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Y2 LCRS Pharm Fwong > 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

Morphine
Codeine
Papaverine
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 inmorphine?

A

Required for binding, altering this site would affect affinity of the molecule to receptor

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6
Q

How is the structure of codeine different to morphine?

A

Codeine is methyl morphine (methyl group instead of hydroxyl group in position 3)

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7
Q

How is the structure of heroin different to morphine?

A

Heroin is diacetyl morphine

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8
Q

How does this structural difference affect the properties ofheroin?

A

This means that heroin is much more lipid soluble than morphine so it has much more profound effects on the brain

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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

Given that opioids are all WEAK BASES, in what state are they likely to be in:

a. The stomach
b. The small intestine

A

a. The stomach
IONISED – relatively little is absorbed
b. The small intestine
UNIONISED – more readily absorbed

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11
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 because opioid pKa > 8 which is not close enough - <20% of opioids will be unionised, and this is the component that can access tissues

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12
Q

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

A

Methadone/fentanyl
Heroin
Morphine

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13
Q

Where are the majority of opioids metabolised

A

mostly is metabolised in the liver by CYP enzymes.

MORPHINE is the exception where it is metabolised by uridine 5 diphosphate glucoronosyltransferase.

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14
Q

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

A

Morphine-6-glucuronide

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15
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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16
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 (very slow clearance)

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17
Q

What is a use of methadone that is based on its metabolism?

A

It is used to wean people off heroin and morphine – as methadone remains in the blood for longer, it can reduce cravings

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18
Q

What percentage of codeine gets converted to morphine?

A

5-10%

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19
Q

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

A

CYP2D6 – the metabolism process activates codeine to morphine which is the active metabolite (O-dealkylation) - SLOW metabolism (ie slowly metabolised to form morphine
CYP3A4 – deactivates codeine to norcodeine (inactive metabolite)- FAST metabolism

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20
Q

List some endogenous opioid peptides.

A

Endorphins
Enkephalins
Dynorphins/Neoendorphins

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21
Q

Which opioid receptors do the following act on:

a. Endorphins
b. Enkephalins
c. Dynorphins

A

a. Endorphins Mu or Delta (main action through mu)
b. Enkephalins Delta
c. Dynorphins Kappa

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22
Q

What are endorphins and enkephalins involved in regulating?

A

Endorphins: Pain (act on PAG)/Sensorimotor
enkephalins: motor/ cognitive function

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23
Q

What are dynorphins involved in regulating?

A

neuroendocrine functions eg Appetite (hypothalamus)

24
Q

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

A

Amygdala
Nucleus Accumbens
Thalamus
Periaqueductal Grey matter

25
Q

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

A

Hyperpolarisation (increased K+ efflux)
Reduce Ca2+ influx (affects neurotransmitter exocytosis)
Reduce adenylate cyclase activity (general reduction in cellular activity)

26
Q

What are the main effects of opioids?

A

Analgesia

Euphoria (legally causing euphoria in patients)

Depression of cough centre (anti-tussive)

Depression of respiration (medulla)

Stimulation of chemoreceptor trigger zone (nausea/vomiting)

Pupillary Constriction

G.I. Effects

Urticaria

27
Q

Broadly speaking, what are the main methods of analgesia?

A

Increase pain tolerance

Decrease pain perception

28
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

29
Q

What happens as the pain information reaches the thalamus?

A

The thalamus immediately activates the PAG
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.

30
Q

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

A

The PAG activates the nucleus raphe magnus

31
Q

What is the role of NRM?

A

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

32
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

33
Q

Describe the role of the hypothalamus in this system.

A

The hypothalamus constantly feeds into the PAG about the general health of the organism. Eg poor general health=hypothalamus tells PAG that we dont have enough resource to suppress pain=pain remains and so you are more ‘aware’ of it and stay careful which is good since you have poor general health

34
Q

Describe the role of the Locus Coeruleus in this system.

