Final Opiate Drugs Flashcards
What is an alkaloid?
Plant derived compound with a basic nitrogen
What are the two types of alkaloids contained in opium?
Phenanthrenes
Benzylisoquinolines
What are the Phenanthrene drugs?
Morphine
Codeine
Thebaine
What are the Benzylisoquinoline drugs?
Noscapine
Papaverine
What are opiates?
The opioids that are naturally occurring
-plant derived compounds
Substitutions at the 3 position of the phenanthrene ring do what?
Ethers or Esters produce DECREASED potency
(codeine)
Substitutions at the 6 position of the phenanthrene ring do what?
INCREASE activity
(hydromorphone or hydrocodone)
Substitutions at the 14 position of the phenanthrene ring do what?
OH has increased potency (oxycodone)
N-allyl gives antagonist or mixed antagonists (naloxone or naltrexone)
What are the non-phenanthrenes?
Tramadol
Meperidine
Fentanyl
Methadone
What are the genes that encode endogenous opioids?
Pro-opiomelanocortin (POMC)
Preproenkephalin
Preprodynorphin
Nociceptin/Orphanin FQ
What opioid receptors does the pro-opiomelanocortin (POMC) gene encode?
B-endorphin works on Mu receptors
What opioid receptors does the preproenkephalin gene encode?
Leu-Enkephalin = delta receptors
Met-enkephalin= mu and delta receptors
What opioid receptors does the preprodynorphin gene encode?
Dynorphin works on kappa receptors
What opioid receptors does the nociceptin/orphanin FQ gene encode?
Nociceptin, completely different mechanism
What affects do the opioid receptors have on ion channels?
Open GIRK potassium channels (postsynaptic)
Close calcium channels to decrease neurotransmitter release (presynaptic)
*K leaving hyperpolarizes the cell and makes it more difficult for the neuron to fire
*reduces pain signaling
Which opioid receptor specifically is responsible for the hyperpolarization of the cell?
Mu receptors
What are the opioid receptors?
Mu (M-morphine)
Kappa (K-ketocyclazocine)
Delta (D- deference - where it was identified)
Nociceptin (orphanin FQ receptor)
What is the endogenous opioid of Mu receptors?
Endorphin
What is the endogenous opioid of Kappa receptors?
Dynorphin
What is the endogenous opioid of Delta receptors?
enkephalin
What are beta-endorphins?
Endogenous morphine
What are the therapeutic uses of the beta-endorphins?
Analgesia:
-Not as effective for chronic pain, better for breakthrough pain
-Used for patient-controlled analgesia
Sedation
Antitussive
Opioid-induced side effects are mostly what kind of effects?
On-target effects
What are the common side effects of opioids?
-Respiratory Depression
-Constipation
-Pruritus (itching) *not an allergic response
-Addiction
Urinary retention
-Nausea/Vomiting
-Miosis (pinpoint pupils)
Would you use an opioid as an anti-diarrheal?
Yes
-one that stays out of CNS and in the GI tract
Activation of kappa opioid receptors has what affect?
Dysphoric and Aversive
-negative effect, kappa opioid receptor agonists can be combined with mu opioid agonists to reduce the addiction potential
-decreases dopamine release
Which opioid receptor may be useful to combat opioid addiction?
Kappa receptors
Which opioid receptor does not have any FDA approved agonists?
Delta receptor
What are the uses of the delta opioid receptor?
-Reduce anxiety
-Reduce depression
-Treat alcoholism
-Relief hyperalgesia, chronic pain
-May protect against hypoxia, ischemia, and stroke
What side effect is associated with delta opioid receptors?
Seizures
What two areas of the brain are important for reward and linked to addiction?
Ventral Tegmental Area
Nucleus Accumbens
How do opioids function in the brain to increase reward?
Opioid binds the mu receptor
Gi signaling inhibits neurotransmitter release
Less GABA to activate GABA A
Less inhbition of dopamine activity
Increased dopamine release and increased dopamine receptor activation
(mu receptor reduces GABA release which increases dopamine release)
Which opioid drug shows a slower and more sustained peak?
