Analgesic Agents (Week2) Flashcards
A-δ Fibers
(alpha delta)
Free (naked) nerve endings.
Myelinated
Diameter = 1–4 μm.
Transmit “first pain” or “fast pain”
Well-localized discriminative sensation (sharp, stinging, pricking).
Duration of pain coincides with duration of painful stimulus.
C Fibers
Free (naked) nerve endings.
Unmyelinated
Diameter = 0.4–1.2 μm.
Transmit “second pain” or “slow pain”
Diffuse and persistent burning, aching, throbbing sensation.
Duration of pain exceeds duration of stimulus.
The “fast” and “slow” pain pathways are activated in the periphery when _______
the free nerve endings of the A-δ and C fibers are stimulated (damaged)
_______ stimulate the same receptors that are stimulated by the body’s endorphins and enkephalins.
Opioids
Classes of Opioids
- naturally occurring (ex: morphine, codeine)
- semisynthetic (ex: buprenorphine)
- synthetic (ex: fentanyl, sufentantil)
Clinical Uses of Opioids & Routes of Admin
Component of most anesthesia techniques
- Reduce pain and anxiety
- Decreased somatic and autonomic responses (e.g., airway manipulation)
- Improved hemodynamic stability
- Less inhaled or infused anesthetic agent required
- Postop analgesia
Routes
Intermittent: varying plasma concentrations and effect
Continuous: titratable, reduced total dose, less need for reversal
Mechanism of Action of Opioids
Opioids bind to Mu1, Mu2, Kappa, and delta receptors to decrease neurotransmitter release by increasing potassium efflux and MARK cascade and decreasing adenyl cyclase production and calcium influx of ascending and descending pain pathways.
Where is the activation site of supraspinal opiate receptors?
Medulla, midbrain to inhibit neurons in the pain pathway
Mechanism of spinal opiate receptor(s) activation
decreases calcium influx and decreases release of neurotransmitters related to nociception
Where is the activation site of peripheral opiate receptors?
Gastrointestinal (GI), vasculature, lung, heart, immune systems
Mu (μ) opiate receptor
Tell me what you know about its effects on the bosy when stimulated
IUPHAR name for it: MOP
EFFECTS
- analgesia: spinal, supraspinal
- CV: Bradcardia
- Resp: Depression
- CNS: Euphoria, sedation, prolactin release, mild hypothermia, catalepsy, indifference to environmental stimulus
- Miosis (shrinking pupils)
- GI: Inhibition of peristalsis, N/V
- URINARY RETENTION
*Pruritis & physical dependence
Kappa (μ) opiate receptor
Tell me what you know about its effect on the body
IUPHAR name for it: KOP
EFFECTS analgesia: spinal, supraspinal
Resp: Possible depression
CNS: Sedation, dysphoria, psychomimetric reactions (hallucinations/delirium)
Miosis (shrinking pupils) GI: Inhibition of peristalsis, N/V
GU: Diuresis (inhibition of vasopressin release)
*low abuse potential and ?used for antishivering
Delta (δ) opiate receptor
Tell me what you know about its effects on the body when stimulated
IUPHAR name for it: DOP
EFFECTS
analgesia: supraspinal, spinal, modulates mu-receptor activity
Resp: depression
GU: Urinary retention
*Pruritis and physical dependence
Name drugs which are agonists to all three opiate receptors?
Morphine
Meperidine
Fentanyl
Sufentanil
Alfentanil
Remifentanil
Name drugs which are:
Antagonist of Mu receptor
Partial agonist of Kappa receptor
Agonist of Delta receptor
Butorphanol
Nalbuphine
Name drugs which are antagonists of all three opiate receptors?
