25.3 Opiates

what is Codeine?

Codeine is an alkaloid found in opium, but most codeine used in medicine is synthesised from morphine.

With what other drugs is codeine often marketed with?

Codeine is sometimes marketed in combination preparations with paracetamol (acetaminophen) as co-codamol, or with aspirin as co-codaprin. These combinations provide greater pain relief than either agent alone due to the operation of the synergistic effect.

Give the examples for commonly known opiates:

Codeine, morphine, and diamorhine

What must opioids do in order to work?

Cross the blood-brain barrier (BBB)

what is Diacetylmorphine?

Diacetylmorphine is a semi-synthetic opiate, or opioid, derived from morphine.

What are the side affects of heroin?

Drowsiness, warmth, content, relieves stress and discomfort and gives a feeling of detachment from pain.

What are the disadvantages of opioid use?

Euphoria, vomiting, addiction, constipation, sedation

How is heroin consumed?

Heroin can be swallowed or dissolved in water and injected into a vein - this method produces the most intense effect. Alternatively, it can be sniffed, or the fumes from the heated powder inhaled - this method sometimes called 'chasing the dragon'.

Structure difference leads to solubility of morphine and heroine

Heroin consists of two ester groups which are less polar than the two more polar OH groups in morphine. Thus heroin is more lipid soluble than morphine, meaning that it can move many times faster across BBB into the brain.

What is the side group functionality of morphine?

Hydroxyl (phenol)

What mechanism makes diamorphine about 5 times more potent an analgesic​ than morphine?

In the brain, diamorphine is quickly metabolised into morphine, which binds to the opioid receptor, producing strong analgesics

How does the change in polarity of morphine to diamorphine affect diamorphine?

It increases its lipophilicity (ability to dissolve in lipids) and thus enabling it to cross the blood-brain barrier. This is what makes diamorphine about five times stronger that morphine when injected into the blood.

Where is morphine found?

It is found in opium and extracted from the latex in the speed capsule of the opium​ poppy

How is heroin synthesised?

It is made using morphine through a single-step process.

The danger of heroin diamorphine

It is responsible for nearly 50% of all drug-related deaths around the globe

How was heroin first marketed?

It was first made in 1874 and was marketed as a safe non-addictive substitute for morphine.

How do Opiates work?

Kill pain by preventing the transmission of pain impulses in the brain rather than at the source

What are the addiction dangers of codeine?

Like all opiates, codeine is addictive unless used infrequently. However, the withdrawal symptoms are relatively mild and as a consequence codeine is considerably less addictive than the other opiates.

What makes codeine the most used opiate in the world?

Low activity, wide therapeutic window and limited potential for abuse

What is psychological addiction do to the drug user?

Makes them crave the euphoric high a drug creates

What works as methylating agents for the synthesis of codeine from morphine?

Methyl groups containing quarternary ammonium compounds such as trimethylphenyl ammonium chloride.

Which of these 3 is the main organic starting material used to make the others?

Morphine

What are the two main types of opiate?

Morphine and Codeine.

What are classed as strong analgesics?

Morphine and its derivatives (opiates)

Which of the three compounds reduces BBB permeability the most?

Morphine because the hydroxyl groups form hydrogen bonds to water molecules

Synthesis of codeine from morphine

Morphine has two OH groups, one attached to the benzene ring and the other to the cycloalkane ring. The hydrogen on the phenyl group is more acidic and resonance stabilised due to delocalization of a lone pair on oxygen with the benzene ring. Thus a nucleophilic substitution with methyl halide leads to deprotonation (getting rid of H) and replace with CH3 to achieve methylation of morphine.

What difficulties might most analgesics encounter?

Moving through the hydrophilic, polar properties of the blood stream through the blood-brain barrier which is hydrophobic and non-polar

How is opiates also known as?

Nacrcotic Analgesics

What are the changes in behaviour and mood called

Nacrotics

Define opiates

Naturally-occurring narcotic compounds derived from the opium poppy, eg. morphine

Where are Opiates found?

Opiates are derived from Opium found in poppy seeds (cultivation of the opium poppy go back to Mesopotamia more than 5000 years ago)

What do strong analgesics block in the transmission of pain impulses?

