Alkaloids 2 Flashcards
Benzylisoquinoline alkaloids are biosynthesized from….
Tyrosine
A number of different alkaloids are derived from tyrosine e.g. mescaline and tubocurarine.
Raw Opium is obtained from…
Papaver somniferum
There is evidence that some cultures (Sumerians and Egyptians) had been using and had known the narcotic and analgesic properties of opium as early as 4000 BC. In Greek mythology the plant was dedicated to Thanatos (god of death), Hypnos (god of sleep) and Morpheus (god of dreams).
What was raw opium used for in the past?
5 THINGS
Then the use was as an aid to sleep and for the treatment of diarrhoea. Other uses recommended then include, to treat eye problems, gout, insomnia and eradicate head lice.
What is an Opium?
is the dried latex obtained by incision of the unripe capsule of Papaver somniferum.
The latex is dried by applying heat or spontaneous evaporation, and is then moulded into shape and size. Should contain ≥ 9.5 % calculated as anhydrous morphine.
What is latex?
Latex is an emulsion or suspension. It occurs in special structures – laticiferous vessels in the poppy capsule. Incisions are made on the surface of the capsule on a dry day in the afternoon. The latex is scraped off the following day
What is a poppy straw?
refers to whole of the plant (except the root) which is extracted for the alkaloids –
main producers include Turkey, Russia and Australia. Is used as a major source of the alkaloids in a number of European countries. Seeds – are used for its fixed oil and the remaining ‘seed cake’ is used to feed cattle
What is the major constituent of opium
Morphine (god of dreams) was 1st isolated in 1804. The chemical structure proposed in 1923.
The main intermediate in the biosynthesis of morphine is…
Reticuline
Reticuline is converted further through a number of enzyme mediated steps first to thebaine, then codeine before morphine, the most abundant alkaloid, is produced.
Genetically modifying yeast has been shown to make ___________________________
Genetically modifying yeast has been shown to make the bio-synthetic intermediate (S)-reticuline.
Genetically modifying yeast has been shown to make the bio-synthetic intermediate (S)-reticuline, which is immensely important for the biosynthesis of the variety of the opioid alkaloids in the poppy plant. Could then enable new type of semisynthetic opioids to be made available. Also, the full biosynthetic pathway was finally realized with the discovery of the last unknown enzyme involved in 2015 – means possible to produce these alkaloids cheaply
List the structurally related and pharmacologically important alkaloids
Morphine
codeine
Thebaine
State the clinical features of Morphine
Analgesic and narcotic; for severe pain, cough suppressant (acting on the medullary center), causes constipation (increase smooth muscle tone) – use to treat diarrhoea, pre-operative medication – relieve anxiety; side effect includes respiratory depression, tolerance and dependence.
List the preparations of morphine available
solution (Oramorph®), tablets, modified release preparations (e.g. MST Continus® and Zomorph®), suppositories, injection, injection with an antiemetic (e.g. cyclizine) and Kaolin and Morphine Mixture BP
. See BNF for further details.
State ways of dealing with opioid-induced constipation
can use _____________® (a μ–opioid receptor ___________ which acts only in the bowel) or can use __________ to counteract the action. If after ____ days there is no benefit with the stimulant laxative, a faecal softener can be included (e.g. _________). Alternatively, osmotic laxatives (e.g. __ or _______) can also be used. Another option is __________(subcutaneous injection), an opioid receptor antagonist that does not interfere with CNS opioid action; often used in palliative care as an adjunct for __________ therapy.
can use Moventig® (a μ–opioid receptor antagonist which acts only in the bowel) or can use stimulant laxatives to counteract the action. If after 3/4 days there is no benefit with the stimulant laxative, a faecal softener can be included (e.g. dodusate). Alternatively, osmotic laxatives (e.g. latulose or macrogols) can also be used. Another option is methylnaltrexone (subcutaneous injection), an opioid receptor antagonist that does not interfere with CNS opioid action; often used in palliative care as an adjunct for laxative therapy.
