What is a progressive neurodegenerative disorder? | Parkinson's Disease |
What is Parkinson's diseases caused by? | By degeneration of substantia nigra in the midbrain, with irreversible loss of DA-containing neurons in the nigrostrial pathway. |
What part does dopamine play in the prevention of Parkinson's disease? | Dopamine reduces resting tremor by potentiating inhibitory mechanisms in a cerebellar nucleus of the thalamus ( ventral intermediate nucleus) |
The symptoms of Parkinson's disease result from what? | loss of nigrostrial neurons and DA depletion. ACh predominates |
What is the symptomatic triad of Parkinson's disease? | bradykinesia, rigidity and tremor |
What are the secondary manifestations of Parkinson's disease? | defective posture and gait, mask-like face and sialorrhoea,
dementia ( in some cases) |
What is the etiology of Parkinson's disease? | 1) Genetics:
2) Environmental Factors
3) Toxins
4) Drugs |
What is alpha-synuclein? | deposited in dopaminergic neurons of substantia nigra with loss of pigmentation leading to the formation of Lewy bodies ( the pathological hallmark of PD) and dopaminergic cell death |
What is Lewy neurite? | swollen nerve fibers that contain alpha-synuclein and other proteins which interfere with transmission of nerve signals and neuronal functions. |
Does dopamine pass the blood-brain barrier? | NO. Dopamine must be produced within the CNS in order to act in the striatum |
Briefly describe the biosynthesis and metabolsim of dopamine | Please see image attached |
What is the final inactive metabolite of dopamine? | homovanillic acid by either MAO or COMT |
What are the clinical manifestations of Parkinson's disease? | Tremor- "Resting tremor
Rigidity
Bradykinesia |
What are the five dopamine receptor subtypes? | D1, D2 ( found in corpus striatum)
D3, D4, and D5 |
What is the function of D1 and D5? | activates adenlyl cylcase to produce cAMP |
What is the function of D2, D3 and D4? | inhibits adenlyl cyclase to produce less cAMP |
Where is dopamine produced? | cells in the PARS COMPACTA of the SUBSTANTIA NIGRA. |
What are the two pathways through which striatal information reaches Globus Pallidum Internal? | Direct Pathway ( excitatory)
and Indirect Pathway ( inhibitory) |
Explain the mechanism behind the binding of dopamine to the D1 and D2 receptors | Will Discuss Via Google Meets |
What are the objectives of antiparkinsonian pharmacotherapy? | 1) Enhance DA-ergic activity
2) Reduce cholinergic activity |
What are examples of DA agonists? | bromocriptine and cabergoline |
What are examples of drugs that inhibit the metabolism of dopamine? | selegiline and rasagiline |
What is an example of a drug that inhibits the reuptake of dopamine? | amantadine |
What is LEVODOPA? | natural AA precursor of DA
Crosses the BBB via L-amino acid transporter
effective in treating symptoms of rigidity and bradykinesia seen in PD
1-3% only oral dose reaches the brain |
What are the adverse effects of L-DOPA? | Nausea, Vomiting; nearly 80% patients
Postural Hypotension
Cardiac Arrhythmias
Anxiety, Agitation, Hallucinations/ mood changes |
What is the main adverse central adverse reaction of L-dopa? | Athetosis: a condition where the patient experience slow, convulated, involuntary and writhing movements of the hands, fingers, feet and toes |
What is the wearing- off phenomenon? | increasingly shortened benefit period following each dose of l-dopa due to l-dopa's short half life. |
What is L-Dopa Honeymoon? | early phase of treatment (lasts 5-6 years typically) |
What is On-Off Fluctuations? | characterized by sudden, unpredictable shifts of mobility between undertreated and treated states- sudden, unpredictable and very difficult to treat. |
What are examples of COMT inhibitors? | entacapone and tolcapone |
What are examples of dopamine agonists? | ropinirole,pramipexole,rotigotine |
What are examples of MAO-B inhibitors? | selegiline, rasagiline |
What are L-Dopa Interactions? | Avoid high protein meals; AA's compete with L-dopa for entry to the brain. Take on empty stomach or reduce dietary protein.
Vitamin B6: metabolizes L-dopa
Hypertensive crisis if MAOIs are given concomitantly
L-dopa should not be prescribed to treat the extrapyramidal effects of antipsychotics since l-dopa enhances dopamine and its interaction with D2 receptors in the mesolimbic and mesocortical pathways.
Antipsychotics block these receptors and their efficacy could be compromised |
What dopamine agonists are ergot-derivatives? | Bromocriptine and Carbergoline |
What dopamine agonists are non-ergot-derivatives? | Pramipexole and Ropinirole and Apomorphine |
What is the difference between dopamine agonists and l-dopa? | 1) They act directly at dopamine receptors, therefore, it does not need metabolic conversion to an active moiety as in the case of L-DOPA
2) They do not undergo oxidation and thus avoid the generation of free radicals that may contribute to neuronal degeneration
3) Their longer half-life causes fewer motor complications as they provide continuous stimulation of striatal dopamine receptors and reduce frequency of dosing required to maintain adequate drug levels
4)DAs do not require carrier-mediated transport for GI absorption or entry into the BBB; thus dietary restrictions are not required
5) DAs usage is associated with more hallucinations, somnolence, and edema than with levodopa therapy. |
What is the triple combination used for patients with end of dose, wearing off?
What is the major risk ? | Carbidopa, L-Dopa and Entacapone
CVS events |
What is the side effect of tolcapone? | hepatatoxicity |
What is Bromocriptine? | D2- receptor agonist, but weak alpha-adrenoceptor anatagonist.
Commonly used with l-dopa
started at low doses at night, titrating up according to clinical response |
What is Bromocriptine also used for? | prolactin-secreting adenomas,amenorrhea/galactorrhea to hyperprolactinemia, to stop lactation, acromegaly |
What are the adverse reactions of bromocriptine? | nausea, vomitting which may be prevented by domperidone, postural hypotension |
What is cabergoline | Better than bromocriptine
Longer half life.
Used once or twice a week
Alleviates night -time problems in PD due to lack of l-dopa |
What is pramipexole? | Non-ergot D2 and D3 receptor agonist
more effective against tremors
Allows dose of LD to be reduced and smoothens out fluctuations |
What is ropinirole? | new non-ergot
direct D2 receptor agonist
metabolized by CyP450 so clearance may be reduced if used with simultaneous metabolisers |
What are the adverse effects of dopamine agonists? | drowsiness, nausea, vomiting, dry mouth, dizziness, leg swelling, orthostatic hypotension.
sleepiness
compulsive behaviors- shopping, binge eating, gambling, sexual activities |
What is apomorphine? | used in emergency cases
"rescue" medication |
What is amantadine? | antiviral agent used for influenzea |
What are central antimuscarinic drugs? | shows modest improvement in tremor, rigidity and sialorrhea and muscular stiffness |