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Drug Action III > Opioids (MC) - Block 2 > Flashcards

Opioids (MC) - Block 2 Flashcards

1
Q

Describe the lipophilicity of bain drugs?

A

Normally, lipophillic -> longer DOA, howevere, brain drugs will distribute in the brain first

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2
Q

How happens if a drug has an active metabolite with longer DOA?

A

Accumulation of drug

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3
Q

What are the types of opiate receptors?

A

μ,κ and δ
also NOP

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4
Q

What is the function of opiate receptors?

A

Signal through Gi/o proteins -> inhibit adenylate cyclase activity
* Decrease cAMP production K+ efflux and closure of VGCa channels -> hyperpolarization of nerve cell + inhibition of nerve firing

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5
Q

What is the role of sigma receptor?

A

Analgesia

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6
Q

What is the role of kappa receptor?

A
  1. Analgesia
  2. Dysphoria
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7
Q

What is the function of mu receptor?

A
  1. Analgesia
  2. Euphoria
  3. Increaased GI transit
  4. Respiratory depression
  5. Physical dependence
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8
Q

Describe the mechanism of opiate receptor?

A
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9
Q

What are the endogenous opioid peptides?

A

Pro-opiomelanocortin -> B-endophine (Analgesic)
Proenkephalin A -> Met- and Leu-enkephalin (inhibitory neurotrasmitters)
Proenkephalin B -> dynorphin and α-neoendorphin (weight contol and homeostasis)

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10
Q

What is the site of action for opiates?

A

CNA (neuromodulator action on pain-signaling neurons in dorsal horn of spinal cord and on interconnecting neuronal pathways for pain signals)

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11
Q

Opioids are best with what kind of pain?

A

Dull

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12
Q

What is the difference between dependence and tolerance?

A

Dependence: need for a drug to maintain normal functioning (withdraw)
TOlerance: increasingly larger dose required to produce same degree of pharmacologic response (upregulaton of cAMP system or recycling of u receptors)

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13
Q

What is cross tolerance?

A

Ability of one opioid agonist to substitute for another
* opioid rotation

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14
Q

Persistent administration of opioids can cause what?

A

Hyperalgesia: increase sensation of pain due to spinal dynorphine/activation of BK and NMDA receptors

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15
Q

What are commond ADR of opiods?

A
  1. Euphoria
  2. Dysphoria
  3. Constipation
  4. Respiratory depression
  5. N/V
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16
Q

How receptor cause euphoria?

A

µ opioid: decrease in cAMP -> inhibit release of inhibitory GABA from ventral tegemental area -> enhanced dopamine release

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17
Q

What receptor cause dysphoria?

A

κ agonist: inhibits presynaptic dopaminergic neurons -> decrease in dopamine

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18
Q

What receptor causes constipation?

A

µ agonist: inhibits Ach from myenteric plexus and stops propulive peristalsis

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19
Q

Describe the ADME of opioids?

A

Absorption: good but variable
Distribution: Rapid out of blood to periphery
Metabolism: Heavy from glucoronidation
Excretion: glucoridines in urine

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20
Q

What is the most effective form of opiods?

A

IV

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21
Q

What are the DDI of opiods

A
  1. Sedative hypnotics that cause CNS depression
  2. Antipsychotics: sedation and respiratory depression
  3. MOAIs: hyperpyrexic coma, HTN
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22
Q

What is the difference between opioids and opiates?

A

Opioids: morphine-like compounds
Opiates: peptide-like compounds

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23
Q

Describe the SAR of opiods?

A

Aromatic amino in middle, charged amine at the top, hydrogen bond acceptor at the bottom

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24
Q

What isomers are levo? dex?

A

Levo: pain
Dex: antitussives

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25
Q

What is the SAR of a flexible opioids?

A
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26
Q

What are the full µ agonists?