Morphine (longer half life)
What is the % bioavailability of morphine?
25%
*first pass metabolism
What is morphine a substrate of?
CYP2D6
CYP3A4
How does liver disease affect the half-life of morphine?
Increased half-life with liver disease
What % of morphine is excreted in 24h?
90%
Which opioids are prodrugs?
Heroin
Codeine
Tramadol
What is the inactive metabolite of codeine and what active metabolites is it changed to?
Inactive: Norcodeine
Active: Hydrocodone, Morphine
What is the active metabolite of tramadol?
O-desmethyltramadol
*not a pharmaceutical opioid
What is the inactive metabolite of heroin and what active metabolite is it changed to?
Inactive: Normorphine
Active: Morphine
What is the lipophilicity of morphine and how does this impact its passage across the BBB and its duration of action?
Low Lipophilicity
Slow passage across BBB
Long duration of action
What is the lipophilicity of fentanyl and how does this impact its onset and duration of action?
High lipophilicity
Rapid onset
Short duration
CYP3A4 makes what opioids?
(FOUR) makes opioids starting with NOR
What are nor opioid metabolites?
-Made by CYP3A4
-Less active
-Nor= without a methyl group (demethylated)
What enzyme activates codeine to morphine?
CYP2D6
What are the 4 possible CYP2D6 metabolizers?
PM: poor metabolizers
IM: intermediate metabolizers
EM: extensive metabolizers
UM: ultra-rapid metabolizers
Ultrarapid metabolizers of CYP2D6 would experience what effects with codeine?
Activate codeine at a much higher rate, would have more adverse effects
Poor metabolizers of CYP2D6 would have what effects with codeine?
No therapeutic effect
*more common in caucasians
True or False: Fentanyl is a low potency opioid
FALSE
-very potent
When is fentanyl used?
Palliative care
Breakthrough pain
What side effect is a concern with fentanyl?
Respiratory depression
The majority of opioids are what schedule?
Schedule II
The opioids Sufentanil, Remifentanil, and Alfentanil undergo what breakdown in the body?
Breakdown by plasma esterases due to ester linkage
What is the extended-release form of morphine?
MScontin
What is Lortab/Vicodin/Norco?
Hydrocodone + Acetaminophen
What is Percocet?
Oxycodone + Acetaminophen
Besides analgesia, what other property does Tramadol have?
SNRI
When would we use Tramadol?
When you do not want to prescribe a stronger opioid
-Used for neuropathic pain
What is an important point to remember about Meperidine?
Has a toxic metabolite: Normeperidine
(CYP3A4)
*metabolite is not an analgesic
When would we use Meperidine?
Not recommended without good justification because of toxic metabolite
-Treats rigors (shivering)
Who should not receive Meperidine?
Patients with decreased renal function
When do we use Methadone?
For opioid dependence
What is the MOA of methadone?
NMDA antagonist
-This is an ion channel glutamate receptor that is important for the conduction of pain signals
-Blocking this receptor blocks pain coming into the spinal cord and brain
What opioids can be used for cough/antitussive effects?
-Codeine
-Dextromethorphan (limited opioid activity)
Which opioids can be used as anti-diarrheal?
Diphenoxylate with atropine
Loperamide
Eluxadoline
Which opioids act as both Mu and Kappa receptors and what are they used for?
Moderate Pain
-Pentazocine
-Butorphanol
-Nalbuphine
-Buprenorphine (mainly used in opioid replacement therapy)
Which drug can cause colonic contraction?
(used to manage constipation caused by opioids)
Senna
What are the side effects of opioids that show limited or no tolerance (will not go away as the body adapts to the drug)?
**Constipation
-Itch
-Miosis (pin pupils)
Which treatment for opioid dependence is a full agonist?
Methadone
What are the clinical pearls of methadone?
*Slow acting
-Accumulates with repeated dosing
What is the main function of Methadone in preventing opioid use?
Provides relief from withdrawal symptoms
Which treatment for opioid dependence is a partial agonist?
Buprenorphine
Why is Buprenorphine a partial agonist?
