Opioid Agonists and Antagonists 2023 Canvas.pptx

Opioid Agonists and Antagonists Terry C Wicks, DNP, CRNA   Classifications: Opium  Agonists Derivative  Agonist-antagonists s  Antagonists  Present in opium:  Phenanthrenes  Morphine ...

Opioid Agonists and Antagonists Terry C Wicks, DNP, CRNA   Classifications: Opium  Agonists Derivative  Agonist-antagonists s  Antagonists  Present in opium:  Phenanthrenes  Morphine  Codeine  Thebain  Benzylisoquinolines  Papaverine (no analgesic effect)  Noscapine (no analgesic effect) Synthetic & Semisynthe  Synthetic  Opium alkaloids tic Opioids phenylpiperidine :  Meperidine  Morphine  Codeine  Fentanyl  Thebain  Sufentanil  Papaverine  Alfentanil  Noscapine  Remifentanil   μ (mu) morphine: supraspinal and spinal Opioid analgesia, hypoventilation, bradycardia, physical dependence. Receptor  κ (kappa) ketocyclazocine: less respiratory Subtypes depression, provoke dysphoria and diuresis  δ (delta) something isolated from mouse vas deferens: respond to enkephalins  Other important G protein coupled receptors  Muscarinic  Adrenergic  γ aminobutyric acid  Somatostatin receptors  See Stoelting Table 7-2 Mu receptor   Opioid receptors in the brain Mechanis  Periaqueductal grey, locus ceruleus, rostal m of ventral medulla  Spinal cord: dorsal horns (substantia gelatinosa) Action  Periphery: sensory neurons, and immune cells  The endogenous ligands at opioid receptors  Enkephalins  Endorphins  Dynorphins  The opioid must be ionized to bind to the opioid receptor and only the levorotary (L-) isomer exhibits analgesic effects   Binding of an opioid to the μ opioid Mechanis receptor results in analgesia from:  Increased K+ conductance m of (hyperpolarization) Action  Calcium channel inactivation.  Interruption of presynaptic neurotransmitter release of:  Acetylcholine  Dopamine  Norepinephrine  Substance P  Postsynaptic inhibition of evoked potentials may also occur.   All opioid receptors are G gated protein Mechanis receptors tied to intracellular guanine proteins. m of  Binding of opioid results in: Action  The G protein replacing its bound GDP with GTP  Inhibition of adenylate cyclase  Decreased conductance of voltage gated calcium channels  Opening of inward flowing potassium channels  Bottom line: Neuronal hyper-polarization & decreased neuronal activity Receptor  Brain  Periaquaductal grey Locations  Locus ceruleus  Rostral ventral medulla  Spinal cord  Interneurons  Primary afferent neurons  Mu receptors are responsible for supraspinal and spinal analgesia  Kappa receptors stimulation causes less respiratory depression, are less analgesic against high intensity pain stimulation.   Morphine has little, if any, direct myocardial Opioid depressant effects  Orthostatic hypotension may result from: Side  Decreased sympathetic tone Effects:   Vagally mediated bradycardia SA node depression CVS  Negative dromotropic effect  Histamine release may be substantial and is rate and dose related  Morphine does not sensitize the heart to catecholamines  Morphine plus nitrous oxide does cause CVS depression  Opioids have a protective IPC effect Opioid  All opioids provoke dose dependent and gender specific depression of ventilation (mu Side receptor) Effects:  Decreased response to CO2 (PaCO2 rises) Ventilation  Pontine and medullary suppression lead to ventilatory pauses and periodic breathing.  Decreased ventilatory frequency maybe accompanied by increases in tidal volume  Pain is an effective antidote.  Depression of medullary cough centers & ciliary activity in the airways.   Absent increased CO2 opioids decrease cerebral blood Opioid flow, and possibly ICP. Use with caution with head injury d/t: Side  Decreased wakefulness  Production of miosis Effects:  Depression of ventilation CNS  EEG changes resemble sleep patterns.  Skeletal and abdominal muscle rigidity is common with rapid injection of big doses. May be related to:  Opioid receptors  Dopaminergic (+) and GABA (-) responsive neurons  Can be severe enough to interfere with ventilation (chest wall rigidity)  Laryngeal muscle contraction (?)  