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Y2 - PHARM > Opiates/Opioids > Flashcards

Opiates/Opioids Flashcards

1
Q

What is an opiate?

A

An alkaloid derived form the poppy, Papaver somniferum

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2
Q

What are the four most commonly occurring opiates?

A
  1. Morphine
  2. Codeine
  3. Papaverine
  4. Thebaine
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3
Q

What is the significance of the tertiary nitrogen in the structure of morphine?

A
  • It is crucial for receptor anchoring and the analgesic effects of opioids
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4
Q

How can the structure of morphine be altered to turn it into an opioid receptor antagonist?

A
  • The side chain that the tertiary nitrogen is on can be extended by 3+ carbons to turn it into an opioid receptor antagonist
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5
Q

What is the importance of the hydroxyl group in position 3 in morphine?

A
  • Required for binding
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6
Q

How is the structure of codeine different to morphine and what does it mean in terms of its activity?

A
  • Codeine is methyl morphine (methyl group instead of hydroxyl group in position 3)
  • This makes it unable to bind the appropriate targets - it is a prodrug therefore as it must be converted into morphine before it can be functionally active
  • For some reason (I don’t get it) it is also more lipophilic than morpheine, however it is converted into morpheine outside of the brain anyway
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7
Q

How is the structure of heroin different to morphine and how does its structure impact its function?

A
  • Heroin is diacetyl morphine - remember acetyl is a methyl on a carbonyl
  • The acetyl groups are at position 3 and 6
  • Because there is an acetyl group at position 3, heroine cannot bind its appropriate target, unlike morphine, it is a prodrug and must be converted into morphine
  • But, since it is a oxidated version of the hydroxyl group on the position 6 on the morpheine, it is much more lipophilic so can enter the brain via the BBB much more easily
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8
Q

Methadone and fentanyl are both …… ….. drugs

A

Methadone and fentanyl are both synthetic opiod drugs

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9
Q

What is a very important feature of methadone and fentanyl?

A
  • They are extremely lipid soluble
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10
Q

Go over, once again the principles of what state drugs will be in based on their pKa and the pH of their environments (this was also covered in an earlier lecture

A
  • If pH < pKa, the drug will largely be in the ionised form - moves less readily across membranes
  • If pH > pKa, the drug will largely be in the unionised form - so can move across membranes more easily
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11
Q

Given that opioids are all WEAK BASES - pKa > 8, if administered orally, in what state are they likely to be in (and thus what does this mean for how readily they are absorbed at):

1) The stomach
2) The small intestine

A

1)

  • The stomach IONISED – relatively little is absorbed as it is polar so cannot cross the phosholipid bi-layer as readily

2)

  • The small intestine UNIONISED – more readily absorbed as it is non-polar so can cross phospholipid bi-layers more readily
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12
Q

In what state will most opioids be in in the blood?

A
  • Blood has a pH of around 7.4 so the majority of opioids will be ionised in the blood - <20% of opioids will be unionised, and this is the component that can access tissues
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13
Q

What route of administration, intravenous or oral, gives a higher bioavailability for methadone and fentanyl, and why?

A
  • Intravenous gives a higher bioavailability because if you have oral administration there is significant first pass metabolism
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14
Q

List morphine, fentanyl, methadone, heroin and codeine in order of decreasing lipid solubility

A
  1. Methadone
  2. Fentanyl
  3. Heroin
  4. Codeine
  5. Morphine
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15
Q

How is the metabolism of morphine different to the metabolism of other opioids?

A
  • Morphine is metabolised in the liver and then excreted in the BILE
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16
Q

What is the main, active metabolite that is produced from the metabolism of morphine?

A
  • Morphine-6-glucuronide
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17
Q

What happens to this metabolite once it is excreted into the small intestine in the bile?

A
  • It undergoes enterohepatic cycling and returns to the blood where it can exert its effects
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18
Q

Describe the rate of metabolism of fentanyl and methadone

A
  • Fentanyl is metabolised rapidly (it can be broken down by cholinesterases in the blood)
  • Methadone is metabolised slowly so remains in the blood for longer
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19
Q

What is a use of methadone and give 2 properties in its metabolism that make it suited to this use?

A
  • It is used to wean people off heroin and morphine
  • Methadone has 2 properties that make it suited to this function: It is very lipophilic and has a slow clearance
  • Therefore it persists in the fatty tissues and persists in the blood for a long time and can exert its effects and reduce cravings
  • It would be bad if it had a fast clearance as you’d need to keep injecting on and on and this is risky
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20
Q

What are the two enzymes that are involved in codeine metabolism? State their relative rates of action

A
  1. CYP2D6 – activates codeine to morphine (O-dealkylation) - SLOW
  2. CYP3A4 – deactivates codeine - FAST
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21
Q

Why might some people feel a greater effect from codeine than others?