Naloxone
Naltrexone
Nalmefene
Effect of Opioid on the Respiratory System
- Cough suppressant (however a rapid bolus can cause a cough)
- Depress upper and lower respiratory track reflexes
- Decrease ventilatory response to hypercapnia and hypoxia
- Onset of apnea occurs before unconsciousness
- Potential for skeletal muscle rigidity
Effects of Opioids on the Cardiovascular System
- Relatively hemodynamically stable
- Bradycardia resulting from medullary vagal stimulation with little effect on BP in healthy patients •Dose dependent vasodilation
If the drug releases histamine, can induce hypotension
Effects of Opioids on the Gastrointestinal System
- Decrease gastric and intestinal motility
- constipation, ileus
- Prolong gastric emptying time
- Reduce GI track secretory activity
Effects of Opioids on the Endocrine System
- Reduced stress response (immunosuppressive)
- Inhibition of hormones (ex corticotropin) from the pituitary gland (HPA axis)
- Decreased BMR (basal metabolic rate) and temperature by resetting hypothalamus temperature regulation
- Inhibition of vasopressin release
Describe what happens after an opioid such as morphine is injected into the intrathecal or epidural space
it diffuses into the substantia gelatinosa (Rexed’s lamina II) and unites with opioid receptors on the nerve terminal of the primary pain afferent.
The release of substance P is reduced, and, hence, the transmission of impulses through the substantia gelatinosa is inhibited.
THIS IS KNOWN AS SPINAL ANESTHESIA
Mu-1, mu-2, kappa, and delta receptors mediate ______ analgesia.
spinal
Spinal opioid analgesia is mediated primarily by
mu-2 receptors
How does spinal anesthesia side effects differ from systemic opioid administration?
Same side effects as systemic opioids with increased frequency of pruritus and urinary retention
Antagonism of Pruritis
- Nalbuphine most effective as a mu/kappa opioid partial agonist
- Retains analgesia and treats pruritis
- Droperidol, antihistamines, odansetron
- May reverse analgesia: naloxone, naltrexone (be thoughtful administering this one)
Pruritis, what does it occur with? Mechanism of action?
•Rash, itching, warmth in blush are of face, upper chest, arms, nausea & vomiting
Occurs with:
- Histamine (morphine) and nonhistamine-releasing (fentanyl) opiates
- Prominent with neuraxial route (morphine)
Mechanism: Central mu receptors, not local histamine release
Fentanyl Absorption & Dosing
Absorption
•Routes: Transmucosal, IM, IV, epidural, intrathecal, transdermal
Dosing
- Induction dose as adjunct: 1 – 3 mcg/kg
- Infusion: 0.01 – 0.05 mcg/kg/min
- Small dose boluses: 25 – 50 mcg
Distribution & Redistribution of Fentanyl
Distribution (intravenous)
- Onset: 2 – 5 minutes
- Peak effect: 20 – 30 minutes
- DOA: 0.5 – 1 hours
Redistribution
•Extensive uptake in lungs and red blood cells
Metabolism & Excretion of Fentanyl
Metabolism
•Hepatic metabolism to inactive metabolite norfentanyl
Excretion
•Eliminated in feces and urine
Pulmonary first pass of Fentanyl can cause ___
coughing
Special considerations for a Fentanyl patch
- Once applied, it takes 11 hours for peak effect
- Once removed, it takes 18 hours for plasma concentration to decrease by half
Meperidine Absorption & Dosing
Absorption
•Routes: PO, IV, IM
Dosing
•Intravenous small dose boluses: 12.5 – 25 mg
Distribution of Meperidine
Distribution (intravenous)
- Onset: 5 minutes
- Peak effect: 30 - 60 minutes
- DOA: 2 - 4 hours
Metabolism, Excretion & clinical effect of Meperidine
Metabolism
- Hepatic metabolism via CYP450 system to its active metabolite = normeperidine (½ the analgesic & ½ life significantly longer than meperidine)
