Opioid pharmacology

Module 2: IV Anesthetic Agents

• Lecture 3 will cover opioid and dexmedetomidine agents

Opioids

• This class of drugs includes natural and synthetic compounds that share properties similar to opium
• Opioids work by imitating the body's natural endorphins
• Can be classified as: agonists, partial agonists, agonist-antagonists, or antagonists
• Are categorized based on their chemical origin: natural, semi-synthetic, or synthetic forms
• Opium's properties result from 20 distinct alkaloids, chemically categorized into two groups: Phenanthrene (includes morphine) and Benzylisoquinolone (includes papaverine)
• When modified, the morphine molecule maintains its five-ring structure and results in semi-synthetic drugs like heroin and hydromorphone
• Phenylpiperidines and diphenylheptane derivatives contain only two of the original five rings from the morphine molecular structure
• Examples of natural opioids include phenanthrene derivatives like morphine and codeine
• Semisynthetic opioids include morphine derivatives like hydromorphone, heroin, naloxone, and naltrexone, as well as thebaine derivatives like oxycodone
• Synthetic opioids include piperidines such as meperidine, phenylpiperidines such as fentanyl, sufentanil, remifentanil, and alfentanil, and diphenylpropylamines such as methadone

Opioid Potency

• Opioid potency is significantly depending on the specific drug and its chemical structure
• Morphine, often considered the standard for opioid potency is a strong analgesic; several opioids are much more potent
• Fentanyl is estimated to be about 100 times more potent than morphine
• An equianalgesic dose of fentanyl would be 100 mcg IV compared to 10 mg IV of morphine.
• Meperidine is less potent compared to morphine.
• An equianalgesic dose of meperidine would be 100 mg IV compared to 10 mg IV of morphine.

Opioids: Mechanism of Action

• Opioid receptors couple with transmembrane G (guanine) protein-coupled receptors
• These reduce intraneural concentrations of cAMP
• Agonizing the receptor with an opioid makes the receptor instruct the G protein to turn off adenylate cyclase
• This inhibits adenylate cyclase; therefore the intracellular concentration of cAMP is reduced
• A reduced intracellular concentration of cAMP alters ionic currents and reduces neuronal function
• In the presynaptic neuron, opioid receptor stimulation reduces calcium conductance, reducing neurotransmitter release
• In the postsynaptic neuron, opioid receptor stimulation increases potassium conductance
• This hyperpolarizes the neuron, thereby reducing RMP and making it more resistant to stimulation

Endogenous Pain-Modulating Mechanisms

• Opioid receptors are in key regions of the brain, like periaqueductal gray, locus ceruleus, rostral ventral medulla, and the spinal cord's substantia gelatinosa.
• These areas are crucial for processing pain, integrating pain signals, and responding to pain
• Endorphins are believed to block the release of excitatory neurotransmitters (glutamate) from the nerve terminals that transmit pain signals (nociceptive impulses).
• Neurons become hyperpolarized, which reduces both spontaneous discharges and evoked responses
• Endorphins, like opioids, act on opioid receptors
• They generally inhibit the release of excitatory neurotransmitters (like glutamate) and enhance the activity of inhibitory neurotransmitters (like GABA)
• Leads to pain relief, as the excitatory signals that transmit pain are reduced, while inhibitory signals suppress the pain response

Opioid Receptors

• Classified as Mu (μ), Kappa (κ), and Delta (δ) receptors
• Endogenous ligands (a molecule originating within the body) can trigger a biological response

Endogenous Ligands

• Endorphins
• Enkephalins
• Dynorphins
• Can bind to opioid receptors and activate them
• This produces several effects, such as analgesia and euphoria.
• Receptors can be activated by exogenous ligands (substances outside the body) like opioid drugs

Opioid Receptors: Receptor Location

• Located in:
  • Peripheral nervous system.
    • Sensory neurons reduce pain transmission in a-delta and c-fibers
  • Central nervous system
    • Areas include: Dorsal horn, RAS, thalamus and somatosensory cortex
  • Descending Inhibitor Pathway: these activate structures such as the periaqueductal gray and the nucleus raphe magnus,
  • Pathways also stimulate the release of endorphins, serotonin and norepinephrine in the dorsal horn of the spinal cord

