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Year 2 - Pharm Lectures 11+ > Opioids > Flashcards

Opioids Flashcards

1
Q

What is an opiate?

A

An alkaloid derived from the poppy

• Papaver Somniferum

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2
Q

Examples of opiates

A

Morphine
Codeine

Papaverine
Thebaine

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3
Q

Explain Morphine using the structure-activity relationship

A

TERTIARY nitrogen form
• crucial to analgesic effect

The tertiary nitrogen permits
• receptor anchoring

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4
Q

How can changing the structure of morphine have an effect?

A

Making it QUATERNARY decreases the analgesic effects (as can NOT pass into the CNS)

Extending the side chain to 3+ C
• = generate an antagonist

Changes to methyl group will decrease analgesic effect
• create antagonist again

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5
Q

Using the structure-activity relationship, explain heroin/codeine

A

BOTH are derivatives of morphine

Codeine
• a PRO-DRUG
• must undergo metabolism = activated = reveal hydroxyl group
• hydroxyl group at 3’ = required for BINDING

Heroin
• hydroxyl group at 6’
• oxidised = INCREASES lipophilicity = more profound effect on brain (than morphine)

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6
Q

Using the structure-activity relationship, explain methadone/fentanyl

A

Similar to morphine
• methadone - tertiary nitrogen
• fentanyl - 2x tertiary nitrogens

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7
Q

Explain the RoA of opioids in terms of pharmacokinetics

A

Oral
IV

Opioids are WEAK BASES
• pKa > 8

SO more readily IONISED in stomach (as pH <8) & blood = POOR absorption

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8
Q

Lipid solubility of morphine and all its derivatives?

A

Methadone/Fentanyl&raquo_space; Heroin > Morphine

More lipid soluble = more potent

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9
Q

How is morphine different to the other metabolites in terms of pharmacokinetics?

A

It is metabolised in the
• liver
&
• regularly excreted in the BILE

Main metabolite is Morphine-6-Glucuronide
• an ACTIVE metabolite which undergoes enterohepatic cycling (so has MORE of an effect)

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10
Q

Explain the metabolism of Morphine in regards to pharmacokinetics

A

Morphine
– Morphine-6-glucuronide (M6G), u-receptor agonist (potent analgesic activity)

Morphine has a GREATER AFFINITY for:
• u2-receptors than M6G which is related to adverse effects

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11
Q

Explain the metabolism of fentanyl & methadone in terms of pharmacokinetics

A

Fentanyl:
• undergoes FAST metabolism
• CYP3A4 enzymes

Methadone:
• undergoes SLOW metabolism
• 6 CYP enzymes

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12
Q

Which type of opioid is tolerated best in terms of metabolism?

A

The opioid that undergoes CYP-mediated metabolism

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13
Q

Explain the metabolism of codeine in terms of pharmacokinetics

A

Codeine –> morphine

Only 5-10% of codeine is metabolised to produce morphine as there are:
• activating (slow) and
• inactivating
enzymes found in the liver:

Activation (slow):
• via CYP-2D6 (O-dealkylation)
• can have a polymorphism so don’t respond to codeine

Deactivation
• via CYP-3A4

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14
Q

What are most opioids in the body metabolised by?

A

Metabolised by:
• CYP-2D6
and
• CYP-3A4

in the liver

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15
Q

How do opioids generally work and what opioids are naturally found in the body?

A

They act via. specific ‘opioid’ receptors

Endogenous opioid peptides include:
• Endorphins
• Enkephalins
• Dynorphins/neoendorphins

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16
Q

What opiate receptors do the endogenous opioid peptides generally bind to?

A

Endorphins
• Mu or Delta
• pain/sensorimotor

Enkephalins
• Delta
• motor/cognitive function

Dynorphins
• Kappa
• neuroendocrine

(onenote!!!)

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17
Q

What is the cellular MoA of opiate receptors?

A

via. DEPRESSANT actions

18
Q

What are the 3 main depressant mechanisms that opiate receptors use?

A

Hyperpolarisation
• increase K+ efflux

Reduce Ca2+ influx
• for NT exocytosis

Reduce AC (adenylate cyclase) activity
 • for general cell activity
19
Q

What are the general opioid effects?

A 
Opioid effects:
o Analgesia
o Euphoria
o Anti-tussive
 - depression of cough centre
o Respiratory depression 
 – very dangerous
o Stimulation of CTZ (Chemoreceptor Trigger Zone)
  – nausea/vomiting
o Pupillary constriction 
o GI effects
20
Q

What are analgesic effects mediated by?

A

DECREASED pain perception

INCREASED pain tolerance

21
Q

Explain the MoA of opiods in terms of their analgesic effect

A
  1. Sensory from the periphery –> thalamus via the spinothalamic tract
  2. Thalamus and extra-cortical and cortical inputs ACTIVATE the PAG (co-ordinates pain)
  3. PAG activates the NRM (Nucleus Raphe Magnus)
  4. NRM sends inhibitory descending signals to the dorsal horn
    – NRM increases pain tolerance

PAG = Periaqueductal Grey Matter

22
Q

Explain the influence of NPRG on the analgesic MoA

A

NPRG (Nucleus Reticularis Paragigantocellularis
):

o The negative-feedback centre of the brain
o Independent of the thalamus
o This automatically supresses pain before the brain has had a chance to process it

23
Q

What effect does the hypothalamus have on the analgesic MoA

A

Constantly signals into:

• PAG, INDEPENDENT of pain sensation

24
Q

What effect does the LC have on the analgesic MoA?

