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pharm - OBG > 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
(making it quaternary decreases the analgesic effect)

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4
Q

How can the structure of morphine be altered to turn it into anopioid 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 - ie make it a quaternary nitrogen

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5
Q

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

A

Required for binding (methylation of this group seems to reduce potency)

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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 (both OH positions (3 and 6) are oxidised (to carboxylic acid)

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8
Q

How does this structural difference affect the properties of heroin?

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

are opioids weak acids or weak bases

A

their pKa is >8 so they are weak bases and are therefore:

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 - <20% of opioids will be unionised, and this is thecomponent 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

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

A

Opiates are largely metabolised by the hepatic CYP450 system – mainly CYP3A4 and CYP2D6

Morphine is an exception – this is metabolised by uridine-5-diphosphate glucuronysyltransferase (UGT)

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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

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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 – activates codeine to morphine (O-dealkylation) - SLOW

CYP3A4 – deactivates codeine - FAST

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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
b. Enkephalins: Delta
c. Dynorphins: Kappa

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22
Q

What are endorphins and enkephalins involved in regulating?

A

Pain/Mood/CNS

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23
Q

What are dynorphins involved in regulating?

A

Appetite (hypothalamus)

24
Q

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

A

Amygdala
Nucleus Accumbens
Thalamus
Periaqueductal Grey matter (PAG)

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

Depression of cough centre and respiratory centre

Nausea/Vomiting

Pupillary constriction

GI effects

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 (decussates) 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 (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.

30
Q

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

A

The PAG activates the nucleus raphe magnus (NRM)

31
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)

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

34
Q

Describe the role of the Locus Coeruleus in this system.

A

The locus coeruleus is the sympathetic outflow that has a negative (inhibitory) effect on pain perception

A stress response will activate LC
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

Dorsal horn – increase inhibition

PAG – enhance PAG firing

NRPG – activates this

37
Q

What is the usual mechanism of action of opioids?

A

Inhibition of GABA neurones= increased firing of 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 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
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

40
Q

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

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

OPIOIDS DIRECTLY SUPPRESS COUGH CENTRE

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 interferes with the ability of the brain to control respiration

45
Q

How do opioids cause nausea/vomiting?

A

Opioids switch off GABA, which is normally suppressing the chemoreceptor trigger zone (Mu receptor mediated)

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 (constriction)

47
Q

What are the effects of opioids on the GI tract?

A 
Decrease gastric emptying  
Decrease GI motility 
Increase water reabsorption 
CONSTIPATION  
NOTE: this is due to the presence of opioid receptors (kappa and Mu) on myenteric neurones
48
Q

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

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

49
Q

What are some symptoms of histamine release?

A

Itching (pruritis)
Hives (urticarial)
Hypotension

50
Q

What does opioid tolerance tend to be due to?

A

Receptor internalisation (via upregulated levels of arrestin)

51
Q

Which proteins are important in receptor internalisation?

A

Arrestins

52
Q

Describe opioid withdrawal.

A

Psychological craving
Physical withdrawal resembling flu:

-Opioids normally depress cell activity by reducing adenylate cyclase (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

53
Q

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

A

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 –> ^NA released–>shakes, headaches, sickness etc.

54
Q

What are some features of opioid overdose?

A

Coma
Respiratory depression
Pinpoint pupils
Hypotension-(due to histamine release)

55
Q

What is the treatment for opioid overdose?

A

Naloxone (IV)

This is an opioid receptor antagonist

pharm - OBG (25 decks)

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