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Opoid Analgesics Essay, Research Paper
Opioid Analgesics
Opium is the natural extract obtained from the juice of the poppy flower, Papaver somniferum
and is composed of over 20 different alkaloids. “Opiate” is a term used to describe all drugs
derived from opium. Because this excludes all synthetic compounds or endogenous analogues
the term “opioid” has evolved to be all encompassing. Hence Opioid Analgesics refers to all
compounds both natural or synthetic that have similar pharmacological properties to opiates.
They are the most powerful analgesics known to Man and over the past 100 years no one has
succeeded in finding other pain relievers that are as potent. At the same time these drugs are
classic examples of addictive substances, that have and still are exacting a massive toll on
society.
Due to the powerful analgesic effects of these drugs it became important to understand how these
drugs brought about their pain relieving effects. The main aim behind this work was to try to
devise synthetic substances that had the pain alleviating effect of the opioids but none of the
deleterious side effects such as addition.
The first observation that helped throw some light on the mechanism of action was the
observation that the opioids are potent at very low doses a small fraction of a milligram. This
indicated that the opioids probably act very specific cell-surface receptors. This evidence was
further substantiated by the discovery of specific drugs that reverse the effects of the opioids i.e.
opioid antagonists.
The first evidence for opioid receptors in the brain came in 1973 from the results of a series of
binding study experiments which used 3H-naloxone (opioid antagonist) to bind to the receptors.
The potencies of the binding of specific opiates was seen to mimic their opiate-like
pharmacological effects. The specific locations of the opiate receptors in the CNS were
determined using the same radiolabelled naloxone and a sensitive autoradioagraphic techniques
that allowed the locations of the bound naloxone to be determined in thin sections of the CNS.
Thus labelling was seen in the spinal cord, the thalamus (which filters sensory information and
passes it on to the sensory-motor cortex) and the limbic structures which control our
mood/emotional behaviour. This can help explain why opioids can induce feelings of euphoria
and may provide some explanation of the addictive nature of these drugs. Interestingly a number
of other regions of the brain were found to contain opioid receptors that were apparently not
linked with their pain-alleviating properties but helped explain some of the side-effects of the
opioid analgesics.
a) Labelling in the pre-tectal nuclei of the brain stem. This region involved with regulating
pupillary diameter. In the presence of opiates the pupils are characteristically constricted.
b) Other regions in the brain stem were also labelled these included the respiratory centre and the
cough centre. The main way that opiates kill is by suppressing the respiratory centre an effect
that is regulated by the opioid receptors present in this region of the brain. Opioids have also
been typically used to as cough suppressants and sure enough this appears to be explained by the
presence of large numbers of opioid receptors in the cough centre of the brain.
What do we know about the signalling mechanisms used by these receptors?
All opioids act on a group of 7 transmembrane domain, G-protein coupled receptors. Activation
of the receptor typically results in a decrease in cAMP production which results in an inhibition
of Ca2+ channels or and increase in K+ channel activity, both of which have inhibitory actions.
These occur either via an inhibition of neurotransmitter release (morphine reducing ACh release
from parasympathetic terminals in the GIT) or an inhibition of action potential generation in
postsynaptic neurones.
The receptors can be classified in to three main classes:
a) m-opioid receptor
b) k-opioid receptor
c) d- opioid receptor
m-opioid receptor
Location: These receptors are located in the spinal cord, periaqueductal grey matter, thalamus,
limbic system, respiratory and cough centres, hypothalamus and GIT.
Actions: Spinal and supraspinal analgesia, euphoria, respiratory depression, miosis, nausea and
vomiting, depression of cough reflex. They also cause peripheral vasodilation, and inhibit ACh
release from parasympathetic nerve endings.
k-opioid receptor
Located in the dorsal horn of the spinal cord, the hypothalamus and other regions of the CNS. In
fact regions that are similar to those frequented by m-opioid receptor. They, however appear to
act to alleviate pain through a different mechanism as analgesia can still be introduced in people
who are tolerant to m-opioid receptor agonists. They work at both the spinal and supraspinal
levels as do the m-opioid receptor agonists but they induce less respiratory depression and less
miosis than the m-opioid receptor agonists. In contrast to the m-opioid receptor agonists, kopioid receptor agonists induce feelings of dysphoria.
d- opioid receptor
Their functions are unclear. They are found again in both the spinal cord and supraspinal regions
of the CNS, where they too can induce analgesia.
The presence of specific receptors for the opioids begs the question ” If people are not born with
morphine in them, then what is the function of opioid receptors in Man?”
Endogenous Opioids
The presence of opioid receptors suggested that the body much produce its own pain relieving
molecules.
Hughes and Kosterlitz looked at ability of opiates to inhibit electrically induced contractions of
the gut. They used brain extracts and showed that some inhibited the gut contractions and more
importantly that these effects were antagonised by naloxone. They then purified and isolated the
chemicals responsible and showed them both to be short peptides (5 amino acids long). They
were known as the enkephalins. These substances were shown to be solely located in neurones
and were found to be located in nerve terminals in regions close to the locations of the opioid
receptor, thus they were clearly neurotransmitters.
