Barker's lecture 2 part 2 Flashcards
PK of Morphine/Phenanthrenes
Metabolism
-readily absorbed
-first pass metabolism
-bioavailability 25%
Hepatic
-CYP2D6, CYP3A4
-genetic differences
-elimination T1/2 increased with liver disease
Glucuronidation at 3’ and 6’
Morphine-6-glucuronide
still potent
Excretion
-glomerular filtration
-90% excreted in 24h
Some opioid metabolites are still active
Heroin, codeine, tramadol=prodrugs
Fentanyl and methadone do not produce active metabolites
Onset/duration influenced by lipophilicity
Morphine: low lipophilicity, slower passage across BBB, prolonged duration of action
Fentanyl: high lipophilicity, rapid onset, short duration
CYP3A4 (FOUR)–> MAKES OPIOIDS STARTING WITH NOR
Codeine–CYP2D6–>Morphine
CYP3A4–>NOR metabolites which is less active
Fentanyl is a very potent opioid
100x potent over morphine
50x potent over heroin
Used for palliative care, breakthrough pain
Sufentanil, remifentanil, alfentanil
agonists
anesthesia/sedation
breakthrough by plasma esterases due to ester linkage
Hydromorphone, oxymorphone
agonists
no opioid-active metabolites
IV, oral liquid, PCA
Morphine
agonist
ER
Long-acting, lower rush
Hydrocodone, oxycodone
agonist
pre/peri/post procedure pain
Tramadol
Mild opioid analgesic
Has SNRI properties
5-HT/NE reuptake inhibitor, stimulate 5HT release
Management of mild neuropathic pain
Painkiller used when you don’t want to prescribe a stronger opioid
Schedule 4
Meperidine
Used to treat rigors
Has toxic metabolite normeperidine that causes nervousness, tremors, twitches, seizures
Renally excreted
Not recommended without good justification
Methadone
Primarily used for opioid dependence
Long duration of action/long half life
Prolonged QTc
NMDA antagonist
Chronic pain
Why would antagonism at NMDA receptors be useful?
block pain signal that is coming in
may help with analgesia effect
secondary function
Codeine
cough/antitussive
Schedule 2
Schedule 5 in certain formulations
Dextromethorphan
enantiomer of levomethorphan
limited opioid activity
at high doses acts as SSRI, NMDA antagonist
Diphenoxylate with atropine
schedule 5
Loperamide
strong p-gp substrate–low BBB
scheduled 5/decontrolled OTC
Eluxadoline
mu/kappa agonist
delta antagonist
scheduled 4
Pentazocine and Butorphanol
schedule 4
K agonist, partial agonist/antagonism at mu
SE: less dysphoria, hallucinations, increase BP and HR
Nalbuphine
schedule 4
Full agonist at K, antagonist at mu
antagonism produces withdrawal
Buprenorphine
partial mu agonist, weak K agonist and delta antagonist
opioid replacement therapy
Opioid-induced hyperalgesia
prolonged exposure to opiates
secondary pain pathway that kicks in
changes in glutamate pathways
Methadone the full agonist
cross tolerance
Provide relief from withdrawal
slow acting
Slow PK: accumulates with repeated soe
Elimination half-life (8-50hrs)
NMDA antagonist
Buprenorphine partial agonist
ceiling effect
block full agonist effect
antagonist
use 4 hrs after last heroin dose
Provides some activation
agonist
less withdrawal
Naltrexone the antagonist
decent oral bioavailability
will cause withdrawal
works better if patient has been drug free for 1 month or more
PO