Codeine and uses
Widely used as PO4 salt, semi-synthesized from morphine.
Clinical features: cough suppressant (medullary centre), originally claimed non-addictive cf. morphine!!!, mild to moderate analgesic, side-effect constipation (hence not used for long term). NOTE: for both codeine and hydrocodeine there is tighter control on supply (OTC for short term treatment for pain; POM if more than 32 doses) and warning relating to addiction (‘Can cause addiction. For three days use only
Thebaine and uses
Thebaine (Very small chemical changes can make a difference!)
Devoid of analgesic and narcotic activity, mainly used for semi-synthetic conversion to other structurally related drugs.
Facts about Papervine
SAME AS THERBINE (KIND OF)
TALK ABOUT THE TUMOURS
Has a relatively simple structure. Devoid of analgesic and narcotic properties, but displays spasmolytic and vasodilator properties (relaxes smooth muscle). More recently, found to make tumours more sensitive to radiation therapy by inhibiting mitochondria activity and does not affect the radiation sensitivity of normal tissues
Facts about Morphine as a pharmacophore
Morphine is a success story where not only is it therapeutically useful, but is a useful pharmacophore for preparing a wide range of synthetic and semi-synthetic structures which have therapeutic applications.
Derivatives based on the structure of morphine have been prepared in order to reduce the addictive properties and retain or improve on the analgesic potency.
Facts about Semi-synthetic opioid derivatives
Codeine – this is obtained mainly by __________ of morphine; relatively safer to use.
Dihydrocodeine – obtained by ___________of codeine. Moderate to severe pain.
Heroin (___________) – is the __________ of morphine (originally prepared as cough suppressant); highly potent analgesic and addictive narcotic. Mainly used as an analgesic for palliative care. Also can be used (same with morphine) to control distressing cough in _____________. It was originally produced as a cure for opium addiction, but it proved to be even more addictive than morphine.
Pholcodine – has an ___________ on the 3-hydroxyl of morphine; dry cough suppressant and not associated with narcotic properties.
Generally these have been aimed at compounds which are narcotic, cough suppressants and analgesic, but which are less addictive. Some have been found to display anti-narcotic activity and these are useful to treat cases of opiate overdosed victims.
Important functional groups for analgesic activity from the structural changes are realized as the phenol OH group and the ring, and the tertiary amine. Their relative positioning is crucial for binding with the opioid receptors.
Codeine – this is obtained mainly by methylation of morphine; relatively safer to use.
Dihydrocodeine – obtained by reduction of the C 7-8 double bond of codeine. Moderate to severe pain.
Heroin (diamorphine) – is the diacetate of morphine (originally prepared as cough suppressant); highly potent analgesic and addictive narcotic. Mainly used as an analgesic for palliative care. Also can be used (same with morphine) to control distressing cough in terminal lung cancer. It was originally produced as a cure for opium addiction, but it proved to be even more addictive than morphine.
Pholcodine – has an N-(chloroethyl)morpholine on the 3-hydroxyl of morphine; dry cough suppressant and not associated with narcotic properties.
Facts about Apomorphine
a potent ________________and used in inadequately controlled ___________after pre-treatment with two-day pre-treatment with domperidone. Specialist supervision required.
Apomorphine – obtained by boiling morphine in the presence of acid; no analgesic properties, powerful emetic – use to treat cases of poisoning; also a potent dopamine-receptor agonist and used in inadequately controlled Parkinson’s disease after pre-treatment with two-day pre-treatment with domperidone. Specialist supervision required.
……. are obtained through a series of chemical reactions from thebaine, and they are potent antagonists of opioid receptors.
