opium and opioids

what is the backbone of morphine?

• 5 fused rings (a,b,c,d,e)

what is ring A of morphine?

• benzene structure with phenolic OH at C3

what is ring B of morphine?

• saturated cyclohexane ring

what is ring C of morphine?

• cyclohexane ring with one double bond + alcoholic OH

what is ring D of morphine?

• ether link between rings A + C

what is ring E of morphine?

• piperidine w/ N-methyl group at position 17

stimulation of what receptor leads to decreased gastric motility/constipation as a side effect of opioids?

• stimulation of sigma receptors

what are the functional groups of morphine?

• position 3 = phenolic OH

• position 6 = alcoholic OH

• 7-8 = double bond

• position 17 = methyl-N

what type of drug is this?

• morphine

what receptors does morphine stimulate?

• mu receptors + kappa receptors

what are the 2 unwanted central pharmacological actions?

1. development of addiction

2. respiratory depression

respiratory depression and addiction are related to

a) mu receptors only

b) sigma receptors only

c) kappa receptors only

d) mu and kappa receptors

a) mu receptors only

what are the 2 types of structural modifications to morphine to decrease adverse effects / increase analgesic potency?

1. modifying substitution on morphine intact ring system

2. modifying number of ring systems

T/F: morphine produces its effects through both mu and kappa receptors

• true

is morphine acidic or basic? why?

• basic

  • tertiary nitrogen at position 17 = strongly basic

what type of drug is this?

• codeine

what is the structural difference between morphine and codeine?

• codeine has an ether at C3 instead of phenolic OH

  • methoxy derivative of morphien

how is codeine used as an anti-tussive vs analgesic?

• codeine w/ o-demethylation → morphine = anlagesic

• codeine w/o o-demethylation = anti-tussive

is codeine or morphine more lipophilic? how does that affect absorption?

• codeine = more lipophilic than morphine

  • better oral absorption

if you replace the phenolic OH in morphine with an ether, you get

a) hydromorphone

b) hydrocodone

c) codeine

d) oxymorphone

c) codeine

what type of drug is this?

hydromorphone

what is the structural difference between morphine and hydromorphone?

• C6 OH is oxidized → ketone

• C7-8 double bond is saturated

hydromorphone is ___ times more potent than morphine as an analgesic

• 10

T/F: hydromorphone is a more potent analgesic than morphine w/o increasing adverse effects

• false

  • more potent + more dangerous (respiratory depression + addiction)

if you oxidize C6 OH and saturate C7-8 double bond in morphine, you get

a) hydromorphone

b) hydrocodone

c) codeine

d) oxymorphone

a) hydromorphone

what type of drug is this?

• hydrocodone

what are the structural differences between morphine and hydrocodone?

• C6 OH oxidized → ketone

• C7-8 double bond = saturated

• C3 OH → ether

what is the main use of hydrocodone?

• mainly used an anti-tussive

if you metabolize hydrocodone, you get ….

• hydromorphone

what type of drug is this?

• oxymorphone

how is oxymorphone different from hydromorphone?

• additional OH group at C14

is oxymorphone or hydromorphone more potent?

• oxymorphone

  • addition OH at c14 = makes drug agonist exclusively at mu receptors

    • 100x more potent than morphine

what 3 modifications to morphine makes a drug exclusive to mu receptor?

• C6 OH oxidation → ketone

• C7-8 double bond saturation

• additional OH at C14 (hydroxylation)

what type of drug is this?

• oxycodone

what modification to morphine causes a drug to be a pure antagonist at the mu receptors?

• c-6 ketone

• c7-8 double bond saturation

• c14 hydroxylation

• n-substitution bigger than a methyl

what modification to morphine causes a drug to be an antagonist at the mu receptors but an agonist at the kappa receptors

• N-17 methyl of morphine is replaced b a bigger group than a methyl

SATA: which of the following drugs are mixed opioid agonist/antagonists

a) naltrexone

b) nalbuphine

c) nalorphine

d) naloxone

b) nalbuphine

c) nalorphine

SATA: which of the following drugs are pure mu antagonists

a) naltrexone

b) nalbuphine

c) nalorphine

d) naloxone

a) naltrexone

d) naloxone

what type of drug is this?

• mixed opioid agonist/antagonist

  • nalorphine

what type of drug is this?

• mixed opioid agonist/antagonist

  • nalbuphine

what type of drug is this?

• pure opioid (Mu) Antagonist

  • naloxone

what type of drug is this?

• pure opioid (Mu) Antagonist

  • naltrexone

what is the structural difference between naloxone and naltrexone

• - rally N substitution

  • naloxone = alkene

  • naltrexone = cyclic propyl

how is naltrexone administered? what is it used for?

• - orally

• used for rehabilitation + Detoxification

how is naloxone administered? what is it used for?

• intranasal spray / injection

• used to reverse opioid over dose / reverse respiratory depression

T/F: if the N-17 substitution is bigger than a methyl it affects activity at the kappa NOT the mu receptors

• false

  • affects activity at the mu NOT Kappa

  • antagonist at mu, agonist at kappa

what are the benefits of mixed agonist/antagonist

• allows analgesia w/o respiratory depression

• less chance of addiction through mu receptors

structure modification by adding an additional ring system to become 6 rings, the nucleus assumes a new name _______

• Oripavine

what is the one drug with an oripavine nucleus ? how?

buprenorphine

• ring C has a divider → 6 rings

what type of drug is this?

• partial agonists

  • buprenorphine

  • oripavine nucleus

what is the use of buprenorphine? how/why?

• used to treat addiction/rehab

  • inhibits morphine binding to mu-receptors because it has higher affinity to mu receptors

  • partial agonist = guards against withdrawal symptoms

  • very little analgesic feeling

what are the 2 drugs to make the combination drug Suboxone?