Partially agonizes (activates) mu opioid receptors to prevent withdrawal
But also blocks the full agonist effects of opioids
What are the trade names of Buprenorphine?
Subutex *abuse potential
Suboxone (also contains naloxone to block agonist effects when taken IV)
What treatment for opioid dependence is an antagonist?
Naltrexone
How is Naltrexone administered?
IM injection
-ER release
-Once monthly
*also po daily form with decent bioavailability
When should patients take Naltrexone?
Works best if patient has been drug free for 1 month and the risk for withdrawal is decreased
**This drug will cause withdrawal if taken during active opioid addiction
True or False: Naloxone and Naltrexone are interchangeable
False!!!
Naloxone: Antidote to overdose
Naltrexone: Blocks reinforcement of opioids
What are the clinical pearls of Naloxone?
IV or intranasal administration
Limited oral bioavailability
Rapid onset
*Short half-life
What are the clinical pearls of Naltrexone?
Decent oral bioavailability
PO administration
Medium half-life (longer word, longer half-life)
If 1 shot of Naloxone (Narcan) does not bring an overdosed patient cack to consciousness, how long should we wait before administering another dose?
Repeat doses every 2-5 mins if not conscious
What is a concerning symptom of neonatal abstinence syndrome in babies?
Seizures in babies of methadone users
True or False: Opioids can be present in breast milk
True
What drugs can be used in neonatal abstinence syndrome and are linked with shorter hospital stays?
Morphine
Buprenorphine
What are the signs of opioid overdose vs opioid withdrawal?
Overdose:
-Sedation
-Pinpoint pupils
-Decreased respiratory rate
Withdrawal:
-Insomnia
-Dilated pupils
-Increased respiratory rate
What is the reversal agent for opioid overdose?
Naloxone (Narcan)
What is the MOA of Naloxone?
Opioid antagonist
What forms is naloxone available in?
IV
Nasal Spray
What is a risk with using naloxone?
Can cause opioid withdrawal
When should naloxone be prescribed?
Together with opioids
In patients at risk for overdose
–History of overdose
–History of substance use disorder
–High opioid doses (>50 morphine equiv)
–*Concurrent benzodiazepine use (“pams”)
How often can doses of naloxone spray be given?
Every 2-3 minutes
Which drugs can be used to treat symptoms of opioid withdrawal?
Clonidine
Buprenorphine
Methadone
Which opioid is metabolized to morphine and by what?
Codeine
by CYP2D6
Poor metabolizers of codeine will get what effect?
NO effect
(needs to be activated)
Ultra-rapid metabolizers of codeine will get what effect?
Overdose and Toxicity
*especially in children, can cause death
Who should not receive codeine?
Breastfeeding mothers
Children <12
What is the boxed warning for tramadol?
Use of CYP 450 3A4 inducers, 3A4 inhibitors, and 2D6 inhibitors with tramadol require careful consideration of effect on the parent drug and metabolite
What schedule is Tramadol?
IV
What side effect is most common with morphine compared to other opioids?
Itching
When should morphine use be avoided?
*Morphine and it metabolites are renally excreted
-avoid in Stage 4 or 5 chronic kidney disease
What boxed warning is associated with morphine?
Avoid alcohol while taking ER capsules
What boxed warning is associated with Hydromorphone (Dilaudid)?
Warning about dosing errors when prescribing, dispensing, and administering
*Oral solution: Do not confuse mg with mL
*IV: Do not confuse high potency solution (10mg/ml) with others (1,2, or 4)
What is Norco made up of?
Hydrocodone (5, 7.5, or 10mg)
Acetaminophen (325mg)
Which forms of oxycodone are abuse deterrent?
ER capsule, tablets
What is the name for the combination product of oxycodone and acetaminophen?
Percocet
When might fentanyl be a good treatment option?
For a fast on/off pain treatment
*In renal impairment (not excreted by kidneys)
What dosage forms does fentanyl come in?
Buccal tablet
Sublingual liquid
Lozenge
**Injectable solution
Patch
What symptom is LESS of an issue with fentanyl?
