THE NARCOTIC ANALGESICS

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