Opioid receptors

What are the two different types of addiction?

Psychological and physical

What are the advantages of opioid use?

Rapid onset of analgesia, powerful analgesic effect, cough suppression, anti-diarrhoeal

How is codeine synthesised from morphine?

Reaction with CH3I in KOH

How is diamorphine synthesised from morphine?

Reaction with ethanoic anhydride

What are therapeutic uses of codeine?

Sometimes used in a preparation with a non-narcotic drug such as aspirin or paracetamol in the second stage of the pain management ladder and also used in cough medications and in the short-term treatment of diarrhoea

What do Opiates act as?

Strong Analgesics

What allows scientists to establish certain patterns in the physiological​ and psychological effects of opium on the human body?

Systematic observations

Who is diamorphine banned for?

Terminally ill patients with certain forms of cancer or CNS disorders

What important functional group, common to morphine, codeine and diamorphine, is present in the backbone structure?

Tertiary anime --> N-CH3

What is the therapeutic window?

The Therapeutic window is the range of dosages between the minimum amounts of the drug that produce the desired effect and are medically safe, but without unacceptable adverse effects.

What is the target for the opiates?

The brain

Why is codeine weaker than morphine?

The conversion causes a significant drop in the binding at the opioid receptors

What increases how quickly an opioid will penetrate the BB?

The more hydrophobic (non-polar) the compound is

What are opiates derived from?

The opium poppy

What structural features have to be present in order for the opioid painkiller to be active?

The tertiary amine nitrogen with a small alkyl group, the presence of a piperidine ring, a quaternary carbon, a benzene ring, and a C2 'spacer', part of the piperidine ring, between the tertiary nitrogen and the quaternary carbon. The molecules have a rigid structure which helps them bind to the active site of the opioid receptor.

What is the opioid receptor?

The three main areas that bind morphine, codeine, heroin and related opioids. There is an ionic site which binds the tertiary amine nitrogen, which can become positively charged via protonation; a cavity which accepts the piperidine ring; and a flat surface that binds the benzene ring by London (dispersion) forces.

How do powerful analgesics work?

They act on proteins called opioid receptors that are on the surface of nerve cells in the brain, spinal cord, and intestines. The different shapes of the receptors all certain molecules to bind at the site.

morphine, codeine and diamorphine's structural similarity

They all have the same carbon skeleton

What are the similarities between heroin, morphine, and codeine?

They are all powerful analgesics that act on proteins known as opioid receptors located on the surfaces of nerve cells in the brain, spinal cord and intestines. The molecules of these opiates have a common structure, and hence shape.

What are opiates?

They are natural analgesics that are derived from opium, which is found in poppy seeds

Why are opiates also known as narcotics?

They have sleep-inducing properties.

What does it mean by opiates 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

How are strong analgesics used to?

Used to relieve severe pain caused by injury, surgical procedures​, heart attack, or chronic diseases such as cancer.

How was heroin initially marketed?

When heroin was first synthesised in 1874 it was marketed as a safe non-addictive substitute for morphine. However, dependency or addiction quickly developed in some individuals and heroin and other opiates were made illegal in many countries, for example in 1920 in the USA.

When does addiction occur?

When the drug user becomes dependent on a compound

What is diamorphine?

a semi-synthetic opiate, or opioid​, derived from morphine (another word for heroin)

What is blood-brain barrier?

a series of lipophilic cell membranes that coat the blood vessels in the brain and prevent polar molecules from entering the CNS

Side group and structure of Codeine:

(methyl) ether and R-OCH3

What are Alkaloids?

1. The group which the primary bioactive ingredient of opium and morphine belong to. 2. Alkaloids are a diverse group of nitrogen-containing bases extracted from plants.

What percentage of drug-related deaths is heroin (diamorphine) responsible for?

50%

What are alkaloids?

A diverse group of nitrogen-containing bases that are extracted from plants.

What is a prodrug?

