Pharmacology 19 - Opiods Flashcards
What is an opiate?
An alkaloid derived from the poppy Papaver somniferum (natural products)
List common opiates
- Morphine
- Codeine
- Thebaine
- Papaverine
Describe the structure of morphine and how it related to its function
- Tertiary nitrogen (crucial for analgesia, permits receptor anchoring - affinity is dependent on this nitrogen)
- Extension of the side chain to 3+ carbons generates an antagonist
- Hydroxyl group at position 3 is required for binding
- Hydroxyl group at position 6 when oxidised increases lipophilicity 10-fold
- Quarternary carbon centre (less important, not present in fentanyl), aromatic ring, spacer and basic nitrogen group “morphine rule”
Describe absorption of opiods
- Weak bases - ionised in the acidic stomach and poorly absorbed
- Readily absorbed in the SI (as they will be unionised - however, first pass metabolism will decrease bioavailability)
- Most opiods ionised in the blood. 20% unioinised can access tissues, therefore low ability to diffuse across plasma membranes
Compare lipid solubility of various opioids
- Methadone/fentanyl most soluble
- Heroin next (twice as powerful as heroin)
- Morphine least soluble (moderately powerful)
- Codeine is slightly more soluble than morphine, but 10 times less potent
- Generally more lipid soluble = more potent
How do opioids act?
- Act via opioid receptor (mu, delta or kappa)
- Mu generates euphoria and analgesia
List the endogenous opioid agonists
- Endorphins
- Enkephalins
- Dynorphins/ neoendorphins
What are the receptors of endorphins?
Where do they act?
What is their action?
- Mu or delta receptors
- My in the cerebellum, caudate nucleus, nucleus accumbens and PAG
- Pain/sensorimotor (analgesic, euphoria)
What are the receptors of enkephalins?
Where are these receptors found?
What is their action?
- Delta
- Nucleus accumbens, cerebral cortex, hippocampus, putamen
- Motor/cognitive function
What are the receptors of dynorphins?
Where are these receptors found?
What is their action?
- Kappa
- Hypothalamus, putamen and caudate
- Neuroendocrine function
Describe mechanism of action of opioids
Depressant:
- Hyperpolarisation (potassium efflux)
- Calcium influx current is decreased
- Adenylate cyclase activity is decreased (decreasing cAMP)
List the effects of opioids
- Analgesia
- Euphoria
- Depression of couch centre (anti-tussive)
Negative effects:
- Depression of respiration (medulla)
- Stimulation of chemoreceptor trigger zone (nausea/ vomiting)
- Pupillary constriction
- GI effects
How do opioids modulate pain transmission?
- Decrease pain perception and increase pain tolerance. (Affect central pain perception?)
- Depressants - act in the dorsal horn to depress pain perception (mu and kappa receptors)
- Also act in the periaquaductal grey region and in the NRPG by suppressing GABA neurones and removing suppression
How do opioids induce euphoria?
- Binding to mu receptors
- Blocks GABA release at the ventral tegmental area, and therefore increases dopamine release at the nucleus accumbens
- Disinhibition
Descrive normal cough reflex
- Stimulation of mechano/ chemoreceptors (throat respiratory passages or stretch receptors in the lungs)
- Afferent impulses to cough center (medulla)
- Efferent impulses via PNS/ motor nerves to the diaphragm intercostal muscles and lung
- Increased contraction of diaphragmatic, abdominal and intercostal muscles
How do opioids act as anti-tussive agents?
- Interfere with acetylcholine C fibre neurones relaying to vagus nerve from the receptors to cough center
- Block cough centre
- Inhibit 5HT1A receptors which inhibits the efferent impulses
How do opioids cause respiratory depression?
- Interfere with central chemoreceptors, which respond to the concentration of CO2 in the blood
- This is one of the key things that drives breathing via medullary control centre, impairs desire to breathe
- Only happens at overdose
How do opioids cause nausea and vomiting?
- Chemoreceptor trigger zone (samples the blood for noxious stimuli) is controlled by GABA-ergic inhibitory neurones. These neurones have mu opioid receptors, so GABA release is blocked by opiods and chemoreceptors fire.
- This transmitts to medullary vomiting centre causing the vomiting reflex
- Common side effects
How do opioids cause miosis?