A

The locus coeruleus is the sympathetic outflow that has a negative effect on pain perception
A stress response will activate LC and cause pain suppression.
Reason: at a time of stress, you wouldn’t want a painful stimulus to affect your fight or flight response

35
Q

What structure within the spinal cord acts like a ‘mini brain’?

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

36
Q

What are the main targets of opioids within this system?

A

main effect: acts on Dorsal horn in spinal cord – enhance the inhibition by acting on the substantia gellatinosa (by decreasing the GABA inhibition to substantia gelatinosa?)
PAG – enhance PAG firing (by depressing GABA inhibition of PAG)
NRPG – activates this by depressing GABA inhibition

also directly inhibits pain perception at the periphery

37
Q

What is the usual mechanism of action of opioids?

A

Inhibition of GABA neurones

38
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

39
Q

Describe the anti-tussive mechanism effect of opioids.

A
  1. Serotonin is anti-cough. The 5HT1A receptor in the Dorsal Raphe Nucleus (DRN) is the negative feedback receptor for serotonin – activation of this receptor leads to suppression of serotonin release, which leads to activation of the cough centre

Opioids block this receptor so serotonin levels rise in the cough centre, which inhibits the motor neurones that connect the cough centre to the larynx.

  1. Opioids also work by reducing the sensory AFFERENT signalling (C fibres that release Neurokinin/ACh) of the cough reflex between the airway and the medulla. This also leads to less coughing
40
Q

What are the two main neurotransmitters released by sensory neurones going from the airways that then relay to the vagal sensory nerves? (I think this is how it works)

A

Acetylcholine

Neurokinin

41
Q

Describe the peripheral anti-tussive effect of opioids.

A

Opioids stop the transmission of information from the sensory nerves to the vagus

42
Q

What is the most opioid sensitive aspect of respiration?

A

Rhythm generation

43
Q

Which part of the brain is responsible for rhythm generation?

A

Pre-Botzinger complex in the ventrolateral medulla

44
Q

Describe how opioids affect respiration.

A

Opioids inhibit the pre-Botzinger complex
They also depress the firing rate of central chemoreceptors, which normally taste the blood and provide a stimulus to breathe

45
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

46
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

Most overdoses cause blown pupil but opioid is an exception.

47
Q

What are the effects of opioids on the GI tract?

A

Decrease gastric emptying
Decrease GI motility
=CONSTIPATION
NOTE: this is due to the presence of opioid receptors on myenteric neurones

48
Q

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

What structural element of the opioid makes them likely to cause this?

What mechanism ?

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

Opioids with OH at position 6 tend to activate Mast cells and release histamine through a PKA mediated mechanism, NOT via opioid receptors etc

49
Q

What are some symptoms of histamine release?

A

Itching (pruritus)
Hives (urticarial) - this is like red itchy skin - search up pic
Hypotension

50
Q

What does opioid tolerance tend to be due to?

A

Receptor internalisation- long term opioid use causes downregulation of opioid receptors on the target tissue (mediated by increased arrestin proteins), leading to tolerance

51
Q

Which proteins are important in receptor internalisation?

A

Arrestins

52
Q

Describe opioid withdrawal.

A

Psychological craving

Physical withdrawal resembling flu

53
Q

What is thought to be the cause of this powerful withdrawal?

A

Chronic opioid users tend to have upregulated cAMP/adenylate cyclase. This is thought to be an adaptation to long-term opioid depression. When they come off opioids, they are left with unopposed upregulated cAMP. So you get this nerve hyperactivity and symptoms like diarrhea because the gut is hyperactive

54
Q

What are some features of opioid overdose?

A

Coma
Respiratory depression
Pinpoint pupils
Hypotension

55
Q

What is the treatment for opioid overdose? What structural features make this a good for its purpose?

A

Naloxone (IV)
This is an opioid receptor antagonist
Naloxone is pretty much same as morphine but with extended alkyl group- long alkyl groups attached to the N = antagonistic effects

Y2 LCRS Pharm Fwong (40 decks)

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