- Lowers seizure threshold, induces CNS excitability
- Accumulation causes CNS excitation
- Tremors, muscle twitches, seizures
- Risk with renal failure, high dose chronic use
Excretion
•Eliminated by the kidneys
Meperidine is structurally similar to ____ and may cause _____
atropine, tachycardia
Meperidine has significant drug interactions with ___
MAO inhibitors
Meperidine demonstrates similarities to local anesthetics when administered _________
intrathecally
Meperidine (and morphine) can cause ______
histamine related bronchospasm
Meperidine is effective in decrease postoperative shivering because of _________
its effects at the Kappa receptor
Absorption & Dosing of Morphine
Absorption
•Routes: PO, IV, IM, Epidural
Dosing
•Intravenous small dose boluses: 1-5 mg
Distribution of Morphine (IV)
- Onset: 20 minutes
- Peak effect: 30 - 60 minutes
- DOA: 4 - 5 hours
Metabolism & Excretion of Morphine
Metabolism
- Hepatic and renal metabolism to metabolites: 90% morphine-3-glucuronide (inactive) and 10% morphine-6-glucuronide (active)
- morphine 6-glucuronide is a more potent and longer-lasting opioid agonist than morphine
- Caution in patients with renal failure because ACTIVE METABOLITE and portion excreted unchanged can result in narcosis and ventilatory depression
Excretion
•Eliminated by the kidneys (5-10% is excreted unchanged)
Special considerations of morphine
Morphine is the least lipophilic opioid
Morphine is the least nonionized at physiologic pH
Morphine has the longest DOA when administered intrathecally
Morphine (and meperidine) can cause histamine related bronchospasm
Absorption & Dosing of Hydromorphone
Absorption: Routes: PO, IV, epidural, intrathecal
Dosing: Intravenous small dose boluses: 0.2 mg
Disribution of IV Hydromorphone
- Onset: 15 - 30 minutes
- Peak effect: 30 - 90 minutes
- DOA: 4 - 5 hours
Metabolism & Excretion of Hydromorphone
Metabolism: Hepatic metabolism via CYP system to hydromorphine-3-glucuronide (inactive)
Excretion: Eliminated by the kidneys
Absorption & Dosing of Methadone
Absorption
•Routes: PO, IV
Dosing
- Intravenous dose: 0.5 mg/kg
- Dosing is influenced on patient’s chronic opioid regimen
Disribution of IV Methadone
Distribution (intravenous)
- Onset: 5 -10 minutes
- Peak effect: 15 – 20 minutes
- DOA: 4 - 6 hours
- Half-life: 15 – 30 hours
- Highly protein bound (90%)
Metabolism & Excretion of Methadone
Metabolism
•Hepatic metabolism via CYP system
Excretion
•Eliminated by the kidneys
What is unique about methadone?
- Methadone is used primarily for chronic pain and treatment of opioid abstinence syndromes
- Methadone has NMDA receptor antagonism properties
- Compared to other opioids, methadone produces less euphoria, has a long half-life, extensive protein binding and slow release
Absorption & Dosing of Remifentanil
Absorption
•Routes: IV
Dosing
•Intravenous induction dose: 2 - 5 mcg/kg
•r/f opioid induced muscle rigidity
•Intravenous infusion: 0.05 – 0.25 mcg/kg/min
Distribution of IV Remifentanil
- Onset: 1 minutes
- Peak effect: 1 minute
- DOA: 5 – 10 minutes
Metabolism & Excretion of Remifentanil
Metabolism: Ester hydrolysis via blood and tissue esterases
Excretion
•Eliminated by the kidneys
Induction doses of reminfentanil may cause _____
•profound bradycardia and are often administered with ephedrine
Why is Remifentanil beneficial in patients with renal or hepatic failure?
Remifentanil’s metabolism by plasma esterases (not pseudocholinesterases)
Why is Remifentanil beneficial in the OR?
rapid onset, short DOA and titratability
What special consideration does the CRNA need to think about with Remifentanil?
