1. THE NARCOTIC ANALGESICS
Narcotics block the transmission of the nerve signal across nerve gaps, [the minor analgesics blocked prostaglandin synthesis]
The more important ones:
Morphine, codeine,
oxycodone (PERCODAN), hydromorphone (DILAUDID), methadone, + heroin [ = not legal]
meperidine (DEMEROL), pentazocine (TALWIN),
fentanyl (SUBLIMAZE), buprenorphine (BUPRENEX),

2. Morphine:
Opium [est. ~ 10,000 tons] extracted from the poppy Papaver somniferum, Afghanistan estimated 92% of supply.
Currently a glut, Afghan farm price $150/kg!!!, 2$/mg here

3. contains about 10% morphine,
can be recrystallized as white morphine sulfate
(first pure form in about 1803)
Used orally (LAUDANUM) before 1856 when syringe was invented

4. Normal dose to kill pain: 5-10mg injected
analgesic - kills pain
constipator - anti-dysentery side effect
narcotic - induces drowsiness, lethargy
DEPRESSES RESPIRATORY SYSTEM
usual overdose effect
some euphoria
- addictive

5. Morphine binds to opiate receptors that control passage
of Ca2+ and K+ through channels
which in turn control acetylcholine (nerve transmitter)
flow across synapses

6. Codeine (½% of opium), made synthetically (60,000 kg/y USA); only about 10% of pain relief of morphine, though better cough suppressant
Legal OTC if < 2.2 mg/mL or in combination with aspirin or Tylenol,
Egs. 222, 292; Tylenol 1 (8mg); Tylenol 2 (16mg), Tylenol 3 (30 mg)

7. HEROIN
Bayer labs (1874): sold soluble HCl salt as 'cough syrup'
H itself has mp 173oC, white, bitter taste
H.HCl salt has mp oC
H passes the blood-brain barrier faster (bigger rush) than morphine (more fat like) BUT IS BROKEN DOWN TO MORPHINE in brain for use
Street H typically used to be 1-13% pure, now some batches much more pure

8. OPIATES narcotics - induce drowsiness insomnia, irritability
constrict pupil of eye (pin-point pupils)
depress respiration (overdose danger)
reduce bowel activity - constipation diarrhea
reduce all secretions (gastric, bile) chills, cramps,nausea
Timing of effects:
8-12h runny nose, eyes, sweating
12-16h insomnia
16-48h loss of appetite, nausea, vomiting, diarrhea, irritability
48-72h tremors, sneezing, chills, flushes, ejaculation/orgasm, abnormal white cell counts

9. Opiates CROSS TOLERATE,
so need larger doses (increased enzyme production)
injection at any point suppresses symptoms
HENCE ADDICTION: at $2/mg most addicts need
>2 fixes (10-20mg x 2)per day, expensive
Even in hospitals, patients on longer term morphine build up a tolerance
Recent Queen’s U study suggests small injection of the antagonist naloxone returns sensitivity to the drug

10. NATURAL PAIN KILLERS in body are pentapeptides
(small proteins, 5 amino acids long) called ENKEPALINS
Methionine enkepalin = Tyr-Gly-Gly-Phe-Met
Leucine enkepalin = Tyr-Gly-Gly-Phe-Leu
these are often part of larger proteins, eg. b-endorphin contains 31 amino acids, first 5 of which are shown above (Met)
NEUREX Corp. has developed SNX-111, a 26-peptide which is injected spinally to block Ca channels in spinal cord, available now as ZICONOTIDE (US).

11. HYDROMORPHINONE (hydromorphone, DILAUDID)
SYNTHETIC OPIATES
Vicodin
HYDROMORPHINONE (hydromorphone, DILAUDID)
5-7x more potent than morphine so mg
equivalent to 10 mg morphine, but lasts a little less,
only 2-4 h: used in Victoria for cancer patients – pills
can be ground and injected for high ($50/street).

