Opioids Flashcards
What is an opiate?
An alkaloid derived from the poppy - papaver somniferum
What are examples of opiates?
Morphine, codeine, papaverine, thebaine
What is the structure-activity relationship of morphine?
The tertiary form of nitrogen appears to be crucial to he analgesic effect, making nitrogen quaternary appears to decrease the analgesic effect greatly (it can’t pass into the CNS)
- the tertiary nitrogen permits receptor anchoring
- extending the side chain generates antagonists
Changes to the methyl group also decrease analgesic effect, creating antagonists
What is the structure-activity relationship of Codeine and Heroin compared to Morphine
The hydroxyl group at poisiton 3 is required for binding. Unlike Morphine, Codeine and Heroin don’t have these therefore must undergo some metabolism to become activated and reveal it’s hydroxyl group
-> also the hydroxyl group at position 6 increases the lipophilicity of the drug 10 fold when oxidised form but heroin doesn’t have this
What is different in methadone and fentanyl compared to morphine?
Methadone has a tertiary nitrogen and fentanyl has 2
What are routes of administration of opiods?
Oral and IV
List the lipid solubility of the following in order of most soluble to least: Heroin, Morphine, Methadone/Fentanyl. What is the link between lipid solubility and potency?
Methadone/Fentanyl»_space; Heroin > Morphine
More lipid soluble, more potent
How is morphine metabolised in the body
Via morphine-6-glucuronide, u-receptor agonist (potent analgesic activity)
Morphine has a greater affinity for u2 receptors than M6G which is related to adverse effects
What kind of metabolism do better tolerated opiods often undergo?
CYP mediated metabolism
How is codeine metabolised in the body
5-10% of codeine is metabolised into morphine, there are also activating and inactivating enzymes in the liver:
- activation (slow) via CYP-2D6 (O-dealkylation) can have polymorphism so doesn’t respond to codeine
- deactivation via CYP-3A4
What enzymes metabolise most opioids in the liver?
CYP-2D6 and CYP-3A4
Give examples of opioid peptides
endorphins
enkephalins
dynorphins
neoendorphins
What opiate receptor do endorphins act on and what effect do they have?
Mu/Delta receptors in the thalamus, amygdala, nucleus accumbens, PAG
Affecting pain, mood, CVS
What opiate receptor do enkephalins act on and what effect do they have?
Delta in nucleus accumbens, cerebral cortex and amygdala
Affecting pain, mood, CVS
What opiate receptor do dynorphins act on and what effect do they have?
Kappa in hypothalamus
Affecting appetite
What are the three main depressant mechanisms of opiate receptors?
- hyperpolarisation -> increases potassium efflux
- reduce Ca2+ influx -> for NT exocytosis
- reduce AC activity -> for general cell activity
What are effects of opioids?
Analgesia Euphoria Anti-tussive Respiratory depression Stimulation of Chemoreceptor Trigger Zone causing nausea and vomiting Pupillary constriction GI effects
How are the analgesic effects mediated in opioids?
Decreased pain perception
Increased pain tolerance
What is the mechanism of the analgesia effect of opioids?
- Sensory from the periphery into the thalamus via the spinothalamic tract
- Thalamus and extra-cortical and cortical inputs activate PAG (co-ordinates pain)
- PAG activates NRM (nucleus raphe magnus)
- NRM sends inhibitory descending signals to the dorsal horn - NRM increases pain tolerance
- Nucleus Reticularis PAragigantocellularis (NPRG): neg. feedback centre of the brain, independent of the thalamus automatically supresses pain before the brain has a chance to process it
What is the locus coerulus?
a major SNS outflow that is activated during a stress response as during fight/flight you don’t want pain response interfering
How is pain transmission modulated?
Spinal cord: inhibition from the NRM can go directly into decreasing pain transmission in the spinothalamic tract and also projects into the substantia gelatinosa (SG) which can modulate/determine level of inhibition necessary on the sensory neurones from the NRM
What receptors impact the analgesic effect of opioids the most?
Mu receptors
What are the main targets of opioids?
Dorsal horn and periphery - increase inhibition
PAG - inhance firing
NRPG - activates
What is the effect of opioids on GABA and what effect does that have on pain?
Opioids are good at switching off GABA. GABA has an inhibitory effect on many pain tolerance centres so blocking GABA activates the pain tolerance centres
How do opioids cause euphoria?
The opiates bind to Mu receptor and decreases GABA exocytosis leading to inhibition on the VTA so more Dopamine is released
How do opioids supress coughing?
It does this centrally and peripherally:
Centrally:
- 5HT 1A-receptor (neg feedback receptor for serotonin and firing leads to suppression of serotonin and activation of the cough reflex) antagonist so more serotonin so less cough
- medulla direct depression
Peripheral:
- ACh and neurokinin release inhibitor so less transmission down the sensory nerves to the vagus afferents
How do opioids lead to respiratory depression?
- depression of the pre-botzinger complex in the ventrolateral medulla - generating respiratory rhythm so less rhythm with depression
- central chemoreceptors are also inhibited so depress the firing rate of central chemoreceptors
How do opioids lead to nausea and vomiting?
Low dose opioids activate Mu receptors in the Chemoceptor trigger zone and stimulate vomiting. The Mu receptor stimulates disinhibition by swithing off GABA secretion
How do opioids lead to miosis?
Pin prick eyes due to activation of Mu receptors causing a disinhibitory effect by decreasing GABA secretion - stimulate pupil constriction in the Edinger Westphal nucleus
What kind of GI disturbances can opioids cause
- decrease in gastric emptying
- increase in water reabsorption
- decreased GI motility
- constipation
How do opioids cause GI disturbances?
Motor neurones release ACh or substance P to contract SM
Motor neurones release VIP (vasoactive intestinal peptide) or NO to release SM
How do opioids cause urticaria?
Not all opioids cause histamine release - it is the hydroxyl group found on some opioids that cause mast cell degranulation (non IgE mediated) in a PKA mediated reaction
What can you do if a patient shows symptoms of urticaria?
Switch people to a different opioid without OH group to avoid the effect as is due to the hydroxyl group
How can tolerance to opioids build up?
Opioids upregulate levels of arrestin in the tissues, and arrestin promotes receptor internalisation. Over-internalisation of receptors means the tissue becomes less receptive to opioids and so becomes tissue tolerant
What is withdrawal associated with?
Withdrawal is associated with: Psychological craving Physical withdrawal (resembling the flu)
How can dependency to opioids develop?
Opioids normally depress cell activity by reducing AC activity so the body upregulates AC activity and when you remove the opioid the body is overstimulating AC so cell activity is greatly increased for a few weeks after leading to withdrawal
What are features of an opioid overdose?
Coma
Respiratory depression
Pin-point pupils
Hypotension (due to histamine release)
What is the treatment for opioid overdose?
IV naloxone (opioid antagonist) which also has a tertiary nitrogen and so can bind to opioid receptors and has a long side chain of carbons and so has antagonistic properties once bound to the opioid receptors
