DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

(such as the mitochondrial cofactor coenzyme Q 10
) and anti-oxidant
strategies as treatments to prevent or retard degenerative diseases
(Beal, 2005).
Parkinson Disease (PD)
Clinical Overview. Parkinsonism is a clinical syndrome
consisting of four cardinal features:
• bradykinesia (slowness and poverty of movement)
• muscular rigidity
• resting tremor (which usually abates during voluntary
movement)
• an impairment of postural balance leading to disturbances
of gait and falling
The most common form of parkinsonism is idiopathic
PD, first described by James Parkinson in 1817 as
paralysis agitans, or the “shaking palsy.” The pathological
hallmark of PD is the loss of the pigmented,
dopaminergic neurons of the substantia nigra pars compacta,
with the appearance of intracellular inclusions
known as Lewy bodies. Progressive loss of dopamine
(DA) containing neurons is a feature of normal aging;
however, most people do not lose the 70-80% of
dopaminergic neurons required to cause symptomatic
PD. Without treatment, PD progresses over 5-10 years
to a rigid, akinetic state in which patients are incapable
of caring for themselves. Death frequently results from
complications of immobility, including aspiration pneumonia
or pulmonary embolism. The availability of effective
pharmacological treatment has radically altered the
prognosis of PD; in most cases, good functional mobility
can be maintained for many years. Life expectancy
of adequately treated patients is increased substantially,
but overall mortality remains higher than that of the general
population. In addition, while DA neuron loss is the
most prominent feature of the disease, the disorder
affects a wide range of other brain structures, including
the brainstem, hippocampus, and cerebral cortex (Braak
and Del Tredici, 2008). This pathology is likely responsible
for the “non-motor” features of PD, which include
sleep disorders, depression, and memory impairment. As
treatments for the motor features have improved, these
non-motor aspects have become important sources of
disability for patients (Langston, 2006).
It is important to recognize that several disorders
other than idiopathic PD also may produce parkinsonism,
including some relatively rare neurodegenerative
disorders, stroke, and intoxication with DA-receptor
antagonists. Drugs that may cause parkinsonism include
antipsychotics such as haloperidol and thorazine
(Chapter 16) and anti-emetics such as prochloperazine
and metoclopramide (Chapter 46). Although a complete
discussion of the clinical diagnosis of parkinsonism
exceeds the scope of this chapter, the distinction between
idiopathic PD and other causes of parkinsonism is important
because parkinsonism arising from other causes usually
is refractory to all forms of treatment.
Pathophysiology. The dopaminergic deficit in PD arises from a loss
of the neurons in the substantia nigra pars compacta that provide
innervation to the striatum (caudate and putamen). The current
understanding of the pathophysiology of PD is based on the finding
that the striatal DA content is reduced in excess of 80%. This paralleled
the loss of neurons from the substantia nigra, suggesting that
replacement of DA could restore function (Cotzias et al., 1969;
Hornykiewicz, 1973). These fundamental observations led to an
extensive investigative effort to understand the metabolism and
actions of DA and to learn how a deficit in DA gives rise to the clinical
features of PD. We now have a model of the function of the basal
ganglia that, while incomplete, is still useful.
Dopamine Synthesis, Metabolism, and Receptors. DA, a catecholamine,
is synthesized in the terminals of dopaminergic neurons
from tyrosine and stored, released, and metabolized by processes
described in Chapter 13 and summarized in Figure 22–1. The actions
of DA in the brain are mediated by a family of DA-receptor proteins.
Two types of DA receptors were identified in the mammalian brain
using pharmacological techniques: D 1
receptors, which stimulate the
synthesis of the intracellular second messenger cyclic AMP; and D 2
receptors, which inhibit cyclic AMP synthesis as well as suppress
Ca 2+ currents and activate receptor-operated K + currents. More
recently, genetic studies revealed at least five distinct DA receptors
(D 1
-D 5
) (Chapter 13). All the DA receptors are G protein–coupled
receptors (GPCRs) (Chapter 3). The D 1
and D 5
proteins have a long
intracellular carboxy-terminal tail and are members of the class
defined pharmacologically as D 1
; they stimulate the formation of
cyclic AMP and phosphatidyl inositol hydrolysis. The D 2
, D 3
, and D 4
receptors share a large third intracellular loop and are of the D 2
class.
They decrease cyclic AMP formation and modulate K + and Ca 2+ currents.
Each of the five DA receptor proteins has a distinct anatomical
pattern of expression in the brain. The D 1
and D 2
proteins are
abundant in the striatum and are the most important receptor sites
with regard to the causes and treatment of PD. The D 4
and D 5
proteins
are largely extrastriatal, whereas D 3
expression is low in the
caudate and putamen but more abundant in the nucleus accumbens
and olfactory tubercle.
Neural Mechanism of Parkinsonism. Considerable effort has been
devoted to understanding how the loss of dopaminergic input to the
neurons of the neostriatum gives rise to the clinical features of PD
(for review, see Albin et al., 1989; Mink and Thach, 1993; and
Wichmann and DeLong, 1993). The basal ganglia can be viewed as
a modulatory side loop that regulates the flow of information from the
cerebral cortex to the motor neurons of the spinal cord (Figure 22–2).
The neostriatum is the principal input structure of the basal ganglia
and receives excitatory glutamatergic input from many areas of the
cortex. Most neurons within the striatum are projection neurons
that innervate other basal ganglia structures. A small but important
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CHAPTER 22
TREATMENT OF CENTRAL NERVOUS SYSTEM DEGENERATIVE DISORDERS