Naloxone and Naltrexone
Facts about Naloxone
Naloxone (is a POM, but falls into an exclusive category) for reversal of __________ and _____________. Preparations of ______________ with naloxone available. (‘Staff engaged or employed in “lawful drug treatment services” to obtain naloxone from a wholesaler and make direct supplies to patients without a prescription. Anyone can administer naloxone for the purpose of saving a life. The recommended intramuscular dose is ____________ initially, with further _________ doses given incrementally every 2-3 minutes until an effect is noted or the ambulance arrives.
Naloxone (is a POM, but falls into an exclusive category) for reversal of postoperative respiratory and CNS depression from opioid administration. Preparations of oxycodone with naloxone available. (‘Staff engaged or employed in “lawful drug treatment services” to obtain naloxone from a wholesaler and make direct supplies to patients without a prescription. Anyone can administer naloxone for the purpose of saving a life. The recommended intramuscular dose is 400 micrograms initially, with further 400 microgram doses given incrementally every 2-3 minutes until an effect is noted or the ambulance arrives.
Facts about Naltrexone
Naltrexone as adjunct to prevent relapse in former opioid-dependent patients or former alcohol-dependent patients. Not used in opioid-dependent patients since it precipitates withdrawal symptoms. Treatment supervised by specialist. (After leaving prison, patients who receive naltrexone are less likely to relapse and overdose than those who receive standard treatment. PJ Apr 2016)
Recently, naltrexone in combination with ___________ is being tested for obesity management and to reduce hospitalization due to alcohol use disorder.
Recently, naltrexone in combination with bupropion is being tested for obesity management and to reduce hospitalization due to alcohol use disorder.
Facts about Naloxegol (Moventig®)
Is a derivative of naloxone with a polyethylene glycol group on the C6 hydroxyl group.
Is also acts as an opioid antagonist and is useful for opioid induced constipation.
This attachment is primarily important for changing the pharmacology profile.
Does not cross the BBB.
What Nalmefene is indicated for?
a long acting opioid antagonist, has potential for persons that have ‘pathological addiction to gambling’.
What is Oxycodone indicated for?
– intermediate in the synthesis of naloxone; potent analgesic for moderate to severe pain in cancer and post-operative
What Hydromorphone is indicated for?
It is as effective as diacetylmorphine (medical grade heroin); could prevent opioid addicts from using street heroin
Facts about Nalbuphine?
It is similar to morphine but has both agonist/antagonist activity – less addictive.
Facts about Etorphine
powerful analgesic (5,000-10,000 x > morphine); used to treat animals only.
Facts about Buprenorphine
structurally related to etorphine;
has agonist/antagonist activity – can precipitate withdrawal symptoms in opioid dependent individuals; moderate to severe pain,
has long duration of action.
As patches and tablets, possible to have sublingual administration
Facts about Buprenorphine and naloxone
Buprenorphine and naloxone formulated together (Suboxone) as adjunct for treatment of opiate abuse – for some types of patient profiles (medical/social/dependence).
‘Methadone and Buprenorphine are to be used to tackle US opioid crisis
List examples of Synthetic drugs based on the structure of morphine
(adjunct in treatment of opioid dependence; rehabilitation of addicts)
(analgesic)
(prompt and short acting analgesic, moderate to severe; obstetric and pre-operative use)
(cough suppressant)
Methadone (adjunct in treatment of opioid dependence; rehabilitation of addicts)
Dextropropoxyphene (analgesic)
Pethidine (prompt and short acting analgesic, moderate to severe; obstetric and pre-operative use)
Dextromethorphane (cough suppressant)
List examples of synthetic drugs based on the structure of morphine
Dextromethorphane (cough suppressant)
Fentanyl (severe and during operation pain; various preparations e.g. sublingual tablets, nasal spray, transdermal patches).
Pentazocine (moderate to severe pain; is an agonist and antagonist – care with those dependent on opioids).
Facts about Tramadol
Tramadol (analgesia by more than one mechanism, opioid receptors and enhances serotonergic and adrenergic pathways;
(supposedly) less opioid side effects; 12 and 24 hour release preparations also available).