Opioid Receptors: Associated Actions

• Mu (μ)
  • Endogenous Ligand include: Beta-Endorphin or Endomorphin
    • Supraspinal/spinal Analgesia
    • Depression of Respiratory system
    • Bradycardia to the Cardiovascular system -CNS associated Sedation and Euphoria, the release of Prolactin may occur with Mild hypothermia
    • Miosis of the pupils
    • Genitourinary response to this ligand is retention
    • N/V biliary problems in GI
• Delta (δ) - Enkephalin is the endogenous ligand -Supraspinal and spinal analgesia -Respiratory is Depression of Resp System - Pupil reflex no change to pupil -Genitourinary is Urinary retention
• Kappa (κ)
  • Analgesia for Supraspinal and Spinal pain management system -Dynorphin as the Endogenous Ligand
  • Depression of Respiratory system is unknown
  • CVS is in Normal range

Notes

• Mu-1 receptors are linked to analgesia, euphoria, and bradycardia
  • Activation can also cause miosis, hypothermia, and urinary retention.
• Mu-2 receptors are associated with analgesia, respiratory depression, constipation, and physical dependence
• Mu-3 receptors are associated with immune suppression

Opioid Neurologic Interactions

• Ventilation: Shifts the CO₂ response curve to the right and reduces the ventilatory response to CO2 and decrease RR and tidal volume
• Can increase ICP if Ventilation is not maintained Pupil:
  • Edinger Westphal nucleus stimulation will stimulate PNS stimulation of ciliary ganglion and oculomotor nerve (CN 3) which will cause pupil constriction
  • Patient will develop a Tolerance but the Miosis will not improve
    • Chemoreceptor trigger zone stimulation in the postrema of the madulla will promote vommitting
    • Also Possible interaction with your inner ear Vestibular apparatus -Evoked-potentials can have Minimal effects on elicited action

Opioid Cardiovascular Effects

• Bradycardia
• Minimal effect on BP in healthy patients, but a drop in BP with morphine and meperidine (because they release histamine) can be expected
• Dose-dependent vasodilation
• Baroreceptor reflex is not affected
• Myocardial contractility is not affected unless combined with N₂O

Opioid Gastrointestinal Effects

• Contraction of sphincter of Oddi increases biliary pressure (treat with naloxone or glucagon).
• Meperidine causes the lowest increase Gastric emptying tends to prolong as well as Peristalsis GI system slows and leads to Constipation

GentoUrinary Effects

• Urinary Retention from:
  • Detrusor relaxation relaxation is needed to pass urine into ureta and cause spasm
• Urinary Sphincter Contratction

Immnunologic Effects

• Histamine release is most common with (morphine, meperidine, codeine)
• Opioids, as previously mentioned, can also cause Inhibition of cellular and humoral immune function and Suppress natural killer cell function

Opioids and Temperature Control

• Resets hypothalamic temp set point →core body temp will drop

Skeletal Muscle Rigidity

• Use rapid IV administration of opioids will trigger skeletal muscle rigidity -More common with: sufentanil, fentanyl, remifentanil, and alfentanil
  • Mu receptors in the CNS influence dopamine and GABA motor pathways
    • opioids do not directly affect the NMJ or skeletal muscle
    • Requires paralysis and intubation

Opioid-Induced Rigidity Complications

• Hypoxia
• Hypercapnia
• Decrease in:
  • Oxygen consumption, SvO2 Thoracic compliance, FRC, Minute ventilation
• Increase in:
  • CVP, PAP, or PVR

Cough Suppression

• Opioids depress cough effects on the medullary cough centers
• Greatest with opioids that have bulky substitutions as well, which can aid codeine action at the #3 carbon position

Cough Provocation

• Administration of fentanyl, sufentanil, or alfentanil will promote Preinduction can associate with significant stimulus

Morphine

• Peak effect of morphine is about 15-30 minutes, is prolonged compared to fentanyl.
• The analgesic and ventilatory depressant effects may not be evident when initial doses of the drug are administered
• Drug effects may persist as well even after decreasing the drug concentration in plasma

Morphine: Metabolism

• Drug is conjugated to morphine-3-glucuronide that can lead to hyperalgesia, myoclonus and delirium
• Drug is conjugated to morphine-6-glucuronide that can lead to respiratory depression, drowsiness, N/V, and possible coma
• morphine-6-glucuronide is H20 soluble and hard to pass the BBB
• Avoid for patients on dialysis because the kidneys are not able to excrete morphine-6-glucuronide and are prone to accumulate this metabolite and can lead to ↑ respiratory depression and toxicity

Morphine: Cutaneous Changes

• The drug will vasodilate → the skin of the face, neck and upper chest will be flushed and warm → histamine

