Opioids Flashcards
What is an opiate?
An alkaloid derived from the poppy
• Papaver Somniferum
Examples of opiates
Morphine
Codeine
Papaverine
Thebaine
Explain Morphine using the structure-activity relationship
TERTIARY nitrogen form
• crucial to analgesic effect
The tertiary nitrogen permits
• receptor anchoring
How can changing the structure of morphine have an effect?
Making it QUATERNARY decreases the analgesic effects (as can NOT pass into the CNS)
Extending the side chain to 3+ C
• = generate an antagonist
Changes to methyl group will decrease analgesic effect
• create antagonist again
Using the structure-activity relationship, explain heroin/codeine
BOTH are derivatives of morphine
Codeine
• a PRO-DRUG
• must undergo metabolism = activated = reveal hydroxyl group
• hydroxyl group at 3’ = required for BINDING
Heroin
• hydroxyl group at 6’
• oxidised = INCREASES lipophilicity = more profound effect on brain (than morphine)
Using the structure-activity relationship, explain methadone/fentanyl
Similar to morphine
• methadone - tertiary nitrogen
• fentanyl - 2x tertiary nitrogens
Explain the RoA of opioids in terms of pharmacokinetics
Oral
IV
Opioids are WEAK BASES
• pKa > 8
SO more readily IONISED in stomach (as pH <8) & blood = POOR absorption
Lipid solubility of morphine and all its derivatives?
Methadone/Fentanyl»_space; Heroin > Morphine
More lipid soluble = more potent
How is morphine different to the other metabolites in terms of pharmacokinetics?
It is metabolised in the
• liver
&
• regularly excreted in the BILE
Main metabolite is Morphine-6-Glucuronide
• an ACTIVE metabolite which undergoes enterohepatic cycling (so has MORE of an effect)
Explain the metabolism of Morphine in regards to pharmacokinetics
Morphine
– Morphine-6-glucuronide (M6G), u-receptor agonist (potent analgesic activity)
Morphine has a GREATER AFFINITY for:
• u2-receptors than M6G which is related to adverse effects
Explain the metabolism of fentanyl & methadone in terms of pharmacokinetics
Fentanyl:
• undergoes FAST metabolism
• CYP3A4 enzymes
Methadone:
• undergoes SLOW metabolism
• 6 CYP enzymes
Which type of opioid is tolerated best in terms of metabolism?
The opioid that undergoes CYP-mediated metabolism
Explain the metabolism of codeine in terms of pharmacokinetics
Codeine –> morphine
Only 5-10% of codeine is metabolised to produce morphine as there are:
• activating (slow) and
• inactivating
enzymes found in the liver:
Activation (slow):
• via CYP-2D6 (O-dealkylation)
• can have a polymorphism so don’t respond to codeine
Deactivation
• via CYP-3A4
What are most opioids in the body metabolised by?
Metabolised by:
• CYP-2D6
and
• CYP-3A4
in the liver
How do opioids generally work and what opioids are naturally found in the body?
They act via. specific ‘opioid’ receptors
Endogenous opioid peptides include:
• Endorphins
• Enkephalins
• Dynorphins/neoendorphins
What opiate receptors do the endogenous opioid peptides generally bind to?
Endorphins
• Mu or Delta
• pain/sensorimotor
Enkephalins
• Delta
• motor/cognitive function
Dynorphins
• Kappa
• neuroendocrine
(onenote!!!)
What is the cellular MoA of opiate receptors?
via. DEPRESSANT actions
What are the 3 main depressant mechanisms that opiate receptors use?
Hyperpolarisation
• increase K+ efflux
Reduce Ca2+ influx
• for NT exocytosis
Reduce AC (adenylate cyclase) activity • for general cell activity
What are the general opioid effects?
Opioid effects: o Analgesia o Euphoria o Anti-tussive - depression of cough centre o Respiratory depression – very dangerous o Stimulation of CTZ (Chemoreceptor Trigger Zone) – nausea/vomiting o Pupillary constriction o GI effects
What are analgesic effects mediated by?
DECREASED pain perception
INCREASED pain tolerance
Explain the MoA of opiods in terms of their analgesic effect
- Sensory from the periphery –> thalamus via the spinothalamic tract
- Thalamus and extra-cortical and cortical inputs ACTIVATE the PAG (co-ordinates pain)
- PAG activates the NRM (Nucleus Raphe Magnus)
- NRM sends inhibitory descending signals to the dorsal horn
– NRM increases pain tolerance
PAG = Periaqueductal Grey Matter
Explain the influence of NPRG on the analgesic MoA
NPRG (Nucleus Reticularis Paragigantocellularis
):
o The negative-feedback centre of the brain
o Independent of the thalamus
o This automatically supresses pain before the brain has had a chance to process it
What effect does the hypothalamus have on the analgesic MoA
Constantly signals into:
• PAG, INDEPENDENT of pain sensation
What effect does the LC have on the analgesic MoA?
