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Post  counselor on Mon Oct 15, 2012 12:08 pm


The disease was first described by James Parkinson in 1817 under the name of paralysis agitans.
It 'a neurodegenerative disorder with a prevalence of 2 cases out of 100 for the population over 65 years

E 'characterized by four key clinical signs:

• tremor: alternating contractions of muscles and their antagonists at the rate of 3-5 per second. E 'typical contar the movement of the coins.
• Bradykinesia: lack of spontaneous movements, slow onset of voluntary movements.
• Rigidity ': due to increased muscle tone. The rigidity of the muscles of the face determines the so-called facies marble.
• DEFECT POSTURAL inability to maintain an upright position.

Approximately 30% of patients manifest dementia

1. The disease is caused by degeneration of dopaminergic neurons that from the substantia nigra (pars compacta) are the striatum (caudate putamen).
2. The striatum contains normally 80% of brain dopamine. In the person with Parkinson's disease do the content drops to 10% of the normal value.
3. From the striatum there are two direct efferent pathways to the cortex: direct striatal-thalamic-cortical and indirect striatal-thalamic-cortical.
4. Dopamine in the striatum plays an excitatory (via D1 receptors) on the GABAergic neurons via direct thalamocortical evoking thus facilitating mobility.
5. Dopamine in the striatum plays an inhibitory receptors (D2) on GABAergic neurons of the indirect pathway thalamocortical evoking thus reducing motor activity.

• Genetic factors may also help if you do not seem to have an important role
• Toxins such as MPTP (N-methyl ,4-phenyl, 1,2,3,6, tetrahydropyridine) and similar compounds may induce the disease.
The onset of the disease is also facilitated by
• Aging,
• Defects metabolic
• Damage radical


The purpose of therapy is to restore dopaminergic transmission:
• generating dopamine in the CNS
• stimulating dopamine agonists
• inhibiting the metabolism of dopamine
• is obtained by reduction of tremor also
inhibiting cholinergic transmission that is increased in the striatum of patients with Parkinson's disease.

1) Levodopa (L-3-4 dihydroxyphenylalanine)
Originates from tyrosine and gives rise to decarboxylation to dopamine by the enzyme dopa-decarboxylase.

Levodopa is almost pharmacologically inactive. Owes his conversion to dopamine.

Central nervous system
• Changes in the CNS by active transport. To have good penetration of levodopa in the CNS is necessary to block the peripheral decarboxylation.
• Patients treated with levodopa have concentrations of dopamine in the striatum 5-8 times higher than in untreated patients.
• In normal subjects, no significant effects are observed.
• In patients with Parkinson's disease levodopa reduces bradykinesia and rigidity. The tremor decreases, but in a gradual manner.
• It has improved motor manifestations secondary (posture, gait, facial expression, handwriting, swallowing).
• A psychic level is increased interest in his own person, the environment and the family.
• Levodopa does not improve the symptoms of dementia.

Cardiovascular system
The effects of levodopa are due to dopamine.
At therapeutic doses causes:
a) Orthostatic hypotension for action on dopamine receptors in the vessels; to this effect develops tolerance in the course of a chronic treatment.
b) cardiac effects (increased heart rate and contraction force) that are blocked by beta-adrenergic antagonists.

Endocrine System
Are observed:
a) Inhibition of prolactin secretion
b) Increased release of GH in normal subjects only, not in patients with Parkinson's disease.

• It is absorbed from the intestine for active transport.
• The presence of food and of aromatic amino acids in the diet decreases absorption
• Cross the BBB for active transport
• By combining levodopa with a peripheral inhibitor of dopa-decarboxylase (carbidopa or benserazide).
-Reduces the necessary dosages,
-You increase the antiparkinsonian effects and
-Reduces side effects

The side effects are dose-dependent and reversible and may require discontinuation of treatment.

