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Medicinal Chemistry - Winter > 1 & 2 - Pain & Pain Management > Flashcards

1 & 2 - Pain & Pain Management Flashcards

1
Q

Can pain be perceived differently across ethnic origins and gender?

A

Yes

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2
Q

What is the relationship between pain sensitivity and COMT activity? What does this mean?

A
  • Low pain sensitivity has higher levels of COMT activity
  • Therefore, COMT activity has inverse relationship to pain sensitivity
  • This means there is a genetic difference in how people perceive pain
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3
Q

How can pain be classified?

A
  • Based on duration
    1) Acute - mild to severe; most intense at time of injury; generally decreases upon healing or removal of source
    2) Chronic - lasting more than 6 months; persists when initial cause removed or medically resolved; may not have underlying cause; very difficult to treat
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4
Q

Which types of pain are generally acute?

A
  • Nociceptive (somatic or visceral)
  • Post-op or post-traumatic pain
  • Burn
  • Childbirth
  • Acute headache
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5
Q

What can chronic pain be classified into?

A

1) Malignant - cancer, HIV/AIDS, MS, organ failure

2) Non-malignant - lower back pain, chronic degenerative arthritis, OA, RA, migraine

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6
Q

What are the 3 main types of pain, classified by source?

A

1) Physiological
2) Neuropathic
3) Inflammatory

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7
Q

What is physiological pain?

A
  • Cutaneous, somatic, and visceral
  • Cutaneous = skin and surface tissue
  • Somatic = ligaments, tendons, bones, blood vessels; often described as dull or aching; generally able to point directly to pain location
  • Visceral = body organs, internal cavities; described as throbbing or gnawing/aching pain; difficult to locate; may be distant from source
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8
Q

What is nociceptive pain?

A
  • Directly caused by the stimulation of pain nerve endings to tissue injury or disease infiltration
  • Pain resulting as a consequence of peripheral nerve damage
  • Can result from limb amputation, spinal surgery, viral infections (shingles), or worsening disease states (diabetes, AIDS, MS)
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9
Q

What are the first line treatments for neuropathic pain (based on table 4 of reference)?

A
  • Tricyclic antidepressants
  • Calcium channel alpha2-beta ligands (gabapentin and pregabalin)
  • SSNRIs (duloxetine and venlafaxine), only based on NeuPSIG guidelines
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10
Q

What is inflammatory pain?

A
  • Originates from infection or inflammation as a result of initial tissue or organ damage (NSAIDs)
  • Can be further defined as pain arising from tissue damage and infiltration of immune cells
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11
Q

What category of pain does cancer fall under?

A

Sometimes classified separately, b/c can have both nociceptive and neuropathic components, palliative and breakthrough pain

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12
Q

Describe the WHO guideline for pain management

A

1) Pain persisting or increasing – non opioid +/- adjuvant
2) Pain persisting or increasing – opioid for mild to moderate pain +/- non opioid and +/- adjuvant
3) Freedom from cancer pain – opioid for moderate to severe pain +/- non opioid and +/- adjuvant

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13
Q

What are the classes of drugs used in pain management?

A
  • Acetaminophen
  • NSAIDs and coxibs (selective COX inhibitors)
  • Opioids
  • Opioid substitution therapy (methadone, buprenorphine)
  • Tramadol and tapentadol (open-chain opioids)
  • Antidepressants
  • Anti-epileptics
  • 5-HT1 agonists (triptans, headache, migraines)
  • Local anesthetics (topical = lidocaine)
  • Capsaicin
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14
Q

What is one of the oldest recorded medications?

A

Juice or latex from unripe seed pods of the poppy Papaver Somniferum

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15
Q

When was morphine first introduced?

A
  • Early 1800’s

- The first total synthesis of the alkaloid morphine was performed in 1952

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16
Q

What is diacetylmorphine? When was it first marketed and as what?

A
  • Heroin

- Marketed in 1898 as the first non-addictive analgesic, anti-diarrheal, and anti-tussive agent

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17
Q

What is an opioid?

A

All agonists and antagonists, either natural or synthetic

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18
Q

What is an opiate?

A

Drugs derived from opium, poppy plants

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19
Q

What is an opioid receptor?

A

Group of G-protein-coupled receptors w/ opioid ligands

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20
Q

What is a narcotic?

A

All drugs of abuse, not just opioids

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21
Q

What are side effects of opioid analgesics?

A
  • Addictive “narcotic effects”
  • Euphoria
  • Excessive sedation
  • Respiratory depression
  • Withdrawal sx
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22
Q

What are the 3 families of endogenous opioid peptides?

A
  • Enkephalin
  • Endorphin
  • Dynorphin
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23
Q

What is the principle effect of opioids?

A

Inhibition of adenylate cyclase which decreases cAMP production and simultaneously lowers overall perception of pain

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24
Q

Do opioids bind directly to adenylate cyclase?

A

No, bind to a GPCR which downregulates adenylate cyclase

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25
Q

What is the hypothesis for the cause of tolerance?

A

Receptors uncouple from G-protein, causing a need for higher doses b/c opioid can’t have an effect on adenylate cyclase

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26
Q

What is the hypothesis for the cause of addiction?

A

Chronic decrease in cAMP triggers compensatory increase in adenylate cyclase synthesis (enzyme induction) => increased cAMP concentration in brain

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27
Q

Is the mechanism of opiate addiction the same as other drugs?

A

No

28
Q

What is the hypothesis for the cause of withdrawal?

A

Previously inhibited adenylate cyclase produces a flood of cAMP, leading to loss of appetite, muscle spasms, tremors, and even death

29
Q

What is the biochemical effect of opioid peptides?