A
  • Because the gene that encodes the enzyme CYP2D6 (the enzyme that converts codeine the prodrug into the active morphine) is highly polymorphic
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22
Q

List some endogenous opioid peptides

A
  • Endorphins
  • Enkephalins
  • Dynorphins/Neoendorphins
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23
Q

Which opioid receptors do the following endogenous opiod peptides act on:

1) Endorphins
2) Enkephalins
3) Dynorphins

A

1) Endorphins - Mu or Delta
2) Enkephalins - Delta
3) Dynorphins - Kappa

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24
Q

What are endorphins and enkephalins involved in regulating?

A
  • Pain/Mood/CNS
25
Q

What are dynorphins involved in regulating?

A
  • Appetite (hypothalamus)
26
Q

Where in the brain are high concentrations of mu receptors found?

A
  • Amygdala
  • Nucleus Accumbens
  • Thalamus
  • Periaqueductal Grey matter
27
Q

All opiates are depressants. What are the THREE main mechanisms by which opiates have a depressive effect?

A
  1. Hyperpolarisation (increased K+ efflux)
  2. Reduce Ca2+ influx (affects neurotransmitter exocytosis)
  3. Reduce adenylate cyclase activity (general reduction in cellular activity)
28
Q

What are the 7 main effects of opioids?

A
  • Analgesia
  • Euphoria
  • Depression of cough centre
  • Depression of respiratory centre
  • Nausea/Vomiting
  • Pupillary constriction
  • GI effects
29
Q

Broadly speaking, what are the main methods of analgaesia?

A
  • Increase pain tolerance
  • Decrease pain perception
30
Q

Describe the passage of pain information from the stimulus to the thalamus

A
  • The painful stimulus is detected by a sensory neurone
  • This then synapses with a spinothalamic neurone in the dorsal horn, which then passes the information to the thalamus
31
Q

What happens as the pain information reaches the thalamus?

A
  • The thalamus immediately activates the PAG (central pain coordinating region of the brain)
  • The thalamus also sends the pain information to the cortex, which processes the pain and modulates the firing of PAG
  • The way in which the cortex affects PAG firing is based on previous experiences, memories etc.
32
Q

What does the PAG do once it has received the input from the thalamus?

A
  • The PAG activates the nucleus raphe magnus (NRM)
33
Q

What is the role of NRM (nucleus raphe magnus)?

A
  • It sends descending inhibitory neurones down to the dorsal horn
  • The NRM is responsible for reducing painful sensation (pain tolerance)
34
Q

What does the NRPG do?

A
  • NRPG – nucleus reticularis paragigantocellularis
  • It is independent of the thalamus
  • As soon as you sense pain, the NRPG is activated, which then activates NRM
  • You’re trying to suppress pain even before the brain has had a chance to think about it
35
Q

Describe the role of the hypothalamus in this pain system

A
  • The hypothalamus constantly feeds into the PAG about the general health of the organism
36
Q

Describe the role of the Locus Coeruleus in the pain system and when it is activated

A
  • The locus coeruleus is activated by sympathetic outflow in order to have a negative effect on pain perception by inhibiting the dorsal sensory root of pain transmission up to the thalamic tract
  • So a stress - SNS response will activate LC
  • Reason: at a time of stress, you wouldn’t want a painful stimulus to affect your fight or flight response
37
Q

What structure within the spinal cord acts like a ‘mini brain’ and what role does it play in pain pathways?

A
  • Substantia gellatinosa
  • Some of the descending input from the NRM will be processed by the substantia gellatinosa, which then decides the level of inhibition necessary
38
Q

What are the main targets of opioids within the pain system and what does it do here?

A
  1. Dorsal horn – depression of signalling from periphery to the spinothalamic tract - remember opioids are depressants
  2. PAG – increases PAG firing (which suppressesses pain pathway normally so you’re suppressing it more) - oddly it stimulates these areas, it does this by inhibiting GABA firing (GABA depresses normally) so you’re depressing a depressant
  3. NRPG – increases NRPG firing (which suppresses pain pathway normally so you’re suppressing it more) - oddly it stimulates these areas, it does this by inhibiting GABA firing (GABA depresses normally) so you’re depressing a depressant
39
Q

What is the usual mechanism of action of opioids where it enhances pain suppression in the brain?

A
  • Inhibition of GABA neurones
  • It stimulates these pain suppression areas, it does this by inhibiting GABA firing (GABA depresses normally) so you’re depressing a depressant - disinhibition
40
Q

How do opioids cause euphoria?

