Apex- Opioid & Non-opioid analgesics Flashcards
What are pain receptors called
Nociceptors
What is it called when a nociceptor converts a noxious stimulus to an action potential?
Transduction
How is facial pain transmitted?
via cranial nerve V (trigeminal)
*bypasses the spinal cord and conducts pain stimuli directly to the brain
What is pain transduction blocked by? (5)
(converting the stimulus into an action potential)
-Nsaids, opioids, local anesthetic CREAMS, steroids, antihistamines.
What is pain TRANSMISSION blocked by?
(pain transmitted from the periphery to the CNS)
Local anesthetics for peripheral or neuraxial nerve blocks
When doing a peripheral or neuraxial nerve block, do you block pain transmission or transduction?
transmission
Pain is transmitted via what types of fibers?
A delta & C
What are the 2 important excitatory NTs in the dorsal horn?
Glutamate and substance P
Discuss the transmission of pain and where the 1st, 2nd, and 3rd order neurons synapse
- 1st order neuron transmits signal from site of injury
> dorsal horn: can synapse with a 2nd order neuron at the level it enters or travel along the tract of Lissauer before synapsing at a higher or lower level
> after synapsing with the 2nd order neuron it CROSSES to the contralateral side of the spinal cord and ASCENDS to the brain via the SPINOTHALMIC tract
> the 2nd and 3rd order neurons synapse in the thalamus
> 3rd order neuron projects to other brain regions (cortex, limbic system, etc)
Order of steps of the pain process
(modulation, transduction, perception, transmission)
- Transduction
- Transmission
- Modulation
- Perception
allodynia
Pain resulting from a non-painful stimulus (pain from ALL the things)
Drugs that target pain transduction (5) vs transmission (1) vs modulation (6) vs perception (3)
transduction (5)
> NSAIDS
> LA creams
> Steroids
> Antihistamines
> Opioids
transmission (1)
> local anesthetics via peripheral nerve or neuraxial blocks
modulation (6)
>neuraxial opioids
>NMDA antagonist
>alpha-2 agonists
>AchE inhibitors
>SSRIs
>SNRIs
perception (3)
>general anesthetics
>opioids
>alpha-2 agnoists
Re: Modulation: what 2 things is pain augmented (enhanced) by?
Central sensitization & Wind-up
Re: Modulation: what 2 things is pain inhibited by?
- spinal neurons releasing GABA & Glycine
- Descending pathway releases NE, serotonin, and endorphins
Opioid receptor stimulation results increased/decreased:
cAMP
adenylate cyclase activity
calcium conductance
potassium conductance
cAMP - decreased
adenylate cyclase activity - decreased
calcium conductance- decreased (reduces NT release)
potassium conductance- increased (hyperpolarizes nerve so it’s less responsive to stimulation)
Where does pain modulation typically take place?
in the dorsal horn of the spinal cord
MOP receptor is what
Mu
DOP receptor is what
Delta
KOP receptor is what
Kappa
NOP receptor is what
ORL1 ?
6 key physiologic effects of Mu receptor stimulation
- analgesia
- euphoria
- Physical dependence
- resp depression
- bradycardia
- constipation
(Try to answer in systems, from top to bottom)
Endogenous ligands for the Mu, delta, kappa, and NOP receptors
Mu- endorphins
Delta- Enkephalins
Kappa - dynorphins (thinks dysphoria)
NOP - nociceptins
What does pre-synaptic mu receptor stimulation result in?
reduced calcium conductance via N-type calcium channels
>decreased NT release
What does stimulation of mu receptors on the post-synaptic neuron result in?
increase of K+ conductance
>hyperpolarizes neuron
>decreased RMP
>makes it more resistant to stimulation
Where are mu receptors found?