LC (Locus Coeruleus)
• major SNS outflow
Activated during a stress response
• during fight/flight, you do NOT want the pain response interfering with fight/flight
• Pain worse after an accident than during! (as SNS no longer inhibiting pain perception)
Explain the pharmacodynamics of the modulation of pain transmission in analgesics
Spinal cord can modulate pain tolerance
NRM descends the inhibition to the DORSAL HORN:
• some go directly into decreasing pain transmission in the spinothalamic tract
• some project into the SG
SG (Substantia Gelatinosa)
• can modulate/determine level of inhibition necessary on the sensory neurone from the NRM
Where might opioids act within the mechanism of analgesic effects?
The Mu receptors impact the analgesic effects the MOST - so the main targets for opioids are:
- Dorsal horn & periphery (increase inhibition)
- PAG (enhance firing)
- NRPG (activates)
Link between opioids and GABA?
Opioids are very good at switching OFF GABA
• GABA has an inhibitory effect on many of the pain tolerance centres
SO blocking GABA = activates the pain tolerance centres
How do opioids cause euphoria?
Opiates BIND to the Mu receptor
• decreases GABA exocytosis
This reduces the inhibition on the VTA
• = MORE DA is released
Anti-tussive?
Prevent/relieve a COUGH
How do opioids induce anti-tussive effects using phamacodynamics?
Opioids cause 3 effects to supress coughing (centrally and peripherally):
Central:
5HT1A-receptor antagonist:
• 5HT1A-receptor is a -VE feedback receptor for serotonin & firing leads to: suppression of serotonin and activation of the cough reflex
• Inhibition of this receptor INCREASES serotonin so = LESS COUGH
Medulla direct depression
• afferent impulses to cough center in medulla inhibited
Peripheral:
ACh and NK (Neurokinin) release inhibition so
• LESS transmission down the sensory nerves to the vagus afferents
Using pharmacodynamics, explain how opioids cause respiratory depression
Depression of the Pre-Botzinger complex in the ventrolateral medulla
• this generates respiratory rhythm so less rhythm with depression
Central chemoreceptors are also inhibited by opioids via. mu-receptors
• so depress the firing rate of the central chemoreceptors
Using pharmacodynamics, explain how opioids cause nausea & vomiting
Low-dose opioids active Mu receptors in the CTZ (Chemoreceptor Trigger Zone)
• = stimulate vomiting
• the Mu receptor stimulates disinhibition by switching OFF GABA secretion.
Opioids switch ON the PNS nerve - where do you think this is expressed in regards to miosis (constriction)?
Most ODs exhibit dilated pupils (mydriasis) as the decreased brain function reduces the level of constriction
BUT
opiates cause “pin-prick” eyes
Activation of the Mu receptors causes a dis-inhibitory effect by decreasing GABA secretion and thus stimulates the pupil constriction in the Edinger-Westphal nucleus
Using pharmacodynamics, explain how opioids cause GI disturbances
Many opioid receptors (kappa and Mu) are found in the myenteric plexus
• Motor neurones release Ach or substance P to CONTACT SM.
• Motor neurones release VIP (vasoactive intestinal peptide) or NO to RELAX SM
Opioids cause:
• Decrease in gastric emptying = Decreased GI motility
• Increase in water reabsorption = CONSTIPATION (so good at preventing diarrhoea)
Urticaria?
Local Inflammation
Using pharmacodynamics, explain how opioids cause Urticaria
Not all opioids cause histamine release
– it is the -OH group found on some opioids that cause mast cell degranulation (non-IgE-mediated i.e. NOT an allergic response)
You can switch people to different opioids if they display this response (one without the OH group).
This reaction is PKA mediated (not receptor-mediated).
Explain the Tissue Tolerance to opioids
Opioids upregulate levels of ARRESTIN in the tissues.
Arrestin promotes receptor internalisation
The over-internalisation of receptors means the tissue becomes LESS receptive to opioids
and so becomes tissue tolerant (i.e. need to take MORE of the drug to have the same response)
Explain the withdrawal symptoms associated with opioids use
Due to DEPENDENCY
Withdrawal associated with:
o Psychological craving
o Physical withdrawal (resembling the flu):
Opioids normally DEPRESS cell activity by reducing AC activity and so the body responds by upregulating AC activity
When you remove the opioid drug, the body is overstimulating AC and so general cell activity is greatly increased for a few weeks after –> withdrawal (shakes, sickness, headaches etc.)
Features of an opioid OD?
o Coma.
o Respiratory depression.
o Pin-point pupils.
o Hypotension (due to histamine release).
Treatment for those that OD on opioids?
Treatment – I.V. Naloxone (opioid antagonist)
o Naloxone also has a tertiary nitrogen and so can bind to the opioid receptors.
o Naloxone has a LONG side chain of carbons and so has ANTAGONISTIC properties once bound to the opioid receptors
