Opioids & Context Sensitive Half-Time Flashcards
What is an opioid?
Any natural, synthetic, or endogenous substances with morphine-
like properties including:
Analgesia without loss of touch, proprioception, or consciousness
Most common opioid receptor?***
Mu (μ) receptors: Analgesia; respiratory depression; miosis, euphoria, physical dependence, constipation; urinary retention?
Opioid mechanism of action
Inhibit release of and response to excitatory neurotransmitters in nociceptive neurons
Opioid receptors are located where?
Throughout the CNS and peripheral nerves
Which opioids have active metabolites?
Morphine, meperidine have active metabolites
Which opioids have inactive metabolites?
Fentanyl, sufentanil, alfentanil have inactive metabolites
How is Remifentanil different than most opioids when it comes to biotransformation?
Its not metabolized in the liver
Its metabolized via ester hydrolysis by blood plasma esterases – NOT pseudocholinesterase which we associate with Sux)
What part of opioid pharmacokinetics has a genetic component?
Biotransformation in the liver. Why? Bc there are genetic differences in the functionality of the enzyme that metabolizes opioids (CYP2D6) in certain populations
- CYP2D6 specifically transforms oxycodone, hydrocodone, tramadol and codeine into their active forms
———–Therefore, any CYP2D6 deficient people may have inadequate analgesia if given these opioid medications
- CYP2D6 also metabolizes meperidine and methadone so any CYP2D6 deficiency can cause prolonged clinical effect if given these opioid medications
How are opioids excreted? Why is this important?
Excretion – mostly in urine
This is specifically significant for the active metabolites of:
1) morphine (morphine-3-glucuronide [M3G] & morphine-6-glucuronide ([M6G])
2) meperidine (normeperidine)
– CAUTION WHEN GIVING MORPHINE or MEPERIDINE TO RENAL PATIENTS bc the accumulation of these active metabolites can lead to substantial side effects for the renal pts
Morphine
Morphine – the template.
o Dose: 0.01 – 0.1 mg/kg OR 2-8 mg every 5-10 minutes.
Acts at the μ receptors
Can decrease MAC to ~65%
Crosses blood-brain barrier slowly – 5 min onset, but peak in 10-40 minutes
35% protein-bound (albumin)
Rapid redistribution; elimination half-life 1.7 – 3.3 hours.
o Age dependent: 7-8 hrs in neonates; 4.5 hrs for ages 61-80
o High hepatic extraction elimination affected by decreased hepatic flow
o Active metabolites (M3G, M6G) as well as morphine urine
Monitor carefully if used in patients with renal failure
Reversed by naloxone (narcan)
Morphine Effects:
Effects:
o Neuro: Sedation, cognitive impairment, euphoria
↓CMRO2
↓ CBF
↓ ICP if normocarbia is maintained
- Pupillary constriction (miosis),
- Pruritis (itching)
- Muscle rigidity after large doses – can even interfere with manual ventilation
- Nausea/vomiting – stimulates CTZ (chemo trigger zone) in medulla
Resp: ↓ response to CO2;
- hypoventilation,
- apnea but arousable on command
- ↓ cough reflex
- Resp. depression can be within minutes or delayed for several hours
GI: decreased motility (constipation),
- slower gastric emptying
- increase common bile duct tone, and can lead to biliary spasm (sphincter of
Oddi)
GU: urinary retention
Endo: histamine release -> leads to hypotension, dilation of cutaneous blood vessels -> leads to flushing or rash
Prevents stress response at high doses
Prevents inflammatory response with cardiopulmonary bypass
CV: **hypotension at higher doses (greater effect in patients with high baseline sympathetic tone);
- Can cause bradycardia at higher doses
Hydromorphone (Dilaudid)
Hydromorphone (Dilaudid) – similar efficacy as morphine (also a strong agonist)
- 5-10x more potent than morphine
- 1.5 mg hydromorphone IV = 10 mg morphine IV
- *** No active metabolites (good choice for renal patients)
- Length of action: 3-4 hours
- Dose: 2-8 mcg/kg or 0.2-0.4 mg IV Q 5-10 minutes
Is Hydromorphone (Dilaudid) a good choice for renal patients?
