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Stage 3 - Case 1 (Pain) > Lecture 12 & 13: Opioid addiction: Case Study & Chemistry > Flashcards

Lecture 12 & 13: Opioid addiction: Case Study & Chemistry Flashcards

1
Q

What is the definition of an opioid addiction?

A
  • A cluster of physiological, behavioural and cognitive phenomena, when use of an opioid has higher priority than other behaviours
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2
Q

What is the difference between opioid and opiate?

A
  • Opioid: Umbrella term. Either natural or man made. Binds to opioid receptors in the brain. Can be agonist, partial agonist or antagonist
  • Opiate: Naturally ocurring derived from natural source only (morphine, codeine, heroin)
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3
Q

How many days limited use should OTC opioids have?

A
  • Codeine should be limited to no more than 3 day use
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4
Q

What are some patient risk factors with prescription opioids that can indicate opioid dependence?

A
  • Depression, anxiety
  • Previous history of alcohol/ substance misuse
  • Previous history of opioid misuse
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5
Q

What are some drug risk factors with prescription opioids that can indicate opioid dependence?

A
  • High doses
  • Multiple opioids
  • Multiple formulations of opioids
  • More potenjt opioids
  • Concurrent benzodiazepines
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6
Q

What are 5 practical steps to reduce high dose opioids?

A
  • Education
  • Engagement: Give patient choice
  • Effective weaning plan: need agreement
  • Emotional impact: Manage anxiety and depression (offer antidepressant if nec/ signpost)
  • Expectations: Is difficult and may need support
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7
Q

What are the potencies of codeine, dihydrocodeine, oxycodone and tramadol comapred to morphine?

A
  • Codeine: 100mg of codeine = 10mg of morphine (0.1)
  • Dihydrocodeine = 0.1
  • Oxycodone = 6.6mg = 10 mg of Morp (1.5)
  • Tramadol = 0.1
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8
Q

What are some other risk factors for opioid dependence?

A
  • Long term prescribing for non camcer conditions
  • Emotional trauma, reports of concern
  • Refusal for other treatment, not attend appointments
  • Repeated seeking of med
  • Taking doses more than prescribed. Alcohol misuse
  • Appearing sedated
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9
Q

What are some tapering or withdrawal tips?

A
  • Consider other non-pharmacological options for pain management
  • Encourage and prepare
  • Incremental taper of existing drug
  • Consider conversion to methadone or buprenorphine
  • Consider drug/alcohol services
  • Dose of drug can be tapered 10% weekly or 2 weeks
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10
Q

What are some opioid withdrawal signs?

A
  • Shivers
  • Diarrhoea
  • Difficulty sleeping
  • Sweating
  • Widespread or increased pain
  • Body aches
  • Irritability
  • N & V
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11
Q

What should happen when the patient is on opioid substitution therapy and they have acute pain?

A
  • Ongoing reassurance
  • OST doesnt provide analgesia, only manages withdrawal
  • Opioids for analgesia need to be prescribed in addition to maintenance regimen
  • Likely to tolerate effects so larger doses are required
  • Should be prescribed more on top - careful of CNS depression
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12
Q

What should happen if the patient is on methadone and have acute pain?

A
  • Split the dose and adminster 2 or 3 times daily
  • Titrate additional analgesia to effect
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13
Q

What should happen if the patient is on buprenorphine (administered sublingually) and have acute pain?

A
  • Split the dose and administer 2 or 3 times daily
  • Titrate additional analgesia or discontinue and provide alternative analgesia or change to methadone
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14
Q

Which opioid is compared to in opioid tolerance?

A
  • Morphine
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15
Q

How does supervised methandone work in practice?

A
  • Only methadone mixture should be used
  • Observe patient
  • Be aware of avoidance tactics
  • Offer water
  • Designated area for supervision
  • Identity confirmed
  • Usually 3 months minimum
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16
Q

What are the risks of long term opioid use?

A
  • Serious bodily harm, overdose or death
  • Hormone changes (infertility)
  • Drowsiness
  • Increased risk of physical dependence
  • Decreased immune function
  • Poor muscle tone
  • Increased risk of falls
  • Depression & anxiety
  • Dry mouth
17
Q

What are the features of the blood brain barrier?

A

BBB is a specialized structure that protects the brain and allows essential nutrients to pass.
* Endothelial Cell Tight Junctions: Line the brain’s blood vessels are tightly packed, preventing substances from passing.
* Selective Permeability: Only certain molecules to cross, such as glucose and amino acids, while blocking others (toxins and pathogens).
* Transport Mechanisms: Specific transporters for essential nutrients (e.g., glucose transporter) and efflux pumps (e.g., P-glycoprotein) to remove potentially harmful substances.
* Astrocytic End-Feet: Have extensions that envelop the blood vessels, providing support and signaling.
* Basement Membrane: Extracellular matrix layer provides structural support and permeability.

18
Q

What are the main mechanisms for BBB penetration?

A
  • **Passive Diffusion: **Small, lipophilic molecules (gases) can diffuse across.
    * Facilitated Diffusion: Some larger or polar molecules, like glucose and AA, use specific transporter proteins
  • Active Transport: Sodium-glucose transporter actively transports glucose into the brain.
  • Receptor-Mediated Transcytosis: Specific molecules can bind to receptors on the surface of endothelial cells, triggers endocytosis. insulin and certain growth factors
    * Paracellular Transport: Inflammation, the tight junctions between endothelial cells can become more permeable, allowing some substances to pass through.
19
Q

What are the molecular attributes for CNS penetration?