12. Hydrocodone = Vicodin
Hycodan in Canada as an antitussive (cough) 5mg

13. OXYMORPHONE (NUMORPHAN)
1.5 mg equivalent to 10 mg morphine, lasts 3-6 h
extended release version did not work well, caused many addictions, lawsuits in US

14. DEMEROL (1930's) 15% of morphine's effectiveness
Pethidine
DEMEROL (1930's) 15% of morphine's effectiveness
dose mg/4h (up to 75mg if by i.v.)
NO nausea, no affect on pupils
CAUSES sedation, euphoria and is addictive
MORPHINE AGONIST, goes to same receptor sites

15. Newer synthetic “opioids”
Butorphanol Nalbuphine
Stadol, Torbutrol
long used by vets
Nubain – Oct 2006 Canada (Sandoz)
2 mg injected 10 mg injected
both are mixed agonist/antagonist (against different receptors)

16. METHADONE equally potent to morphine or heroin; highly addictive
08: >250,000 users of methadone
METHADONE equally potent to morphine or heroin; highly addictive
orally NO sedation or sleepiness (addict can hold a job),
STOPS Withdrawal symptoms, blocks action of heroin
only need one dose per day if oral ( mg)(slower acting),
cheap 10 cents per dose
Best supplied in orange juice, since if injected can get rush ($1/mg on street for powder)
Addicts claim harder to get off methadone than heroin

17. Propoxyphene
DARVON 50mg is equiv to 10 mg morphine,
sold in 100mg oral capsules, somewhat addictive
overdoses kill per year in USA by respiratory depression
PHYSICIAN WARNING: do not prescribe to suicidal patients, MAX 600mg/day
mg dose causes convulsions.

18. THE FENTANYLS - DESIGNER DRUGS
R1 R2 R3 Name
H H H fentanyl
Me H H 3-Me-fentanyl
H H F p-F-fentanyl
H Me H a-Me-fentanyl
Fentanyl (SUBLIMAZE) ~150 x morphine,
used in major surgery 2-3mg/kg,
DOSE mg injected
very short acting, very addictive
illegal ones ~10 x more active

19. Sufentanil Alfentanil “Sufenta” “Alfenta”
Newer, legal ones:
Sufentanil Alfentanil
“Sufenta” “Alfenta”
Dose mg mg injected

20. RUSSIA - OCT 23 2002 - Chechen terrorists took ~ 800 people hostage in a Moscow theater
Russia pumped fentanyl gas thru ventilation system on day 3, but refused to identify gas to local medics
130 people died, Russian military lost no one.
Antidote = Naloxone!!
3-Me-fentanyl: ~3000 x morphine - overdoses easy, death

21. A DRUG GONE WRONG
In 1980's, MPPP was a popular, easy to make-at-home drug
Ca. 25x stronger than Demerol (CO2Et compd)
Poor batch control led to ester elimination to give MPTP
(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)
Several hospitals reported patients suffering from rigidity and Parkinson’s-like symptoms
All had taken ‘street heroin’ that was in fact MPTP

22. Crosses into brain, kills dopamine producing cells, induces tremors, rigidity, loss of muscle control, i.e. PARKINSON's symptoms
[Nov Can. Chem. News]
Barry Kidston, U. Maryland grad student
First synthesized MPPP and injected himself; after several months, he brewed a bad batch, and was hospitalized, eventually the doctors tried L-DOPA which improved his fate –
for 2 yrs, until he died of an overdose of cocaine!

23. ANTAGONISTS FOR HEROIN
Inject
Oral
[oxymorphone with new R groups]
NARCAN = Naloxone.HCl
mg injected, repeat in 3 min if nec.
is best antidote for heroin overdose
[no overdoses of naloxone recorded]

24. BLOCKS action of heroin, no narcotic activity,
no respiratory depression
prevents addicts getting high (pregnant mothers....)
Methenex = methadone + naloxone = no rush
ReVia = Naltrexone.HCl
= ORAL,
50mg/day for 3 days,
or one 150 mg dose

25. THE AZOCINES - mixed agonist-antagonists
Pentazocine = TALWIN
~60mg injected dose or ~180mg oral dose
is equiv to 10mg injected morphine
blocks euphoric effect of morphine,
but less respiratory depression

26. injected oral Sufentanil 0.01-0.04 - Fentanyl 0.1-0.2 -
EQUIVALENT DOSES to 10 mg morphine injected
injected oral
Sufentanil
Fentanyl
Alfentanil
Oxymorphone
Hydromorphone
Butorphanol
Morphine
Nalbuphine
Oxycodone
Propoxyphene
Pentazocine
Meperidine
Codeine

27. VIGABATRIN ‘V’ SABRIL (Aventis)
[an anti-epilepsy drug in Canada]
reduces the effect of heroin, methamphetamine, alcohol
V is an inhibitor of GABA transaminase,
the enzyme which breaks GABA down
If GABA is high, less dopamine
(the brain exciting amine) is produced
GABA Vigabatrin
g-aminobutyric acid