Yes bc it has NO active metabolites (good choice for renal patients)
Methadone
- ***A strong μ-receptor agonist AND NMDA antagonist (similar to ketamine)
- much longer duration of action than morphine
- ***used for the treatment of opioid withdrawal and chronic pain
The only opioid with local anesthetic properties?
Meperidine (Demerol).
As a result of this anesthetic property, at high doses, it can decrease contractility
Meperidine (Demerol) effects in general
***Euphoria
Similar effects to morphine: sedation, miosis, euphoria, N/V, dizziness; histamine release
What kind of metabolites does Meperidine (Demerol) have?
***Active metabolite (normeperidine) -> excreted in urine
Active metabolite (normeperidine) belongs to which opioid?
- Meperidine experiences high hepatic extraction -> produces active metabolite called normeperidine.
- Meperidine-> Normeperidine active metabolite -> excreted in urine
- Both Meperidine & Normeperidine can cause:
o Can cause CNS excitation, tremors, myoclonus, seizures
o The CNS excitation effect is why we limit the Max daily dose of meperidine to: 600 – 1000 mg per day.
Meperidine + Renal pts
Bc of meperidine’s renal excretion in urine, we should be careful using meperidine in renal patients and consider using lower doses of it.
- High doses are especially dangerous in patients with renal disease
Where is meperidine (demerol) used most commonly?
PACU for reducing shivering
Smaller doses for shivering are probably ok in renal patients
Dose of meperidine (demerol) for analgesia:
0.1 – 1.0 mg/kg
10x that of morphine
Dose of meperidine (demerol) for shivering:
12.5 – 50 mg IV
Smaller doses for shivering are probably ok to use in renal patients
Fentanyl potency compared to morphine:
Fentanyl is ~100x more potent than morphine
Fentanyl solubility compared to morphine
Fentanyl is much more lipid soluble than morphine -> very lipid-soluble -> therefore it rapidly crosses membranes = rapid onset and redistribution to inactive sites
Is Fentanyl protein-bound?
Yes, highly protein-bound
How does Fentanyl’s protein-bound status change according to pH?
Fentanyl is highly protein-bound but its dependent on the body’s pH.
If the body experiences acidosis -> Fentanyl will unbind from protein -> more free fentanyl floating around in the blood
Fentanyl metabolism
Rapid hepatic metabolism – high extraction ratio
Fentanyl onset:
- “Short acting” – as a single bolus dose
- Bolus onset = 10 seconds
- Bolus recovery starts within 5 minutes; complete by 60 minutes
o Large / multiple doses or infusion -> start to see saturation effect where it builds up in other tissues & can cause prolonged resp depression and slower recovery
o Clinical duration is normally limited by its redistribution
Fentanyl Dosing
o Premedication: 25-50 mcg IV
o Adjunct to induction: 1 – 5 mcg/kg IV
o Intraoperative: 0.5 – 2.5 mcg/kg IV intermittently up to 3-5 mcg/kg/hr
o Infusion: 0.5 – 2 mcg/kg/hr (up to 10 mcg/kg/hr)
Side effects of Fentanyl:
o Chest wall rigidity – making it difficult to ventilate
o can cause Myoclonus / seizure-like activity
o Pruritis, N/V (common with any opioid)
o Respiratory depression, especially when given with midazolam
**Noteworthy Fentanyl interactions with other meds:
Fentanyl + Midazolam = synergistic effect for Respiratory depression
***Which synthetic opioid has a short duration even in large doses?
Alfentanil
= Short duration even in very large doses – commonly used as an infusion
Remifentanil (Ultiva) General info
- Ultrashort-acting opioid
- **Differs from other opioids in that it is not metabolized in the liver but rather by blood and tissue esterases (NOT pseudocholinesterase) via Ester Hydrolysis
- Metabolism is much faster than redistribution
- Usually given as an Infusion (bc pt will exhibit rigidity if remifentanil is given in a rapid bolus)
At high doses, it can decrease MAC by up to 90%
What is the primary mechanism by which Remifentanil (Ultiva) stops working?