- Nausea and vomiting
- Cardiac arrhythmias (sinus tachycardia, extrasystoles, atrial flutter and atrial fibrillation), to be treated with beta-adrenergic antagonists.
- Orthostatic hypotension.
- Behavioural disorders: confusion, severe depression, insomnia, anxiety, manic symptoms.
- Dyskinesias

a) phenothiazines, butyrophenones cancel the therapeutic effects of levodopa.
b) non-specific MAO inhibitors may give a hypertensive crisis.
c) Anticholinergic drugs enhance the effects of levodopa, provided that high doses of anticholinergic drugs do not reduce the absorption of levodopa.

- The association levodopa + carbidopa is the reference therapy for Parkinson's disease.
- At the beginning of treatment (induction phase) using gradually increasing doses to reduce side effects (this stage lasts weeks).
- Then istaura a maintenance regimen. Will have good results for about 2 years. After 5 years the functional status of the subject gets worse and you get side effects.
1) Development of abnormal involuntary movements.
2) Phenomenon of '"on-off" switch that is the subject of mobility to its immobility.

2) dopaminergic agonists
In the treatment of Parkinson's disease dopamine agonists may have advantages over levodopa:
• Do not require metabolic conversion can be greatly reduced in the advanced stages of the disease
• Do not involve dopamine metabolism and therefore do not cause the genesis of radical
• They have greater duration of action of dopamine

Bromocriptine and pergolide
Are derived semisintetitici ergot.

Bromocriptine is D2 receptor agonist and partial antagonist of D1.
The agonist pergolide is both that of D1 D2.

Good is the absorption from the gastrointestinal tract
Relevant metabolic clearance and excretion in the bile.
At the beginning of treatment: nausea, vomiting, and orthostatic hypotension
During therapy, constipation, hallucinations, dyskinesia.

- They are used either alone or in combination with levodopa in patients exhibiting the phenomenon on - off.

3) ropinirole and pramipexole
Ropinirole is a selective agonist for the D2 receptor.
Pramipexole shows high affinity for D3 receptors, but also has high affinity for D2 and D4 for.

Ropinirole and pramipexole are used by only the start of therapy, then it is used in combination with levodopa and carbidopa in the more advanced stages of the disease.

4) Inhibitors of COMT
E 'was withdrawn from the market for liver toxicity

It 's always used in conjunction with levodopa and carbidopa.
Has the same side effects of levodopa.

5) MAO inhibitors (MAOIs)
Selegiline and amantadine.

E 'a highly selective inhibitor of MAO-B, localized mainly in the CNS.

• Do not give hypertensive crisis after intake of foods rich in tyramine.
• However, increasing the central effects of levodopa accentuates even unwanted ones such as abnormal involuntary movements.

May be used alone at the beginning of the disease.
Can delay the onset of levodopa therapy, because it slows down the progression of the disease probably by reducing oxidative stress due to reduced dopamine metabolism.


1) Causes release of dopamine
2) Delay the reuptake of dopamine neurons
3) It has antimuscarinic effects.

Only at high doses (200 mg per day) are observed:
Insomnia, dizziness and unsteadiness, drowsiness, blurred pronunciation of words.
Nausea, vomiting, anorexia.

Amantadine potentiates the effect of levodopa
E 'useful motor fluctuations
And 'less potent than levodopa when used alone.

6) antimuscarinic drugs
The compounds most 'used are trihexyphenidyl, benzatropine, orphenadrine, biperiden.

- The lack of dopamine in the striatum intensifies the effects of excitatory cholinergic system.
- Anticholinergics attenuate this component.

- Reduce tremor markedly.
- They have less effect on rigidity and bradykinesia.
- Reduce the excessive drooling.

Cycloplegia, constipation, urinary retention.
In the CNS can cause mental confusion, delirium, drowsiness and hallucinations.