A
  1. Morphine (MS contin, avinza, kadian)
  2. Codeine
  3. Heroin
  4. Hydromorphone
  5. Hydrocodone
  6. Oxymorphone
  7. Oxycodone
  8. Levorphanol
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27
Q

Describe the PK of morphine?

A

Poor bioavailability, most hydrophillic opiods

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28
Q

What is codeine’s relation to morphine?

A

Prodrug: 10-12 potecy lower, but PO F is better

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29
Q

How is codeine metabolized?

A

O-dealkylation mediated by CYP2D6 (people can be def or have ultrafast metabolizers)

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30
Q

How is codeine not given inj?

A

Pruritus, hypotension

31
Q

How is heroin metabolized?

A

Prodrug metabolized by CYP2D6 eventhough it contains an ester

32
Q

Describe the features of hydromorphone?

A

6 – 10x increase in analgesic action because of ketone, however also increases in toxicity

33
Q

Describe the features of hydrocodone?

A

Prodrug of hydromorphone and lower frequency of ADRs

34
Q

How does oxymorphone differfrom hydro?

A

Added OH at 14-postion to hydromorphone increasing analgesic action and affinity for µ-receptor
* High addiction liability

35
Q

What is oxycodone?

A

Prodrug of oxymorphone with much better PO F and lower potency

36
Q

Describe the potency and F of full µ receptor agonist formulations?

A

High potency = low bioavailabiltiy
Low potency = high bioavailabity

37
Q

Levorphanol

MOA, PK, ADR

A

MOA: μ,κ, and δ agonist; inhibits serotonin-norepinephrine reuptake, NMDA receptor antagonist
PK: Can accumulte due to long DOA
ADR: Unwanted or excessive sedation

38
Q

Describe the structure of levorphanol?

A

Enhanced molecular flexibility – no E ring or 7,8-double bond

39
Q

What are examples of flexible µ agonist?

A
  1. Methadone (dolophine)
  2. Meperidine
  3. Fentanyl (Duragesic, Ionsys)
  4. Sufentanil
  5. Alfentanil
  6. Remifetanil
40
Q

What makes methadone special?

A

Doesn’t have piperidine ring, but due to flexibility it can mimic one

41
Q

Methadone

PK, Interactions

A

Long DOA causes drug accumulation
* good for addiction recovery because of high F, and long DOA
* Lots of active metabolites

Interactions: R- isomer is metabolized by CYP2C19
* S+ metabolized by CYP2B6
* Metabolized by CYP3A4

42
Q

How is the chemistry of methadone unique?

A
  1. Administered with alkalinizing agent to raise pH of saliva for better buccal absorption
    * Very sensitive to pH
  2. S+ isomer antagonizes NMDA receptor -> helps with neuropthic/opioid-resistant pain but can cause CV tox
43
Q

What is the indication for methadone?

A

Replacement for heroin/other opiates in dependent individuals, because it hass less intene sx than heroin but greate DOA

44
Q

How long is methadone withdrawl?

A

Less severe lasting 24-36 hrs

45
Q

Meperidine

MOA, PK, ADR

A

MOA: typical µ agonist activity except inhibition of GI motility and cough
PK: poor F, short acting
* some anti-spasmodic activity
* More lipophillic, crosses BBB easily
* ADR: hypotention, stimulates histamine release, negative inotropic action on heart

46
Q

How is mepiridine not commonly used?

A

Produce nor metabolite and can induce neurologic side effects

47
Q

What make fentanyl special?

A
  • 50-100x more potent than morphine
  • High lipophilicity -> quick BBB penetration
  • Short DOA do to residribution once leaving the brain
48
Q

Why is fentanyl given as a patch or nasal spray?

A

Undergoes extensive metabolism from CYP3A4

49
Q

BBW of fentanyl?

A
  1. Unintentional od, toxicity, and intentional abuse
  2. Respiratory depression
  3. Heat can increase release for transdrmal patches
50
Q

How does sufentanil differ from fentanyl?

