20: Opioids Flashcards
What are opiates?
An naturally derived alkaloid from the poppy plant
e.g. Morphine, Codein
What are opioids?
Any (natural and synthetical) drugs with opiate-like activity
- opiates + e.g. heroin etc.
What are the structurally important parts of a opiate to fulfill its function?
- Tertiary Nitrogen
- Aromatic Ring
- (Hydroxy groups at position 3 and 6 –> influence binding properties)
What is the role of the tertiary Nitrogen in the chemical structure of Opioids?
What might alteration of the structure create?
Very imporant for Analgesia
- For Analgesia
- allows anchoring to receptor –> determines affinity
- If the side chain (methyl group of nitrogen) is changed: easy generation fo antagonist
What is the role of the 3’-hydroxy group in opioids?
It is needed for binding to the receptor
- Codein has altered 3’ hydroxy group and therefore can’t bind to receptor –> is a produc first need to be converted
What is the role of the 6’ hydroxy group in opoates?
It determinesand lipophility
- can be exchanged for something else to increase lipophility
What is the ROA of Opioids?
IV/PO
What are the pharmacokinetic properties of Opioids?
They are weak bases (pka= 8) –> 20% in blood+ late GI tract unionised
- PO administration
- absorbtion increases the further down the GI tract (less ionised)
- First pass metabolism
- In Blood:
- 20% unionised– >can enter tissue
Sort the follwing opioids according to their lipid solubility
Morphine
Heroin
Codeine
Methadone
Fentanyl
Methadone/Fentanyl >> Heroin > Morphine
General rule of thumb – More lipid soluble, more potent.
Sort the Following Opiates according to their Potency
Morphine
Heroin
Codeine
Methadone
Fentanyl
- Fentanyl!!! (100x)
- Methadone
- Heroin
- Morphine
- Codeine
What is the normal/average duration of action of Opioids?
Depending on metabolism but normally around
2-6 h
(except methadone)
Summarise the Metabolism of Morphine
Metabolised by Cytochrome P450 enzymes into
- Inactive metabolites
- Active metablites
- Morphine 3-G glucuronide
- Morphine 6-G glucuronide
- no respiratory depression but euphoric effect (due to lower affinity for µ receptor)
Explain the metabolism of Heroin and Codeine
Both are prodrugs that first need to be metabolised inro Morphine by CYP enzymes
Explain the Metabolism of Fentanyl
Cleared relatively fast and metabolsed into non-toxic inactive metabolite Norfentanyl
Why does Codein has a relatively low potency?
Because of its metabolism
- Codeine is a prodrug that first needs to be converted to Morphine
- First Step: only 5-10 % Activation to Morphine is slow (CYP2D6)
- Secound Step: inactivation of Morphine is fast (CYP 3A4)
What are the three different opioid receptors?
Which endogenous opioids bind to them?
- µ-receptors (Mainly resposible for effects)
- Endorphins
- Delta-receptors
- Enkephalins
- Kappa receptors
- Dynorphins
What is the role of the delta-opioid receptors?
Endogenous substances: Enkephalins
- They are involved in motor and cognitive function
What is the role of the kappa opioid receptors?
Which endogenous substance binds to it?
Dynorphins bind to it
Involved in Neuroendocrine functions
Which opioid receptors do Endorphins bind to?
Bind to the µ or delta receptor but: main effects via µ receptor
Where are the µ-opioid receptors located?
What is their function and which substance bind to it?
Endorphins bind to µ receptors
- Located in the
- Cerebellum
- Nucleus Accumbens
- PAG
- Caudate Nucleus
- Involved in
- Pain and
- Sensorimotor
What is the effects of the opiate Receptor? (MOA? )
Depressant
- Hyperpolarisation ( K+)
- Reduction of Ca2+ inward current
- Reduction of Adenylate cyclase activity
What are the effects of opioids?
- Analgesia
- Euphoria
- Depression of cough centre (anti-tussive)
- Depression of respiration (medulla)
- Stimulation of chemoreceptor trigger zone (nausea/vomiting)
- Pupillary Constriction
- G.I. Effects
Explain the Analgesic effects of Opioids
Opioids
- Decrease pain perception
- Transmission at the dorsal horn
- and in periphery
- Increase pain tolerance
- Disinhibition of
- NRPG (natural pathway that is activated for pain perception to be not too overwhelming)
- Periaqueduct Gray (PAG)
- –> higher activity= higher pain tolerance
- Disinhibition of
Explain the process of pain tolerance and how it is regulated
It alters the way we feel Pain
- Pain perception arrives at the Thalamus from periphery
- Sends signals to the PAG (Periaqueduct grey) and Cortex
- According to positive/negaive memories, the cortex and the hypothalamus alter PAG acivity (increased activity= increase pain tolerance)
- PAG activats nucleus raphe magnus (NRM) that supressses pain transmission in the dorsal horn
- NRM can also be altered via SNS activity (via the LC (locus correolus) and reduces pain percepiton
- NRPG always gets activated and increases pain tolerance to not make the pain too overwhelming
Explain how the pain threshold can be altered at the level of the dorsal horn
The NRM (Nucleus Raphe Magnus) signals
- directly supresses pain transmisstion
- indirectly (more powerful pathway)–> +ve into the substantia gelatinosa in the spinal chord and thereby - transmission of painful stimuli
Explain the euphoric effects of Opiates
Via dishinhibition of Ventral Tegmental area (normally inhibited by GABA) and therefore increase Dopamine secretion in nucleus accumbens
Explain the Anti-tussive effects of opioids
Anti-coughing effects
- decrease afferent signaling of cough sensation
- decrease signaling of nerve fibres (C-fibres)
- and decrease receptor activation of 5HT1A in medullary cough centre
- And thereby afferent signaling (medulla does not sent out signal)
Explain the effects of opioids on respiration at normal and at high doses
At normal doses: small effect
But at high doses: causes respiratory depression
- interferes with central chemoreceptors (PaCO2)
- drive to breath is reduced via reduced potential of sensing the PaCO2 around
How do opioids induce nausea and vomiting?
Occurs at normal doses
- disinhibition of vimiting centre (switch off of GABA neurons) at level of the Chemoreceptor trigger Zone
- “thinks” toxin is there (signal not inhibited) –> vomiting
Explain the effects of opioids on the pupil
Opioids induce miosis via
- direct stimmulation of the PNS
- disinhibition of Edinger-Westphal nucleus
How do opioids cause GI disturbance?
What are the effects?
It causes constipation
- Decrease of Enteric NS
What is Urticaria?
Explain the effects of opioids on urticaria
Nesselsuch
It causes non-IgE mediated histamin release (aka. non- allergic)
Looks like an allergic response in the skin but isn’t due to opioid induced histamine release
What are the side effects of opioids?
- Respiratory depressant
- Miosis
- Nausea and vomiting
- GI distobrance
- Urticaria (Nesselsucht)
Explain the concept or tolerance of opioids
Is achieved via an upregulation of arrestin
- Arrestin mediated receptor internalisation
Why do opioids make dependant (and why do people experience withdraw symptoms?
As response to downregulatiory effect of Opioates on cAMP
–> upregulation of adenyly cyclase
It then opioids are withdrawn: cAMP overload
- overactivity (e.g. of muscles etc.)
What are the signs of an opioid overdose?
How do you treat an opioid overdose?
- Coma
- Respiratory depression
- Pin-point pupils
- Hypotension
–> Naloxone (opioid antagonist) i.v.
What is the role of the PAG in pain tolerance?
It is the integrating centre in pain tolerance pathway
Pain tolerance= supresses pain because should not get overwhelming