Anticholinergic drugs are used in patients who:
• moderate symptoms (especially tremor).
• Do not tolerate levodopa.
• do not derive benefit from levodopa.
Non-pharmacological treatment approaches:

Stereotactic surgery
Nuclei as the globus pallidus and the subthalamic nucleus may be a target for Deep Brain Stimulation (DBS).
People candidates for this type of surgery are elderly people in the advanced stage of the disease, which have side effects from the use of levodopa already quite important.
Stem cell therapy
Embryonic stem cells stimulated in vitro with the product of the Nurr1 gene differentiate into dopaminergic cells
By introducing these cells by stereotactic brain of rats with Parkinson's disease slow down the progression until it stops.
This technique is currently only experimental


The disease was described for the first time by Alois Alzheimer in 1907.
It has a prevalence of 10% in people over 65 years.

The neuropathological signs in the CNS include:

1. Plates extracellular proteinaceous material aggregate into fibrils. Are due to deposition of -amyloid which is derived from the enzymatic proteolysis of amyloid precursor protein (APP).

2. Intracellular protein aggregates in dystrophic neurons are due to twisted strands of the protein tau, which is abnormally phosphorylated. These fibrils distort the normal functions of the neuron.

3. Neuronal loss. The most affected areas are the frontal, temporal and parietal cortex, hippocampus, nucleus of Meynert and the locus coeruleus. The cholinergic neurons are those more damaged.

4. Inflammation reactive glia (microglia and astrocytes). Studies are ongoing to assess the benefits of treatment with anti-inflammatory drugs.

The disease begins with small mnemonic deficit but progresses to generate:
• inability to remember names and people
• inability to live alone
• difficulty of language
• possible hallucinations
• total loss of autonomy even to feed

The amyloid hypothesis argues that managers plaques are extracellular fragment of APP of 40-42 amino acids, and the -amyloid 42 amino acids is considered the most fibrillogenica
The cutting of APP to generate -amyloid is operated by  - and -secretase (which are part of complex polyprotein called presenilins, PS1 and PS2)

The amyloid hypothesis remains that the extracellular plaques could represent an epiphenomenon rather than the causative event.

Dementia occurs rarely (2% of cases) in familial form genetically determined.
In these cases there are modifications of genes that encode:
• the PS1 and PS2 (presenilins), proteins involved in
-Axonal transport
-Control of apoptosis


Cholinergic neurons of the nucleus of Meynert go to the frontal cortex are damaged.
In dementia of Alzheimer the neurotransmitter acetylcholine is the most damaged, even if it is not the only neurotransmitter modified.

Therapeutic approaches currently pursued are:
• increase the availability of acetylcholine with anticholinesterase drugs
• administered NMDA receptor antagonists

1) anticholinesterase

E 'was the first anticholinesterase used for Alzheimer's dementia, because it crosses the BBB well
Is no longer used for its hepatotoxicity

And 'one of the most widely used drugs
It 'metabolised by CYP2D6 and CYP3A4.
Evokes undesirable effects cholinomimetic such as:
• Nausea, vomiting and diarrhea,
• Bradycardia
• Increased acid secretion
• Bronchospasm
• It can also be epileptogenic action

Has shorter half-life of donepezil, and require twice daily dosing
It 'metabolized primarily by plasma esterases
Evokes undesirable effects cholinomimetic

It 'metabolized by CYP 2D6 and CYP 3A4.
Evokes undesirable effects cholinomimetic

2) antagonists of the NMDA receptor


Its receptor profile is quite complex because
• E 'non-competitive antagonist of the NMDA receptor
• It has good affinity for serotonergic receptors
• It has modest affinity for several other receptors:
Recettoridella dopamine
Adrenergic receptors
Glycine receptors

It is mainly eliminated unchanged in the urine

Agitation, confusion, and headache

E 'was approved in 2003 for use in Alzheimer's dementia by the FDA.
Is usually associated with donepezil.
Can improve cognitive performance in fome moderate-severe dementia.

Other therapeutic approaches
Many clinical studies are in progress to evaluate the effect of
• Anti-Inflammatory
• Antioxidants
• Statins
• Antagonists of glutamic acid

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