Several other classes of opioid peptides were also discovered. These included:
a) The endorphins
b) The dynorphins
These together with the enkephalins were found to be encoded on three distinct genes. These
genes formed precursor proteins from which the active peptides were cleaved.
Beta-endorphin (31 amino acids) which is the natural ligand for both the m and d-opioid
receptors, is encoded on a complex gene that also encodes for ACTH and MSH. It is found colocalised with ACTH in the pituitary where it is believed to be co-released at times of stress.
The dynorphins (Dynorphin A) which are ligands at k-opioid receptor are encoded on a gene that
also produce one of the enkephalins (Leu-enkephalin).
The enkephalins are the natural ligands for both the m and d-opioid receptors. They (Metenkephalin and Leu-enkephalin).
Clinical Uses of Opioid Analgesics
Morphine and all morphine-like drugs are equally capable of alleviating pain with the exception
of codeine. The choice of analgesic depends on a number of things:
1) Pain intensity
2) Pain Duration
3) Which dosage form
4) Benign or terminal pain
5) Which route
Pain Intensity
Morphine-like drugs that are useful for treating severe pain have a high analgesic efficacy. These
include Diamorphine (heroin), Levorphanol and phenozocine. They therefore suffer from a
variety of drawbacks as a consequence of their high efficacy. These include:
a) drowsiness and sedation
b) respiratory depression
c) euphoria (abuse potential)
d) Tolerance
Drugs with a lower analgesic efficacy such as codeine and pentazocine do not have the above
side effects.
Pain Duration
The duration of pain may also help in deciding the choice of analgesic. There are three possible
ways of altering the duration of the analgesia:
a) Type of analgesic (e.g. fentanyl rapid onset lasts for 30 min. useful for pain immediately
following operation; pethidine similar used during childbirth).
b) Route of administration (e.g. morphine i.v. onset is immediate, duration up to 4 hrs; morphine
suppositories onset 90 min duration up to 6 hours).
c) Keep the drug and route the same but alter the formulation.
Benign or Terminal Pain
In this case of acute pain this is too much of a problem, as single one off doses of high efficacy
analgesics have no long term effects. However, in the case of chronic pain that requires repeated
long-term dosing with high efficacy analgesics use maybe limited due to dependence. In the case
of a chronic benign pain this maybe a problem, however, people with a terminal condition this
type of repeated dosing is acceptable.
Treatment of Diarrhoea
Kaolin and morphine is the classical treatment for diarrhoea. m-opioid receptors on the
presynaptic terminals of parasympathetic fibres suppress ACh release and so reduce the
persistaltic movements of the GIT. Because of this peripheral site of action opioids do not
require access to the CNS to act as anti diarrhoeals. This explains why another treatment for
diarrhoea (tincture of opium) has its effects at doses lower than those required to induce
analgesia. Loperamide is another morphine-like drug used solely to treat diarrhoea. It penetrates
the blood-brain barrier poorly and as such has a low abuse potential.
Treatment of Cough
As the site of action is the CNS morphine is not used as a cough suppressant because of its abuse
potential. Although originally diamorphine (heroin) was marketed as a non-addictive cough
remedy. It took 25 years for its addictive nature to be described. This delay was mainly due to its
route of administration and the observation that those people taking the heroin were not
themselves seeking or expecting psychoactive effects. The main morphine-like drugs that are
used to treat cough include codeine, pholcodine and dextromethorphan.
Treatment of breathlessness of acute heart failure and pulmonary oedema
Morphine or diamorphine are used in these cases as they both cause sedation and thus reduce
anxiety, and also cause some respiratory depression. Both these effects help to reduce the
struggle to breathe.
Treatment of Opioid Addiction
Methadone is characteristically used in the treatment of heroin addicts. It works because it has a
much greater duration of action than morphine and therefore does not cause the sudden
euphoria/dysphoria that morphine does. As it acts at the same receptor as morphine it can prevent
the euphoric effects of morphine. It ability to treat addicts is also due to its longer plasma half
life which reduces the problems of withdrawal.
Mixed agonists antagonists
These opioid drugs appeared to be precisely what the doctor ordered. Analgesics with non of the
potential for dependence. Examples of these compounds include phentazocine and
buprenorphine.
Pentazocine: Weak antagonist used as an agonist. It has actions at the kappa receptor and has no
effect at the morphine receptor. As such there are very few of the morphine side-effects such as
respiratory depression. However, the main drawbacks of this compound is that it has a relatively
low analgesic efficacy, it causes dysphoria and is also open to abuse.
Buprenorphine: Again a weak antagonist used as an agonist. These too have low affinity for the
mu receptor and a relatively high affinity for the kappa receptor. Therefore some of the unwanted
side-effects of morphine are not seen. It also has the advantage of being administered sublingually and therefore is easy to give. It also has a lower analgesic efficacy compared to
morphine and is still abused.
Uses of Opioid Antagonists
Opioid Overdose
Overdosing on opioids can lead to the onset of a coma due to the sedative effects of the drug but
also due to the ability of the drugs to suppress ventilation. This can be treated effectively by the
use of opioid antagonists such as naloxone. Care must be taken however as the antagonists are
equally capable of initiating the withdrawal process.
Antagonists are also used to therapeutically to reverse respiratory depression that occurs postoperatively or in obstetrics.
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