A drug that is converted into a more active form inside of the body, for example, a small proportion of codeine is converted by a liver enzyme to morphine and a range of other compounds

Define a strong analgesic

A drug that works by temporarily binding to opioid receptors in the brain and thereby prevents the transmission of pain impulses without depressing the central nervous system.

Define opioids

A more general term used to describe all compounds with structure similar to morphine, eg. codeine and diamorphine (heroin)

What is morphine?

A natural opiate found in opium, which is extracted from the latex in the seed capsule of the opium poppy.

What is the blood-brain barrier?

A series of lipophilic cell membranes that coat the blood vessels in the brain and prevent polar molecules from entering the CNS

What is a toxic substance?

A toxic substance is a chemical that is dangerous or causes illness or death in small amounts.

Which group does the opiate belong to?

Alkaloids

What are opioids?

All compounds with structures similar to morphine

What are the similarities between the 3 opioids?

All the structures have the same basic skeleton but have some changes in the side groups

What is codeine?

An alkaloid found in opium that is used in medicine and made from morphine

Why do morphine and other opiates have a very high potential for misuse?

Because in addition to their painkilling properties, large dose of opiates cause a strong feeling of euphoria, provide relief from all forms of distress and stimulate sociability

Why is codeine considered to be semi-synthetic?

Because it is prepared from morphine

Why are opiates also known as narcotic analgesics?

Because of their effects on the human body. In addition to their painkilling properties, large doses of opiates cause a strong feeling of euphoria, provide relief and stimulate sociability

Why do opiates have analgesic properties?

Because we possess opioid​ receptors in the brain to which the bind temporarily, this blocks transmission of impulses between brain cells that would signal pain. They interfere with the perception of pain without depressing the central nervous system.

Why does 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.

How is diamorphine made from morphine?

By a reaction with ethanoic anhydride in an acetylation reaction which forms aspirin and ethanoic acid. Both hydroxyl groups are substituted for ester groups in this reaction as well, which reduces the polarity of the molecule.

How do strong analgesics work?

By blocking the transmission of pain impulses by temporarily binding to opioid receptors in the brain

Synthesis of heroin from morphine

By functional group modification to the structure of morphine where the two OH groups on morphine are effectively replaced by two ester groups. Heroin is prepared from morphine by the esterification reaction with ethanoic anhydride

What is the physical structure of morphine?

C17H19NO3

What is the physical structure of codeine?

C18H21NO3

What is the physical structure of diamorphine?

C21H23NO5

What are functional groups of heroin?

arene, ether, alkenyl, ester (ethanoate), tertiary amino

List the functional groups of codeine

arene, ether, alkynyl, hydroxyl, tertiary amino

What are functional groups of morphine?

arene, ether, alkynyl​, hydroxyl, tertiary amino

how is codeine marketed?

codeine is sometimes marketed in combination preparations with paracetamol as co-codamol, or with aspirin as co-codaprin.

Where is codeine commonly found?

cough syrup

What does the high does of opiates cause to the body?

drowsiness, confusion and potentially fatal asphyxia caused by respiratory depression

Side group and structure of Diamorphine:

ester and R-OCOCH3

how can heroin be injected?

heroin can be swallowed or dissolved in water and injected into a vein.

How do hormones release pain?

hormones resemble the natural opiates and trigger body's opiate receptors by binding to neuro-receptors in the brain

Side group and structure of Morphine:

hydroxyl (phenol) and R-OH

What is the blood brain barrier (BBB)?

it's a selective semi-permeable membrane with cells bound tightly together​. It allows the movement of some chemicals from blood to the brain but blocks most other chemicals.

What are the consequences of codeine?

like all opiates, codeine is addictive unless used frequently. However, the withdrawal symptoms are relatively mild and as a consequence codeine is considerably less addictive than the other opiates.

Difference between the three

morphine has 2 polar OH groups, codeine has an OH and an OCH3 group, heroin has two less polar ester or ethanol groups, CH3COO groups

Which method of injection produces the most intense effect?

when you are dissolving in water and injecting into a vein.

What does the functional group modification of morphine do?

result in the semi- synthetic drugs heroin and codeine

What are the side effect of diamorphine?

tolerance, addiction and CNS depression