Flashcards in Parkinsons drugs Deck (40):
how is the extrapyramidal system affected in parkinsons?
it controls communication between the brain and skeletal muscles.
• The symptoms of Parkinson's disease result from the loss of dopamine-secreting (dopaminergic) cells in the pars compacta region of the substantia nigra.
four major dopamine pathways in the brain
primary defect in :
1. nigrostiatal pathway ( mediates movement and is the most conspicuously affected in early Parkinson's disease)
mesocortical, the mesolimbic, and the tuberoinfundibular.
non striatal pathway symptoms
the non-striatal pathways is the likely explantion for much of the depression, dementia and psychosis that may be associated with Parkinson's disease.
Parkinson's disease SX
The major symptoms of PD include:
• Tremor at rest
• Rigidity (increased tone/stiffness in the muscles)
• Bradykinesia (slowness of movement) and akinesia (lack of spontaneous movement)
• Postural instability - Gait characterized by slowness and reduced amplitude, with small, rapid, stutter-steps forward. Stooped or flexed posture is common.
• Masked facies/ Drooling
• Speech problems (hypophonia and
indistinct articulation) vocal cords can be affected, causing monotonous, whispery, soft speech qualities
• Difficulty swallowing
• Micrographia (small, cramped handwriting)
• Urinary incontinence typically occurs late in
additionalor later sx
• Additional signs and symptoms commonly associated with Parkinson’s include:
• Fatigue (up to 50% of cases)
• Depression (occurs in 40 to 70% of cases)
• Anxiety or panic attacks
• Dementia is a later development in
approximately 20-40% of all Parkinson’s patients
how do sx start?
Symptoms usually begin in the upper extremities and are usually unilateral or asymmetrical at the onset of the disease.
The chemical agent MPTP (methyl-phenyl –tetrahydropyridine) is a neurotoxin precursor which destroys dopaminergic neurons in the substantia nigra.
what enzyme converts Levodopa into dopamine?
dopa- decarboxylase, an enzyme present in the basal ganglia and in other tissues.
• Levodopa is a dopamine precursor that is transformed into dopamine
L-dopa SE and C/I
severe protracted nausea.
vomiting and anorexia
hypotension, choreiform movements
insomnia and anxiety
Fortunately, this side effect has now been limited because of the formulation L-dopa with Carbidopa.
should never be taken in conjunction with an MAO inhibitor.
how do we prevent Levodopa from being prematurely converted into dopamine in the adrenal glands or other peripheral tissues?
usually combined with a
peripheral dopa-decarboxylase inhibitor
such as Carbidopa or Benserazide
This leaves more Levodopa available to reach the brain and also allows for a reduced original dosage thus reducing the peripheral side effects.
The most commonly used medications which contain Levodopa with a peripheral dopa-decarboxylase inhibitor include:
• Levodopa with Carbidopa/ Sinemet
• Levodopa with Benserazide/ Prolopa
• Levodopa in combination with both Carbidopa and Entacapone/ Stalevo
The most frequent side effects of these dopaminergic drugs are -------
nausea, sleepiness, dizziness, involuntary writhing movements and visual hallucinations.
Levodopa and all its formulations should never be used in conjunction with an MAO inhibitor because the combination can lead to a hypertensive crisis.
• Patients with psychiatric conditions such as schizophrenia should avoid Levodopa as it may cause a worsening of psychotic symptoms.
• Levodopa should not be given in conjunction with a dopamine blocking antipsychotic agent.
L-dopa with Carbidopa/ Sinemet
• Class: Dopamine precursor (L-dopa) with a peripheral dopamine decarboxylase inhibitor (Carbidopa).
• Indication: Parkinson’s disease
• MOA: Increases dopamine levels in the brain, especially in the substantia nigra.
• Char: PO. TID-QID. Dopamine cannot cross the blood barrier, but the precursor, L-dopa can cross the blood brain barrier.
L dopa/sinemet dosing
Sinemet is supplied as tablets in three strengths:
Sinemet 10-100, containing 10 mg of carbidopa and 100 mg of levodopa
Sinemet 25-100, containing 25 mg of carbidopa and 100 mg of levodopa
Sinemet 25-250, containing 25 mg of carbidopa and 250 mg of levodopa
The usual starting dose is one Sinemet 25-100 tablet taken three times per day
L-dopa with Carbidopa/ Sinemet SE
• Side effects: Prior to addition of Carbidopa, nausea was the most frequent side effect experienced by patients taking L-dopa. While nausea may still occur when Carbidopa is added to L-dopa, this side effect has been significantly reduced. Commonly reported side effects include hallucinations, nightmares, dyskinesias (uncontrolled movement) and serpentine like movement (chorea).
Dopamine agonists general
• Dopamine agonists are often used early in the treatment of Parkinson’s disease so that initiation of L-dopa therapy may be delayed.
Dopamine agonists can also be added at the same time as L-dopa is used in a effort to keep the L-dopa dose as low as possible.
• Dopamine agonists bind at various dopamine receptor sites: D1, D2, D3 or D4.
Sinemet is commonly given with other anti-Parkinson’s drugs such a
Mirapex (both dopamine agonists) or
Dopamine agonists examples
• The dopamine agonists include:
• Bromocriptine/ Parlodel
• Carbergoline/ Dostinex
• Pergolide/ Permax*
• Pramipexole/ Mirapex
• Ropinirole/ Requip
*Permax is no longer marketed in the US because its use was found to increase the risk of cardiac valve dysfunction.
tx of restless leg with parkinson drugs
Both Pramipexole (Mirapex) and Ropinirole (Requip) have FDA approval
• Class: Dopamine agonist
• Indication: Parkinson’s disease. Also used
in the treatment of prolactin secreting
adenomas and acromegaly.
