Pharmacology Drug Therapy Of Parkinson's Disease I-Iv

Front 1

What is the central pathological feature of Parkinson's Disease?

Back 1

Loss of neurons in the substantia nigra pars compacta

Front 2

What is the result of the loss of neurons in the substantia nigra pars compacta?

Back 2

Striatal dopamine deficiency

Front 3

What use are antimuscarinic drugs in Parkinson's disease?

Back 3

They are effective for the treatment of certain aspects of motor disability, particularly tremor.

Front 4

What is the pathway for dopamine formation?

Back 4

Tyrosine is imported into the cell. Tyrosine hydroxylase converts tyrosine to L-dopa. Aromatic amino acid decarboxylase converts L-dopa to Dopamine.

Front 5

What drugs are dopamine precursors?

Back 5

L-dopa (levodopa; typically in combination with carbidopa).

Front 6

What drugs are dopamine agonists?

Back 6

Pergolide
Pramipexole
Ropinirole
Bromocriptine
Cabergoline

Front 7

What drugs affect dopamine release?

Back 7

Amantadine

Front 8

What drugs are monoamine oxidase (MAO) inhibitors?

Back 8

Selegiline
Rasagaline

Front 9

What drugs are catechol-O-methyltransferase (COMT) inhibitors?

Back 9

Entacapone
Tolcapone

Front 10

Describe the use of amantadine

Back 10

The antiglutamatergic properties of amantadine are utilized to treat abnormal movements (terms dyskinesias) that often develop during the course of PD.

Front 11

What are the symptoms of PD?

Back 11

Motor disability and a number of non-motor symptoms including depression, sleep disturbance, psychosis, urinary urgency, and constipation.

Front 12

What are issues with long term levodopa treatment?

Back 12

Although the discovery of levodopa revolutionized the treatment of PD patients, it was later discovered that after only five years of treatment, more than 75% of PD patients develop a shortened duration of response to levodopa ("wearing off") or disabiling levodopa-induced abnormal involuntary movements, termed dyskineasias, that are difficult to medically manage and significantly impair quality of life. Management of these complications requires alterations in the dose and timing of medication, as well as, treatment with combinations of drugs.

Front 13

What is the most significant risk factor for PD?

Back 13

Age. The mean age of onset is 44, and the incidcence increases markedly with age, from 20/100k overall to 120/100k at age 70.

Front 14

What are the clinical manifestations of the PD induced striatal dopamine deficiency?

Back 14

The may lead to "parkinsonism", a symptom complex characterized by:
(1) tremor at rest
(2) rigidity
(3) slowness/absence of voluntary movement (bradykinesia/akinesia)
(4) postural instability

Front 15

What is the most common cause of parkinsonism?

Back 15

Parkinson's disease, accounting for ~80% of cases

Front 16

Describe the PD tremor

Back 16

It is typically 4-6 Hz, occurs at rest and is decreased with voluntary movement. Thus, PD tremor does not typically impair activities of daily living.

Front 17

Describe the PD rigidity

Back 17

Rigidity refers to the increased resistance to passive movement observed when the physician moves the patient's limbs.

Front 18

What is bradykinesia?

Back 18

Slowness of movement

Front 19

What is hypokinesia?

Back 19

Reduction in movement amplitude

Front 20

What is akinesia?

Back 20

Absence of normal unconscious movements

Front 21

How do bradykinesia, hypokinesia, and akinesia manifest in PD patients?

Back 21

They manifest as a variety of usmptoms, including paucity of normal facial expression, decreased voice volume, drooling (failure to unconsciously swallow), decreased size and speed of handwriting, and decreased stride length during walking.

Front 22

Describe the consequences of bradykinesia

Back 22

It may significantly impair a patient's quality of life, causing it to take much longer to perform everyday tasks such as dressing or eating. PD patients also typically develop a flexed posture and may lose normal postural reflexes, leading to falls and, in a minority of cases, confinement to a wheelchair.

Front 23

Describe abnomalities of affect associated with PD

Back 23

PD patients may become passive or withdrawn, and develop a lack of initiative, preferring to sit quietly unless encouraged to participate in activities. Responses to questions are delayed, and cognitive processes are slowed ("bradyphrenia"). Depression is common. Demenia is significantly more frequent in PD, especially in older patients.

Front 24

What are the pathological hallmarks of parkinson's disease?

Back 24

Loss of SNpc DA neurons and the presence of proteinaceous cytoplasmic inclusions, termed Lewy bodies (LB).

Front 25

Describe cell loss in PD

Back 25

Cell loss is concentrated in ventrolateral and caudal portions of the SNpc whereas during normal aging the dorsomedial aspect of SNpc is affected. This pattern of cell loss parallels the level of expression of the dopamine transporter (DAT), and is consistent with finding that depletion of DA is most pronounced in the putamen, the site of projection for these neurons.

Front 26

Describe cell loss at the time of symptom onset in PD

Back 26

There is approximately 80% depletion of striatal dopamine and 60% loss of SNpc DA cell bodies. DA neurons in the adjacent ventral tegnmental area (VTA) are much less affected.

Front 27

Describe the neuropathology of PD outside the DA neurons.

Back 27

Neurodegeneration is commonly found in noradrenergic (locus coeruleus), serotonergic (raphe) and cholinergic (nucleus basalis of Meynert, dorsal motor nucleus of vagus) systems, as well as in cortex (especially cingulate and entorhinal cortices), olfactory bulb and in the autonomic nervous sytem.

Front 28

How is the diagnosis of PD made in live patients?

Back 28

It is made on clinical grounds, but definitive diagnosis requires the identification of both LBs and DA neuron loss.

Front 29

What are Lewy bodies?

Back 29

LBs are cytoplasmic aggregates composed of a number of proteins, including alpha-synuclein, parkin, ubiquitin, neurofilaments, and they are found in all affected brain regions.

Front 30

Describe the common molecular pathway between genetic and sporadic forms of PD

Back 30

The finding the LBs from sporadic PD patients contains proteins that are mutated in inherited PD suggests that a common molecular pathway is disturbed in the genetic and sporadic forms of the disease, although the role of LBs with respect to cell death is controversial.

Front 31

What are the three principles of medical therapy for PD?

Back 31

-Individualize therapy according to lifestyle needs of patients
-Individualize therapy according to predominant symptom and severity of disease
-Use minimum dosage of a drug necessary to control key symptoms.

Front 32

Describe how to individualize therapy according to the lifestyle needs of the patient

Back 32

Younger patients who are still working (and whose livelihood may be threatened by the disease) typically require more aggressive treatment than older patients. Because treatments are symptomatic and not curative, treatment decisions revolve around the goal of a) keeping the patient mobile and b) maintaining those activities valued by the patient

Front 33

Describe how to individualize therapy according to predominant symptom and severity of disease

Back 33

Patients early in the course of PD with isolated tremor may be treated with an anticholinergic drug or amantadine. Bradykinesia and rigidity are best treated with dopaminergic agents.

Front 34

Why is it important to use the minimum dosage of a drug necessary to control key symptoms of PD?

Back 34

All of the drugs used to treat PD have significant adverse side effects, including the ability to produce confusion and hallucinations. Therefore attempting to eradicate all the symptoms of PD with escalating amounts of medication will often lead to significant side effects of potential harm to the patient.