Week 6 - Medicinal Chemistry: Pharmacological ways to treat Alcohol, Smoking, Opioid & Benzo addiction

Question 1

Alcohol Addiction Background

Answer 1

Short term addiction - accidental alchol poisoning frpm binge drinking
Long term addicition - chronic liver disease, stroke, some cancers

• Men have double alcohol mortality / deaths
• Most deprived areas have doubled mortality

Question 2

List the 4 pharmacological treatments for AUD

Answer 2

1. Disulfiram
2. Acamprosate calcium
3. Nalmefene
4. Naltrexone hydrochloride

Question 3

Explain Disulfiram MoA

Answer 3

Its an ALDH inhibitor
- inihibts ALDH (enzyme) from breaking down acetylaldehyde into acetate
- irreversibly covalently binds to ALDH
- cysteine on ALDH undergose disulfide exchange with disulfiram = inactive ALDH fromed
- prevents oxidation of acetalaldehyde
- buildup of acetylaldehyde makes patient feel ill = wont want to drink
- acetylaldehyde formed from ethanol (alcohol)

Disulfiram Dose:
- 200-500mg daily
- start on low dose then titrate up slowly

Acetaldehyde:
- is toxic (can form carcinogens)
- causes upset stomach, headache, hangover

Question 4

Explain Acamprostate Calcium MoA

Answer 4

Enhances GABA signalling at GABA A
- when alcohol consumed = ethanaol acts on CNS + binds to GABA A receptor and ↑ GABA effects
- when ethanol no longer consumed = GABA A no longer sensitive to GABA

Acamprostate Calcium CAUSES:
- patient to no longer get a high from alcohol = stop drinking

Acamprostate Calcium STRUCTURE:
- is a 2:1 salt
- ca2+ (2+ charge) so have 2 of the acrompostate structure (which is -ive) = equal charge
- Ca2+ helps molecule get thorugh BBB

Question 5

Explain Nalmefene and Naltrexone MoA

Naltrexone also used for OPIOID addiction

Answer 5

• ↓ amount of alcohol consumed
• prevents relaspe in opioid free patients
  
  • antagonist at Mu opioid receptor
  • 25mg/daily titrate up to 50mg/daily

STRUCTURES of both:
- Given as hydrochloride salts (NH+ and Cl-)
- has 4 chiral carbon centres
- has phenol group (-OH)
- has ether group (-O-)
- has tertiary amine group (-N-)
- this group makes the molecule basic
There is ONLY 1 DIFF.
- Naltrexone has carbonyl group (C=O)
- Nalmefene has double bond (C=O)

Question 6

List the 2 NRT options

Answer 6

1. Varencline
2. Bupropion hydrochloride

NRT gives patients nicotine in another form

Question 7

Explain Varencline MoA

Answer 7

Selective nicotine receptor partial agonist

• Start 1-2 weeks before target stop date
• Given as salt as its a basic drug
  TAKE:
• 500μg once daily for 3 days
• 500μg twice daily for 3 days
• 1mg twice daily for 11 weeks

STRUCTURE:
- Secondary amine (R2-N-H)
- becomes protonated = +ive charge
- has pKa of 9
- Pyridine nitrogen (N in a ring)
- has pKa of 5
- Not planar
- NO chiral centres
- Is a MESO compound

Question 8

Explain Bupropion hydrochloride MoA

Answer 8

Is a noradrenaline reuptake inhibitor
- ↓ severity of withdrawal symptoms + craving

• Start it 1-2 weeks before target stop date
  - 150mg daily for 6 days
  - 150mg twice daily
• STOP use if abstinence not achieved at 7 weeks

STRUCTURE:
- 1 chiral centre
- a secondary amine (R2-N-H
- used as a hydrochloride salt
- given as racemic mixture

Question 9

Heroin

Diamorphine or diacetylmorphine

Answer 9

• Heroin is prodrug of morphine
  - has 2 ester groups that are cleaved to form morphine (an Mu opioid agonist)
  - morphine tolerance develops quickly
• Given for pain relief but missused by addicts

STRUCTURE:
- morphine formed isnt planar
- can NOT cross BBB
- values are lower than BBB requirements
- able to cross BBB
- has slightly lower than required LogP and LogD values

Question 10

List the 3 treatment for Opioid dependance

Answer 10

1. Methadone
2. Buprenorphine
3. Naltrexone

Question 11

Explain Methadone MoA

Answer 11

Replaces heroin use

• Is a long-acting Mu Opioid agonist
  
  • has same MoA as heroin
• Given as racemic mixture + as hydrochloirde salt
• START with 10-30mg/daily
• INCREASE to 60-120mg/daily (start seeing no withdrawal symptoms)

STRUCTURE:
- has tertiary amine (-N-)
- pKa of 9.1 = basic
- NO hydorgen bond donors
- is a small molecule
- ORALLY active and can cross BBB
- follows lipinski’s rules + BBB rules

NOTE: methadone is still addictive

Question 12

Explain Buprenorphine MoA

Answer 12

PARTIAL agonist at Mu receptor
Antagonist at delta + kappa receptors

• Given as sublingual tablet
  - but if have issues with adherance = prolong
• TAKE 12-24mg/daily
• Less sedating than methadone

STRUCTURE:
- Is a morphine analogue (has similar structure)
- has 5 rings
- Has amine salt
- protonated to form HCl salt = lowers LogD
- Formulated + given as hydrochloride salt
- salt helps as molecule is hydrophobic / lipophilic due to high LogP
- has 7 chiral carbon centres

Question 13

Benzodiazepines (BDZs) Dependance

Benzo = benzene ring | Diazepine = 7 membered ring with 2N

Answer 13

BDZs are used to treat insomnia and anxiety SHORT TERM
- gradually lower dose
- avoid long term use due to tolerance, dependance and withdrawal symptoms
- can easily become addicted to BDZs

BDZs bind to GABA A receptor

NOTE: BDZs should NOT be COMBINED with alcohol AND opioids = TOXICITY + FATAL overdose
- with opioids have risk of repiratory depression + death
- very high risk when combined with fentanyl (synthetic opioid)