Dementia + Alzheimer's treatments + MED CHEM

What are the stages of medicines used to manage dementia?

- To prevent dementia

- At the start of dementia

- During later stages of dementia

What are the types of medicines used to treat dementia?

- Acetyclholine esterase inhibitors e.g., Rivastigmine

- NMDA antagonists e.g., Memantine

- Antioxidants e.g., Ginkgo

- Anti-inflammatories e.g., ibuprofen

- Neurotrophic factors e.g., oestrogen

- Antiamyloid agents e.g., tramiprostate

What medicines are used to prevent dementia?

- NSAIDs

- Antihypertensives

- Beer (small consumption)

- Oestrogen

- Fish once a week

What medicines are used at the start of dementia?

- Donepezil (AChEi)

- Galantamine (AChEi)

- Rivastigmine (AChEi)

Why are acetylcholine esterase inhibitors useful in the treatment of AD?

- AD leads to a loss of cholinergic neurons.

- AChEIs increase the duration of acetylcholine in the synapse by preventing its breakdown, allowing it to continue signaling.

- This enhances the activity of the remaining cholinergic neurons, helping to alleviate some symptoms of AD.

Describe donepezil.

- 5-10mg OD

- Give in morning as can cause sleep disturbances.

- Selective reversible AChEi

- Must wait 4 weeks before altering doses.

-

- Half life is 70 hours.

Describe Galantamine.

- 4-12mg BD

- Selective reversible AChEi

- Enhances response of nicotinic receptor to ACh.

- Half life is 7-8 hours.

Describe rivastigmine.

- 1.5-6mg BD

- Non-selective reversible AChEi.

- Non-competitive

- Can cause a rash if pathc is used so give emollient to treat.

- Half life is 1 hour.

What are the possible outcomes after AChEi treatment?

- Improvement

- Non-decline

- No response

How should AChEis be given?

- Slow titration is recommended.

- Rivastigmine is best choice for patients taking multiple medicines.

What are side-effects of AChEi?

- GI issues e.g., N&V, diarrhoea, loss of appetite.

- Sleep disturbances.

- Head ache,

- Incontinence

- Bradycardia

What medicines can cause cognitive impairment?

- Antihistamines e.g., diphenhydramine.

- Tricyclic antidepressants.

- Antipsychotics

- Hyoscine

- Pain killers

What medicines are used in the later stages of dementia?

Memantine

Describe Memantine.

- An NMDA receptor antagonist which is neuroprotective.

- Monotherapy is recommended for managing Alzheimer's disease who are intolerant to AChEi.

Describe the action of memantine.

- Memantine is a non-competitive NMDA antagonist.

- It reduces glutamate excitotoxicity, limiting neuronal death in AD.

- This helps stabilize or mildly improve cognition.

What is the dose of memantine?

5mg daily for one seek and then increase per week until 20 mg is reached.

What are side-effects of memantine?

- Headache

- Constipation

- Dizziness

- HTN

- Dyspnoea

What treatments are used for patients that have dementia but not Alzheimer's?

All unlicensed

Describe the SAR for non-covalent anticholineesterases e.g., donepezil.

- Carbonyl is essential, H-bond with phenylalanine on receptor

- Para (bottom) methoxy is essential, a second methoxy increases specificity.

- 5 carbon ring is essential next to aromatic.

- Piperidine ring is essential as nitrogen position is correct.

- CH2 is essential between 5 carbon ring and piperidine

- Benzene at the end is essential, adding electron donating groups worsens activity however still active.

Describe the SAR of carbamates e.g., rivastigmine.

- Amide is essential as undergoes reaction with catalytic triad.

- Aromatic is important as provides hydrophobic interactions.

- Tertiary amine is essential as provides ionic interactions at physiological pH.

Show the reaction between carbamate and catalytic triad in active site.

Carbamate is stabilised by added resonance from nitrogen lone pair.