Download Principles of Pharmacology and Toxicology (BIOL3020)

Heroin

Very addictive and illegal!

Belongs to the opioid family
- Derived from the opium poppy (Papaver
somniferium)
- Semi-synthesized from morphine providing a
stronger and more immediate effect.
http://upload.wikimedia.org/wikipedia/commons/
8/87/Opium_poppy.jpg

Pain reliever and cough suppressant
Street Names:
- Black Tar, Mud, Smack, Junk, China White, Mexican Brown,
Horse, H, Skag, Dope=


Diacetylmorphine: the International Nonproprietary Name

Diamorphiane: the British Approved Name; legally
prescribed drug


The -OH group of morphine is replaced by –OCH3 producing
codeine

Both –OH groups of morphine replaced by –OCOCH3 produces
heroin
Morphine


Codeine
Heroin


Morphine:
- used for medicinal reasons
- prescribed pain killer
Heroin:
- illegal to manufacture, possess, or sell
- used as a pain-killer as well as a recreational drug
- highly addictive!
Pure Heroin


White powder
Has a bitter taste
http://www.pbs.org/wnet/wideangle/shows/centralasia/i
mages/heroin5.jpg
-
The opium gum is converted to morphine in labs
near the fields and to heroine in labs near the
producing countries.
-
The dealers then dilute it with sugars, starch, or
powder milk prior to selling
-
Sometimes quinine is also added to imitate the
bitter taste so the user is unable to tell the
quantity of heroin in the sample.
http://www.spiegel.de/img/0,1020,817155,00.jpg

Can be mixed with other narcotics for various
effects

Sniffed, snorted or smoked for high purity

Powder form can be heated to melt and then
injecting the liquid form into veins using a
syringe
- 3-5 times more potent than the powder form.

Easily overdosed and can lead to death

Possible transmission of HIV and other
diseases due to the sharing of needles [1-3]
http://www.russianspy.org/wpcontent/uploads/2006/11/heroin.jpg
http://i.current.com/images/asset/
889/022/26/PN7mpv.jpg

Varies in color from white to dark brown due to additives or impurities left from
the synthesis process

Comes in granule, powder, solution, or pill forms

The dealers then dilute it with sugars, starch, or powder milk prior to sellingso the
user is unable to tell the quantity of heroin in the sample

Sometimes quinine is also added to imitate the bitter taste.
http://upload.wikimedia.org/wikipedia/commons/archive/5/5b/20070725121556!Her
oin_asian.jpg

After intake, heroin crosses the blood-brain barrier:
- Converts into morphine by removal of the acetyl groups

Binds quickly to µ,κ, or δ opioid receptors
- µ: results in analgesia, euphoria, CNS depression, respiratory
depression, and miosis
- Κ and δ: also analgesia but kappa receptors are mostly found in
the spine.

Feeling of a quick surge of pleasure targeted in the gut

“High” or a “rush”

Pain relief [2,3]

The intensity dependant on dose of heroin is taken in and therefore how quickly
the heroin enters the brain and binds to the µ-opioid receptors

Warm flushing of the skin

Dry mouth

Extremities feel heavy

Nausea and Vomiting

Several hours of drowsiness

Clouded mental function by effect on the CNS

Slows the heart as well as breathing
Flushing of the skin
http://www.vlib.us/medical/HMSO/skin1.jpg



Alters the Paleomammalian brain

Manipulates emotions with increased feelings of pleasure and
euphoria
Blocks pain signals transmitted by the spinal cord
Changes the brain stem

Controls reflexes

Slows down breathing [2,3]


Addiction

Increased tolerance

Physical dependence

Euphoric reward decreases

Need higher doses for the same effect

Increased repetition
Severe shortening of breath or suffocation

Increase in intensity and occur more often

Restlessness

Insomnia

Muscle and bone damage

Can cause death to the fetus of a pregnant user [2-4]

Major affect on gastric movements

Cold sweats

Quivers

Nail biting

Yellowing and darkening of the nails

Endogenous Substance:

The natural neurotransmitters are endorphins

Used to combat pain

Endorphins production reduced when present

Difference
- Endorphins: naturally produced by the body and are quickly
broken down after they are released;
- Heroin: more addictive; stays in the body for a longer period of
time

Reduced endorphin production creates strong dependence on
heroin [5]
Mimicry of Endorphins:


Heroin is first converted into morphine then mimics
endorphins, creating a sense of well-being
Direct agonist that directly binds to the µ-opioid receptor
and activates it
 Mimics and substitutes for endorphins

Leads to increases in dopamine release in the limbic
system
 Increased dopamine concentration produces the “high” [6]


Pleasurable sensation from heroin occurs due to the reward centre being
stimulated

Dopamine: Key neurotransmitter in the reward system

Three types of neurons are involved in the reward process:

