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YR2 LCRS 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 4 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

Crucial for receptor anchoring + 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 on the tertiary nitrogen 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 i.e. codeine is a prodrug

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6
Q

How is the structure of codeine different to morphine?

A

Codeine is methyl morphine (methyl group instead of OH 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 of heroin?

A

Heroin is much more lipid soluble than morphine so has much more profound effects on the brain as it can access tissues more easily

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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

Stomach: IONISED, so little is absorbed

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 pH ~ 7.4: so majority will be ionised in blood

<20% will be unionised + 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. What is the general rule of thumb about solubility?

A 
Fentanyl 
Methadone
Heroin 
Morphine
The more lipid soluble, the more potent
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13
Q

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

A

Morphine is metabolised in the liver + then excreted in BILE

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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 Morphine-6-glucuronide once it is excreted into the small intestine in the bile?

A

It undergoes enterohepatic cycling + 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 (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

Used to wean people off heroin + 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 3 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

Endorphins: Mu or Delta
Enkephalins: Delta
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

Neuroendocrine effects

24
Q

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

A

Cerebellum
Nucleus Accumbens
Caudate nucleus
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, harder to depolarise)
Reduce Ca2+ influx (affects neurotransmitter exocytosis)
Reduce adenylate cyclase activity (general reduction in cellular activity)

26
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
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

Painful stimulus is detected by a sensory neurone

This synapses with a spinothalamic neurone in the dorsal horn, which then passes the info. to the thalamus

29
Q

What happens as the pain information reaches the thalamus?

A

Thalamus immediately activates the PAG (pain integrating centre of the brain)
Also sends pain info. to the cortex, which processes the pain + 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

PAG activates the nucleus raphe magnus (NRM)

31
Q

What is the role of NRM?

A

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
Independent of the thalamus, automatically activates pain tolerance
As soon as you sense pain, NRPG is activated, which then activates NRM
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 the modulation of pain transduction. When would pain be exacerbated?

A

Hypothalamus constantly feeds into PAG about the general health of the organism
Painful stimuli exacerbated in poor health, to prevent overexertion when already sub-par

34
Q

Describe the role of the Locus Coeruleus in this system.

A

Locus coeruleus is the sympathetic outflow that has a negative effect on pain perception
A stress response activates LC
Reason: at time of stress, don’t want 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 the system of pain transduction?

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
GABA neurones would normally suppress NRPG + PAG, so Opioids work via dis-inhibition, cause PAG + NRPG to fire at a higher rate

38
Q

How do opioids cause euphoria?

A

Opioids bind to mu receptors on GABA neurones + switch them off
Removes inhibitory effect of GABA neurones on the dopaminergic neurones projecting from the ventral tegmental area to the nucleus accumbens
Leads to increase in dopamine release at the nucleus accumbens

39
Q

Describe the cough response

A

Stimulation of mechano-/chemoreceptors in airways
Afferent impulses to cough centre in medulla via vagus nerve
5HT1A receptors allow passing info to effector arm
Efferent impulses via parasympathetic + motor nerves to diaphragm cause contraction to elicit cough

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 central and peripheral anti-tussive effect of opioids.

A

Reduce 5HT1A receptor function in dorsal raphe nucleus, increases 5HT levels, depressing impulses from inspiratory motor neurones
Stop transmission of info. 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
Also depress 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
Leads to activation of CTZ, which then stimulates vomiting via the medullary vomiting centre

46
Q

Why do opioids cause pinpoint pupils?

A

Preganglionic parasympathetic nerve to the eye is the oculomotor nerve (CN III)
This begins in the Edinger-Westphal nucleus
There are many GABA neurones with mu opioid receptors within the EW nucleus
Removal of the inhibitory GABA input stimulates firing of the oculomotor nerve= MIOSIS

47
Q

What are the 4 effects of opioids on the GI tract?

A 
Decrease gastric emptying  
Decrease GI motility 
Increase water reabsorption 
CONSTIPATION  
(due to presence of opioid receptors on myenteric neurones)
48
Q

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

A

Opioids bind to mast cells in skin + promote histamine release
Hydroxyl group at position 6 appears to be vital to this

49
Q

What are 3 symptoms of histamine release?

A

Itching (pruritis)
Hives (urticarial)
Hypotension

50
Q

What does opioid tolerance tend to be due to?

A

Receptor internalisation

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 the powerful opioid withdrawal?

A

A MOA 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 causing shakes, headaches, sickness etc.

54
Q

What are 4 features of opioid overdose?

A

Coma
Respiratory depression
Pinpoint pupils
Hypotension

55
Q

What is the treatment for opioid overdose?

A

Naloxone (IV)

An opioid receptor antagonist

56
Q

What structural elements are important for opioid activity?

A

Tertiary nitrogen
Aromatic ring
Hydroxyl group at position 3

57
Q

What is the active metabolite of both codeine and heroin?

A

Morphine

YR2 LCRS Pharm (34 decks)

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