Hypotension
When can non-injectable fentanyl be used?
ONLY in patients who are opioid tolerant
What is considered “opioid tolerant”?
Taking morphine 60mg per day (or equivalent) for at least 1 week
When using the fentanyl patch dosing chart, what is an important point to remember?
*Can only use the chart to go from oral to transdermal and not the other way around
-because there is a built-in buffer to prevent overdose
What are the counselling points for the fentanyl patch?
Do not cut patches
Do not let the patch get too warm while wearing
Apply one patch every 72 hours
What is the last line opioid treatment for chronic pain?
Methadone (Methadose)
(used primarily to treat addiction)
What significant side effect is associated with Methadone (Methadose)?
QTc prolongation
What are the clinical pearls to remember for Meperidine (Demerol)?
-Not used much, many SE
-Avoid in elderly
-Avoid in renal impairment
-Caution in hepatic impairment
NEVER USE THIS
What patients should not receive tramadol?
History of seizure
Which opioids have non-po options?
Morphine
Hydromorphone (Dilaudid)
Fentanyl (Duragesic)
Methadone but not used commonly
Meperidine but not used
Which opioids have long-acting formulations?
Tramadol
Morphine
Hydromorphone
Hydrocodone
Oxycodone
If a patient has an allergy to an opioid, what other opioids can be used?
Fentanyl
Methadone
Meperidine
Tramadol
(do not have an allergic cross reaction)
Which opioids can we not convert to oral morphine?
Codeine
Methadone
Tramadol
The CDC guideline for prescribing opioids applies to which patients?
Outpatients > 18 years old
Acute, Subacute, or Chronic pain
NOT:
-sickle cell disease pain
-caner pain
-palliative or end of life care
True or False: Nonopioid therapies are at least as effective as opioids for many types of acute pain
True
What is the 1st recommendation when considering prescribing opioids?
Maximize non-pharm and non-opioid options FIRST
(also preferred for subacute and chronic pain)
What is the second recommendation when considering prescribing opioids?
Always start with immediate-release opioid options, never long-acting
Prescribe the lowest effective dose of opioids (especially in naiive patients)
For patients already receiving opioids: weigh benefits and risks when changing opioid dosage
-if they do not outweigh risks, gradually taper down dose
What is the third recommendation in opioid prescribing?
-When used for acute care, do not prescribe a greater quantity than needed for the expected duration of pain severe enough to require opioids
-Evaluate benefits vs risks with patients 1-4 weeks into starting therapy
-Regularly reevaluate risks vs benefit
What is the fourth recommendation for opioid prescribing?
Implement strategies to mitigate risk (naloxone)
Occasionally review the patient’s history of controlled substance prescriptions to determine if the patient is receiving dosages or combinations that put them at risk for overdose
Consider toxicology testing to assess for other prescribed or nonprescribed substance use
Caution with concurrent prescription of opioids and benzodiazepines
Treat opioid use disorder
Do not do detoxification without medications for opioid use disorder
What is the tapering schedule that should be followed to taper off opioids?
On for more than a year: decrease dose by 10% each month
On for less than a year: decrease dose by 10% each week
What is the max day-supply of opioids a physician can prescribe if it is their first time prescribing opioids to the patient and there are no extenuating circumstances?
7 day supply
True or False: Hospitalized patients can only have one order of an opioid for each severity of pain
True
(severe, moderate, mild)
What is the treatment for low back pain?
Non-pharm
1st Line:
–Acetaminophen
–NSAID
2nd Line:
–SNRI
–TCAs
What is the treatment for osteoarthritis?
Non-pharm
1st Line:
–Acetaminophen
–NSAIDs
2nd Line:
–Intra-articular hyaluronic acid
–Capsaicin
What is the treatment for fibromyalgia?
Non-pharm
FDA-approved: Pregabalin, Duloxetine
Other: TCA, Gabapentin, Venlafaxine
What is the treatment for neuropathic pain?
1st line:
–SNRIs
–Gabapentin/Pregabalin
2nd Line:
–Topical Lidocaine
–TCAs
