Pharmacology - Narcotics Flashcards
What are the three types of endogenous opioids?
enkephalins, endorphins, and dynorphins
What accounts for “Stress analgesia” (e.g. in war etc.)
β-endorphin and ACTH share common precursor and are co-released with stress - result is release of cortisol + endogenous opioids
3 common functions of endogenous and exogenous opiods:
inhibition of pain perception,
modification of
gastrointestinal/autonomic function
reward properties
Name and function of 4th endogenous opioid discovered in 1995
nociceptin/orphanin FQ
drug reward and reinforcement, feeding, learning and memory
4 types of opioid receptors and corresponding chromosomes
MOR - mu opioid receptor, chromosome 6)
DOR - delta opioid receptor, chromosome 1)
KOR - kappa opioid receptor, chromosome 8)
NOR - N/OFQ opioid receptor, chromosome 20).
Common features of opioid receptors
All are G protein-coupled receptors, with extracellular,
transmembrane, and intracellular domains.
Classes have homology in the receptor types
How are opioid receptors activated?
Ligands are recognized on the extracellular domain; G proteins bind to the
cytoplasmic aspect of the receptor, and activate/bind GTP
Signaling pathway initiated by ligand binding to opioid GCPRs
- Adenylyl cyclase activity is inhibited
- Voltage-gated Ca2+ channels on the cell membrane close
- K+ current is stimulated through several channels
- PKC and PLCβ are activated
How do mu opioid receptors influence neuronal excitability?
via “disinhibition” of presynaptic release of GABA
What does activation of opioid receptors do?
agonists inhibit release of substance P and
ascending transmission of pain from dorsal horn neurons by activating pain
control circuits descending from the midbrain
T/F exogenous opioids are alkyloids where as endogenous opioids are peptides
true
binding site of peptides
extracellular loops in combination
with the core
What accounts for different effects and side effects as well as metabolism of different ligands?
small chemical modifications of the
ligands result in changes in signal transduction sequences
T/F tollerance toward and opioid over time results in decreased side effects
True
tollerance is associated with:
decreased effectiveness, and decreased side effects,
with repeated administration
Molecular basis for tolerance involves:
phosphorylation or receptor internalization
Side effects of opioids
Analgesia Mood alteration; stimulation of reward centers Miosis Convulsions Decreased respiration Cough suppression (antitussive) Nausea and emesis Constipation Urinary retention dermal vasodilatation and urticaria (hives)
What causes opioid induced uticaria (itching/hives)
Opioids stimulate mast cell degranulation and release of histamine
can be managed with an antihistamine (non sedating are preferred to avoid synergy with analgesic e.g. loratadine, fexofenadine)
What causes nausea and emesis
Direct stimulation of the
medullary trigger zone for emesis
Delayed gastric emptying
T/F cough suppressant activity is unrelated to respiratory depression
True - may be mediated
through receptors unrelated to GPCRs
Mechanism for opioid induced decrease in respiration
direct stimulation
of brainstem respiratory centers
T/F Opioids lower seizure threshold
true
What causes opioid induced miosis? What receptor is involved?
direct stimulation of oculomotor complex to effect papillary constricution (mimicking parasympathetic response)
Mechanism for mood alteration/reward
opioids directly stimulate the dopamine pathway in the ventral striatum (VTA)
– stimulates limbic functions (e.g. motivation and affection)
T/F opioid induced miosis and constipation lessen with tolerance
False
T/F oral, sublingual, transmucosal, rectal absorption of opioids undergo significant first pass metabolism
True
T/F opioid absorption is slow
False - rapid!
Steps of opioid metabolism:
Occurs in liver - glucuronidation is primary metabolic
pathway
Opioids and their metabolites are then excreted by the kidney
Factors that require dose adjustment to prevent overdose:
cirrhosis,
chronic or acute renal
insufficiency,
dehydration
Who should NOT have regular opioid dosing but can be treated on PRN basis?
oliguric or anuric patients
Peak serum concentration times based on administration method (IV, subQ, intramuscular, oral)
5-10 minutes I.V.
