Parkinson's Disease Drugs Flashcards
What are the symptoms of Parkinson’s?
Three S’s : slow, stiff, shaky
Slow = bradykinesia
Stiff = rigid
Shaky = resting tremor
This presents as motor changes:
- “Pill rolling” tremor in hands
- Slow shuffling gait
- Difficulty initiating movements (e.g. getting out of chair)
- Tiny handwriting
- Reduced facial expressions
- Soft voice
Disease progression more rapid if:
-older, male patient
-rigidity is the main symptom
-other comorbidities (stroke, etc.)
Disease progression slower if:
- Younger person, tremors are the primary symptom.
What is the cause of Parkinson’s?
Cell death of dopaminergic neurons in the SUBSTANTIA NIGRA PARS COMPACTA
Eventually other neurons in other brain regions die too
(b/c it’s a progressive movement disorder)
*common for both hemispheres to be eventually affected
When do symptoms appear?
when about 70% of nigrostriatal neurons are lost
What are the Basal ganglia & motor control?
Basal ganglia are needed to INITIATE movements
At rest, the thalamus is tonically inhibited by the striatum
Outputs from the striatum lead to both activation and inhibition from the thalamus
*Dopamine from the SNpc excites the direct pathway (D1 receptors) and inhibits the indirect pathway (D2 receptors). Net result= movement
*Removes tonic inhibition
What is Parkinson’s disease?
Dopamine neuron die, so the tonic inhibition is not removed.
When dopamine is lost, the thalamus remains inhibited.
Compare the Nigrostriatal Pathway (Normal vs. Parkinson’s)
Normal:
- GABA neurons are inhibited by dopamine and stimulated by acetylcholine
Parkinson’s Disease
- Dopaminergic neurons die, leaving a relative excess of acetylcholine
*Not enough dopamine, too much acetylcholine in the striatum (main message for patho)
What are the enzymes that have ~ ability to degrade dopamine? & what is the main one?
Main one: MAOB
Other enzymes that have ~ability to degrade dopamine: MAOA, MAOB, COMT
How would you treat Parkinson’s disease? (i.e. where in the CNS would you target?)
- Replace dopamine
- Increase dopamine receptor activity (agonists)
- Block dopamine breakdown
- Enhance dopamine release
Strategies to treat Parkinson’s Disease:
- Replace dopamine
- Increase dopamine receptor activity (agonists)
- Block dopamine breakdown
- Enhance dopamine release
________ dopamine signalling in the striatum
INCREASE
What is the dopamine synthesis in substantia nigra?
1 used (a prodrug)
Levodopa (L-DOPA)
used b/c dopamine doesn’t cross BBB
What is the L-DOPA Pharmacology?
UPTAKE
- Peak plasma concentration 1-2 h after ingestion
- 1-3 h half life
L-DOPA is always given in combo with drugs that:
________ peripheral dopamine metabolism
DECREASE
What are the drugs (added to Levodopa) to increase dopamine signalling?
- Entacapone (blocks COMT)
-Carbidopa (blocks DOC)
- Benserazide (blocks DOC)
Levodopa + carbidopa =
STANDARD therapy (peripheral metab. is inhib. & more gets to brain)
Levodopa + carbidopa + entacapone =
for late stage patients
Levodopa + carbidopa CR (controlled release)
…
What are drugs to increase dopamine signalling?
- Increase dopamine receptor activity (agonists)
- Block dopamine breakdown
- Enhance dopamine release
Monoamine Oxidase A (MAOA):
Metabolizes norepinephrine (noradrenaline) and serotonin (5-HT)
Monoamine Oxidase B (MAOB):
Metabolizes dopamine
Monoamine oxidase B inhibitors:
Rasagiline, selegiline
- Rasagiline (2nd gen) - better bioavailability, fewer side effects
- Monotherapy or adjunct that enhances effects of L-DOPA
(drug to increase dopamine signalling)
Dopamine agonists:
Ropinirole (po), rotigitine (patch)
- Second generation drugs, better than first (bromocriptine)
- Act on D2 receptors (inhibitory receptors; seems to be more effective for initiating movement)
- Often preferred by young PD patients (due to less motor complications (“wearing off”) (fewer SE’s)
Enhance dopamine release:
Amantadine
- Only of short-term benefit (< 6 months) (therefore, not readily used)
- Better for younger PD patients because of anti-cholinergic side effects
What are the common side effects of increasing dopamine signalling?
- Dyskinesias (ABNORMAL INVOLUNTARY MOVEMENTS)
(b/c of too much dopamine)
CNS effects
- NAUSEA & VOMITING (area postrema; 80% of patients)
- Anorexia
- Behavioral changes
- Insomnia, confusion, dizziness
- Psychosis, schizophrenia-like behavior, hallucinations
Peripheral effects
- Hypotension (postural) and cardiac arrhythmias
Most can’t sit still b/c of the drugs
What are the unique SE’s?
Levodopa
- Wearing off or “on-off” effect (15-20% of patients)
- Give with entacapone or switch to ropinirole
Increased libido
Ropinirole
- Increased libido (sometimes inappropriate sexual behavior)
- Pathological gambling or spending (due to overactivation of reward pathway)
Amantadine
- Less dyskinesia
- Increased confusion (in the eldery, due to anticholinergic effects)
- Nightmares
- Rose coloured mottling of the legs (livedo reticularis)
What is Domperidone(peripheral D2 receptor antagonist)?
Many drugs that increase dopamine signalling cause nausea and hypotension due to activity on peripheral dopamine receptors
Therapeutic effects
- Does not cross the BBB
- Blocks peripheral dopamine receptors
- Decreases nausea, increases blood pressure
What are the drug interactions of Parkinson’s dopamine treatments?
How to treat psychosis? MOST ANTI-PSYCHOTICS ARE DOPAMINE ANTAGONISTS.
SSRIs (especially rasagiline, ropinirole)- can lead to serotonin syndrome (=> death due to too much serotonin in their brain; anti-depressants)
Monoamine oxidase A inhibitors- a problem with rasagiline, ropinirole, levodopa (increased toxicity
Drugs to increase dopamine signalling:
- Entacapone
- Carbidopa
- Domperidone (peripheral D2 antagonists)
- Amantadine
- Levodopa
- Rasagiline
- Ropinirole
_______ cholinergic activity in the striatum
Decrease
What is Benztropine or Trihexyphenidyl(Muscarinic Antagonists) Therapeutic Effect?
- Not a first line therapy
- Used mainly in young patients with severe tremor
- NOT RECOMMENDED in elderly (can amplify confusion and memory deficits)
- Inhibition of striatal cholinergic activity
What is Benztropine or Trihexyphenidyl(Muscarinic Antagonists) SE’s?
- Dry mouth
- Blurred vision
- Urinary retention
- Constipation
- Mental confusion, hallucinations, delusions
- *Contradindicated in Glaucoma (M3 receptors in iris)
What are the 1st LINE drugs to increase dopamine in the striatum?
- Levodopa (prodrug)
– Peripheral L-dopa enzyme inhibitors (carbidopa, entacapone) - MAO-B inhibitors (rasagiline)
- D2 receptor agonists (ropinirole)
What are the 2nd LINE drugs to increase dopamine in the striatum?
- Dopamine releaser (amantadine)
Drugs to decrease acetylcholine activity in the striatum
- Anticholinergics (benztropine)
Drugs to help with side effects (due to peripheral activity)
Peripheral D2 receptor antagonist (domperidone)