- Peripheral NS
>A-delta & C fibers - CNS
>dorsal horn
>RAS
>thalmus
>somatosensory cortex - Descending inhibitor pathway
>periadquaductal gray
>nucleus raphe magnus - Immune cells
>leukocytes
What does stimulation of mu receptors in the descending spinal pathway?
stimulates the release of endorphins, serotonin, and NE in the dorsal horn of the spinal cord
(via mu receptors in the periaqueductal gray and nucleus raphe Magnus)
What happens when opioids bind to an opioid receptor (chemical processes)
- opioid binds
- G-protein is activated
- Adenylate cyclase is turned off
- Less cAMP is produced
- CA+ conductance is decreased (presynaptic)
- K+ conductance is increased (post-synaptic)
T/F all opioid receptor stimulation result in bradycardia
False- just Mu
Which opioid receptor does not produce miosis
Delta
Which opioid receptor produces diuresis?
Kappa
T/F- all opioid receptors result in N/V, increased biliary pressure and decreased peristalsis
false- just mu
Stimulation of which opioid receptor does NOT result in pruritis
kappa
What’s associated with Mu-3 stimulation
Immune suppression
Which mu-subtype targets spinal analgesia only (not supraspinal)
Mu-2
Which Mu-subtype is associated with resp depression
Mu-2
-resp depression, phsycial deprendence > constipation
Which mu-subtype is associated with bradycardia
Mu-1
Which mu-subtype is associated with supraspinal and spinal analgesia?
Mu-1
T/F: delirium and hallucinations are caused by mu receptor stimulation
False- kappa
(kappa/dynorphan/dysphoria)
Opioids produce bradycardia through Mu receptor stimulation. What is the exception to this and why?
Meperidine - it can increase HR due to an atropine-like ring in its structure
Where are opioid receptors located in the:
Brain (3), Spinal Cord (2), & Periphery (2)
Brain:
>periaquaductal gray
> locus coeruleus
>rostral ventral medulla
Spinal Cord:
> primary AFFERENT neurons in the DORSAL HORN
>interneurons
Periphery:
>sensory neurons (A delta & C)
>immune cells
The mechanisms by which opioids contribute to urinary retention (2)
Detrusor relaxation (contraction needed to pass urine into the urethra)
& urinary sphincter contraction
How do opioids affect RR & TV?
decrease RR
increase TV
(just think, when your relaxed, you take a slow deep breath) - so they should be taking slow deep breaths if comfortable
Is gastric emptying time increased or decreased by opioids?
increased (prolonged, takes more time to empty)
Relative potency to Morphine:
Meperidine:
Hydrocodone:
Alfentanil:
Remifentanil:
Fentanyl:
Sufentanil:
Meperidine: 0.1 x
Hydrocodone: 7 x
Alfentanil: 10 x
Remifentanil: 100 x
Fentanyl: 100 x
Sufentanil: 1000x
T/F: dependence occurs when a patient requires higher doses of a drug to achieve a given effect
False- tolerance
Dependence occurs when a person taking the drug will go through withdrawal upon d/c’ing the drug
Early (3) and Late (2) S/S of opioid withdrawal
Early: diaphoresis, insomnia, restlessness
Late: abdominal cramping & N/V
What are the:
phenanthrene derivatives(2):
Morphine derivatives(4):
Thebaine derivatives(2):
Piperidines(1):
Phenylpiperidines(4):
Diphenylpropylamines(1):
(Natural (N), Semi-synthetic (SS), or synthetic (S)
phenanthrene derivatives: (N)
>Morphine & Codeine
Morphine derivatives: (SS)
>Hydromorphone (Dilaudid)
>Heroine
>Naloxone (IV narcan)
>Naltrexone (PO narcan)
Thebaine derivatives: (SS):
Oxycodone (Percocet)
Hydrocodone (Vicodin)
___________________
Piperidines: (S)
>Meperidine
Phenylpiperidines: (S)
> Al, Remi, Fent, Su
Diphenylpropylamines:(S)
>Methadone
10mg of morphine is equivilant to:
Meperidine:
Hydromorphone:
Alfentanil:
Remi:
Fentanyl:
Sufentanil:
Meperidine: 100mg
(10mg*/0.1x)
(standard mso4/relative potency)
Hydromorphone: 1.4mg
(10/7)
Alfentanil: 1,000mcg
(10/10 = 1mg)
Remi: 100mcg
(10/100 = 0.1mg)
(1 zero left, always lead)
Fentanyl: 100mcg
(10/100 = 0.1mg)
Sufentanil: 10mcg
(10/1000 = 0.01mg)
When will you start having withdrawal s/s, when will they peak, and how long will they last?
