HNS52 Drugs Used For Neurodegenerative Diseases Flashcards
Neurodegenerative diseases
Deterioration of neurons (cannot regenerate) —> Affect brain function
Common brain regions:
- Basal ganglia (movement, reward)
- Hippocampus (memory)
2 different groups of neurodegenerative diseases
- Movement problems (Parkinson’s disease)
- Memory problems / Dementia (Alzheimer’s disease)
Huntington’s disease: both categories
Parkinson’s disease
- 2nd commonest neurodegenerative disease (after Alzheimer’s disease)
- No cure
Movement disorder (四寶):
- ***Resting tremors in limbs (手震)
- most common 1st symptom
- asymmetric (one side of body first before the other)
- evident in one hand with arm rested - ***Muscle rigidity (僵硬)
- ↑ muscle tone in flexor + extensor —> constant resistance to passive movements of joints - ***Bradykinesia (慢動作)
- difficulty with daily activities
- decreased blinking, slowed chewing and swallowing (eventually lost) - ***Abnormal posture and gait (姿勢不正確)
- small steps
Pathophysiology:
Degeneration in Substantia nigra
—> Loss of Dopaminergic neurons in Nigrostriatal pathway
—> ↓ Dopamine release to Basal ganglia
Basal ganglia control + Treatment strategy
Dopamine: Stimulate Basal ganglia —> Stimulate movement
—> Balanced by ACh (from Striatum): ***Inhibition of Basal ganglia —> Inhibition of movement
—> Well-balanced controlled muscle activity
Lack of Dopamine + Inhibition by ACh
—> Lack of muscle control
∴ Treatment strategy: Re-establish balance between Dopamine and ACh in brain
- ↑ Dopamine activity in Nigrostriatal system
- ↓ Muscarinic cholinergic activity in Striatum
Causes of Parkinsonism
- Impaired release of Dopamine —> Idiopathic parkinsonism (Parkinson’s disease) (Majority)
- Drug-induced parkinsonism (Antipsychotics)
- Reserpine (depleting dopamine store)
- Haloperidol (dopaminergic blocker, Typical antipsychotic) - Toxin damaging dopaminergic neurons
- Viral infection (Encephalitis)
- Trauma-repeated head injury
Levodopa (L-dopa)
- Precursor of dopamine
- ***High therapeutic index (drug of choice for symptom control esp. in elderly)
- **Readily cross BBB (dopamine cannot) —> converted to Dopamine in brain by **DOPA decarboxylase (also present in periphery)
- Large dose required when given alone —> broken down by ***DOPA decarboxylase in periphery
- ***Well-absorbed in GI tract
- Extremely short t1/2 —> “on/off” effect (***Apomorphine to counteract)
Drugs NOT to be given concurrently with L-dopa
- Non-selective MAOI (e.g. Phenelzine) —> **excess dopamine in periphery —> converted to NA, adrenaline —> **hypertensive crisis (life-threatening)
- Pyridoxine (vit B6) —> ***co-factor for DOPA decarboxylase —> ↑ peripheral breakdown of L-dopa
- Antipsychotics —> block dopamine receptors —> parkinsonism-like symptoms
Adverse effects of L-dopa
Overstimulation of central dopamine receptors:
- ***Dyskinesia (involuntary muscle movement)
- ***Hallucinations
- Restlessness
- Confusion
Conversion of L-dopa to Dopamine in periphery:
- ***N+V (∵ stimulate Dopamine receptor in CTZ)
- ***Postural hypotension (∵ vasodilation)
- Arrhythmia
Peripheral DOPA decarboxylase inhibitors
- Carbidopa
- peripheral inhibitor —> do not cross BBB
- combination with L-dopa (L-dopa:Carbidopa = 4:1) —> Sinemet
—> ↓ breakdown of L-dopa in periphery