Onset of morphine is slow-sleep/sedation often occurs prior to analgesia Opioid  Biliary Tract/biliary smooth muscle  Spasm of biliary smooth muscle Side  Pain relieve by naloxone or NTG Effects: GI  Increases in bile duct pressure  Fentanyl: 99%  Morphine: 53%  Meperidine: 61%  Pentazocine: 15%  Biliary spasm does not occur in most patients receiving opioids  Sphincter of Oddi spasm occurs in about 3% in patients receiving fentanyl   Opioids cause spasm of GI smooth muscle: Opioid Side  Constipation  Biliary colic Effects: GI  Delayed gastric emptying Tract  Decreases peristalsis of the small and large intestine  Increases tone at:  Pyloric sphincter  Ileocecal valve  Anal sphincter  Increased absorption of water leads to constipation  Little tolerance develops to these effects Opioid  D/T direct stimulation of the CTZ on the floor of Side the fourth ventricle Effects:  Stimulation of Nausea dopaminergic receptors  Treatment with and dopaminergic antagonist Vomiting reduces symptoms  Butyrophenones (droperidol)  Phenothiazines (promethazine) Opioid Side  Genitourinary System  Significant placental  Increased ureteral transfer Effects: peristalsis and  Exaggeration of opioid increased detrusor Others tone ventilatory depression  Increased tone of by: urinary sphincter  Amphetamines  Facial, neck, & upper  Phenothiazines chest flushing (d/t  MAOs histamine?)  TCAs  Conjunctival erythema  Possible interference  Pruritus with hypothalamic- pituitary adrenal axis.   Occurs with all opioids Tolerance  Tolerance can occur without dependence, & but not the reverse Dependen  Tolerance: requirement of an increased dose to attain the same effect ce  The rate of development tolerance and physical dependence is inversely proportional to opioid potency  Includes:  Analgesia  Euphoria & sedation  Depression of ventilation  Emetic effects   Classic explanation for tolerance involves receptor desensitization by reduced transcription and a Tolerance decrease in the absolute number of receptors. &  Second proposed mechanism: Dependen  Early blockade of adenylate cyclase inhibits cAMP production and cAMP pathways ce  cAMP pathways gradually recover, and tolerance develops  Increased cAMP production may be responsible for physical dependence and withdrawal symptoms.  Symptoms of withdrawal are diminished by small doses of opioids and clonidine (alpha2 agonist)  NMDA glutamate receptors are important in the development of opioid tolerance and increased pain sensitivity.   Depression of respiration leading to apnea Opioid  Symmetric miosis leading to mydriasis (hypoxemia)  Treatment: mechanical ventilation & an opioid antagonist Overdos e   Onset is most rapid with opioids with the Withdraw shortest duration of action al  Duration of peak intensity and duration follow a similar pattern Symptom  Symptoms  Abdominal cramps s  Nausea  Vomiting  Diarrhea  Lacrimation  Coryza  Restlessness  Insomnia See Stoelting Table 7-3  Specific Opioid Agonists Morphine, Meperidine, Fentanyl, Sufentanil, Alfentanil, Remifentanil Morphine  Pharmacokinetics Kinetics  IM absorption is good  Onset of action 15-30 minutes  Duration @ 4 hours  Peak brain concentrations lag behind peak plasma concentrations  High degree of ionization  Poor lipid solubility  Hyperventilation increases non-ionized fraction  Hypercarbia increases cerebral blood flow-and morphine effects Morphine  Conjugation with glucuronic acid in liver and kidney Metabolis  Morphine metabolites are excreted m and in the urine (slight fraction is Eliminatio excreted in bile)  Active metabolite morphine-6- n glucuronide has analgesic effects and a greater duration of action than morphine  Renal failure impairs elimination of morphine metabolites Meperidine  Structurally similar to:  Fentanyl  Sufentanil  Alfentanil  Remifentanil  Local anesthetics  Also, structurally similar to atropine, possessing mild atropine like anti-spasmodic effects on smooth muscle  Approximately 1/10 the potency of morphine Meperidine  Hepatic metabolism produces normeperidine by demethylation (90%) Metabolis  Normeperidine has an elimination halftime of 15 m and hours (normal) to 35 hours (renal failure) Eliminatio  Normeperidine has ½ the analgesic potency of meperidine n  Urinary excretion after hydrolysis is the principal avenue of elimination  Normeperidine is a CNS stimulant.  