• MOA: Mimics dopamine in stimulation of
dopamine receptor sites.
• Char: PO. Crosses blood brain barrier.
Used to delay need for L-dopa treatment or to augment L-dopa therapy.
The usual adult dose of Bromocriptine for Parkinson's disease is as follows:
1.25 mg tablet taken twice daily (with meals) then titrated up by 2.5 mg/day increments every 14 to 28 days as needed until symptoms improve. The maximum dosage of Bromocriptine for treating Parkinson’s disease is 100 mg/day.
Bromocriptine/ Parlodel SE
• Side effects: The usefulness of Bromocriptine and all of the dopamine agonists is limited by the large number of potential side effects such as
nausea, hypertension or hypotension, confusion, hallucinations, headache, depression, dyskinesia and possible seizures. Pulmonary fibrosis has been reported as an uncommon adverse effect when bromocriptine was used in extremely high doses.
Bromocriptine is a potent agonist at dopamine D2 receptors and various serotonin receptors. It also inhibits the release of glutamate by reversing the glutamate GLT1 transporter.
what to watch out for with bromocriptine:
Blood pressure levels should be monitored regularly, especially during the first weeks of therapy. Severe headache, hypertension, seizures, stroke, and myocardial infarction have occurred sometimes at the initiation of therapy. Particular attention should be paid to those patients who have recently received other drugs that can alter the blood pressure.
• Anticholinergics are useful in treating the tremor and/ or drooling associated with Parkinson’s disease but less useful in treating bradykinesia and rigidity. These drugs include:
• Benztropine/ Cogentin
• Ethosopropazine/ Parsitan
• Procyclidine/ Kemadrin
• Trihexyphenidyl/ Artane
the natural Belladonna alkaloids (Atropine, Belladonna, Hyoscyamine, and Scopolamine) are examples of:
work by transmitting all parasympathetic signals to end organs (i.e. the heart, lungs, GI tract) by binding to muscarinic receptors.
Anticholinergics agents such as Atropine are also used as an antidote to treat poisoning due to organic phosphorous (organophosphate) pesticides such as Diazinon, Malathion and Parathion, certain types of mushrooms (i.e. Amanita), and poisoning by nerve gas.
• Class: Anticholinergic
• Indication: Parkinson’s disease, especially when tremor or drooling are prominent symptoms. Appears to also help with cognitive symptoms due to Parkinson’s disease. In addition, used to diminish side effects of the antipsychotic drugs.
• MOA: Anticholinergic antagonist at muscarinic receptor sites.
• Char: PO. Used as single therapy or as an added adjunct to other medications. As a single therapeutic agent for Parkinson’s disease, Benzotropine and the other anticholinergics have minimal efficacy.
Benztropine/ Cogentin dosing
In patients with Parkinsonism, therapy with Cogentin is usually initiated with a single daily dose of 0.5 to 1 mg at bedtime. In some patients this will be adequate, while in others 4 to 6 mg a day may be required.
Benztropine/ Cogentin SE
• Side effects: Dry mouth, blurred vision, urinary retention, constipation, confusion, drowsiness, disorientation, memory impairment, visual hallucinations and possible exacerbation of pre-existing psychotic symptoms.
what dose Congentin OD look like
CNS depression, preceded or followed by stimulation, confusion, nervousness, listlessness, intensification of mental symptoms or toxic psychosis, dizziness, muscle weakness, ataxia, dry mouth, mydriasis, blurred vision, palpitations, tachycardia, elevated blood pressure, nausea, vomiting, dysuria, numbness of fingers, headache, hot, dry, flushed skin, delirium, coma, shock, convulsions, and respiratory arrest.
How do we treat Benztropine/ Cogentin OR Atropine overdose??
Physostigmine 1 to 2 mg, SC or IV, reportedly will reverse symptoms of anticholinergic intoxication.
Amandatine/ Symmetrel general MOA
• Amantadine has pharmacological actions as both an anti-Parkinson’s medication and as an antiviral drug.
• The precise mechanism of action of Amantadine for the treatment of Parkinson's disease and levodopa-induced extrapyramidal reactions is not known but it appears to be related to antagonism of N-methyl-D-aspartate (NMDA) receptors--> Antagonism of NMDA appears to result in diminished dopamine reuptake
Amandatine is used alone to treat early PD or used as an adjunct in later stages of PD, usually in patients with levodopa- related dyskinesias.
which neurotransmitter does NMDA mimic?
In contrast to glutamate, NMDA binds to and activates only that receptor site but does not appear to react to other glutamate receptor sites.
• Class: Anti-Parkinson’s and anti-viral agent • Indication: Parkinson’s disease and
• MOA: Unclear but probable NMDA
receptor antagonism accounts for anti-
• Char: PO. Chiefly used in attempt to delay
the onset of time of initiating Parkinson’s therapy with L-dopa.
Amandatine/ Symmetrel SE
• Side effects: Light headedness, confusion, drowsiness, nightmares, dry mouth, constipation, urinary retention, nausea and vomiting.
• The benefits of therapy with Amantadine are often short lived, with patients exhibiting diminished or absent response to Amantadine after 6 months or less.
Parkinson’s treatment optionsParkinson’s treatment options
• The order of efficacy of the medications used to treat Parkinson’s disease is as follows:
• L-dopa > Bromocriptine > Amantadine > anticholenergics
MAO-B inhibitors such as Selegiline (Eldepryl) are sometimes used to treat the early stages of PD
MAO-B vs MAO-B as related to Parkinson tx
Unlike the MAO-A inhibitors that may be used in the treatment of depression, he MAO-B inhibitors generally do not show the hypertension and excess catecholamine release problems as a consequence of eating tyramine-rich foods such as aged cheeses or raisins.