A

LC (Locus Coeruleus)
• major SNS outflow

Activated during a stress response
• during fight/flight, you do NOT want the pain response interfering with fight/flight
• Pain worse after an accident than during! (as SNS no longer inhibiting pain perception)

25
Q

Explain the pharmacodynamics of the modulation of pain transmission in analgesics

A

Spinal cord can modulate pain tolerance

NRM descends the inhibition to the DORSAL HORN:
• some go directly into decreasing pain transmission in the spinothalamic tract
• some project into the SG

SG (Substantia Gelatinosa)
• can modulate/determine level of inhibition necessary on the sensory neurone from the NRM

26
Q

Where might opioids act within the mechanism of analgesic effects?

A

The Mu receptors impact the analgesic effects the MOST - so the main targets for opioids are:

  • Dorsal horn & periphery (increase inhibition)
  • PAG (enhance firing)
  • NRPG (activates)
27
Q

Link between opioids and GABA?

A

Opioids are very good at switching OFF GABA

• GABA has an inhibitory effect on many of the pain tolerance centres

SO blocking GABA = activates the pain tolerance centres

28
Q

How do opioids cause euphoria?

A

Opiates BIND to the Mu receptor
• decreases GABA exocytosis

This reduces the inhibition on the VTA
• = MORE DA is released

29
Q

Anti-tussive?

A

Prevent/relieve a COUGH

30
Q

How do opioids induce anti-tussive effects using phamacodynamics?

A

Opioids cause 3 effects to supress coughing (centrally and peripherally):

 Central:
5HT1A-receptor antagonist:
• 5HT1A-receptor is a -VE feedback receptor for serotonin & firing leads to: suppression of serotonin and activation of the cough reflex
• Inhibition of this receptor INCREASES serotonin so = LESS COUGH

Medulla direct depression
• afferent impulses to cough center in medulla inhibited

 Peripheral:
ACh and NK (Neurokinin) release inhibition so
• LESS transmission down the sensory nerves to the vagus afferents

31
Q

Using pharmacodynamics, explain how opioids cause respiratory depression

A

Depression of the Pre-Botzinger complex in the ventrolateral medulla
• this generates respiratory rhythm so less rhythm with depression

Central chemoreceptors are also inhibited by opioids via. mu-receptors
• so depress the firing rate of the central chemoreceptors

32
Q

Using pharmacodynamics, explain how opioids cause nausea & vomiting

A

Low-dose opioids active Mu receptors in the CTZ (Chemoreceptor Trigger Zone)
• = stimulate vomiting
• the Mu receptor stimulates disinhibition by switching OFF GABA secretion.

33
Q

Opioids switch ON the PNS nerve - where do you think this is expressed in regards to miosis (constriction)?

A

Most ODs exhibit dilated pupils (mydriasis) as the decreased brain function reduces the level of constriction
BUT
opiates cause “pin-prick” eyes

 Activation of the Mu receptors causes a dis-inhibitory effect by decreasing GABA secretion and thus stimulates the pupil constriction in the Edinger-Westphal nucleus

34
Q

Using pharmacodynamics, explain how opioids cause GI disturbances

A

Many opioid receptors (kappa and Mu) are found in the myenteric plexus
• Motor neurones release Ach or substance P to CONTACT SM.
• Motor neurones release VIP (vasoactive intestinal peptide) or NO to RELAX SM

Opioids cause:
• Decrease in gastric emptying = Decreased GI motility
• Increase in water reabsorption = CONSTIPATION (so good at preventing diarrhoea)

35
Q

Urticaria?

A

Local Inflammation

36
Q

Using pharmacodynamics, explain how opioids cause Urticaria

A

Not all opioids cause histamine release
– it is the -OH group found on some opioids that cause mast cell degranulation (non-IgE-mediated i.e. NOT an allergic response)

You can switch people to different opioids if they display this response (one without the OH group).

This reaction is PKA mediated (not receptor-mediated).

37
Q

Explain the Tissue Tolerance to opioids

A

Opioids upregulate levels of ARRESTIN in the tissues.
 Arrestin promotes receptor internalisation

The over-internalisation of receptors means the tissue becomes LESS receptive to opioids
 and so becomes tissue tolerant (i.e. need to take MORE of the drug to have the same response)

38
Q

Explain the withdrawal symptoms associated with opioids use

A

Due to DEPENDENCY

Withdrawal associated with:
o Psychological craving

o Physical withdrawal (resembling the flu):
 Opioids normally DEPRESS cell activity by reducing 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 (shakes, sickness, headaches etc.)

39
Q

Features of an opioid OD?

A

o Coma.
o Respiratory depression.
o Pin-point pupils.
o Hypotension (due to histamine release).

40
Q

Treatment for those that OD on opioids?

A

Treatment – I.V. Naloxone (opioid antagonist)

o Naloxone also has a tertiary nitrogen and so can bind to the opioid receptors.
o Naloxone has a LONG side chain of carbons and so has ANTAGONISTIC properties once bound to the opioid receptors

Year 2 - Pharm Lectures 11+ (23 decks)

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