Neurodegeneration Flashcards
levodopa
Enhancer of DA synthesis
Precursor of DA that crosses BBB
Decreases rigidity, tremors, and other symptoms of parkinsonism
After 3-5 years patients experience decline in response to medication (“wearing off” effect)
Orally available, rapidly absorbed from small intestine
Only 1-3% of L-DOPA reaches brain, rest is metabolized peripherally by aromatic amino acid decarboxylase
Short half life (1-2hrs)
Side Effects:
- Peripheral side effects due to conversion to NE
- Nausea, vomiting, anorexia, cardiac arrthymias, orthostatic hypotension
CNS side effects:
- Visual and auditory hallucinations, abnormal involuntary movements (dyskinesia), may cause mood changes:
- Depression,
- Psychosis
- Anxiety
Drug of choice for Parkinsonism, especially late stage
L-DOPA+carbidopa
Increase DA synthesis
Combined therapy
Carbidopa (aromatic I-amino acid decarboxylase INHIBITOR blocks the metabolism of L-DOPA peripherally to allow availability
Allows reduction of L-DOPA by 4-5 fold to reduce the side effects of DA
entacapone
Enhancers of DA Synthesis
Inhibits catechol-O-methyltransferase to further decrease peripheral metabolism of Levodopa to allow availability of L-DOPA availability for the brain
apomorphine
Dopamine Receptor Agonist
Acute treatment for patients with ADVANCED Disease
or “Off” periods (marked bradykinesia, immobility)
Administered via subQ injection NOT IV
- IF IV may lead to thrombus formation/pulmonary embolism
SIDE EFFECTS:
- Nausea, vomiting, arrthymias, postural hypotension, hallucinations, pronounced sleepiness
bromocriptine
DA receptor Agonist
D2 agonist
D1 partial agonist
Effective as monotherapy early in disease or as adjunct to L-DOPA in later states of Parkinsonism
Orally active
Being with low dose:
- 1.25 mg/twice daily
- Gradually increase to reach therapeutic effect while keeping SE minimal
- Increase 2.5 mg every 2 weeks until benefit occurs
- Usual maintenance is 10-30 mg/day
Side Effects:
- Cardiovascular Effects:
- Cardiac arrthymias, postural hypotension
- Neurological effects: Depression ,hallucinations, sleepiness, impulsivity, confusion
GI problems: N/V
Contraindications: Patients with mental problems
pramipexole
DA receptor AGONIST
D2 Agonist
D3 Agonist
Effective monotherapy early in disease
Orally active
Begin with low doses and gradually increase until desired effect is seen
ropinirole
DA receptor AGONIST
D2 Agonist
D3 Agonist
Effective monotherapy early in disease
Orally active
Begin with low doses and gradually increase until desired effect is seen
amantadine
Mixed action Parkinson’s drug therapy
Alleviates: Bradykinesia and rigidity
- Not helpful for tremors
- Useful for patients with mild to moderate disease prior to initiating L-DOPA
Mechanism:
- Moderately increase DA release
- Blocks cholinergic Muscarinic receptors
- Blocks glutamatergic NMDA receptors
Side Effects:
- Hallucinations/confusion
- Nausea
- dizziness
- Rash on low extremities
- Special caution when prescribing to patients with CHF and GLAUCOMA
Was developed as an antiviral for treatment of influenza
benztropine
Antagonist of Muscarinic Cholinergic Receptors
Parkinson’s disease drug therapy
Used to alleviate:
- Tremor
- Rigidity
- NOT helpful in bradykinesia
Monotherapy or along with other drugs
Mechanism:
- Loss of nigrostriatal neurons from Parkinson leads to increased firing of striatal cholinergic interneurons for overstim of M receptors
- M receptor antagonist will block this effect
Side Effects:
- Typical antimuscarinic effect
- Blurred vision (loss of accomodation)
- Urinary retention
- Constipation
- Aggravation of glaucoma
- Delirium, psychosis, memory impairment
trihexyphenidyl
Antagonist of Muscarinic Cholinergic Receptors
Parkinson’s disease drug therapy
Used to alleviate:
- Tremor
- Rigidity
- NOT helpful in bradykinesia
Monotherapy or along with other drugs
Mechanism:
- Loss of nigrostriatal neurons from Parkinson leads to increased firing of striatal cholinergic interneurons for overstim of M receptors
- M receptor antagonist will block this effect
Side Effects:
- Typical antimuscarinic effect
- Blurred vision (loss of accomodation)
- Urinary retention
- Constipation
- Aggravation of glaucoma
- Delirium, psychosis, memory impairment
rasagiline
MAOb inhibitor
Decrease DA catabolism
Not metabolized to amphetamine like substance
selegiline
MAOb inhibitor
Decrease DA catabolism
Decreases production of hydrogen peroxide, limit formation of neurotoxic free radicals
Adjunctive therapy in parkinson’s patients receiving levodopa
Little benefit if taken alone
Orally active
Half life: 7-9hrs
Renal Excretion
Metabolized to methamphetamine and amphetamine
Insomnia
donepezil
Acetylcholinesterase Inhibitor
Treatment in Alzheimers
Block catabolism of acetyl choline to increase amount of ACh in presynaptic terminals
Produce modest improvement in some patients, may retain for several years
Good oral bioavailability
Variable pharmacokinetic and half life time
Half life: 70 hours
Metabolized by p450 enzymes:
- CYP3A4
- CYP2D6
Side effects:
- Tremors
- Bradycardia
- Nausea
- DIarrhea
- Anorexia
galantamine
Acetylcholinesterase Inhibitor
Treatment in Alzheimers
Block catabolism of acetyl choline to increase amount of ACh in presynaptic terminals
Produce modest improvement in some patients, may retain for several years
Good oral bioavailability
Variable pharmacokinetic and half life time
Half life: 7 hours
Metabolized by p450 enzymes:
- CYP3A4
- CYP2D6
Side effects:
- Tremors
- Bradycardia
- Nausea
- DIarrhea
- Anorexia
rivastigmine
Acetylcholinesterase Inhibitor
Treatment in Alzheimers
Block catabolism of acetyl choline to increase amount of ACh in presynaptic terminals
Produce modest improvement in some patients, may retain for several years
Good oral bioavailability
Variable pharmacokinetic and half life time
Half life: 1.5 hours
Metabolized by:
PLASMA CHOLINESTERASE
Side effects:
- Tremors
- Bradycardia
- Nausea
- DIarrhea
- Anorexia
