolerance. If you block glutamate release at the spinal cord level - you lessen opioid tolerance. What drug can be given?
- Ketamine is a glutamate receptor antagonist that can be used to limit opioid tolerance
