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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
What is the SAR of a flexible opioids?
26
What are the full µ agonists?
1. Morphine (MS contin, avinza, kadian) 2. Codeine 3. Heroin 4. Hydromorphone 5. Hydrocodone 6. Oxymorphone 7. Oxycodone 8. Levorphanol
27
Describe the PK of morphine?
Poor bioavailability, most hydrophillic opiods
28
What is codeine's relation to morphine?
Prodrug: 10-12 potecy lower, but PO F is better
29
How is codeine metabolized?
O-dealkylation mediated by CYP2D6 (people can be def or have ultrafast metabolizers)
30
How is codeine not given inj?
Pruritus, hypotension
31
How is heroin metabolized?
Prodrug metabolized by CYP2D6 eventhough it contains an ester
32
Describe the features of hydromorphone?
6 – 10x increase in analgesic action because of ketone, however also increases in toxicity
33
Describe the features of hydrocodone?
Prodrug of hydromorphone and lower frequency of ADRs
34
How does oxymorphone differfrom hydro?
Added OH at 14-postion to hydromorphone increasing analgesic action and affinity for µ-receptor * High addiction liability
35
What is oxycodone?
Prodrug of oxymorphone with much better PO F and lower potency
36
Describe the potency and F of full µ receptor agonist formulations?
High potency = low bioavailabiltiy Low potency = high bioavailabity
37
Levorphanol | MOA, PK, ADR
**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
Describe the structure of levorphanol?
Enhanced molecular flexibility – no E ring or 7,8-double bond
39
What are examples of flexible µ agonist?
1. Methadone (dolophine) 2. Meperidine 3. Fentanyl (Duragesic, Ionsys) 4. Sufentanil 5. Alfentanil 6. Remifetanil
40
What makes methadone special?
Doesn't have piperidine ring, but due to flexibility it can mimic one
41
Methadone | PK, Interactions
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
How is the chemistry of methadone unique?
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
What is the indication for methadone?
Replacement for heroin/other opiates in dependent individuals, because it hass less intene sx than heroin but greate DOA
44
How long is methadone withdrawl?
Less severe lasting 24-36 hrs
45
Meperidine | MOA, PK, ADR
**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
How is mepiridine not commonly used?
Produce nor metabolite and can induce neurologic side effects
47
What make fentanyl special?
* 50-100x more potent than morphine * High lipophilicity -> quick BBB penetration * Short DOA do to residribution once leaving the brain
48
Why is fentanyl given as a patch or nasal spray?
Undergoes extensive metabolism from CYP3A4
49
BBW of fentanyl?
1. Unintentional od, toxicity, and intentional abuse 2. Respiratory depression 3. Heat can increase release for transdrmal patches
50
How does sufentanil differ from fentanyl?
Increased lipophilicity due to thienylethyl and 4-methoxymethyl -> 5-10x potency than fentanyl Redistributes from brain to periphery in 17 minutes
51
How does alfentanil differ from other flexible µ aonists?
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
What is remifentanil?
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
What are dual action opioids?
Agonists of μ-receptors AND inhibit NE and/or 5-HT reuptake
54
What are the benefis of dual action opioids?
Lower dependence on µ receptor stimulation for full analgesic efficacy -> decrease risk for ADR
55
Examples of dual action o?
Tramadol (Ultram) Tapentadol
56
What makes tramadol special?
MOA is time-dependent - more µ receptor activity, less inhibition of NE/5HT reuptake
57
How is tramadol metabolized>
O-dealkylation by CYP2D6
58
What is the opioid that can cause seritonin syndrome? Why
Tramadol, because 1R, 2R isomer inhibits 5-HT reuptake
59
ADR of tramadol?
Agitation, coma, HR/BP changes, hyperreflexia, loss of coordination, GI distress, seizure, and suicide, wihdrawl
60
What does a tramadol WD look like?
Paranoia, panic, sensory perception distortions, hallucinations
61
What make tapentadol different from tramadol?
Time-independent μ-receptor agonist and selective inhibitor of NE reuptake -> less physical dependence
62
What are examples of partial µ agonists?
1. Buprenorphine
63
Describe the structure of buprnor[phine?
Large lipophillic side chain that helps increase H binding
64
What are the benefits of partial agonists?
precipitates withdrawal in patients dependent on full agonists but suppresses symptoms of full-blown withdrawal * Displaces + blocks euphoric effects of heroin
65
What makes buprenorphine special?
Pseudoirreversible binding, slow dissociation (minimized withdrawal sx), **difficult to reverse receptor-mediatd side effects**
66
What are the side effects of buprenorphine?
Mixed agonist-antagonist: psychotomimetic effects (hallucinations, nightmares, anxiety)
67
Examples of κ Agonists/ μ Antagonists?
1. Nalbuphine 2. Butorphanol 3. Pentazocine
68
Nalbuphine | MOA, ADR, PK
**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
Butorphanol | MOA, ADR
**MOA:** No furan oxygen + 6α-OH increases potency * Ceiling effect for respiratory deprssion **ADR:** dysphoria, more sedation than nalbuphine
70
Pentazocine | MOA, ADR
**MOA:** κ agonist with weak μ antagonist or partial agonist properties **ADR:** dysphoria
71
What is the difference between naloxone and natrexone?
**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
Does naloxone/naltrexone have withdrawl sx?
No
73
What is the warning with naloxone?
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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