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Opiod Analgesics
- anything with morphine-like activity
- opiates---poppy plants--- Dorothy
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Morphine (MSIR)
- opiod analgesic
- where tolerance is absent oral LD90 is approximatley 200 mg --- respiratory depression
- antitussive
- enterohepatic recirculation leads to it being more detected in the blood over a long period of time
- decrease pH of urine --- increase excretion of morphine; increase in pH of urin --- increase excretion of M6G
- M3G antagonist
- really potent: ng/ml
- M6G- glucoronidated form is 100x more potent, important for BBB
- metabolized by 2B7
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glucoronidation
metabolizes the majority of drugs through Phase II metabolic enzymes
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UDP glucoronosylatransferases
- two types: UGT1 and UGT2
- UGT1A1: associated with bilirubin and steroids
- 2B15 is subject to polymorphism
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Codeine
- opiate/analgesic
- demethylated to morphine via 2D6
- prodrug for pain
- PM: therapeutic failure
- UM: idiosyncratic response; metabolites are toxic to infant
- antitussive (codeine cough syrup)
- codeine is a morphine methyl ether
- metabolically reduced to dihydrocodeine with increased potencey
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Heroin (Diamorf/Junk)
- semisynthetic opiate
- AKA: diacetylmorphine
- each ester is subject to hydrolysis by CES1 --- 2 monoesters and morphine (all active)
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Semi-synthetic opiates
- Morphine Series:
- (hydromorphone and oxymorphone)
- start with morphine or codeine
- 1. oxidizes alcohol --- ketone
- 2. reduces the alkene --- alkane
- 3. adds OH that increases PD
- Codeine Series:
- Hydrocodoen and oxycodone
- 1. oxidizes alcohol --- ketone
- 2. reduces the alkene --- alkane
- 3. adds OH that increases PD
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Combination products: APAP and codeine
- FDA limites APAP to 325 mg when taking hydrocodone and oxycodone --- liver toxicity
- Zyhdro is a non-APAP form of hydrocodone
- Oxycodone (RIP Heath Ledger/ "hillbilly heroin") DDIs
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CYP3A4 mediated DDIs
- taking ketoconazole --- inhibition --- no effect
- increases oxycodone exposure (AUC) increasing SEs (nausea, drowsiness, analgesia)
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Meperidine (Demerol)
- synthetic opioid
- long term pain management --- CNS toxic normeperidine accumulation
- used when a patient is allergic to morphine (minimal pharmacophore of morphine)
- -"designer heroin" contains toxic MPTP byproduct
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Depehnoxylate (Lomotil) and Loperamide (Imodium)
- synthetic opiods
- antidiarrheals with little abuse potential
- structurally similar to meperidince
- not water soluble in order to stop diarrhea
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Loperamide (Imodium)
- enter BBB through quinidine inhibition of Pgp
- PGx: synonymous/nonsynonymous SNPS, indels
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Phase III Drug Disposition
- = transport NOT metabolism
- P-gp is also called multidrug resistance protein (MDR1 or ABCB1)
- inducible
- P-gp acts as a drug efflux pump
- sex dimorphism: men express more P-gp, women express more 3A4
- grapefruit juice induces P-gp
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Levorphanol (Levo-Dromoran)
- synthetic opiod analgesic
- dextromethorphan
- 2D6 phenotype probe
- non-superimpossable mirror image of dextromethorphan
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Tramadol (Ultram)
- synthetic opioid
- racemic synthetic codeine congener
- racemic switch will not be logical --- racemate is more active than either isomer
- d-isomer is a mu agonist
- i-isomer is a NE reuptake (NET) inhibitor (alpha 2 agonist)
- O-demethylated metabolite is most active
- *note resemblance to venlafaxine and codeine
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Tapentadol
- monotherapy for chronic pain and depression
- superimposable on codeine and venlafaxine
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Fentanyl (Sublimase)
- synthetic opioid
- way more potent than meperidine (fast SL absorption --- lollipops)
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X Propoxyphene (Darvocet)
- CIV analgesic to manage mild pain
- banned because of fatal heart arrhythmias
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Opioid substitution therapy
- used to treat addiction/analgesic
- ex: methadone, LAAM
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Methadone (Dolophine)
- opioid substitution therapy
- 2D6 PM decreased clearance increases risk of OD
- N,N-demethylated to inactive cyclic metabolite
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LAAM (levo-alpha-acetylmethadol)
- opioid substitution therapy
- does not cyclic intermediate due to absence of the ketone group
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Opioid SAR
- 3 types: allyl, cyclopropyl, cyclobutyl
- 3 functions: partial agonists, mixed agonists/antagonists, antagonists
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opioid partial agonist
cannot produce a profound agonist effect
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Butorphanol (Nasal Spray)
- opioid partial agonist
- SAR: cyclobutyl
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Pentazocine
- opioid partial agoinst
- SAR: allyl
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Buprenoprphine
- opiod partial agonist
- SAR: cyclopropyl
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Nalbuphine
- mixed opioid agonist/antagonist
- Rx but not controlled substance
- SAR: cyclobutyo
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Opioid antagonist
treat opioid/ethanol dependence, opioid OD
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Naolxone (Suboxone)
- opioid antagonist
- SAR: allyl
- when combined partial agonist = REWARD
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Naltrexone (vivitol)
- opioid antagoninst
- SAR: cyclopropyl
- tx: opioid addiction, alcoholism
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Morphine and Fentanyl
opioid agonists
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Endorphins
- endogenous opioid (morphine)
- beta-endorphins --- jogger high
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Opioid PD
- receptors agonists produce presyntaptic inhibitory effects on the excitatory neurons
- chronic use leads to addiction/tolerance:
- 1. increase adenylate cyclase
- 2. opioid can change affinity through internalization
- withdrawal: cAMP accumulation
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