Opioids Flashcards
Opium and Opioids mentioned in history (4)
- Opos: Greek for “juice”
- Opium poppies sprung from the tears of Aphrodite when she mourned for her
beloved Adonis - The first written reference appears in a Sumerian text data 4000 BC
- Homer’s Odyssey (8th BC Greece) describe opiate use as a drug called “Nepenthe”: But then Helen ”…had a happy thought. Into the bowl in which their wine was mixed, she slipped a drug that had the power of robbing grief and anger of their sting and banishing all painful memories
Where do opium poppies grow?
Golden triangle : b/w Myanmar, Thailand + Laos
A Brief History of uses (7)
- Beneficial (analgesic, hypnotic) and harmful effect known for centuries
- 1527: Paracelsus formulated Laudanum
- 17th C: China outlawed tobacco so opium became popular
- Opium was the cause of China-England wars when China outlawed opium
- 1803: Serturner isolated morphine
- Mid 1800’s medicinal use of morphine widely spread
- 1939: First synthetic opioid, meperidine
What are opioids? (5)
– Endogenous or synthetic substance with morphine-like effects, antagonized by naloxone
– ‘Opiate’ synthetic morphine-like drug with non-peptide structure
– Opioid actions include analgesia, respiratory depression, euphoria and sedation
- Led to discovery of receptor subtypes
– Morphine analogues - Agonists - morphine, diamorphine (heroin), codeine
- Antagonists – naloxone
– Synthetic derivatives: pethidine, fentanyl, methadone
Heroin
Heroin was first made by Alder Wright in 1874 from morphine
Methadone (5)
- During WWII the supply of opium was cut off from Germany so painkilling morphine became short in supply
- Methadone was developed as a synthetic derivative in Germany around 1937 to 1939 by Gustav Ehrhart
- Successful analgesic acting on opioid receptors
- Used as a treatment for opiate dependence in 1960s after WWII heroin epidemic
- The pain-relieving effects last about six hours after a single dose. After long-term use, in people with normal liver function, effects last 8 to 36 hour
Fentanyl (4)
- Fentanyl was first made by Paul Janssen in 1960
- 100x more potent than morphine
- Given for acute pain, postoperative pain anaesthesia, obstetrics, chronic pain (patches), palliative pain
- As of 2017, fentanyl was the most widely used synthetic opioid in medicine.
Oxycodone (3)
Synthetic opioid developed by Purdue Pharma to treat moderate to severe pain
- The extended-release form of this medicine is for around-the-clock treatment of pain. This form of oxycodone is not for use on an as-needed basis for pain.
- In the U.S., extended-release oxycodone is approved for use in children as young as 11 years old. The approved uses is for relief of cancer pain, trauma pain, or pain due to major surgery, in children already treated with opioids
Opioid use for pain treatment (5)
morphine -9%
Tramadol-11%
Fentanyl-17%
Oxycodone-26%
Others=37%
Agonists
bind to the mu-opioid receptor and stimulate physiological
activity
Partial agonists
bind to the mu receptor but do not produce maximum
stimulation
Antagonists
have no intrinsic
pharmacological effect, but bind to the receptor and can block the action of an agonist
Morphine - heroine
morphine w/ addition of an acetyl group = heroine (=synthetic)
History of opioids in the brain (6)
1973 Discovery of opioid receptors
1975 Discovery of enkephalin
1976 Evidence for multiple opioid receptors
1979 Cloning of opioid peptide precursors
1992 Cloning of opioid receptors
1994/1995 Cloning of ORL1(NOP) receptor and nociceptin
4- Opioid peptide families and opioid receptors (4)
beta-endorphin (beta has high affinity for mu + de) = MOP (mu) + DOP (delta)
Enkephalins= Dop (delta)
Dynorphins= KOP (kappa)
Nociceptin/OFQ = NOP (ORL-1)
Mu opiate receptor vs peptides (2)
receptor = GPCR
peptides = made up w/ A.A.’s - same seq homology b/w all important endo peptides
Pharmacological effects of Opioids (3)
(highly localised in reward system + thalamus-pain) mu: superspinal, spinal = analgesia major -ve RD(death) , in GI =constipation
delta: spinal analgesia, little bit of RD,
kappa: possibly peripheral pian (itching), responsible for dysphoria
Respiratory depression (4)
– decreased sensitivity (desensitised) of respiratory centre to CO2 (medulla)
= asphyx
– Mediated by mu receptors
– Most troublesome side effect, occurs at therapeutic doses
- Commonest cause of death in opiate poisoning
Opioid Analgesics (3)
- Enalodine, U50488 (KOP)/low dependence liability BUT psychotomimetic effect (withdrawn)
- Peripheral acting KOP for peripheral pain and itching
- DOP agonists poor analgesics but have antidepressant properties. However, proconvulsant effects
Opioid effects on body systems (5)
- Cough reflex
– Codeine used in cough medicine to suppress cough - Mechanism unclear, can occur at subanalgesic doses
- Nausea and vomiting (Q. how?)
– Occurs in 40% of patients
– Opioid action in CTZ (delta) and vomiting centre (mu) - Pupil constriction
– Pinpoint pupils used as diagnostic feature in opiate poisoning - Other causes of respiratory depression & coma cause pupil
dilatation - GI tract
– inc. tone and dec. motility, constipation - Other actions
– Morphine releases histamine from mast cells - itching
Effector mechanisms: Opioid receptors: mu, delta, kappa/ inhibition: (5)
– G-protein coupled receptors (Gi/Go) - inhib cAMP (dec cAMP)
- inc. K+ channel opening= hyperpolarization
- dec. opening of voltage-gated Ca2+ channels (less +ve = further hyperpolarisation)
- Reduce neuronal excitability (K+) and reduce neurotransmitter release (Ca2+)
- Inhibition of adenylyl cyclase, decrease cAMP, PKA
Pain pathway - normal (5)
1) Injury caused by mechanical, chemical, inflammation = pain
2) detected by the peripheral nociceptors, in the afferent neurones= depolarisation of the neurone
3) initiating an AP to travel up the periphery nerve, to the dorsal root ganglia project on the dorsal horn
4) propagation of AP’s= release of Glutamate and Substance P, which projects onto neighbouring neurones
5) = launches pain signal upwards to the brain, causing the sensation of pain
Opioids in peripheral neurones
1) opioids inhibit adenylyl cyclase
2)= causing a decrease in the cyclic adenosine monophosphate (cAMP)
3)This results in an increased number of potassium channels opening, causing hyperpolarisation, and the closing of voltage-gated calcium channels.
4) = This causes further hyperpolarisation, reducing the neuronal excitability and neurotransmitter release, reducing the likelihood of neuronal stimulation
Opioids on Dorsal spinal cord - pre + post synaptic (4)
1) act on the neurone, pre and post synaptically
2) Presynaptic action causes inhibition of Glutamate and Substance P
3) post synaptic action causes hyperpolarisation of the neurones, causing difficulty to stimulate it.
This joint mechanism completely inhibits the transmission of pain.