METABOLISM bc its metabolism is much faster than its redistribution. This is bc its
metabolized in by blood and tissue esterases (NOT pseudocholinesterase) via Ester Hydrolysis
Remifentanil (Ultiva) Dose
Dose:
o Induction: 0.5 – 1.0 mcg/kg over 30 seconds (with propofol)
o Infusion: 0.1 mcg/kg/min (TCI of 5-7 ng/mL) with low-dose propofol infusion
o MAC: 0.05 – 0.25 mcg/kg/min; even less (0.005 mcg/kg/min if midazolam or propofol are also used + you want to be very vigilant for resp. depression and arrest when used with these other drugs
Strong Mu(μ) receptor agonist opioids
1) Morphine
2) Hydromorphone (Dilaudid)
3) Methadone
4) Meperidine (Demerol)
5) Fentanyl
6) Remifentanil (Ultiva)
Opioids cause these classic symptoms:
sedation mioisis (pupillary constriction) pruritis (itching) Nausea and vomiting hypoventilation constipation urinary retention histamine release hypotension
Which opioid has no active metaboltites?
Hydromorphone (Dilaudid)
Which opioid is used to treat opioid withdrawal and chronic pain?
Methadone
Which opioid is a μ-receptor agonist AND NMDA antagonist?
Methadone
Which opioid is notable for causing euphoria?
Meperidine (Demerol)
Which opioid is notable for causing sz?
Meperidine (Demerol)
Which opioid is especially dangerous in patients with renal disease at high doses?
Meperidine (Demerol) bc of its active metabolite normeperidine that is normally excreted in urine but can build up when renal function is deficient
Which opioid is notable for being very lipid-soluble and highly protein-bound?
Fentanyl
Which opioid is notable for causing chest wall rigidity and/ or causing respiratory depression, especially when given with midazolam?
Fentanyl
Which opioids are good for controlling mild-moderate pain?
Partial mu-receptor Agonists bc they have lower efficacy
- Codeine
- Hydrocodone (Lortab)
- Oxycodone or OxyContin
- Tramadol
Opioid IV Drugs “Rule of 10”
IV:
100 mg meperidine ~ 10 mg morphine
~ 1 mg hydromorphone ~ 100 mcg fentanyl
~ 10 mcg sufentanil
Is opioid withdrawal life-threatening?
Typically, No.
Opioid-Induced Hyperalgesia (OIH)
- When opioids cause you more pain instead of analgesia. The pain can actually get worse if you’re given more opioids.
- More common with phenanthrene opioids (codeine, hydrocodone, hydromorphone, morphine, oxycodone, oxymorphone)
Suspected to be caused by opioids binding to NMDA receptors in addition to mu-receptors. The NMDA receptors activation by the opioids are what’s causing increased pain. This is evidenced by the fact that Nalxone has no effect on these pt’s perceived pain.
Best treatment is to gradually reduce or completely discontinue the opioid
You can switch them over to non-phenanthrene opioids, give them non-opioid analgesics like NSAIDS or NMDA antagonists like Ketamine, or Buprenorphine (mu receptor agonist + k-receptor antagonist)
Opioid Withdrawal
Severe-flu-like symptoms
Typically not life-threatening
Opioid Tolerance=
When pts no longer have the expected clinical effect to a given dose of drug
Occurs after 2-3 weeks of continued opioid therapy
Pts don’t ever exhibit tolerance to opioid-induced constipation
Opioid Addiction
= physical and psychological dependence on opioids
- usually takes ~25 days to develop, some studies have found it can begin within 48 hrs