Elderly patients have less protein binding and greater sensitivity to the drug. Meperidine : Clinical  Can be used intrathecally due to its blockade of sodium channels Uses  Decreases post-operative shivering  Kappa opioid receptor stimulation  Alpha2 agonist activity  Is not useful for treatment of diarrhea and is not a cough suppressant  Prolonged infusions (PCA) may lead to normeperidine toxicity Meperidine  Tachycardia secondary to atropine like : Side effects  Negative inotropy & decreased myocardial Effects contractility  Delirium & seizures  Ventilatory depression (maybe more than morphine)  Promptly crosses the placenta  Mydriasis (atropine like effects…again)   Due to greater lipid solubility onset of Fentanyl: action is more rapid and potency is greater than morphine 75-125  Short duration of action reflects rapid times redistribution to inactive tissues more  Fat  Skeletal muscle potent  Pulmonary uptake approaches 75% of an than initial dose. When this reservoir is morphine saturated:  Duration of analgesia increases  Ventilatory depression increases  Plasma concentration falls more slowly   Metabolism by hepatic CYP450 (CYP3A): Fentanyl:  N-demethylation leads to production of metabolites Metabolis possessing minimal activity  Norfentanyl (principal metabolite) m and  Hydroxyproprionyl-fentanyl Eliminatio  Metabolites are excreted by the kidneys  Elimination half time of fentanyl is prolonged n d/t is high lipid solubility and sequestration in peripheral tissues (Vd)  Prolonged infusions (>2 hours) lead to saturation of inactive tissues and increases in Context Sensitive Half Time greater than sufentanil.   Fentanyl (2-20 ug/kg IV) can be used as an adjuvant Fentanyl: for inhalation general anesthesia and in smaller doses for procedural sedation. Clinical  Large doses of fentanyl demonstrate: Uses  Lack of myocardial depression  Absence of histamine release  Suppression of stress response to surgery  Disadvantages:  Does not completely suppress sympathetic response to painful surgical stimulation  Unpredictable amnestic effects  Postoperative ventilatory depression  Intrathecal (20-25 ug) or epidural (50-100 ug) fentanyl potentiates local anesthetic neuraxial analgesia Fentanyl:  Persistent of recurrent depression of respiration d/t  P0ssible ion trapping in acid gastric fluid Side  Possible redistribution from the lungs at the end of surgery Effects  Bradycardia due to depression of the carotid sinus baroreflex control of heart rate may also lead to:  Decreased BP  Cardiac Output  No EEG evidence of seizure despite occasional myoclonus with rapid IV administration.  Slight increases in ICP despite unchanged PaCO 2, causes are uncertain but may be related to vasodilation and increased CBF. Sufentanil  Analgesia potency is 5-10 times that of fentanyl d/t greater affinity for opioid receptors.  Like fentanyl:  Rapid effect site equilibration time (6.2 minutes)  Initial effects attenuated by widespread redistribution  Significant 1st pass pulmonary uptake  Sufentanil is highly protein bound to alpha1 glycoprotein (92%) with a smaller Vd Sufentanil:  Metabolism by N-dealkylation produces inactive metabolites, however, O-demethylation Metabolis produces metabolites with approximately 1/10 m potency of the parent compound.  Clearance of sufentanil is sensitive to changes in hepatic blood flow.  Metabolites are excreted in the urine and feces.  Only 1% of sufentanil is excreted unchanged in the urine.  