ps 333 the rest of sem

codeine

metabolized locally into morphine

• similar to heroin

fully synthetic “designer opioids”

modified versions of controlled substances

• improved potency, but variable and uncertain dosing

  • higher OD

• easier to make + cheaper

• not subjective to laws

  • technically unscheduled

  • ex: krokodil, derived from codeine, has the active ingredient desomorphine

    • powerful analgesic

    • “russian heroin”

    • amateur chemistry used to make it results in toxic biproducts that can cause scaly, grangenous wounds

  • an inadvertently by-product of a home-synthesized drug caused parkinson-like effects in users ‘frozen addicts’

    • an impurity is metabolized into neurotoxin that kills dopamine neurons

short history of opium

sumerians of mesopotamia - poppy plant = joy plant

• prob used for medicine for analgesic effects

short history of opium: china

used for medicinal and purposes for over 7000 yrs; recreational use came later

• origins in asian + later mediterranean regions

• traders brought opium to china in 9th century

• chinese initially used opium for medicinal purposes, but later began to smoke it for its euphoric effects

  • prob the 1st to smoke

• smoking opium created addictions fueled by British owned opium from India

• led to opium wars fought between China + Britain

  • brits won

short history of opium: europe + U.S.

widespread in britain and U.S. at all levels of society in mid-1800s

• advertised as cures

• available by mail order

morphine + heroin

1803, morphine was identified as principle active ingredient

• end of 19th century, heroin was introduced by Bayer Company in Germany

• Bayer marketed heroin as a cough suppressant lacking the dependence-producing properties of morphine

  • they were wrong

  • banned 1924, making it ILLEGAL for doctors to prescribe heroin for any reason

  • Laudanum = cough suppresant + analgesic

    • alc + opium

• search for “holy grail” of opioids - drug that provides similar analgesia as morphine w/o respiratory depression + addiction

• misuse potential of morphine and especially of heroin was not fully realized until beginning of 20th century

• 1900s, 250,000 opioid dependent ppl in U.S.

  • actually 3x the number

contemporary opioid use: 1960-present

1960s

• Vietnam war: soldiers exposed to high grade opioid products

• greater public acceptance of drug use + experimentation

1970s - present

• opioids have become one of the most highly prescribed of all drugs

opioid prescriptions have been

declining in recent years

• but still in middle of an opioid epidemic in U.S.

  • a whopping ~64% of ALL drug ODs in U.S. from April 2020-April2-21 were specifically attributed to synthetic opioids, such as fentanyl

    • 4th wave of opioid crisis

opioid PK: administration

morphine

• weak base pH~8.5

  • poorly absorbed from GI tract

    • typically given IV in hospital

    • Oral route less effective than IV

      • not rapidly absorbed form digestive system, so effects are slowed but prolonged (good for steady levels)

heroin

• parenteral (IV - fallen into disfavor)

  • dirty needles → the consequences

• snuff (intranasal)

• smoked

opioid PK: absorption + distribution

heroin

• passes BBB easily

  • must be metabolized into morphine to act on opioid receptor

  • same for codeine

morphine

• does not pass BBB easily

• taken orally = only ~15% gets to brain due to poor absorption + significant first pass metabolism by CYP3A4

many opioids are bound to blood proteins, which extends their half life

• in particular, methadone has a half life of 10-25 hrs in bound form

  • long half life = steady

opioid PK: metabolism + excretion

morphine half life: ~2 hrs

• ~90% of morphine is metabolized for elimination in the urine + feces via concentrations in the bile

• ~10% of morphine is excreted in the urine unchanged