- Switch on the parasympahteitc nerve
- Act on mu opioid receptors to switch off GABA release in the Edinger-Westphal nucleus
How do opioids cause gastrointestinal disturbance?
- Cause constipation
- Act on the enteric nervous system to slow everything down
Describe normal innervation of the GI system
- Sensory neurone connected to mucosal chemoreceptors and stretch receptors detect chemical substances in the gut lumen or tension in the gut wall caused by food.
- Information relayed to submucosal and myenteric plexus via interneurons.
- Motor neurones release acetylcholine or substance P to contract smooth muscle or vasoactive intestinal peptide or nitric oxide to relax smooth muscle.
How do opiods cause urticaria?
- Massive histamine release from mast cells under the skin
- Hives-like rash
- Chemically driven by the opiod structure (not receptor mediated)
- Codeine particularly causes this response
Describe tolerance to opioids.
- Largely because of increase in arrestin caused by opioids.
- Opioids therefore cause down regulation of opioid receptors in the cells to try to reduce risk of overdose
List symptoms of opioid withdrawal
- Psychological craving
- Physical withdrawal (resembling flu)
- Caused by cells upregulating activity to compensate for opioid use (upregulation of cAMP) resulting in more active cells when the drugs are no longer taken
List symptoms of opioid overdose
- Coma
- Respiratory depression
- Pin-point pupils
- Hypotension
What is the treatment of opioid overdose?
Naloxone (opioid antagonist) iv.
What is an opioid?
Anything with an opiate-like action (not necessarily a natural product)
Compare heroin to morphine
- Heroin has instead of two hydroxyl groups, two acetyl groups
- Diacetylmorphine
Compare codeine to morphine
- Morphine with a methyl group instead of a hydroxy group
- Methylmorphine
Why are codeine and heroin prodrugs?
- As they have no OH group at position 3
- Therefore, significantly lower affinity than morphine
Why is heroin the most lipid soluble?
As it has oxidised OH group at carbon 6, and therefore can access tissues better than morphine although it does not have as high an affinity for receptors
Describe administration of opioids
Taken orally or intravenously
What are the active metabolites in opioid metabolism?
- Morphine to Morphine 3-glucoronide
- Morphine to morphine 6-G glucoronide
- These metabolites are active in causing euphoria, but not in causing respiratory depression
- Methadone and fentanyl have no active metabolites
- Heroin and codeine have morphine as an active metabolite
Compare clearance of the opioids
- Morphine, heroin, codeine and fentanyl have similar clearance
- Clearance of methadone is really slowly performed, therefore it is active for 24-32 hours
- Therefore, methadone can store up in the adipose tissue (similar to cannabis, slowly released back into the bloodstream)
Describe opioid metabolism
- Most by cytochrome p450 enzymes
- Codeine needs to be converted to morphine to have an effect, using CYP2D6 (O-dealkylation, slowly activates), and is then deactivated by CYP3A4 (rapidly)
- 10% of codeine is converted to morphine (active drug)
- Fentanyl is quickly metabolised, and methadone slowly metabolised
Describe pain pathway (pain perception)
- Pain sensed peripherally. Goes to the dorsal horn of the spinal cord (spinothalamic tract)
- Pain perception - to the thalamus and from thalamus to cortex (thalamus distributes the signal to different parts of the brain)
- Cortex processes that information
Describe pain tolerance pathway
- Cortex and thalamus project to the periaquaductal grey centre (integrating centre determines the level of response). Thalamus immediately activates the PAG. Cortex determines where you need more or less pain tolerance (activation/ inhibitory)
- Nucleus raphe magnus projects down into the periphery (spinal cord) and interferes with the signal at the dorsal horn in an attempt to decrease pain perception
- Pain tolerance is automatically activated by the nucleus reticularis paragigantocellularis (NRPG)
- Hypothalamus samples the current status of health and signals to the PAG to inhibit stimuli when healthy, or enhance stimuli when at a low state of health
- Locus coeruleus (sympathetic arm of the brain, part of the fight and flight response) inhibits pain during fight or flight, not linked to pain cycle
How does the substantia gelatinosa affect pain perception?
- Present in the spinal cord dorsal horn
- Inhibits passage of painful stimuli up the spinothalamic tracts (happens automatically, but much more powerful through the substantia gelatinosa)
- Receives a lot of other peripheral information and modifies the signals