—> ↑ availability of dopamine to CNS - Benserazide
- peripheral inhibitor
- combination with L-dopa (L-dopa:Benserazide = 4:1) —> Madopar
Dopamine receptor agonist
- Bromocriptine
- Pergolide
- Pramipexole, Ropinirole
- Rotigotine
- Apomorphine
- Bromocriptine
- Ergot derivative (from fungus)
- act on D2-like receptors (D2, D3, D4)
Use:
- useful to delay use of L-dopa in younger patients
- ***minimal effects on bradykinesia
- can be used in conjunction with Sinemet —> relieve rigidity and tremor
SE:
- Hallucination, Delirium
- N+V
- Arrhythmia, Postural hypotension
- ***Erythromelalgia: red, painful, swollen feet / hands (blood vessels blocked)
- Pergolide
- Ergot derivative
- act on D1-like + D2-like receptors (D1-D5)
Use:
- used in conjunction with Sinemet and Anticholinergics
SE:
- Confusion
- Hallucinations
- Postural hypotension
- Urinary tract infection
- Pramipexole, Ropinirole
- Non-ergot derivative (Synthetic)
- act on D2-like receptors
Use:
- ***1st line in younger patients
- Adjunct to Sinemet treatment in advanced PD
- fewer GI SE
SE:
- Dyskinesia
- Insomnia / Somnolence
- Dizziness
- Postural hypotension
- Rotigotine
- Non-ergot derivative
- act on D2-like receptors
Use:
- ***Transdermal patches in PD for swallowing problems (NEUPRO patch)
SE:
- Hypersensitivity reactions / skin problems (redness, rashes, irritation)
- Dizziness
- Headache
- Nausea
Selegiline + Rasagiline - Selective MAO-B inhibitor
MOA:
Inhibit ***MAO-B
—> prevent metabolism of Dopamine in periphery + brain
—> ↑ Dopamine level
(Non-selective MAOI: Phenelzine, Tranylcypromine
Selective MAO-A inhibitor: Moclobemide)
Use:
- Adjuvant therapy: Enhance effects of Sinemet, Madopar
SE:
- Hypertensive crisis in high dosage (conversion to NA / adrenaline in periphery)
Entacapone + Tolcapone - COMT inhibitors
MOA: Block COMT (Catecholamine-O-methyl transferase) (NOT cross BBB)
- Prevent peripheral conversion of L-dopa —> ***3-O-methyldopa
—> prevent 3-O-methyldopa competing with L-dopa for active carrier to transport across GI tract, BBB) - Prevent conversion of Dopamine —> 3-methoxytyramine
Use:
- ONLY as adjuncts to Sinemet, Madopar
SE:
- Diarrhoea
- Postural hypotension
- Dyskinesia
- Sleep disorder
- Hallucinations
- Hepatic necrosis (Tolcapone only)
Amantadine - Dopamine facilitator
- Antiviral against influenza
MOA:
- Unknown mechanism
1. **↑ Dopamine release from surviving nigral neurons
2. **Inhibit reuptake of Dopamine in synapse
Use:
- more effective than Anticholinergics in improving ***bradykinesia, rigidity when used along Sinemet, Madopar
- Adjuvant in severe patients (NOT 1st line)
SE:
- Restlessness, agitation, confusion
- Postural hypotension
- Peripheral edema
- Skin rash
***Summary of drugs acting on dopaminergic system
- Levodopa (+ Peripheral DOPA decarboxylase inhibitors)
- Sinemet (Levodopa + Carbidopa)
- Madopar (Levodopa + Benserazide) - Dopamine agonist
- Bromocriptine (D2-like)
- Pergolide (D1+D2-like)
- Pramipexole, Ropinirole (D2-like, 1st line)
- Rotigotine (D2-like, patches)
- Apomorphine - Selective MAO-B inhibitor
- Selegiline
- Rasagiline - COMT inhibitor
- Entacapone (Stalevo: Levodopa + Carbidopa + Entacapone)
- Tolcapone - Amantadine
Central anticholinergics
DO NOT confuse with AChE inhibitor!!!