Chronic renal failure causes prolonged ventilatory depression.   Sufentanil (0.1-0.4 ug/kg) produces longer Sufentanil: analgesia and less respiratory depression than fentanyl (1-4 ug/kg). Clinical  Compared to large doses of fentanyl and Uses morphine, sufentanil results in:  More rapid induction of anesthesia  Earlier emergence from anesthesia  Earlier extubation  Preserves hemodynamic stability in patients with good LV function  Does not blunt the BP and hormonal responses to median sternotomy  Like fentanyl, make provoke significant chest wall and abdominal muscle rigidity.   Alfentanil is 1/5 as potent as fentanyl and a Alfentanil duration of action 1/3 that of fentanyl  Onset of action is shorter than either fentanyl of sufentanil d/t rapid effect site equilibration [(1.4 minutes v. 6.8 (F) or 6.2 (S)].  Low pKa allows 90% of the drug to exist in the nonionized state which allows for greater penetration of the blood brain barrier despite lower lipid solubility than fentanyl.  Alfentanil is highly bound to alpha1 acid glycoprotein  Vd is ¼ to 1/6 that of fentanyl Alfentanil  Hepatic CYP450 metabolism of alfentanil is Metabolis rapid and 96% of alfentanil is cleared within 60 m minutes  Interindividual variability of alfentanil pharmacokinetics varies 10-fold.  Context Sensitive Half Time: Because of the relatively small Vd of alfentanil, and lack of redistribution to peripheral tissues the context sensitive half time for alfentanil is longer than that of sufentanil (up to 8 hours duration) Alfentanil:  Alfentanil has a rapid onset and offset of action Clinical  Effective at blunting the hemodynamic Uses responses to noxious stimulation  Suitable for continuous IV fusion (25-150 ug/kg/hr) combined with inhalation agents  Provokes less PONV than equipotent doses of fentanyl or sufentanil   Remifentanil is a selective μ opioid agonist Remifenta equipotent to fentanyl nil  Effect site equilibration time is similar to alfentanil  Remifentanil undergoes hydrolysis by non- specific plasma and tissue esterase to inactive metabolites  Pharmacodynamics  Rapid onset  Rapid offset  Rapid titration of effects  Lack of accumulation  Rapid recovery after discontinuation of infusion   Pharmacokinetics: Remifenta  Small Vd  Very rapid clearance nil  Low interindividual variability of response  Base dose on lean body weight  Virtually no change in Context Sensitive Half Time with any duration of infusion  Metabolism:  Metabolized by non-specific plasma & tissue esterase  Elimination half time appears to be approximately 6 minutes or less  Clinical uses  General anesthesia  Sedation  Labor analgesia [PCA]   Because of its short duration of action post Remifentani operative analgesia must be augmented by longer acting opioids l: Side  Remi decreases CBF and CMO2 (high dose) Effects  Possible side effects include:  PONV  Depression of ventilation  Mild decreases in BP & HR  Postoperative hyperalgesia (acute tolerance) is common feature of remifentanil administration  Relieved by NMDA receptor antagonists, ketamine and magnesium Tramadol  Moderate activity for μ (mu) receptors, weak κ (kappa) & δ (delta) receptors  1/5-1/10 analgesic potency of morphine  Racemic mixture two enantiomers  One inhibits norepinephrine uptake  One inhibits 5-hydroxytryptamine  Reduces shivering  High incidence of nausea and vomiting   Codeine:  Oxymorphone Other  Limited first pass effect when taken  10 times as potent as morphine with less Opioids & orally nausea and vomiting  Effective cough Significant suppressant  Physical dependence is significant Features  IV administration provokes histamine  Oxycodone release.  Oral agent twice as potent as oral  Hydromorphone morphine  5 times as potent as  Similar duration of morphine action  Less hydrophilic than morphine & has a  Hydrocodone more rapid onset and  Oral opioid with shorter duration of potency and duration action similar to morphine Pentazocine Butorphanol Nalbuphine Opioid Agonist- Buprenorphin Antagonists e Nalorphine Bremazocine Dezocine.   