Download File - Riske Science

Lesson 5: Opiates
D3 - Monday, March 14, 2016
Understandings
• The ability of a drug to cross the blood–brain barrier
depends on its chemical structure and solubility in water
and lipids.
• Opiates are natural narcotic analgesics that are derived
from the opium poppy.
• Morphine and codeine are used as strong analgesics.
Strong analgesics work by temporarily bonding to receptor
sites in the brain, preventing the transmission of pain
impulses without depressing the central nervous system.
• Medical use and addictive properties of opiate compounds
are related to the presence of opioid receptors in the brain.
Applications and Skills
• Explanation of the synthesis of codeine and diamorphine
from morphine.
• Description and explanation of the use of strong analgesics.
• Comparison of the structures of morphine, codeine, and
diamorphine (heroin).
• Discussion of the advantages and disadvantages of using
morphine and its derivatives as strong analgesics.
• Discussion of side-effects and addiction to opiate
compounds.
• Explanation of the increased potency of diamorphine
compared to morphine based on their chemical structure
and solubility.
Opiates – Strong Analgesics
• A completely different group of compounds,
the opiates (also known as opioids), act as
strong analgesics. This means that they kill
pain by preventing the transmission of pain
impulses in the brain, rather than at the
source
• Opiates are natural analgesics that are derived
from opium, which is found in poppy seeds.
History
• Opiates are derived from the juice of the unripe
seed pods of the poppy Papaver somniferum.This
juice is known as opium (the Greek word for
‘juice’) and contains a mixture of approximately
25 different nitrogen- containing compounds
(known as alkaloids), the most important of
which is morphine. Morphine was first isolated in
1803 and is chiefly responsible for the biological
effects of opium – it accounts for approximately
10% of the opium mixture. Codeine, a milder
analgesic than morphine, is also found naturally
in opium, although in smaller proportions
China Opium Den – 1800s
How Opioids Work
• The analgesic properties of the opiates arise
because we possess so-called opioid receptors
in the brain to which they bind temporarily.
This binding blocks the transmission of
impulses between brain cells that would signal
pain. In other words, strong analgesics
interfere with the perception of pain without
depressing the central nervous system.
Opioid Receptors
• We also have opioid receptors other places in our body
• Opiates cause a number of effects on the body through
binding to opioid receptors. These include analgesia,
sedation, a feeling
of well-being and suppression of the cough reflex.
• Fun fact – heroin was initial a cough medicine, cocaine
(in the form of coca leaves) have been chewed by
indigenous South Americans to combat altitude
sickenss
• They are used medically for pain relief and the
treatment of coughs and diarrhea.
Narcotics
• Because these analgesics act on the brain,
they may cause possible changes in behavior
and mood, so they are also known as
narcotics. Opioids are the most effective
painkillers for severe pain, but due to their
side-effects and potential problems with
dependence, their usage must be monitored
through medical supervision.
Blood-Brain Barrier
• The target for the opiates is the brain. This presents a
challenge as the brain is surrounded by a membranebound structure, known as the blood–brain barrier,
which protects it by restricting the chemicals that can
enter from the blood.
• Like all membranes, this structure is made largely of
lipids which are non-polar molecules. The blood–brain
barrier is therefore a hydrophobic, non-polar
environment, not easily crossed by polar molecules.
For a drug to penetrate this barrier and enter the brain,
it will be more effective when it itself is non-polar and
lipid soluble.
Difficulties Crossing Blood Brain
Barrier
• For all drugs that need to work on the CNS,
crossing the blood brain barrier is a huge
challenge (think: antidepressants, opioids,
etc.)
• The analgesic properties of the opiates
depend largely on their ability to move from
the blood, where aqueous solubility is
important, into the brain where lipid solubility
is important to cross the barrier.
So how do we make these drugs?
• We will consider three of these here: codeine,
morphine, and diamorphine (known as
heroin) and how they are made from
morphine
Structures
• Notice that these three drugs have a common
basic structure that accounts for their similar
properties, as well as some different functional
groups.
• Morphine is the principle drug derived from
opium. When administered through intravenous
injection it has about six times the bioavailability
as when taken orally. The two –OH groups in
morphine give it some polarity which limits its
ability to cross the blood–brain barrier
Codeine
• Codeine is found at low levels in opium but is
more commonly prepared from morphine. It is
therefore known as a semi-synthetic drug.
• To make codeine, you convert of the –OH groups
into the methyl ether, so is known as methylation
• This means it can cross the blood brain barrier
more easily BUT it causes a decrease in the
binding to the opioid receptors and therefore
makes it a weaker analgesic
• https://www.youtube.com/watch?v=faKI6klXwY&feature=youtu.be
Heroin
• Diamorphine (heroin) is produced from
morphine by an esterification reaction in
which both –OH groups are converted into
ethanoate (ester) groups by reaction with
ethanoic acid (CH3COOH) or ethanoic
anhydride ((CH3CO)2O).
• This reduces the polarity significantly, making
diamorphine much more lipid soluble than
morphine and so more able to cross the
blood–brain barrier. This is why it is faster
Pro-Drugs
Diamorphine has a much greater potency than
morphine, reaching the brain cells faster and in higher
concentration. It is more active by a factor of two. Note
that this also applies to its greater side-effects as well as
to its characteristics of tolerance and dependence. Inside
the brain diamorphine must undergo metabolic change
before it can act at the opioid receptors. The ester links
are broken by enzymes called esterases. For this reason
diamorphine is described as a pro-drug, meaning that its
metabolic products, mostly morphine, actually bring
about its effects. The molecular structure of diamorphine
can be thought of as a way of ‘packaging’ the morphine
so that it can reach its target more ef ciently.
Advantages of Opioids
• Pain Management!
• WHO Three Step Ladder
Side Effects
•
•
•
•
constipation
suppression of the cough reflex
constriction of the pupil in the eye
narcotic effects, which are discussed below.
Addiction
• Obviously, opioids are ripe for addiction; they
produce a euphoria and build tolerance requiring
users to need more and more
• Helping heroin addicts to break their dependence
is a slow and dif cult process. Sometimes an
alternate analgesic, methadone, is administered.
Methadone is taken orally and has a longer
duration of action. This can reduce drug craving
and prevent symptoms of withdrawal.
Documentary
• https://www.hbo.com/addiction/thefilm/cent
erpiece/617_segment_6.html
Questions
Answers