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),
 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

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
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
 RO
R = R' = H MORPHINE
NMe
R = H; R' = Me CODEINE
O
R = R' = COMe HEROIN

R'O

Morphine binds to opiate receptors that control passage

of Ca2+ and K+ through channels

which in turn control acetylcholine (nerve transmitter)

flow across synapses
 RO
R = R' = H MORPHINE
NMe
R = H; R' = Me CODEINE
O
R = R' = COMe HEROIN

R'O

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)
HEROIN
Bayer labs (1874): sold soluble HCl salt as 'cough syrup'
RO
R = R' = H MORPHINE
NMe
R = H; R' = Me CODEINE
O
R = R' = COMe HEROIN

R'O

H itself has mp 173oC, white, bitter taste

H.HCl salt has mp 243-244oC
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
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
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
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).
 SYNTHETIC OPIATES
O O O O
NMe NMe NMe NMe
O O O OH O OH

HO MeO HO MeO
hydromorphone hydrocodone oxymorphone oxycodone
DILAUDID NUMORPHAN PERCODAN
Vicodin
'hilly billy heroin"

HYDROMORPHINONE (hydromorphone, DILAUDID)

5-7x more potent than morphine so 1.5 - 2 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).
Hydrocodone = Vicodin
Hycodan in Canada as an antitussive (cough) 5mg
OXYMORPHONE (NUMORPHAN)
1.5 mg equivalent to 10 mg morphine, lasts 3-6 h
2003 - extended release version did not work well,
caused many addictions, lawsuits in US

O O
NMe NMe
O OH O OH

HO MeO
oxymorphone oxycodone
NUMORPHAN PERCODAN
'hilly billy heroin"
 N NMe2 NMe2

CO2Et CO2Et
COEt

meperidine propoxyphene
methadone
DEMEROL DARVON
Pethidine

DEMEROL (1930's) 15% of morphine's effectiveness

dose 50-150mg/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
 Newer synthetic “opioids”
HO
HO

O OH
O OH
N
N
HO

Butorphanol Nalbuphine
Stadol, Torbutrol Nubain – Oct 2006 Canada (Sandoz)
long used by vets

2 mg injected 10 mg injected

both are mixed agonist/antagonist (against different receptors)

 NMe2
08: >250,000 users of methadone

COEt
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 (30-120 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
 NMe2
Propoxyphene
CO2Et

DARVON 50mg is equiv to 10 mg morphine,

sold in 100mg oral capsules, somewhat addictive
overdoses kill 1000-2000 per year in USA by
respiratory depression
PHYSICIAN WARNING: do not prescribe to
suicidal patients, MAX 600mg/day
800-1200mg dose causes convulsions.
 THE FENTANYLS - DESIGNER DRUGS
R1 R2 R3 Name
R1
COEt H H H fentanyl
N N
R2 Me H H 3-Me-fentanyl
H H F p-F-fentanyl
R3 H Me H a-Me-fentanyl

Fentanyl (SUBLIMAZE) ~150 x morphine,

used in major surgery 2-3mg/kg,
DOSE 0.1-0.2 mg injected
very short acting, very addictive
illegal ones ~10 x more active
Newer, legal ones:

COEt
N
N COEt
S N N N N N N

CH3O CH3O

Sufentanil Alfentanil
“Sufenta” “Alfenta”

Dose 0.01-0.04 mg 0.4-0.8 mg injected

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

 1982
OCOEt California

bad batch
A DRUG GONE WRONG N control
N

MPPP MPTP

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
Crosses into brain, kills dopamine producing cells,
induces tremors, rigidity, loss of muscle control, i.e.
PARKINSON's symptoms

[Nov. 2005 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!

 ANTAGONISTS FOR HEROIN

O
N R
NALOXONE R= CH2 Inject
O OH
NALTREXONE R= CH2 Oral
HO [oxymorphone with new R groups]

NARCAN = Naloxone.HCl
0.4 - 2 mg injected, repeat in 3 min if nec.
is best antidote for heroin overdose
[no overdoses of naloxone recorded]
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
THE AZOCINES - mixed agonist-antagonists

PENTAZOCINE R= CH2
H N R

HO CYCLAZOCINE R= CH2

Pentazocine = TALWIN
~60mg injected dose or ~180mg oral dose
is equiv to 10mg injected morphine
blocks euphoric effect of morphine,
but less respiratory depression
 EQUIVALENT DOSES to 10 mg morphine injected

injected oral
Sufentanil 0.01-0.04 -
Fentanyl 0.1-0.2 -
Alfentanil 0.4-0.8 -
Oxymorphone 1.5 -
Hydromorphone 2 4-6
Butorphanol 2 -
Morphine 10 20-30
Nalbuphine 10 -
Oxycodone - 30
Propoxyphene 50 100
Pentazocine 60 180
Meperidine 75 300
Codeine 120 200
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
H2N COOH
H2N COOH

GABA Vigabatrin
g-aminobutyric acid