Test 4: Opioids Pharmacodynamics Flashcards
What pain fibers do opioids work best on?
-Treat “Second pain” sensations: Slowly conducted sensations from unmyelinated C-fibers
-Less effective for “First pain” sensations: quickly conducted sensations from small, myelinated A-Delta Fibers
How do opioids differ from local anesthetics?
They block pain, but don’t produce the differential blockade that LA’s produce.
-No effect on touch, temp, etc.
Are opioids anesthetics?
NO. They do not reliably produce unresponsiveness.
Opioids are most effective for what kind of pain?
Continuous, visceral, dull pain.
-Organ pain
-But, at high doses, can relieve any pain.
What are the CNS effects of opioids?
-Sedation & Euphoria: contribute to the feeling of well-being in awake patients (varies depending on agent and receptor)
-Dysphoria: occurs with strong Kappa agonists or when opioids are taken in the absence of pain.
How do opioids elicit Analgesic effects?
1) Inhibit the ascending transmission of nociceptive stimuli
-From the dorsal horn of the spinal cord
2) Activate pain control pathways that descend from the midbrain
-Via the rostral ventromedial medulla to the spinal cord dorsal horn
What is the effect of opioids on neuromonitoring (EEG & EP)?
The effect of opioids on electroencephalographic and evoked-potential activity is minimal, therefore neurophysiologic monitoring can be conducted during opioid anesthetic techniques.
What is the effect of opioids on Intracranial Pressure (ICP)?
Opiate administration can indirectly cause an increase in intracranial pressure if respiratory depression-induced hypercarbia occurs.
Katzung:
Opioid analgesics affect cerebral circulation minimally except when PCO2 rises as a consequence of respiratory depression. Increased PCO2 leads to cerebral vasodilation associated with a decrease in cerebral vascular resistance, an increase in cerebral blood flow, and an increase in intracranial pressure.
What is Physical dependence?
The need for the drug in order to function properly.
-Physical dependence is defined as a characteristic withdrawal or abstinence syndrome when a drug is stopped or an antagonist is administered.
What is Tolerance?
A gradual loss in effectiveness with repeated doses.
-Decrease in duration comes first, followed by a decrease in effect.
Katzung:
-Tolerance develops most readily when large doses are given at short intervals and is minimized by giving small amounts of drug with longer intervals between doses.
-Tolerance also develops to the antidiuretic, emetic, and hypotensive effects but not to the miotic, convulsant, and constipating actions.
What is Cross-Tolerance?
Patients tolerant to one drug (ex: Morphine) show a reduction in analgesic response to other agonist opioids.
-Particularly occurs with Mu agonists.
-Can be partial or incomplete
How does Tolerance develop?
Both acute and chronic tolerance will develop with opiates.
-The mechanism of tolerance is complex and does not appear to be due to a change in receptor number.
-Receptor internalization, activation of N-methyl-D-aspartate (NMDA) receptors, second messenger changes, and G protein uncoupling (changes in the binding sites) may all play a role.
How do Opioids effect Awareness?
-Opioid agonists are NOT anesthetics
-Mu agonists (even high doses) do not reliably produce unresponsiveness or amnesia.
-High dose opiates do not eliminate the risk of awareness.
-Cannot be considered a complete anesthetic or used alone
What is Hyperalgesia?
Increased sensitivity to pain. Exaggerated response.
-Can be due to damage to nociceptors or peripheral nerves.
Katzung:
-Spinal dynorphin and activation of the bradykinin and NMDA receptors have emerged as important candidates for the mediation of opioid-induced hyperalgesia.
What are the Respiratory Effects of opioids?
-Dose-dependent depression
-Most significant adverse effect (can be life-threatening if airway is not secured)
-Alters the response to hypercarbia and hypocapnia (depresses the hypoxic drive to breathe - important for COPD and OSA patients).
What are risk factors that increase the risk for respiratory depression with opioids?
-High dose opioids
-Advanced age
-CNS depressants
-Renal insufficiency
Which patients are at an increased risk for M&M in the post-operative period due to respiratory depression from opioids?
Morbidly obese or OSA patients
Pediatrics < 60 weeks PCA
How do opioids produce respiratory depression?
Via stimulation of the Mu and Delta Receptors in the Ventilatory control center in the medulla.
What do opioids do to the CO2 response curve?
RIGHT shift in the CO2 response curve.
-Decrease responsiveness to increased CO2 and decreased O2
-Higher pCO2 is needed to maintain adequate respiration
What is the Pupillary Reflex Arc?
1) Opiate depression of GABA interneurons leads to stimulation of the Edinger-Westphal Nucleus
2) E-W Nucleus sends a PNS signal via the Ciliary Ganglion to the Oculomotor nerve
3) Pupil constricts
T/F: Opioid addicts will develop tolerance to Miosis. (Blue Box)
False: Tolerance does NOT develop to miosis. (Blue Box!)
When does Miosis occur with opioid administration?