30 minutes subQ or intramuscular administration,
one hour for oral
What is “bolus effect”? When does it occur?
swings in plasma concentration, with sedation
occurring as a result of high blood levels and breakthrough pain when the serum
levels are at trough
most commonly with intravenous or intramuscular
administration
Pain medications for mild pain vs moderate pain vs severe pain (3 step-laddar from WHO) :
Step 1: mild ASA (aspirin) Acetaminophen NSAIDs \+/- adjuvants
Step 2: moderate A/Codeine A/Hydrocodone A/Oxycodone A/Dihydrocodeine Tramadol \+/- adjuvants.
Step 3: severe Morphine Hydromorphone Methadone Levorphenol Fentanyl Oxycodone \+/-adjuvants
T/F acceptable adjuvants to narcotics include acetaminophen, NSAIDS, tricyclics, anticonvulsants
True
benefit of adjuvants
“spare” use of
higher dose opioids
T/F morphine-6-glucuronide (M-6) is an active metabolite while morphine-3-glucuronide (M-3) is inactive
True
T/F codiene itself is largely inactive but undergoes demethylation to active morphine
true
T/F only 10% of the ingested dose of codeine is demethylated
to morphine
True
Conversion of codeine to morphine is dependent on
the CYP2D6 pathway
T/F 10% of Caucasions are unable to convert codeine to morphine and have nausea and vomiting instead of analgesia
true
T/F antitussive effect of codiene involves
non-opioid receptors that bind codeine itself
true
synthetic codeine analog, and a weak mu
agonist, which has a demethylated metabolite that is a more potent analgesic
developed to be less addictive but still has adictive potential
less constipating than morphine
effective for moderate pain
Tramadol
highly lipid soluble, strong opioid used intravenously and in a
transdermal patch.
Fentanyl
T/F suspected MOA of tramadol is inhibition of
norepinephrine and serotonin uptake
True
extended duration of action with 90%
bound to plasma proteins. accumulates in tissues - used as maintenance treatment for heroine addiction
Methadone
Doing changes of methadone and fentanyl patches should be restricted to
1/week because of long half life
opioid no longer in use due to toxic metabolite that causes mental status changes and seizures
Meperidine
metabolite normeperidine
2 most common opioid antagonists
Naloxone
Naltrexone
approved for use in the treatment of alcoholism
Naltrexone
useful in the treatment of acute opioid toxicity. Can only
be administered parenterally (IM, SQ, IV), and has a short half life
Naloxone
MDD of acetaminophen
3000 mg in 24 hours
Withdrawal symptoms brought about by abrupt discontinuation of opioids in tollerant patients
ideal dose reduction paradigm?
yawning, sweating, piloerection, vomiting, pain shit-squirts muscle spasms
reduced by half every 2 to 3 days
T/F With
parenteral dosing half life is shorter and doses must be given
MORE frequently and can result in bolus effect
solution is continuous IV/intrathecal infusion
true
Dosing paradigms for immediate vs extended release opioids vs transdermal fentanyl patches
immediate release preparations is every 4 hours
extended release preparations is every 8-24 hours,
usually every 12 hours
every 72 hours
T/F Oral breakthrough
prescriptions should always be immediate release preparation,
actual dose is calculated as 10% of the total 24 hour dose
True
What is Equianalgesic dosing?
dose equivalent when switching from one opioid to another
oral doses are
usually two or three times higher than parenteral doses (e.g. I.V. /I.M) because of first pass metabolism
T/F cross tolerance to another opioid is usually incomplete so dosing is adjusted downward by 25-50% of the calculated equianalgesic
dose.
true
T/F True opioid allergies are rare - history of urticaria alone probably side effect, not an allergy, but urticaria and bronchospasm might be
true
T/F overdoses have quadupled in past 12 years
true
What is I-STOP? What has it resulted in?
NYS Prescription Monitoring Program - Starting in 2015 prescribers must check a state
database before writing prescriptions for opioids + pharmacies file data for prescriptions to central database
less opioid prescribing