Meperidine

• Synthetic phenylpiperidine stimulating mu and kappa receptors
• DOA = 2-4 hours, which is shorter acting compared to morphine
• Undergoes significant first-pass effect so its the drug is not often utilized from the oral route

Meperidine: Metabolism

• Demethylated in the liver by CYP450 to normeperidine
  • Normeperidine is 1/2 as potent as its parent compounds
  • Elimination half-life of normeperidine = 15 hours, but this will ↑ in patients with CRD (Chronic Renal Disease)
  • Normeperidine → reduces seizure thresholds and ↑ CNS excitability (causes tremors, seizures)
  • Exercise Caution with: elderly population and patients with CRKD on dialysis

Meperidine: Elimination

• Half-Time is at the 3-5-hour mark
  • 60% is bound to plasma proteins → care is needed when considering elderly patients who often have decreased the volume of protein for your compounds to pair to which will make their blood vulnerable to ↑ free drug levels

More on Meperidine

• MAO inhibitors: deaminates serotonin in the synaptic cleft and Co-administration can cause HTN Common examples of MAO: phenelzine, isocarboxazid, and tranylcypromine
  • Features of serotonin syndrome: akathisia, mydriasis, tremor, AMS, clonus and muscle rigidity
  • Anticholinergic Effects: similar to atropine/tachycardia/mydriasis/dry mouth
• Shivering Effect: Kappa (stimulation will lead to decreased action and can be replaced instead Potent alpha-2 agonist → anti shivering effects
  • Histamine release (Mast cell activation causes an ↑ histamine release

Hydromorphone

• Some textbooks state that: drug does have an active metabolite, hydromorphone-3-glucuronide, that should be excreted by the kidney (Kidneys) Less hydrophillic drug → faster onset of analgesia
• Less histamine release compared to morphine

Opioid Metabolites Considerations

• Look carefully when considering:
  • Active vs Non-active compounds with your opioids in your drugs.
  • Liver, Kidney, and tissue breakdown of those molecules in all of your patients.
  • Also be fully aware of the individual needs for each of your patients.

Fentanyl

• Phenylpiperdine-derivative synthetic opioid agonist
  • Compared to morphine, a fentanyl rapid distribution due to lipid solubility is a key to how the drug works in the BBB quickly
    • Due to that high distribution, most of the stores are tied up into large, inactive sites to store the medication
  • Administration is key, if in multiple doses it may saturate for a longer action or progressive saturation which can cause the pt to need the drug for a longer duration or even respiratory depression

Fentanyl: Metabolism

• N-demethylation produces norfentanyl, which is the principal metabolite that is excreted in the urine by the kidneys and can linger for almost 3 days (72 hours)
  • Elimination half-time:is longer when compared to morphine and distribution to tissue
  • 80% of the drug will push into the brains distribution in a five minute window
• When infusing and administering a continues course longer than two hours (2 Hr)the effect will wear or create an inverse reaction

Fentanyl Uses

• Large doses of fentanyl as the sole anesthetic have the advantage of stable hemodynamics: - Fentanyl lacks direct myocardial depressant effects
  • Has no histamine release
  • Suppresses the stress response to surgery
• Does lack Amnesia properties and can cause post op problems

Sufentanil

• Thienyl analogue of fentanyl which can alter how the chemical reacts and can reduce clearance compared to others
• Elimination half-time is intermediate compared to fentanyl and alfentanil.
  • Vd and elimination half-time of sufentanil is increased in obese patients as well which can lead to the high lipids pulling from plasma
    • Its lipophilic properties help push to all locations include the brain

Sufentanil-Metabolic Effects

• High hepatic extraction with a quick break down by N-dealkylation which helps eliminate it from the system
• High lipid solubility that can retain the drug for longer and absorb it back, renal extraction
  • Patient will need adequate flow to the liver for a quick breakdown vs possible renal issues
  • Sufentanil over time will develop a higher need for the pt because it will not take as effective as when they started

Alfentanil

• Weak base whose pKa =6.5 that is used for the fastest action with only 90% drug availability and that helps the BBB pass the desired amount
  • The drug is not widely distributed to the rest of the body, so most of the drug is entering the brain.

