the narcotic analgesics
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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
O
NMe
RO
R'O
R = R' = H MORPHINE
R = H; R' = Me CODEINE
R = R' = COMe HEROIN
Morphine binds to opiate receptors that control passageof Ca2+ and K+ through channels
which in turn control acetylcholine (nerve transmitter)
flow across synapses
O
NMe
RO
R'O
R = R' = H MORPHINE
R = H; R' = Me CODEINE
R = R' = COMe HEROIN
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'
O
NMe
RO
R'O
R = R' = H MORPHINE
R = H; R' = Me CODEINE
R = R' = COMe HEROIN
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. -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
NMe
HO
O
O
NMe
MeO
O
O
NMe
HO
O
OH O
NMe
MeO
O
OH
hydromorphone hydrocodone oxymorphone oxycodoneDILAUDID NUMORPHAN
'hilly billy heroin"
PERCODAN
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).
Vicodin
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
NMe
HO
O
OH O
NMe
MeO
O
OH
oxymorphone oxycodoneNUMORPHAN
'hilly billy heroin"
PERCODAN
N
CO2Et
meperidineDEMEROL
COEt
NMe2
methadone
CO2Et
NMe2
propoxypheneDARVON
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
Pethidine
Newer synthetic “opioids”
O
N
HO
OHO
N
HO
HO
OH
Butorphanol Nalbuphine
Stadol, Torbutrollong used by vets
Nubain – Oct 2006 Canada (Sandoz)
2 mg injected 10 mg injected
both are mixed agonist/antagonist (against different receptors)
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
COEt
NMe208: >250,000 users of methadone
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.
CO2Et
NMe2
Propoxyphene
THE FENTANYLS - DESIGNER DRUGS
NR2
R1
NCOEt
R3
R1 R2 R3 Name
H H H fentanyl
Me H H 3-Me-fentanyl
H H F p-F-fentanyl
H Me H -Me-fentanyl
Fentanyl (SUBLIMAZE) ~150 x morphine,
used in major surgery 2-3g/kg,
DOSE 0.1-0.2 mg injected
very short acting, very addictive
illegal ones ~10 x more active
Newer, legal ones:
N N
COEt
S
CH3O
N N
COEtNN
N N
CH3O
O
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
A DRUG GONE WRONGN
OCOEt1982
California
N
bad batchcontrol
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
HO
O
OH
RNALOXONE R=
NALTREXONE R= CH2
CH2
[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]
Inject
Oral
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
NH
HO
R
CH2
CH2
CYCLAZOCINE R=
PENTAZOCINE R=
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 oralSufentanil 0.01-0.04 -Fentanyl 0.1-0.2 -Alfentanil 0.4-0.8 -Oxymorphone 1.5 -Hydromorphone 2 4-6Butorphanol 2 -Morphine 10 20-30Nalbuphine 10 -Oxycodone - 30Propoxyphene 50 100Pentazocine 60 180Meperidine 75 300Codeine 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
COOHH2NCOOHH2N
GABA Vigabatrin
-aminobutyric acid
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