A

Increased lipophilicity due to thienylethyl and 4-methoxymethyl -> 5-10x potency than fentanyl

Redistributes from brain to periphery in 17 minutes

51
Q

How does alfentanil differ from other flexible µ aonists?

A
  1. Lower pKa due to tetrazoline ring -> Ratio of unionized/ionized in blood is higher than fentanyl and sufentanil -> distributes + redistributes across BBB more rapidly
  2. Faster onset than fentanyl
52
Q

What is remifentanil?

A
  1. Equipotent with fentanyl
  2. More unionized at 7.4 due to EW ester on N -> rapid distribution
  • Ester is hydrolyzed by esterase to inactive COO- -> liver and kidney function doesn’t matter
53
Q

What are dual action opioids?

A

Agonists of μ-receptors AND inhibit NE and/or 5-HT reuptake

54
Q

What are the benefis of dual action opioids?

A

Lower dependence on µ receptor stimulation for full analgesic efficacy -> decrease risk for ADR

55
Q

Examples of dual action o?

A

Tramadol (Ultram)
Tapentadol

56
Q

What makes tramadol special?

A

MOA is time-dependent - more µ receptor activity, less inhibition of NE/5HT reuptake

57
Q

How is tramadol metabolized>

A

O-dealkylation by CYP2D6

58
Q

What is the opioid that can cause seritonin syndrome? Why

A

Tramadol, because 1R, 2R isomer inhibits 5-HT reuptake

59
Q

ADR of tramadol?

A

Agitation, coma, HR/BP changes, hyperreflexia, loss of coordination, GI distress, seizure, and suicide, wihdrawl

60
Q

What does a tramadol WD look like?

A

Paranoia, panic, sensory perception distortions, hallucinations

61
Q

What make tapentadol different from tramadol?

A

Time-independent μ-receptor agonist and selective inhibitor of NE reuptake -> less physical dependence

62
Q

What are examples of partial µ agonists?

A
  1. Buprenorphine
63
Q

Describe the structure of buprnor[phine?

A

Large lipophillic side chain that helps increase H binding

64
Q

What are the benefits of partial agonists?

A

precipitates withdrawal in patients dependent on full agonists but suppresses symptoms of full-blown withdrawal
* Displaces + blocks euphoric effects of heroin

65
Q

What makes buprenorphine special?

A

Pseudoirreversible binding, slow dissociation (minimized withdrawal sx), difficult to reverse receptor-mediatd side effects

66
Q

What are the side effects of buprenorphine?

A

Mixed agonist-antagonist: psychotomimetic effects (hallucinations, nightmares, anxiety)

67
Q

Examples of κ Agonists/ μ Antagonists?

A
  1. Nalbuphine
  2. Butorphanol
  3. Pentazocine
68
Q

Nalbuphine

MOA, ADR, PK

A

MOA: κ Agonists/ μ antagonists -> no cross tolerance with full or partial μ agonists
* κ Agonists produce less respiratory deprssion, constipation, euphoria, and addiction potential

ADR: sedation and diuresis
PK: Higher doses have definite ceiling to respiratory depression
* May be resistant to naloxone reversal

69
Q

Butorphanol

MOA, ADR

A

MOA: No furan oxygen + 6α-OH increases potency
* Ceiling effect for respiratory deprssion

ADR: dysphoria, more sedation than nalbuphine

70
Q

Pentazocine

MOA, ADR

A

MOA: κ agonist with weak μ antagonist or partial agonist properties
ADR: dysphoria

71
Q

What is the difference between naloxone and natrexone?

A

Naloxone: 2x more potent, 4 carbons on nitrogen vs 3 for better distribution
Naloxone: orally inactive because allylic oxidation and phase II conjugation in GIT/liver
* Added the buprenorphine to prevent patients from crushing and injecting for euphoria

72
Q

Does naloxone/naltrexone have withdrawl sx?

A

No

73
Q

What is the warning with naloxone?

A

Short DOA, but severely depressed patient may recover but relapse into coma in 1-2 hrs

Drug Action III (23 decks)

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