Fentanyl & Meperidine:
Morphine & Heroin:
Methadone:
Fentanyl & Meperidine:
>2-6 hours
>6-12 hours
> 4-5 days
(think most potent, fastest symptoms, peaks, and in and out the fastest)
Morphine & Heroin:
>6-18 hours
>36-72 hours (days 1.5-3)
> 7 - 10 days ( 1-2 weeks)
Methadone:
>Onset 24-48 hours
>Peak: 3-21 days
>Duration: 6- 7 weeks
Active metabolite of Morphine
M6G
Morphine is broken down how?
in’s conjugated to morphine-3 & morphine-6 glucuronide.
*M6G = active metabolite that accumulates with renal failure and chronic morphine administration
How is meperidine broken down?
It’s demethylated in the liver into normeperidine (active)
> accumulates in renal failure and elderly and increases risk of seizures
If M6G is water-soluble and doesn’t cross the blood-brain barrier, why does it matter if it accumulates in patients on dialysis?
What law?
Bc it will accumulate and the larger concentration gradient between the blood and the brain helps M6G enter the CNS.
Law of Mass Action
if someone has a pseudocholinesterase deficiency, will it prolong the effects of remifentanil?
No- Remi is not metabolized by pseudocholinesterases (Sux is)
Remi is metabolized by nonspecific plasma esterases
What is Remifentanyl dosed on and why?
Lean body weight
bc although lipophilic, it behaves like a drug with a low Vd becasue it is rapidly metabolized in the plasma
Which opioid causes mydriasis and why?
Meperidine because it’s constructed from an atropine-like ring (increase HR too)
What receptors does meperidine stimulate?
Mu & Kappa (antishivering effect)
What’s the risk of administering meperidine to a patient on isocarboxazid?
Serotonin syndrome
4 S/S of serotonin syndrome
- Hyperthermia
- Hyperreflexia
- MS changes
- Seizures
What pharmacologic characteristic accounts for the rapid onset of action of alfentanil?
A. Low protein binding
B. Low degree of ionization
C. High potency
D. High lipid solubility
B. Low degree of ionization
(remember PKA determines the onset of action)
-only 10% is ionized, and it’s the UN-ionized (the other 90%) that crosses the BBB to exert its effect
-it’s highly protein bound (alpha-1-acid glycoprotein)
-high potency and high lipid solubility go together so eliminate that
PKA of alfentanil
-weak acid or weak base?
_____% Non-ionized
6.5 (less than physiologic pH)
-weak base
90% non-ionized (available to cross the BBB quickly)
Alfentanil has a (high/low) volume of distribution and a (high/low) degree of plasma protein binding
low Vd
high protein binding
(alpha-1-acid glycoprotein)
(remember it’s a weak base so it’s going to bind to the acid protein)
Which opioid has the highest and lowest Vd?
Highest: Fentanyl (4L/kg)
Lowest: Remi (0.4L/kg)
Which opioids are the highest and lowest protein bound?
Most: Remi & Su (93%) (Al = 92%)
Least = Morphine (35%)
Fent - 84%
Meperidine = 70% (and only 7% non-ionized/active)
Which opioid is the most and least NON- ionized?
most = alfentanil - 90%
least = meperidine- 7%
PKA’s of the opioids minus dilaudid ranked from lowest to highest
Alfentanil- 6.5 *
Remi- 7.2 (AR)
MSO4 - 7.9
Sufent - 8.0
Fent - 8.4
Meperidine- 8.5 *
Because Alfentanil has a comparatively (lower/higher) hepatic extraction ratio, its metabolism is more susceptible to alterations in which CYP enzyme function?
lower hepatic ER
CYP 3A4
(think alfent - CYP A)
Which drug, co-administered with alfentanil can inhibit its metabolism and result in prolonged resp depression?
