Opioid receptor activation inhibits presynaptic release of postsynaptic response to excitatory neurotransmitters (ACh, substance P) from nociceptive neurons.
- Hepatic Biotransformation and metabolized by the cytochrome P system (Except reminfentanil- plasma esterase)
- High hepatic extraction ratio: clearance depends on liver blood flow
- Active metabolites: Morphine, hydromorphone, and meperidine
- Inactive Metabolites: fentanyl, sufentanil, and alfentanil
- Codeine: Prodrug that is metabolized to morphine
- Hydrocodone: prodrug that is metabolized to hydromorphone
- Morphine and meperidine end products excreted in the kidneys
- Normeperidine: seizures (not reversed by naloxone)
- Morphine 6-glucuronide: more potent and longer lasting than morphine
- Vagus nerve mediated bradycardia (EXCEPTION- Meperidine increases HR due to atropine similarity)
- Decrease in BP due to bradycardia, ventilation, and decreased sympathetic reflex
- Histamine release: meperidine, hydromorphone, and morphine
- Ventilatory Depression: specifically RR
- Increased PaCO2
- Blunt hypercapnic response (rightward shift of CO2 response curve)
- The apneic threshold-the greatest PaCO2 at which a patient remains apneic- rises, and hypoxic drive is decreased.
- Rapid administration of larger doses of opioids (fentanyl, sufentanil, reminfentanil, and alfentanil) can induce chest wall rigidity severe enough to prevent adequate bag mask ventilation
- Morphine and meperidine can cause histamine-induced bronchospasm (Histamine)
- Decrease: CMRO2, CBF, CBV, & ICP
- Stimulation of the medullary chemoreceptor trigger zone is responsible for opioid-induced nausea and vomiting
- Prolonged dosing can produce "opioid-induced hyperalgesia" in which patients become more sensitive to painful stimuli.
- IV meperidine (10-25mg) is effective for decreasing shivering
- Slow GI motility and peristalsis
- Biliary spasm is reversed by naloxone or glucagon
Neuroendocrine stress response to surgical stimulation is measured in terms of the secretion of specific hormones (catecholamines, ADH, cortisol). Large doses of opioids block the release of these hormones more completely than volatiles
- Avoid: Meperidine + MAOIs
- Synergistic Effect: propofol, barbs, benzos, and CNS depressants
- Erythromycin prolongs alfentanil
- 100x more potent than morphine
- First pass pulmonary uptake of 75%
- Short duration of action, 7 min onset
- 2mcg/kg prior to induction decreases dose needed to block surgical stimulation
- Advantages: No direct myocardial depression, No histamine release, Suppress the stress response to surgery
- Disadvantages: Failure to prevent sympathetic nervous system response to painful stimulation at any dose, Patients may still be aware, Post op depression of ventilation, muscle rigidity
- Synthetic Opioid (mu and kappa)
- Structurally similar to atropine
- 1/10 Potency of Morphine
- Duration: 2-4hours
- Normeperidine: 50% as active and produces seizures/myoclonus
- Meperidine is effective in decreasing postoperative shivering (may be due to its potent alpha2 agonist effects).
- Not used in high doses due to negative inotropic effects & histamine release.
- SA: orthostatic hypotension, increased HR, decreased myocardial contractility, decreases ventilation,
- Serotonin syndrome: autonomic instability (HTN, tachycarida, diaphoresis, hyperthermia, behavioral changes) seen with drugs that increase serotonin levels.
- Onset 15-30min, Peak effects in 45-90min, Duration 4hrs
- Poor lipid solubility, high ionization, high protein binding, rapid glucuronidation
- CO2 induced increase in CBV and enhances delivery of morphine to the brain are more important than the fraction existing the ionized/nonionized state
- Does NOT undergo significant first pass uptake into the lungs.
- Morphine-6-glucuronide produces analgesia and ventilatory depression (5-10% vs 75-85% 3-glucuronide) and is inhibited by MAOIs
- Elimination impaired by renal failure
- CV: no direct myocardial depression or hypotension. Decreased sympathetic response resulting in venous pooling (decreased venous return, CO, and BP). Drug induced bradycardia (decreased SA node and AV conduction) and histamine release causes decreased BP. May decrease tachycardia and HTN in response to pain, but once the response has occurred, additional opioid is ineffective. Decreased SVR and BP w/ Benzos and w/N2O will result in CV depression
- Ventilation: Dose dependent depression of ventilation. Decreased hypercapnia response and slower, deeper (higher Vt) breaths. Physostigmine (increases CNS ACh) may antagonize ventilatory depression but not analgesia.
