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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
Explain the pharmacodynamics of the modulation of pain transmission in analgesics
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
Where might opioids act within the mechanism of analgesic effects?
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
Link between opioids and GABA?
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
How do opioids cause euphoria?
Opiates BIND to the Mu receptor • decreases GABA exocytosis This reduces the inhibition on the VTA • = MORE DA is released
29
Anti-tussive?
Prevent/relieve a COUGH
30
How do opioids induce anti-tussive effects using phamacodynamics?
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
Using pharmacodynamics, explain how opioids cause respiratory depression
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
Using pharmacodynamics, explain how opioids cause nausea & vomiting
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
Opioids switch ON the PNS nerve - where do you think this is expressed in regards to miosis (constriction)?
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
Using pharmacodynamics, explain how opioids cause GI disturbances
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
Urticaria?
Local Inflammation
36
Using pharmacodynamics, explain how opioids cause Urticaria
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
Explain the Tissue Tolerance to opioids
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
Explain the withdrawal symptoms associated with opioids use
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
Features of an opioid OD?
o Coma. o Respiratory depression. o Pin-point pupils. o Hypotension (due to histamine release).
40
Treatment for those that OD on opioids?
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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