-Occurs at lower doses than analgesia or respiratory depression
-Qualitative, not quantitative sign
-Reversible with narcan (if patient not breathing)
-Due to Mu receptor agonist (pupillary reflex arc). Mu receptor right on iris itself.
How do opioids cause anti-tussive effects?
-Depresses the cough center in the medulla
-Glottic protective reflexes are intact - not taking away mechanical ability to cough. Still have reflexes intact if needed.
-Therapeutic: helps to decrease stimulation with ETT. Provides “tube tolerance”
Which opioids are particularly good at cough suppression?
Codeine and Heroin
How do opioids increase PONV?
By stimulating the Chemoreceptor Trigger Zone in the Area Postrema of the Medulla.
-Floor of the 4th Ventricle.
-Increased in ambulatory surgery patients due to possible vestibular nerve involvement. PONV is exacerbated by movement.
-Patient responses vary
T/F: Opiate analgesia is safe for people with cardiovascular compromise (Blue Box!)
True
What are the cardiovascular effects of opioids?
-Decrease HR due to increased vagal nerve tone to the Medulla of the brainstem (can be attenuated with anti-muscarinics)
-Bradycardia with little effect on BP
-Dose-dependent vasodilation (both venous & arterial) due to depression of the vasomotor centers of the brain. Decreases PL & AL
-Decrease in BP is mild in healthy patients, but can be pronounced in patients with increased sympathetic tone
-No change in contractility, baroreceptor function, or autonomic response.
Which opioids release Histamine?
Morphine, Meperidine, and Codeine
-Causes vasodilation (arterial and venous), tachycardia, and hypotension
-Can be blocked/blunted with H1 and H2 antagonists
Does fentanyl and its cogeners release histamine?
No
Do opioids have an effect on nerve conduction?
No. Opioids have no major effects on nerve conduction at the neuromuscular junction or at the skeletal muscle membrane.
Large IV doses of most opioids can cause what muscular symptoms?
Generalized hypertonus of skeletal muscle can be produced by large IV doses of most opioid agonists.
-Muscle rigidity leads to a loss of chest wall compliance and truncal rigidity (“Tight Chest”). Results in difficult mask ventilation.
-Can cause constriction of pharyngeal/laryngeal muscles, leading to vocal cord rigidity and closure
-Mechanism behind this is unknown, but theorized to be related to central Mu receptors interacting with Dopamine and GABA pathways.
-Increased frequency with concurrent administration of N2O
-Can be attenuated with muscle relaxants (if early) or Narcan (if end of case)
Which opioid agents are the most likely to cause muscle rigidity?
-Fentanyl and Remifentanil most common
-Also seen with Alfentanil and Sufentanil
The itchy rash/hive reaction associated with opioids is due to what?
Histamine release locally.
-Seen most often with Demerol, Morphine, and Codeine
The feeling of warmth in the face, upper chest, and arms (true pruritus) associated with opioids is due to what?
Stimulation of Central Mu receptors.
-Most common with neuraxial administration (ex: Duramorph in a spinal)
How do you treat pruritus associated with opioids?
-Naloxone (reverses activity of Mu receptors)
-Nubain (Agonist/antagonist that reverse itch but not analgesia- blocks Mu and not Kappa)
-Droperidol
-Antihistamines (benadryl)
-Ondansetron (MOA unknown)
How do opioids contribute to constipation and post-op ileus?
-Decreased gastric motility, prolonging gastric emptying time
-Reduce secretory activity throughout GI system (dec gastric acid secretion)
Inc risk for aspiration, especially with patients having multiple surgeries day after day (ex: trauma patient receiving staged procedures)
What drugs are used for the treatment of GI side effects associated with opioids?
Peripherally acting Mu Opioid Receptor Antagonists (PAMORAs) that promote peristalsis.
-Alvimopan (Entereg)
-Methylnaltrexone (Relistor)
Work locally in the GI tract, and do not affect centrally produced analgesia.
What is the effect of opioids on the biliary duct?
-Dose dependent increases in biliary duct pressure
-Increases Sphincter of Odi tone (can give Glucagon to offset this)
-Risk for false-positive cholangiograms
What are the opioid effects on the Endocrine System?
-Reduction of stress response
-Immunosuppressant effect (bad for cancer patients. Most common with Morphine)
-Release of Vasopressin from post. pituitary
-Inhibition of Anterior Pituitary Hormones: Corticotropin, Gonadotropin, and Thyrotropin
-Potential for decreased BMR and decreased temperature with chronic use of opioids
How do opioids decrease temperature?
By resetting the equilibrium point of temperature regulation in the hypothalamus.
What are the effects of opioids on the Bladder?
-Usually produce an anti-diuretic effect
-But, Kappa receptor agonists can cause diuresis.
These two effects are usually balanced out because we don’t have any solely Kappa Agonist drugs.
How do opioids produce an anti-diuretic effect?
-Decrease tone at the bladder detrusor muscle
-Constrict the urinary sphincter (inc urinary sphincter tone)
These two result in urinary retention
-Especially common SE with intrathecal and epidural opioid administration.