These drugs bind to μ receptors and produced Features of limited responses (partial agonist) or no effect (competitive antagonists) Agonist-  These drugs also produce limited responses at κ Antagonist and δ receptors. s  Advantages:  Production of analgesia with limited depression of ventilation and low abuse potential  Ceiling effect above which further agonist effects do not appear  Disadvantages:  Reduction in the analgesic effect of previously administered agonists  Dysphoric reactions Opioid Antagonist  These agents bind to the μ receptor and exert no agonist activity s  Opioid agonists are displaced from the μ receptor.  Agents:  Naloxone  Naltrexone  Nalmefene   Binds to all three opioid receptors Naloxone  Naloxone 1-4 ug/kg promptly reverses opioid induced analgesia and respiratory depression  Short duration of action (30-40 minutes) may necessitate redosing if used to treat the effects of a long-acting opioid.  Uses:  Post op ventilatory depression  Neonatal respiratory depression secondary to maternal opioid use  Treatment of deliberate/accidental opioid overdose  Detect suspected opioid dependence Other  Naltrexone: Highly effective orally. Is  Methylnaltrexone does not cross the blood- Antagonist used to promote brain barrier. May long term opioid s abstinence and antagonize opioid nausea in the CTZ or alcohol abuse due to delayed gastric  Nalmefene: Potency emptying is equal to  Alvimopan: A μ receptor naloxone, with a antagonist for treatment longer duration of of opioid induced ileus action. Elimination and constipation. half-time > 10 Metabolized by gut flora hours. Other  Opioid allergy is extremely rare. Side effects misinterpreted as allergy include: Considerati  Histamine release ons  Orthostatic hypotension  Nausea and vomiting  Long term exposure to opioids and/or abrupt withdrawal of opioids can provoke immune suppression. So can pain…  PCA: Self titration of opioids avoids peaks and valleys of analgesia and over sedation:  Increases patient satisfaction  Increased safety  Reduced provider workload Neuraxial Opioids Analgesia without sympathectomy, weakness, or sensory blockade…   Μu receptors are Mechanis present in the m of substantia gelatinosa of the spinal cord. Action  Analgesic effects are due to both spinal cord effects and from systemic absorption  Poorly lipid soluble drugs have a longer latency and duration of action.   Epidural opioids are taken up by epidural fat, systemic absorption and diffusion across the Neuraxial dura. Opioid  Dural penetration is proportional to lipid solubility Kinetics  Least with morphine  Greatest with sufentanil  Opioids are rapidly absorbed by the epidural venous plexus.  Blood concentrations after epidural dosing are similar to those produced by IM injection  Highly lipid soluble opioids have limited rostral migration.  Intrathecal morphine ascends d/t bulk flow of CSF Neuraxial  Most side effects are dose dependent  Urinary retention: More Opioids:  Pruritus common in males  Inhibition of sacral Side  Localized to the face, neck, and parasympathetic outflow  Detrusor muscle relaxation Effects thorax  May be related to  Depression of ventilation stimulation of opioid reflects systemic receptors in the absorption of opioid trigeminal nucleus  Rate is approximately 1%  Effectively relieved  Delayed depression more by small doses of commonly associated with naloxone neuraxial morphine   Sedation tends to be dose related and is Neuraxial most common with sufentanil Opioids:  Reactivation of herpes simplex labialis virus (cold sores) 2-5 days after epidural morphine Side  Maternal administration of epidural opioids Effects during labor may produce depression of ventilation in newborns  Neuraxial opioids may delay gastric emptying  Inhibition of shivering and heat loss  Spinal cord injury from injection of preservative containing solutions