• - cbuprenorphine

• naloxone

what structural modification to buprenorphine makes it a mu-antagonist?

• N-substitution = cyclopropyl methyl group

drugs missing ring D are

a) benzomorphan

b) 4-phenylpiperadines

c) morphirans

d) 4-analinopiperadines

e) phenylpropylamines

c) morphirans

drugs missing ring D and C are

a) benzomorphan

b) 4-phenylpiperadines

c) morphirans

d) 4-analinopiperadines

e) phenylpropylamines

a) benzomorphan

drugs missing ring D, C, and B are

a) benzomorphan

b) 4-phenylpiperadines

c) morphirans

d) 4-analinopiperadines

e) phenylpropylamines

b) 4-phenylpiperadines

drugs missing ring D, C, and B & have a nitrogen atom inserted between A and E are

a) benzomorphan

b) 4-phenylpiperadines

c) morphirans

d) 4-analinopiperadines

e) phenylpropylamines

d) 4-analinopiperadines

drugs with only ring A remaining by Ring E are

a) benzomorphan

b) 4-phenylpiperadines

c) morphirans

d) 4-analinopiperadines

e) phenylpropylamines

e) phenylpropylamines

what type of drug is this?

• Morphiran (Missing ring D)

  • Levorphanol
    

what is Levorphanol used for?

• central analgesic (less potent than morphine)

• advantage = less constipating effects

what type of drug is this?

• Morphiran (missing ring D)

  • Dextromethorphan

what is Dextromethorphan used for? what structural element determines that?

• antitussive

  • methoxy group on benzene ring

T/F: Dextromethorphan can be an analgesic after O-demthylation, similar to codeine

• true

what type of drug is this?

• Morphiran (missing ring D) / mixed agonist/antagonist

  • Butorphanol
    

what structure in butorphanol determines that it a mixed agonist/antagonist

• N-substitution is cyclobutyl methyl group (Bigger than a methyl)

what is butorphanol used for?

• injection in hospitals → MIld pain treatment

  • no addiction or respiratory depression

• nasal spray → Migraine pain

T/F: Butorphanol is a controlled substance

• false

  • not a controlled substance

SATA: which of the following drugs are prodrugs that can become analgesics after O-demethylation?
a) Codeine

b) Levorphanol

c) Dextromethorphan

d) hydrocodone

a) Codeine

c) Dextromethorphan

d) hydrocodone

SATA: which of the following drugs are morphirans

a) levorphanol

b) pentazocine

c) dextromethorphan

d) butorphanol

a) levorphanol

c) dextromethorphan

d) butorphanol

what type of drug is this?

• benzomorphan (missing ring D + C)

  • pentazocine
    

what is pentazocine used for?

• very mild analgesic activity w/ no respiratory depression

pentazocin has analgesic activity at

a) mu receptors

b) Kappa receptors

c) Sigma receptors

d) all of the above

b) Kappa receptors

• because at kappa = mild analgesic activity

what type of drug is this?

• 4-phenylpiperadine (Missing rings D,C,B)

  • Meperidine

How are 4-phenylpiperadines (missing rings D,C,B) classified as a class?

a) mild analgesia

b) decreased respiratory depression

c) increasing GIT constipating effects

d) antitussives

• c) increasing GIT constipating effects

is meperidine an antagonist or agonist at the mu-receptors?

• agonist at the mu receptors (N-methyl substitution)

how is meperidine administered?

• ONLY injection

  • ester functional group = easily hydrolyzed by esterases

    • hydrolysis of ester also forms a zwitter-ion (can not cross blood brain barrier)

  • injection= minimize loss

what type of drug is this?

• 4-phenylpiperadine (missing ring D,C,B)

  • Diphenoxylate

what is Diphenoxylate used for? what is its target receptor?

• used orally as antidiarrheal

  • Lomotil = brand name

• targets sigma receptors in GIT

is diphenoxylate analgesic?

• no

  • N-substitution is not a methyl

what type of drug is this?

• 4-phenylpiperadine (missing ring D,C,B)

  • Loperamide

what is loperamide used for?

• used as an anti-diarrheal

  • not an analgesic drug

what type of drug is this?

• 4-analinopiperadines (missing rings D,C,B + has a nitrogen between rings A + E)

  • fentanyl

why is fentanyl more powerful than morphine?

• N-subsitution is bigger than a methyl

  • more affinity + potent

what type of drug is this?

• phenylpropylamines (only ring A + E → propyl amine)

  • methadone

is methadone more or less potent than morphine?

• less potent than morphine but higher affinity

  • higher affinity to mu receptors because of increased lipophilicity

T/F: methadone is a full mu-agonist

• false

  • methadone is a partial agonist (high affinity w/ little intrinsic activity)

what is the indication for methadone?

• rehab programs

what causes methadone’s metabolism to be slower?

• alpha-methyl group nearby

  • steric hinderance

what type of drug is this?

• phenylpropylamine (only ring A + E → propyl amine)

  • Propoxyphen

describe the strength + affinity of propoxyphene

• no affinity to mu receptors (no central activity)

• little analgesic activity ~ NSAIDs/aspirin

if someone is addicted to morphine, codeine, or fentanyl and overdosed, how can you get rid of the plasma concentration faster?

• make urine more acidic w/ ammonia chloride

  • acidic conditions w/ basic drug = make it more ionized

what happens if you make the urine more alkaline w/ antacids when a person is on morphine, codeine, or fentanyl?

• increases duration of action

list the 4-analinopiperadines

• fentanyl li

list the phenylpropylamines

• methadone

• propoxyphen

list the benzomorphan drug

• pentazocine

list the 4-phenylpiperadines

• meperidine

• diphenoxylate

• loperamide