•may contribute to post-operative hyperalgesia, therefore the CRNA should create a plan for postoperative analgesia
Absorption & Dosing of Sufentanil
Absorption
•Routes: IV
Dosing
- Intravenous induction dose: 0.1 – 0.3 mcg/kg
- Intravenous infusion: 0.0015 – 0.01 mcg/kg/min
Distribution of Sufentanil
Distribution (intravenous)
- Onset: 1 – 3 minutes
- DOA: Dose dependent
Metabolism & Excretion of Sufentanil
Metabolism
•Metabolized by the liver
Excretion
•Eliminated by the kidneys
Context sensitive half-time
how long does it take for the plasma concentration to decrease by half once an infusion of a medication has been turned off
Special considerations for Sufentanil
- Sufentanil is one of the most potent
- In general, an infusion of sufentanil has a longer context sensitive half-time than remifentanil infusion being administered for a similar duration
Medication class of Buprenorphine
mu partial agonist
Mechanism of Action of Buprenorphine
strongly binds to mu receptors
•Strongly binding to a receptor is not synonymous with strong clinical effects as this partial agonist has a ceiling effect
Use, Peak, and considerations of Buprenorphine
Use: Moderate analgesia with limited respiratory depression
Peak effect: 3 hours | DOA: 10 hours
Special Considerations
Ceiling effect, difficult to supplement with other opioids, active metabolites
Naloxone Medication Class & Use
Class: nonselective opioid antagonist
Use: Reverses opioid induced respiratory depression, analgesia, sedation, nausea, puritis and constipation
Absorption & Dosing of Naloxone
Absorption: IV, intranasal, SQ
Dose: 40 mcg boluses (titrate slowly)
Onset and Side Effects of Naloxone
Onset: 1 minute | DOA: 30 minutes (shorter than most opioids)
Side effects: pulmonary edema, tachycardia, hypertension
Naltrexone
- Similar antagonist and receptor binding properties with naloxone
- Extended-release formulation is used for alcohol withdrawal programs
- Used with opioid addiction to block euphoric effects of opioids
What medication class is Ketorolac?
•nonselective COX 1 and 2 inhibitor
Absorption & Dosing of Ketorolac
Absorption: Oral, IV, IM
Dosing (intravenous): 15 - 30 mg
- Dose decreased in elderly and CKD
- Administered during emergence
Distribution of Ketorolac
Distribution:
•Onset: 30 min | DOA: 4 – 6 hours
Metabolism & Excretion of Ketorolac
Metabolism: Hepatic
Excretion: Renal (60% unchanged)
Advantages of Ketorolac
Advantages
- Decrease post-operative opioid requirements
- Low incidence of nausea and vomiting
- Lack of respiratory depression
Things to consider w/ use of Ketorolac
Considerations
- Communicate with surgical colleagues prior to administration
- Bone healing delays by NSAIDs, not used in ortho surgery, OK with stable and healing fracture
- Bleeding risk in intercranial surgery
- Caution in patients with asthma r/t bronchoconstriction d/t decrease leukotriene productions
- Caution in patients with renal disease r/t renal vasoconstriction d/t decrease prostaglandin production
Class & Absorption of Acetaminophen
Class: Analgesic and antipyretic
Absorption: Oral, PR, and IV
Dosing of Acetaminophen (Offirmev)
Dose (intravenous):
- Pediatric: 15 mg/kg
- Adult: 1G over 10 minutes
- PO dose administered preoperatively, or IV dose administered during emergence
- Max dose: 4 g/day
- Dosing decreased in patients with liver dysfunction
Distribution of Acetaminophen
Distribution:
•Onset: 10 min | DOA: 4 – 6 hours
Metabolism & Excretion of Acetaminophen
Metabolism: Hepatic: increased doses yields large concentrations of N-acetyl-p-benzoquinone imine to produce hepatic failure
Excretion: Renal
What are the advantages of Acetaminophen?
Advantages
- Decrease post-operative opioid requirements
- Low incidence of nausea and vomiting
- Lack of respiratory depression
What are the disadvantages of Acetaminophen?
- Black box warning: Hepatoxicity
- Be aware of liver enzymes (if appropriate)
- Be are of patient’s cumulative dose
- Reversal agent is N-acetylcysteine
Medication Class of Gabapentin (Pregablin)
Antileptic
Mechanism of Action of Gabapentin
Although these agents have been shown to bind to voltage-gated calcium channels and N-methyl-D-aspartate (NMDA) receptors, their exact mechanism of action remains speculative
Special Considerations for Gabapentin
- Can be administered preoperatively (orally) to decrease post-operative opioid requirements
- Can contribute to post-operative sedation
Opioids that release histamine = ____
morphine & meperidine
Opioids that do not release histamine = _____
fentanyl, sufentanil, alfentanil, remifentanil
What can you give together to block CV vasodilation, tachycardia and hypotension
•H1 and H2 antagonists