Alfentanil Metabolism

• N-dealkylation and O-demethylation by CҮРЗА4 so be aware of other drugs working at the functions and other functions
• Erythromycin will inhibit the breakdown and co-administration can lead to respiration problems
• Continuous use will lead to an adjustment and change because of it, its best to use for up to 8hours of use

Administration of Alfentanil

• Best when acute and offset is expected that its best for events like (laryngoscopy, retrobulbar block)
  • At a dose of 15 mcg/kg IV is effective in blunting the BP and HR response to laryngoscopy, administer this 1.5minutes before laryngoscopy

Remifentanil

• Mu receptor agonist that has rapid action as and has a smaller 4-minute distribution, hydrolysis is key
  • Infusion is based on lean body weight for proper distribution The type of drug helps in this case the small action for the patient will help with short term action or quick action, but will leave the body just as quick
• The drug will pull from plasma and the high is what helps it distribute correctly

Remifentanil Uses

• Is the analgesic component of a TIVA which allows rapid recovery from the respiratory depression and excessive sedation If a HTN effect is expected after prolonged use know that an increase is to be expected
• Over time with acute situations, the patient will exhibit pain levels and may have to be given a different route
• The drug can lead to HTN after the procedure of the surgery
• Give with Ketamine, Magnesium will combat the HTN effect
• The drug will require a secondary follow up relief route to counter the pain from before

Methadone

• Used in the chronic treatment of opioid abuse, chronic pain syndromes and cancer pain
• Works as a: Mu receptor agonist, NMDA receptor antagonist, and inhibits the reuptake of MAO in the synaptic cleft
  • Orally Administer medication that has 80% availability

Methadone: Metabolism

• Its most noticeable action is 3-6hours; the drug has a longer duration than most for what its intended
• Watch for qt prolongation if there's a rectifier potassium ion channel which increase the chance of cardiac events
• An EKG at the moment of intake may show problems to watch carefully and may prompt alternative steps

Partial Opioid Agonists

• Termed an agonist-antagonist
• These drugs will never reach max effect like a full agonist
• Common traits will involve small amounts of analgesic action and a low HTN reaction ceiling
  • Its also unlikely that a acute opioid response will happen with the drug being more effective in previously un administered

Partial Opioid Agonists and Subtypes

• Buprenorphine will be an agent for more full and long effect while and can be given via transdermal patch
• Kappa agonists (nalb and butorphanol) will be short term and useful during post op shivering or pt with a history of heart problems
• All of the medications will lead to a problem with mu receptor activation and Naloxone has problems reversing the action

Naloxone

• Mu receptor agonist, great for action that may need to reverse quick
• Watch to always redose because the actions are short term
• Continuous administration and even a follow up may need to be considered.

Naloxone Actions

• Best to apply during the following conditions
  • Overdose of drug
  • If the Pt has Pruritus
  • 30-60min Half Life
• The drug is metabolized by the liver with glucuronic acid
• Watch side effects; and avoid injecting too much too fast (2-3minutes)

Naltrexone

• Orally Available medication that last up to 24hrs due to lack of significant first-pass - Long term alcohol and even maintenance will need this treatment.

dexmedetomidine

• Alpha-2 agonist used for its seditive effects due to acting in the pons and in the locus coereus
• 1mcg/kg dose administered is 10minutes with a 1-10minute onset - After the med stops, the effect goes away after 10-30minutes

ALPHa-2 Antagonism/ Dexmedetomidine

• Key to the drug is the feedback and its reaction to the signal and its action to reduce and stabilize at equilibrium Alpha,2, stimulation leads to inhibition to adenylate cyclase, this leads to cyclic action inside that is calmed through the chemical pathways which lead to the brain stem

Dexmedetomidine

• Works as a stable and more potent solution, its best use cases are in its sedation for decreasing the level of arousal in certain cases (SNS/anxiety)
• Some other compounds may activate the GABA receptors and create even more problems A few of the compounds may even cause anxiety in the patient.
• Highly protein bound(> 90% and undergoes extensive hepatic metabolism ->methyl and glucuronide conjugates are excreted by the kidneys

Dexmedetomidine cardiovascular effects

• Decreases both cardiovascular and respiratory symptoms while giving the benefits that come
• Administration rate and speed can effect the effects
  • Fast can cause hypertension or fluctuations in blood pressure and not allow for the SNS and equilibrium effect to be achieved
• Its other benefits on top of its main effects are
  • Decrease in emergency
  • Alpha 2 stimulation and glutamate actions
  • Evoked action unchanged

dexmedetomidine, conclusion

• As a whole, the drug its best know effects is giving a controlled and precise effect while under going minor problems in patient recovery and has an overall minor impact on patients.

Discussion of opioid pharmacology, including alfentanil, remifentanil, fentanyl, and methadone. Topics covered are drug metabolism, drug interactions, and managing opioid-induced hyperalgesia. Includes drug administration considerations and therapeutic uses.