A
  • Higher Log P: lipophilicity
  • Fewer H-bond donors
  • Fewer rotatable bonds (more rigid)
  • Most CNS drugs contain an amine
20
Q

What are some analogues to morphine?

A
  • Oxycodone
  • Dihydrocodeine
  • Diamorphine
  • Hydrocodone
  • Codeine
21
Q

What is in the structure of morphine and what are their main effects on opioid receptors?

A
  • 5 rings
  • Tertiary amino group
  • Activity: mu (analgesia), kappa (analgesia/sedation), delta (analgesia favoured by enkephalins)
22
Q

What is the structure activity relationship of morphine to the receptor?

A
  • Amine nitrogen: Protonated, charged and forms ionic bond. Negatively charged receptor and positive charge on amine
  • Phenol: H bonded to receptor
  • Aromatic ring: Van der waals interaction, defined interaction (pie-pie)
  • Change substituents to get different analgesic activity
23
Q

What are some physico chemical properties of morphine (both physical and chemical)

A
  • Morphine and hydrate are sparingly soluble in water
  • Morphine is a weak base it can produce salts with strong acids (HCL, H2SO4) produces hydrochloride and sulfate salts
  • Salts are 300x more soluble
24
Q

How is diamorphine synthesized from morphine?

A
  • Treated with acetic anhydride or acetyl chloride. Adds 2 acetyl (ester) groups
25
Q

How is codeine synthesized from morphine?

A
  • Normally MeI is a good electrophile and tertiary amine is a good nucleophile so SN2 reaction favoured -> get methiodide salt of morphine
  • However, to avoid reaction you make a salt -> better nucleophile than amine. Cause phenol is a weak acid you treat with KOH to make salt
  • Then use MeI on this to selectively make codeine
26
Q

How much more BBB penetration does codeine and heroin have compared to morphine?

A
  • Codeine - 10 x BBB
  • Heroin - 100 x BBB
27
Q

How much of the morphine is converted into each isomer and what were they?

A
  • Approx 60% of dose is converted to 3 - glucuronide w/ 10% to morphine 6 - glucuronide
  • 6 isomer is 2x more potent
28
Q

Why are things that cross the BBB basic (have amine)

A
  • Amines have a pKa of 8 +
  • In any psychological pH they are charged threfore increase conc of charged species
  • Will have equilibrium will have low conc of unionised that will go across the membrane. The ionised will keep making unionised to balance equilibrium
29
Q

What is the reaction to get from codeine (inactive prodrug) to morphine (active) and norcodeine

A
  • O-Demethylation/Dealkylation using CYP450 enzymes
  • N-Demethylation/Dealkylation using CYP450
30
Q

What does adding extra functional groups to probe for extra binding regions do to the activity?

A
  • Small chain length (allyl, cyclopropylmethyl) - Agonism decreases and antagonism increases
  • Bu - 0 activity
  • Pentyl, Hexyl - Agonists
  • CH2CH2Ph - 14x activity of morphine
31
Q

What happens to the activity when you remove Ring E - the one with the tertialry amine?

A
  • Complete loss of activity
  • The protonated amine is important for binding to receptor
32
Q

What happens to activity when you remove ring D - with oxygen on?

A
  • Oxygen not essential for analgesic activity
  • Produce morphinians - more potent and longer acting due to higher log P
  • Higher toxicity and binds to same receptor as morphine
  • Phenol group isnt essntial for activity but aromatic ring and amine are
33
Q

What happens to activity when you remove rings C and D?

A
  • Produce benzomorphans and retain analgesic activity
  • Produce phenazocine -> long term analgesic with low dependence (more potent)
34
Q

What happens to activity when you remove rings B C and D?

A
  • Produce 4-phenylpiperidines
  • 6x activity throughintroduction of the phenolic group
  • Not essential for analgesic activity
  • Pethidine weaker analgesic -> rapid onset and shorter duration. Can cause side effects (addiction & resp centre depression)
  • Fentanyl - very lipophilic, high Log P
35
Q

How are Phenylpiperidines metabolised (removal of ring B, C and D)?

A
  • Oxidative dealkylation using CYP450 to split and produce 2 products. Norfentanyl and spontaneously rearranges to produce aldehyde
  • Then hydroxylation of norfentanyl in acid and excreted and oxidation of aldehyde - COOH
36
Q

What happens to activity when you remove rings B,C, D and E?

A
  • Methadone - comparable activity to Morphine
  • Orally active, less severe emetic and constipation effects
  • Single chiral centre
  • Has an amine that is protonated at physiological pH - loops itself around to produce intra H-bond (achieves shape)
37
Q

What are the different phase 1 and 2 metabolism reactions that methadone undergoes?

A
  • Phase 1: N-Dealkylation (more common), Reduction
  • Phase 2: Glucuronidation and Sulfation
38
Q

Why does adding a small change make a dramatic effect to activity?

A
  • There are 2 accessory hydrophobic regions in the analgesic receptor - structure will act as an agonist or antagonist depending on which binding region is used
  • Methyl group of morphine not long enough and cant reach extra hydrophobic regions
  • Aromatic ring pushed beyond antagonist hydrophobic binding region - correct distance to bind against the binding region - enhanced activity
  • Allyl groups bind well to antagonist region and weak interaction to agonist region (antagonist w/ weak agonist properties)

Stage 3 - Case 1 (Pain) (13 decks)

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