A
  • Opioids bind to mu receptors on GABA neurones and switch them off
  • This removes the inhibitory effect of GABA neurones on the dopaminergic neurones projecting from the ventral tegmental area to the nucleus accumbens –> increase in dopamine release at the nucleus accumbens. Disinhibition
41
Q

Describe the coughing pathway and then one endogenous thing that inhibits it and its own negative feedback pathway

A
  • Irritation in the lungs are detected by mechano- and chemoreceptors
  • C-fibres transmit this sensory information to the vagus and afferent impulses to the cough centre (medulla) uses ACh and NK
  • Efferent PSNS / motor nerves — diaphragm, IC and lung — COUGH
  • Note that 5HT (serotonin) inhibits the efferent arm and 5HT1ARs have a negative feedback on this effect to allow the cough pathway progression
42
Q

Describe the central anti-tussive effect of opioids

A
  • The 5HT1A receptor in the Dorsal Raphe Nucleus (DRN) is the negative feedback receptor for serotonin – firing of this receptor leads to suppression of serotonin, which leads to activation of the cough centre. Because serotonin is anti-tussive
  • Opioids desensitise this receptor so serotonin levels rise in the cough centre, which inhibits the motor neurones that connect the cough centre to the larynx
43
Q

Describe the peripheral anti-tussive effect of opioids

A
  • Opioids inhibit the transmission of information from the C-fibre sensory nerves to the cough centre and vagus
44
Q

What are the two main neurotransmitters released by sensory neurones going from the airways to activate the vagus?

A
  • Acetylcholine
  • Neurokinin
45
Q

What is the most opioid sensitive aspect of respiration?

A
  • Rhythm generation
46
Q

Which part of the brain is responsible for rhythm generation?

A
  • Pre-Botzinger complex in the ventrolateral medulla
47
Q

Describe how opioids affect respiration

A
  • Opioids inhibit the pre-Botzinger complex which is involved in rhythm generation of breathing
  • They also depress the firing rate of central chemoreceptors, which normally generate a tonic drive based on PaCO2 in the blood and therefore interferes with the ability of the brain to control respiration
  • So overall it leads to respiratory depression
48
Q

How do opioids cause nausea/vomiting?

A
  • Opioids switch off GABA, which is normally suppressing the chemoreceptor trigger zone
  • This leads to activation of the chemoreceptor trigger zone, which then stimulates vomiting via the medullar vomiting centre
49
Q

Describe the normal pathway with the eye and the light response for miosis

A
  • Light goes in via the optic nerve and one of the places it goes to is the pretectal nucleus
  • Here, fibres go up to the Edinger-Westphal Nucleus with parasympathetic nerves and oculomotor nerve that then go up to the ciliary ganglion and finally terminate at the muscles involved in miosis
50
Q

Why do opioids cause pinpoint pupils?

A
  • The preganglionic parasympathetic nerve to the eye is the oculomotor nerve (CN III)
  • This begins in the Edinger-Westphal nucleus
  • There are lots of GABA neurones with mu opioid receptors within the Edinger-Westphal nucleus
  • The removal of the inhibitory GABA input stimulates firing of the oculomotor nerve – MIOSIS
51
Q

What are the effects of opioids on the GI tract?

A
  • Decrease GI motility and gastric emptying
  • Decreases gut secretions
  • Increase water reabsorption - CONSTIPATION
  • NOTE: this is due to the presence of opioid receptors on myenteric neurones
52
Q

Explain how opioids can cause, what looks like, an allergic response?

A
  • Opioids bind to mast cells in the skin and promote histamine release (skin mast cells appear to be particularly sensitive)
  • The hydroxyl group at position 6 appears to be vital to this
53
Q

What are some symptoms of histamine release?

A
  • Itching (pruritis)
  • Hives (urticarial)
  • Hypotension
54
Q

What does opioid tolerance tend to be due to?

A
  • Receptor internalisation
  • Driven by arrestin proteins
55
Q

Which proteins are important in receptor internalisation?

A
  • Arrestins
56
Q

1) Describe opioid withdrawal symptoms
2) What is thought to be the cause of this powerful withdrawal?

A

1)

  • Psychological craving
  • Physical withdrawal resembling flu - shakes, headaches etc

2)

  • One of the mechanisms of action of opioids is to reduce adenylate cyclase activity
  • With long-term use of opioids, the body attempts to compensate by upregulating adenylate cyclase
  • Stopping opioids will result in increased adenylate cyclase activity in tissues → shakes, headaches, sickness etc
57
Q

What are some features of opioid overdose?

A
  • Coma
  • Respiratory depression
  • Pinpoint pupils
  • Hypotension
58
Q

What is the treatment for opioid overdose? How is the structure of this treatment useful in its function?

A
  • Naloxone (IV)
  • This is an opioid receptor antagonist
  • It has an extended tertiary amine side chain which gives it its antagonistic property
59
Q

Describe how the gut causes gut contraction and secretions in the presence of food boluses

A
  • Sensory neurones connected to chemoreptors and mechanoreceptors detect the presence of food in the gut
  • They send signals via interneurones to the submucosal and myenteric plexus
  • Motor neurones release ACh or substance P to contract smooth muscle cells in the gut or vasoactive intestinal peptide and nitric oxide to relax the smooth muscle

Y2 - PHARM (27 decks)

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