Endorphin neurons

GABA neurons

Dopamine neurons [4,5,7]
Dopamine
GABA
Electric Signal
Inhibitory Signal
µ-Opioid
Receptors
GABA Receptors
GABA Neuron
2. Neurotransmitter GABA inhibits the
release of dopamine
µ-Opioid
Receptors
Dopamine intercepted
No reward
Dopamine Neuron
1. Normally, Dopamine is released
continuously
(Normal Conditions)
Incentive
GABA Neuron
Dopamine
2. When bound, the opioid
receptors prevent electric signals
from releasing GABA [5,7]
Inhibitory Signal
Electric Signal
µ-Opioid Receptors
Endorphin
GABA not released
GABA
GABA Receptors
Endorphins immediately begin
dissociating and break down
after being bound to opioid
receptors
Dopamine free to
proceed to target
µ-Opioid
Receptors
Endorphin Neuron
1. Electrical signal is applied on an endorphin
neuron, the vesicles are exocytosed and are able
to bind to the µ-opioid receptors on the GABA
neuron [5]
Dopamine Neuron
3. Inhibition of GABA allows the dopamine neuron
to release dopamine, resulting in the feeling of
pleasure and well-being [5,7].
Incentive
Dopamine
Inhibitory Signal
Electric Signal
Endorphin
µ-Opioid Receptors
Dopamine Neuron
Endorphin Neuron
The dopamine neuron possesses µ-opioid receptors.
Binding inhibits dopamine from reaching its target.
Endorphins can therefore produce stimulatory and inhibitory effects [5].
Dopamine
GABA Neuron
Inhibitory Signal
µ-Opioid Receptors
Electric Signal
Endorphin Neuron
Morphine
Endorphin
GABA not released
GABA
GABA Receptors
Dopamine free to
proceed to target
µ-Opioid
Receptors
Heroin converts into morphine and mimics the
endorphins by binding tightly to the µ-opioid
receptors. As the GABA supply decreases,
dopamine is more free to proceed to its target
and stimulate pleasurable reward [5,7].
Dopamine Neuron
Reward
(Heroin Conditions)

Morphine also binds to µ-opioid receptors of the
dopamine neuron, decreasing inhibition of dopamine
activity

However, the release of dopamine is independent as it is
not being inhibited or intercepted by the inhibitory
signals due to the binding of morphine to the GABA
neuron µ-opioid receptors [7]
Morphine
µ-opioid
Receptors
Endorphin
P Substance
Prevention of P
Substance release
P Neuron
Morphine: competitive agonist as it
binds to receptors on the P neuron,
blocking the release of more P
substance (pain signals) [5,7]
Endorphin Neuron
Adjacent Neuron Receptors
Adjacent Neuron
Morphine also acts as a competitive
antagonist as it will also block the
receptors on the adjacent neuron from
receiving P substance [5,7]

Morphine eventually dissociates from receptors and
slowly breaks down

Difference:
- Endorphin: short term effect; dissociate almost
immediately; quick break down
- Heroin: longer lasting; stays bound for a longer period
of time

Heroin can easily lead to overdose and can most
dangerously cause suffocation


Can severely affects breathing rhythm
- neurons regulating breathing patterns also possess µ-opioid
- morphine acts like an antagonist, inhibiting signal
transmission to the breathing muscles and slowing down the
breathing
An overdose can cause lungs to collapse and therefore
prevent all breathing causing suffocation [2-5]

Heroin contracts the pupils to as small as less than one millimete

Many areas in the gastro-intestinal tract contain many opioid receptors

Heroin inhibits bowel activity leading to constipation

The vomiting centre is stimulated by heroin

The cough centre is suppressed by heroin

After continuous use, ability to feel pleasure is reduced or terminated if heroin is not
taken often

Body has reduced or complete inability to release dopamine in a natural way [25]



OPIOID AGONISTS
Methadone: standard drug treatment for heroin addicts

Mimics morphine

Binds to and activates the same µ-opioid receptors as
heroin/morphine, and produces the same cellular effects as
heroin/morphine

PRO: more sterile, no crime or violence involved, reduces relapse

CON: still harmful!
Levomethadyl Acetate Hydrochloride (LAAM) produces effects similar to
methadone in the brain and to reduce relapse

Longer duration of action than methadone [8]


OPIOID ANTAGONISTS
Naloxone

Reduces heroin craving post-withdrawal

Induces rapid detoxification in heroin addicts

Naltrexone

similar to naloxone, but is longer-acting

Nalmefene

Most effective since block more µ-opioid receptors

Buprenorphine mimics the brain’s natural neurotransmitters, resulting in
gradual reduced withdrawal

Partial agonist

Acts as both an opioid agonist and antagonist [8]
[1]
Clatts MC, Giang LM, Goldsamt LA, Yi H. 2007. Novel Heroin Injection Practices: Implications for Transmission of HIV and
other Bloodborne Pathogens. American Journal of Preventive Medicine; 32(6): 226-233.
[2]
Michels II, Stöver H, Gerlach R. 2007. Substitution treatment for opioid addicts in Germany. Harm Reduction Journal; 4: 5.
[3]
Jaffe JA and Kimmel PL. 2006. Chronic Nephropathies of Cocaine and Heroin Abuse: A Critical Review. Clinical Journal of the
American Society of Nephrology; 1: 655-667.
[4]
Lenoir M and Keiflin R. 2006. Heroin Addiction: Anticipating the Reward of Heroin or the Agony of Withdrawal. The Journal of
Neuroscience; 26(36): 9080-9081
[5]
Belgraver M, Erkamp B, Dragutinovic, Kerssemakers R. 2007. Heroin and the Brain. Jellinek Preventie Amsterdam:
http://www.eztest.com/web/index.php?option=com_wrapper&Itemid=39
[6]
Terenius L. 1997. Opioid Peptides and Receptors in Drug Abuse. Department of Clinical Neuroscience; 11: 171-176.
[7]
Yao L, McFarland K, Fan, Peidong, Jiang Z, Inoue Y, Diamond I. 2005. Activator of G protein signaling 3 regulates opiate
activation of protein kinase A signaling and relapse of heroin-seeking behavior. Proceedings of the National Academy of
Sciences of the United States of America; 102(24): 8746-8751.
[8]
Wasilow-Mueller S and Erickson CK. 2001. Drug Abuse and Dependency: Understanding Gender Differences in Etiology and
Management. Journal of the American Pharmaceutical Association; 41(1): 78-90.