Erythromycin
(enzyme inhibitor) (the enzymes needed to metabolize Alfent are inhibited by erythromycin and will prolong metabolism leading to prolonged effects of the drug)
2 main differences in the kinetics of alfentanil compared to the other opioids?
lowest PKA (6.5)
- highest non-ionized fraction (90%)
*Fast onset
What opioid has the lowest non-ionized fraction at physiologic pH?
Meperidine
(only 7% is non-ionized)
Attenuate vs Augment
Attenuate = lessen
Augment = enhance
Which 2 agents can be used to attenuate opioid-induced hyperalgesia?
-Ketamine
-Clonidine
-Morphine
-Mag Sulfate
-Ketamine & Mag sulfate
*remember at RMP, the NMDA receptor is plugged by MAG- so making the plug thicker, by giving mag sulfate will make it harder for glutamate to displace the mag core to depolarize the cell.
Context-sensitive half-time of Remifentanil
4 minutes (REMI) - 4 letters, half time 4 minutes
Maintenance infusing dosing of Remi
0.1-1 mcg/kg/min
Methadone provides analgesia by all of the following ways EXCEPT:
-mu receptor agonism
-NMDA receptor antagonism
-monoamine reuptake inhibition
-cholinergic receptor antagonistm
-cholinergic receptor antagonism
3 indications for methadone
-chronic tx of opioid abuse
-chronic pain syndromes
-cancer pain
3 mechanisms by which methadone decreases pain
- mu agonist
- NMDA antagonist
- inhibits reuptake of monoamines in the synaptic cleft
T/F: methadone can prolong the QT interval
True
What is Oliceridine?
2 contraindications
an IV opioid selctive for the mu-receptor.
-for patients with acute pain when other agents fail to provide adequate relief
Contraindicated in GI obstruction or paralytic ileus
List the following as full agonists, partial agonists, or antagonists
Nalmefene
Buprenorphine
Morphine
Butorphanol
Naloxone
Fentanyl
Nalbuphine
Nalmefene (ant)
Buprenorphine (p)
Morphine (f)
Butorphanol (p)
Naloxone (ant)
Fentanyl (f)
Nalbuphine (p)
Partials:
Buprenorphine, Butorphanol, Nalbuphine
Dose and Duration of Naloxone
1-4mcg - q2-3 mins max 10-15mg (max 2mg/dose)
30-45 minutes
Which opioid antagonist does NOT reverse opioid-induced respiratory depression?
METHylnaltrexone
(METHs also good for making you poop)
The primary mechanism by which naloxone can cause pulmonary edema
SNS stimulation
(neurogenic pulm edema)
What is the most important site for pain modulation?
Dorsal horn of the spinal cord
-Rexed’s laminae 2 & 3
A patient receiving a fentanyl PCA appears sedated and is only arousable to tactile stimulation. Clinical findings in this patient MOST likely include: (2):
-decreased blood pH
-decreased tidal volume
-increased ICP
-increased A-a gradient
-decreased blood pH (resp acidosis)
-increased ICP
-increased PaCO2 increases ICP if ventilation is not controlled
Which opioid inhibits nerve conduction:
Morphine
Hydromorphone
Meperidine
Sufentanil
Meperidine
*similar structure as local anesthetics and atropine
*inhibits sodium channels in the axon
The endogenous pain modulation pathway terminates in the:
-Rostroventral medulla
-ventral root ganglion
-periaqueductal grey
-substantia gelatinosa
substantia gelantinosa
*Periaquaeductal gray > rostroventral medulla > substantia gelatinosa
(the endogenous pain pathway = the descending inhibitory pain pathway)
Which agent is associated with the GREATEST amount of rostral spread when injected into the intrathecal space?
-Morphine
-Fentanyl
-Meperidine
-Hydromorphone
Morphine (most water soluble, going to stay in the intrathecal space most)