- Depress cough
- Nervous system: some level of chest wall rigidity with no alteration to the neuromuscular blocking drugs
- GI: Biliary smooth muscle spasm (reversed by Naloxone & glucagon). NTG reverses pain due to biliary spasm or myocardial ischemia. Delayed gastric emptying, biliary colic, and constipation.
- Nausea&Vomiting: Due to direct stimulation of the chemoreceptor trigger zone in the floor of the fourth ventricle.
- 5-10x more potent than fentanyl due to greater affinity for opioid receptors.
- May cause transient muscle spasm and vocal cord constriction.
- Elimination half-life: Moderate, between fentanyl and alfentanil.
- Onset of action: Similar to fentanyl @ 6-10min
- Pulmonary uptake: 60% first pass
- Higher protein binding to AAG accounts for smaller Vd than fentanyl
- Metabolism: extensive hepatic extraction (clearance sensitive to changes in hepatic flow, not alterations in drug metabolizing capacity of liver). Renal failure may lead to prolonged effect and prolonged ventilatory depression.
- Context-sensitive half time: May have a more favorable recovery profile when given over a long period of time (8hours)
- CV: bradycardia may decrease CO
- Less potent than fentanyl: 1/5-1/10
- Duration of Action: 1/3 of fentanyl
- More rapid onset of action: 1.5 min vs 7min
- Elimination half-life: shorter than fentanyl and sulfenanil
- 90% exists as nonionized form and readily crosses BBB
- Metabolism: high hepatic efficiency, but erythromycin may inhibit metabolism
- Context-sensitive: Longer infusions have a longer offset than sulfenanil.
- Effective at blunting catecholamine release and BP and HR response to intubation
- Lower incidence of PONV in outpatients
- Decreased central DA transmission suggests caution in untreated Parkinsons.
- Similar potency to fentanyl
- BBB-equilibration similar to alfentanil
- Metabolism: plasma esterases due to its unique ester linkage (not affected by cholinesterase activity or anticholinergics)
- Short duration of action
- Precise and rapidly titratable due to rapid onset and offset
- Noncumulative effects
- Rapid recovery after administration stopped
- Prop/remi combo results in synergistic ventilation depression
- Small Vd, rapid clearance, and low inter-individual variability compared to other IV anesthetics
- Pharmacokinetics similar in obese and lean patients confirm dosing should be based on ideal/lean body mass.
- Context half-time: 4min regardless of infusion duration.
- May induce seizure-like activity
- PONV, depression of ventilation, and mild decreases in BP/HR may occur.
- 10% is demethylated to morphine
- Antitussive and mild/moderate analgesic
- Minimal sedation, nausea, vomiting, and constipation
- Morphine derivative: 5x as potent
- Rapid elimination: Dosing every 4 hours
- More sedation and less euphoria than morphine
- Additional hydroxyl to hydromorphone
- 10x more potent than morphine (2x hydromorphone)
- Causes more nausea and vomiting
- Max plasma concentration in 30min
Vicodin (Oral preparation): hydrocodone + acetominophen for chronic pain
- Non-selective antagonist at all 3 opioid receptors
- Selective during the following conditions: 1.Treat opioid induced depression of ventilation in the postoperative period, 2. Treat opioid-induced depression of ventilation in neonate due to maternal administration of an opioid, 3.Facilitate treatment of deliberate opioid overdose, 4.Decet suspected physical dependance.
- Short duration of action: 30-45min
- Supplemental doses often needed for sustained opioid antagonism.
- Dose: 1-4mcg/kg IV for reversal of opioid-induced analgesia and depression of ventilation
- SA: nausea and vomiting related to the dose and speed of injection, reversal of analgesia and therefore increased sympathetic nervous system activity (tachycardia, HTN, pulmonary edema, cardiac dysrhythmia)
- Shock: Dose dependent improvement in myocardial contractility in those with hypovolemic shock.