- ***Benztropine
- Trihexyphenidyl (Benzhexol)
- Biperidine
- Procyclidine
- Orphenadrine
MOA:
↓ Cholinergic output from Striatum / Block Cholinergic receptor
—> ↓ Inhibition of Basal ganglia
—> ↓ Inhibition of movement
Use:
- much less efficacious than Sinemet
- ***Adjuvant in PD
- Reduce primary symptoms (e.g. tremor, rigidity, akinesia) (***NOT bradykinesia) + secondary symptoms (drooling)
SE:
- Sedation (CNS effect)
- Urinary retention
- Dry mouth
- Constipation
- Mental confusion
Treatment for drug-induced parkinsonism (Antipsychotics)
(Too little Dopamine in body)
- Lower drug levels (antipsychotics)
- Change drug to less potent one
- Use an anticholinergic agent (↓ ACh) if have to maintain antipsychotic dose
Treatment guideline to idiopathic PD
Dopamine agonist / Sinemet —> inadequate control —> add Sinemet —> inadequate control / wearing off —> Sinemet dose more frequently / higher dose —> + COMT inhibitor / MAO-B inhibitor —> Surgery (DBS)
***Adjunct:
For tremor: Anticholinergic
For drug-induced dyskinesia: Amantadine
For “off” episodes: Apomorphine
Huntington’s disease / chorea
Genetic disorder due to single defective “dominant” gene on ***chromosome 4
**Hyper-reactivity of dopaminergic pathways
—> due to **diminished GABA functions in Basal ganglia
—> ***inhibition of indirect pathway
—> promote movement
Symptoms:
- Involuntary movements
- Dementia
- Depression
- Cognitive decline
Treatment for Huntington’s disease
Symptomatic and only partially successful
- Medication for movement symptoms:
- **Tetrabenazine —> **deplete dopamine —> suppress chorea
- ***Antipsychotic (Haloperidol, Risperidone) —> SE of suppressing movement - Medication for psychiatric symptoms:
- Antidepressant (Fluoxetine)
- Mood-stabilising drugs (Carbamazepine) —> treat irritability
Alzheimer’s disease
- Neurodegenerative condition
- Loss of cognitive function —> eventually mobility
- Chronic, progressive dementia (no cure)
- Female > Male
Clinical Features:
- β-amyloid accumulations
- Neurofibrillary tangles formation (numerous) (Tau protein)
- ***Loss of cortical cholinergic neurons
Affected regions:
1. **Cortical shrinkage
2. **Hippocampus shrinkage
—> enlarged Ventricles
Symptoms:
- forgetfulness
- getting lost in familiar setting
- lose interest in family
- deterioration of work performance
- disorientation (time and place)
- behavioural changes
- slower walking / falls
Stages:
- Pre-dementia
- mild cognitive impairment - Mild (early)
- difficulty remembering newly learned information - Moderate
- disorientation
- mood and behavioural changes
- deepening confusion about events, time and place - Severe
- difficulty speaking, swallowing and walking
Treatment options of Alzheimer’s disease
- AChE inhibitors (↑ ACh)
- Improve cholinergic transmission within CNS
- **Donepezil —> all stages
- **Rivastigmine (patch) —> all stages
- ***Galantamine —> mild-moderate (also Nicotinic receptor allosteric modulation)
SE:
- N+V
- Diarrhoea
- Abdominal cramps
- Anorexia —> appetite and weight loss
- Agitation
- Dizziness
- Urine incontinence
- Memantine
- **NMDA receptor antagonist (uncompetitive) —> moderate-severe
- Protect CNS neurons from **excitotoxicity actions of glutamate on NMDA glutamate receptors —> Improve cognitive ability
- Add-on therapy
SE:
- Headache
- Dizziness
- Confusion
- Constipation
- Diarrhoea
