Opioid MedChem Flashcards
1
Q
Opium/Morphine/Thebaine
A
- Opium has been used since the 1800s
- Morphine is a major constituent of opium, about 10% of total
- Codeine and thebaine are other phenanthrene alkaloids that represent smaller parts of the species
- Thebaine = C-ring modification of morphine used to synthesize other opioid agonists/antagonists
2
Q
Morphine Pharmacological Properties
A
- CNS: analgesia, drowsy, mood change, mental clouding
- Eye: pupil constricted, enhanced responsiveness to light
- Respiration: continuous depression of respiration
- GI: perstaltic movements are markedly decreased => constipation, delayed digestion
3
Q
Morphine MoA
A
- Opiate receptors are glycoproteins found in the CNS
- Enkephalins and endorphins are naturally occuring opioid peptides that compete for receptors and have analgesic effect
- Classes of receptors based on binding assays in different tissues and behavioral effects
4
Q
Mu Receptors
A
- Classified by antagonist and agonists
- Naloxone, naltrexone, morphine
- Effects: Analgesia, respiratory depression, euphoria, tolerance dependence
5
Q
Kappa Receptors
A
- Found in spinal cord and CNS
- Ketocyclazocine interacts here
- Effects: Analgesia, sedation, pupillary constriction
6
Q
Delta Receptors
A
- Peptides
- Enkephalins interact
- Analgesia is only effect
7
Q
Opioid Clinical Uses
A
- Severe, acute pain relief (best pain medicine available): colic, MI, surgical procedures, burns, trauma, edema
- Severe chronic pain: malignancies, other drugs used as well
8
Q
Agents Used
A
- Propoxyphene: commonly used agent and one of the least effective
- Morphine: standard drug for severe pain
- Meperidine/Pentazocine: greatly used, suffer from dependencies, shorter acting and less respiratory depression
- Pentazocine and Codeine: non-narcotic analgesics
9
Q
Morphine Compound
A
- Bioavailability increased by IM/SC/IV
- Oral administration in controlled release tablets but first pass metabolism makes it suffer
- Adjust chains coming off of hydroxyls or N on D-ring to get derrivations of morphine and to adjust for metabolism
- Major route of metabolism: O-3 and O-6 glucuronide formation, the latter being a potent analgesic
- N-dealkylation also occurs well
10
Q
Codeine Compound
A
- Goes through O-dealkylation
- Suggests morphine may be the more active species
- 10x less potent than morphine orally and IM
- Used for mild to moderate pain and is often combined with APAP
- Useful antitussive
- Doesn’t bind to mu receptors, lesser affinity
- Hydroxyl group is converted to another group, which is necessary to be a morphine analog
- Only about 10% is converted to morphine which is where you get its minimal analgesic effects
11
Q
Heroin Compound
A
- Rapidly hydrolyzed to 6-monoacetylmorphine
- Suggests the metabolite may be responsible for its pharmacological effects
12
Q
C-Ring Changes
A
- Main adjustments are C-14’s group, modifying double bonds, and changing the hydroxyls
- Get results like hydromorphone and oxymorphone (morphine analogs) which are 5-10x more potent than morphine
- Further changing other hydroxyls gives codeine analogs like hydrocodone and oxycodone
13
Q
Meperidine/Other Piperidines
A
- Metabolism is N-demethylation and ester hydrolysis
- 1/5-1/10 morphine on a weight basis
- Significant respiratory depression
14
Q
Fentanyl
A
- Transdermal system available for chronic management in patients requiring opioid analgesic
- Replaced at 72 hour intervals
- Also injectable versions of fentanyl like sufentanil and alfentanil
- Nitrogen separates A and D ring
- 100x more potent than morphine
15
Q
Mu Opioids Basic Structures
A
- Aromatic Ring
- Quaternary Carbon
- Basic Nitrogen
- 3-carbon separation (Ph to N)
- R = alkyl, phenyl, or benzyl
- Some polar function
16
Q
Open Chain Compounds
A
- Methadone and Propoxyphene
- PO efficacy
- Long duration of action
- Extensively used in withdrawal and maintenance programs
- Less potent, but less prone to abuse
17
Q
Diphenoxylate/Loperamide
A
Diphen
- Used for its effects on lower GI
- Rapidly metabolized to carboxylic acid
- Doesn’t reach CNS in large concentrations
- Loperamide is an OTC drug for diarrhea that also doesn’t reach significant [CNS]
- Bind to peripheral mu receptors to decrease opioid induced constipation
18
Q
Antagonist/Mixed Agonist/Antagonists
A
- Lies in N-substituents
- Most all N-three carbon substituted compounds have antagonist activity
- Body’s version = N-allylnormorphine
- Those with larger chains have agonist activity
- Pure antagonists don’t give analgesic effects
- Mixed compounds can be good to excellent analgesics but many also cause anxiety and/or hallucinations
19
Q
Pure Antagonist Compounds
A
- Naloxone
- Naltrexone
20
Q
Mixed Agonist/Antagonist Compounds
A
- Pentazocine
- Nalbuphine
- Buprenorphine
- Butorphanol
- Dezocine
- Tramadol
21
Q
Pentazocine
A
- Agonist in man
- Much lessened addiction liability
- Very weak antagonist
- PO dosage forms are available
22
Q
Tramadol
A
- Mixed agonist/antagonist compound
- Affects mu receptors and inhibits reuptake of NE and 5HT
- Metabolite is more potent than parent compound in assays
23
Q
General Opioid Receptor Properties
A
- Sequences of the receptors have been determined based on cDNAs
- All are G-protein coupled receptors with 7 transmembrane domains
- Found on cell surfaces
24
Q
Opioid Peptides
A
- Receptors are for endogenous ligands
- Originate in brain and pituitary gland
- 3 Families: enkephalins, endorphins, and dynorphins
- Precursor to endorphins primarily found in the brain where peptides are thought to act
- Precursors to the other two are widely distributed throughout the CNS
- Attempting to make synthetic peptides to replace amino acids on enkephalins to retain activity but reduce hydrolysis, so far none have been successfully marketed
