Module 4.3.1 (Pharmacology of Drugs for Parkinsons) Flashcards
What is parkinson’s disease?
Parkinson’s disease results from the degeneration of dopaminergic neurons that arise in the substantia nigra and project to other structures in the basal ganglia.
> It is characterized by two major pathologic processes: (a) premature selective loss of dopamine neurons; (b) the accumulation of Lewy bodies, composed of α-synuclein, which become misfolded and accumulate in multiple systems of patients with Parkinson disease.
> Early non-motor features such as depression, sleep disturbances, constipation and anosmia may precede the diagnosis
Basal Ganglia include the
- striatium
- substantia nigra
- globus pallidus
- subthalamus
> imbalance between dopamine and ACh
In normal striatum, neurons that release dopamine will do what?
inhibit neurons that release GABA (an inhibitory transmitter)
In normal striatum, neurons that release AcH, will?
Excite the neurons that release GABA
Therefore what happens in the absence of dopamine?
The excitatory influence of ACh goes unopposed ⇒ excessive stimulation of neurons that release GABA
- Overactivity of the GABAminergic neurons contributes to the motor Sx that characterise PD
Outline which drugs are as used in pakrinsons disease for the following:
A) Dopamine agonists
B) Anticholinergics
C) Monoamine oxidase type B inhibitors
D) Other drugs
A)
- Apomorphine
- Bromocriptine
- Cabergoline
- Pramipexole
- Ropinirole
- Rotigotine
B)
- Benzatropine
- Trihexyphenidyl (also known as benzhexol)
C)
- Rasagiline
- Safinamide
- Selegiline
How does levodopa work? Where is it absorbed from?
Levodopa increases the concentration of dopamine in the brain
- Absorbed from dudodenum
- Protein in food reduces absorption
What is the 2 metabolism pathways of levodopa?
Metabolism by 2 pathways in peripheral tissue:
- Converted to dopamine by dopa decarboxylase
- Metabolised to 3-O-methyldopa by catechol-O- methyltransferase (COMT)
> large first pass
> only about 1% of administred dose of levodopa reaches brain tissue
dopamine doesn’t cross BBB, but precursor levodopa is transported into CNS and converted to dopamine in brain. Need large doses of levodopa because much of drug is decarboxylated to dopamine in the periphery ⇒ SE eg N, V, cardiac arrhythmias & hypotension. Therefore what is levodopa given with? What is the advantages of this?
Hence levodopa is given with a dopa decarboxylase inhibitor:
- Carbidopa
- Benserazide
decreases the dose of levodopa needed and decreases the severity of SE
- Dopa decarboxylase inhibitor does not cross BBB
- ↓ the metabolism of levodopa in the GIT & peripheral tissues –> increase availability of levodopa to the CNS
> Another advantage of combining carbidopa with Levodopa is the reduced risk of cardiac
abnormalities. Dopamine can have a direct affect on beta-adrenoreceptors that can
result in cardiac arrhythmias. With less peripheral dopamine there are less issues
with cardiac stimulation.
What are the peripheral and CNS adverse effects of levodopa?
Peripheral effects
- Anorexia, N & V –> Due to stimulation of the CTZ of the medulla.
- Orthostatic hypotension.
- Adrenergic action on the iris causes mydriasis
- Saliva & urine may ⇒ a brownish color bec of the melanin pigment produced from catecholamine oxidation
CNS effects
- Visual & auditory hallucinations
- Abnormal involuntary movements (dyskinesias)
- Episodes of sudden unpredictable loss of mobility (‘off’ effects)
- Mood changes
- Depression
- Psychosis
- Anxiety
What are the drug interactions for levodopa with the following:
A) Dopamine antagonists
B) Dopamine agonists
C) Non-selective MAOI
D) Antacids
E) Methyldopa
A)
- Antipsychotics, metoclopramide, prochlorperazine
- Antagonise levodopa activity & ↓ its therapeutic effect
B)
- ↑ adverse effects of levodopa
C)
- Inhibit the breakdown of dopamine and may cause hypertensive crisis in pts receiving levodopa
D)
- May ↓ the absorption of levodopa from controlled release products eg Madopar HBS, Sinemet CR –> space dose apart at least 2 hours
E)
- ↑ effect of levodopa
MOA of amantadine?
- ↑ dopamine release from nigrostriatal neurons and blocks cholinergic receptors
- Acts as a N-methyl-D-aspartate (NMDA) antagonist in the glutamatergic pathway from subthalamic nucleus to globus pallidus.
- Has antiviral activity against some strains of influenza A
> Prevents release of viral RNA into host cell.
AE (CIR) of Amantadine
Common
- N, V, dry mouth, constipation
- Livedo reticularis
Infrequent
- Urinary retention
Rare
- Confusion
What are two monoamine oxidase type B inhibitors? What is the MOA?
Rasagiline
Selegiline
- Selectively & irreversibly inhibit MAO Type B (which metabolizes dopamine)
- Do not inhibit MAO type A
- By ↓ metabolism of dopamine, selegiline & rasagiline ↑ dopamine levels in the brain
AE (CIR) and can tyramine reach food be eaten with MAO-B inhibitors?
Common
- N, V Orthostatic hypotension Headache Dyskinesia Accidental injury Arthralgia Rash
- Rasagiline can cause anorexia, weight loss.
Infrequent/rare
- Hallucinations
- Arrhythmias
Note
- Unlike other MAOIs, MAO-B inhibitors rarely cause hypertension when tyramine-rich food are eaten (and drug used at recommended doses)
- MAOI dietary restrictions apply if moclobemide + MAOB inhibitor used concurrently
What is Catechol-O-methyltransferase (COMT)?
COMT is an enzyme present at adrenergic & dopaminergic synapses
- Normally, methylation of levodopa by COMT to 3-O-methyldopa is a minor pathway.
- BUT when peripheral dopamine decarboxylase activity is inhibited by carbidopa, a significant concn of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS –> so we dowan this therefore we use COMT inhibitors
What are some common AE of pramipexole and rotigotine? –> dopamine receptor agonists
Pramipexole common AE
- Amnesia Visual disturbances Paradoxical worsening of RLS
Rotigotine common AE:
- Application site reactions Insomnia Paradoxical worsening of RLS