A

Function as NTs/modulators and co-exist w/ other NTs, making it difficult to elucidate biological function

30
Q

What is proenkephalin A a precursor for?

A

Met- and Leu-enkephalin

31
Q

What is proenkephalin B (prodynorphin) a precursor for?

A

Dynorphin and alpha-neoendorphin

32
Q

What is proopiomelanocortin (POMC) a percursor for?

A

Beta-endorphin

33
Q

What is pronociceptin a precursor for?

A

Nociceptin (orphan opioid receptor)

34
Q

What is the amino acid sequence of Met-enkephalin?

A

Tyr-Gly-Gly-Phe-Met

35
Q

What is the amino acid sequence of Leu-enkephalin?

A

Tyr-Gly-Gly-Phe-Leu

36
Q

What is the amino acid sequence of dynorphin (dyn 1-13)?

A

Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys

37
Q

What is the amino acid sequence of beta-endorphin?

A

Tyr-Gly-Gly-Phe-Met-Thr-Ser-24 amino acids

38
Q

What are the 3 major types of opioid receptors?

A

Mu, kappa, and delta

39
Q

What is the definition of an opioid?

A

A substance which produces biological effects through interaction w/ opioid receptor subtypes, and whose actions are reversed by naloxone

40
Q

What are some selective agonists for the Mu opioid receptor?

A
  • Morphine
  • Sufentanil
  • Meptazinol
  • Etonitazene
41
Q

What are some selective antagonists for the Mu opioid receptor?

A
  • Naloxone
  • Naltrexone
  • Cyprodime
  • Naloxonazine
42
Q

What are properties of Mu opioid receptor agonists?

A
  • Analgesia
  • Euphoria
  • Increase GI transit time
  • Immune suppression
  • Respiratory depression
  • Tolerance
  • Physical dependence
43
Q

What allows enkephalins to form cyclic structures? What does this cause?

A
  • Intramolecular H bonds

- Cause beta bends (180 degree turn)

44
Q

For opioid analgesics, the tyrosine residue is analogous to _____

A

Tyramine residue

45
Q

What is the difference between tyrosine and tyramine?

A

Tyramine is tyrosine attached to NH3+

46
Q

What are the requirements for the T-binding region and 2-hydrophobic regions of opioid analgesics?

A
  • T-binding region must have a group capable of forming H bonds
  • 2-hydrophobic regions must be equidistant apart (Gly-Gly)
  • Also must have ionic binding region
47
Q

Which type of enkephalins need to fit into all 3 sites? Which do not?

A

Naturally occurring enkephalins will fit into all 3 sites, but synthetically derived ones don’t need to

48
Q

What affect does the addition of a halogen have on an opioid peptide? Which halogen has the greatest effect?

A
  • Increases potency
  • Increases selectivity if added to phenyl group in 6 position
  • Bromine has greatest effect; fluorine has smallest
49
Q

What are the 3 distinct regions of a 31-amino acid residue of a beta-endorphin?

A

1) N-terminus has a Met-enkephalin unit
2) Hydrophobic region in middle (Pro13 to Phe18)
3) C-terminal amphiphilic alpha-helix (AA 14-31)

50
Q

What does amphiphilic mean?

A

Compound possesses hydrophilic and lipophilic properties

51
Q

How many chiral centers does morphine have? How many optical isomers?

A
  • 5 chiral centers

- 16 optical isomers

52
Q

Does morphine have good oral bioavailability?

A

No, extensive first pass metabolism (primarily glucuronidation at 3-OH position in liver)

53
Q

What percent of an oral dose of codeine is metabolized to morphine?

A

10%

54
Q

What happens if a px w/ no CYP2D6 is given codeine?

A

Will not metabolize it to morphine, so will not experience analgesia

55
Q

How is codeine metabolized to morphine?

A

O-demethylation by CYP2D6

56
Q

What metabolism does morphine undergo?

A
  • N-demethylation to normorphine, which has decreased activity
  • 6-glucuronidation to active metabolite
  • 3-glucuronidation to inactive metabolite
  • Oxidation to high analgesic activity
57
Q

What is the difference btwn meperidine and morphine?

A

Meperidine has rapid onset, short duration, less constipation, and less cough than morphine

58
Q

What is the duration of fentanyl?

A

1-2 hours (short)

59
Q

Does fentanyl or sufentanil have a faster onset and a longer duration?

A
  • Sufentanil has faster onset

- Fentanyl has longer duration

60
Q

What is important to note about remifentanil?

A

IV onset = 1-3 minutes and offset = 3-5 minutes (rapid hydrolysis)

61
Q

What effects does embutramide have?

A
  • Strong sedative
  • Produces respiratory depression
  • Produces ventricular arrhythmia
62
Q

What does a binding assay measure?

A
  • Binding affinity for certain receptors
  • Measures how good your compound is at displacing another ligand, which measures its affinity for that particular receptor
63
Q

What does an inhibition assay measure?

A

How well your molecule inhibits a certain process from occurring

64
Q

When comparing IC50 of different compound, which compound will be the most potent?

A

The one w/ the lowest IC50

65
Q

When comparing binding ratio for different receptors (ex: mu receptor/delta receptor), which compound will be more selective for the mu receptor?

A

The one w/ the highest ratio

66
Q

Which halogens produce better potency and why?

A

Fluorine and chlorine because more electronegative

67
Q

Which halogen is more selective and why?

A

Iodine b/c larger size

Medicinal Chemistry - Winter (15 decks)

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