Parkinson's disease(PD) is a manifestation of an imbalanced between dopaminergic and cholenergic activity transmitted by the extrapyramidal nervous system.
Conceptually dopamine is believed to act principally as an inhibitor neurotransmitter and acetylcholine as an excitatory neurotransmitter in the extrapyramidal system (3).
Dopamin acts by inhibiting the rate of firing of neurons that control the extrapyramidal motor system(4).
Although dopamin is more important, a proper balance with the cholenergic neurotransmitter is also necessary for normal function.About 80% in the brain is concentrated in the basal ganglia mostly in the caudate nucleus and putament. In patients PD the basal ganglia content of dopamin is only about 10% of normal.(3)
First described by James Parkinson in 1817 was often called the shaking palsy.
Usually begins between the age of 40 and 70 years old and is uncommon below 30 years of age. In the USA alone there are approximately 500.000 patients with Parkinson disease(PD) and about 40.000 new cases develops each year,men somewhat more often than woman.(3.4)
Alzheimer's disease is six times more frequent in patients with PD.
PATHOGENESIS :
Involves a loss of pigmented cells in the substantia nigra and other pigmented nuclei such as the locus ceruleus and dorsal motor nucleus of the vagus.
Dopaminergic nerve fibers in the basal ganglia degenerate, leading to a depletion of dopamine in the basal ganglia of the brain.
Consequently, depletion of dopamine leads to decreased inhibition of this system,resulting in many of the clinical signs.
Although, many predispoisng factors have been suggested including enviromental agents,the etiology of PD remains obscure.
CLINICAL PICTURE
As dopmine content in basal ganglia is only 10% in PD, as a result,there is an excess of excitatory cholinergic activity manifesting as tremor,skletal muscle rigidity and disturbance of posture.
This is characterized by expression less facies,slowness of voluntary movement,shuffling gait resting tremor,cogwhell rigidity,stopped posture and a monotonous voice.
Resting tremor is the most characteristic abnormality in PD, and it is presenting symptom in 70% cases. The tremor often referred to as pill-rolling tremor,is noted to be prominent in the resting extrimity,disappearing briefly with intentional movement.
Bradykinesia or slowness in both the initiation and excecution of movement is a hallmark of PD.
Patients are also noted to have facial immobility characterized by infrequent blinking and little emotional respons.As the disease progresses;micrographia develops,the voice becomes progressively less audible, walking is reduced to shuffling and the patient frequently loses balance.
In addition to these classic peripheral manifestation,of PD approximately one fifth of afflicted patients become mentally depressed and one third of patients develop cognitive and memory deficits that may progress to delirium (Lieberman 1979).
Symptoms similar to PD has been labeled as Parkinson
Syndrome (PS),can be suspected after CNS trauma,encephalitis,brain tumor,metallic intoxication,and drugs such as phenothiazine,butyro phenones,and reserpine.
TREATMENT :
No cure for PD is known,treatment of PD is always palliative and never curative (2,3).
The goal of treatment of PD is to enhance the inhibitory effect of dopamine or reduce the stimulatory effect of acetylcholine by administration of centrally acting drugs.(2).
Medical treatment depend largely on the seriousness of symptoms and stage of the disease.
Hoehn and Yahr have developed a universally recognized scale consisting of 5 stages.(1)
Stage I : Unilateral involvement
II : Bilateral involvement but no postural
abnormalities.
III : Bilateral involvement with mild postural
imbalanced,the patients leads an independent
life.
IV : Bilateral involvement with postural instability;the
patients requires substantial help.
V : Severe fully developed disease;the patients
restricted to bed and chair.
In general, patients in stage I&II may require no medication,or only anticholinergic (benzotropine biperidine,procyclidine) or dopamine agonist such as amantadine or combination of both.
These anticholenergic may relieve the slow frequency pill-rolling rest tremor typical of PD. The mayor standby in treatment of PD is L-dehydroxy phenil alanine(L-dopa or levodopa in stage III,IV and V). Levodopa as the immedia-
ted metabolic precursor of dopamine,it is administered in an effort for increase brain concentrating of dopamine.(4)
Levodopa undergoes decarboxylation in both the peripher and CNS to produce dopamine. Approximately 95% of orally administered levodopa is rapidly decarboxylated to dopamine by the enzyme dopa decarboxylase,reduced absorbtion of levodopa as result of slowed gastric emptying as caused by opioids or anticholinergic and increase gastric acidity.
The resulting dopamine cannot easily cross the blood brain barrier to exert a benefical therapeutic effect,whereas increased plasma concentration of dopamine often lead to undesirable side effect. At least 30 metabolites of levodopa has been identified,most are converted to doamine,small amounts of which are subsequently metabolized to nor epinephrine and epinephrine(3).
One problem with levodopa is that half life is short (about 1 to 3 hours) there-
fore even brief interruption in the drug theraphy are undesirable and can be an acute exacerbation of the symptoms of PD so requires frequent dosing interval to maintain a therapeutic tissue concentration.(2)
Abrupt discontinuation of levodopa therapy may result in a precipituous return of symptoms of PD. For this reason levodopa therapy should be continued throughout the perioperative period,being included in the preoperative medication.
Levodopa has been shown to improve the akinesia,postural disorders and at times the rest tremor.
The side effect of levodopa can be hypotension,depression with delusions,de-
velopment of involuntary movement such as choreoathetosis,dystonia of limbs
necks and trunk,restlessness,grimacing and dyskinesia of tongues and lips.
Orthostatic hypotension (30%),unknown reason in early theraphy.It is interest that dopamine resulting from levodopa will inhibits nor epinephrine production in the sympathetic nervous system through a negative feedback loop or inhi-
bits renin release and promote increases renal blood flow,glomerulo filtration rate and sodium excretion.
In addition dopamine will replace nor epinephrine at some sites and because of its weaker pressor action,fail to support the blood pressure adequately.
Levodopa affects the gastroinstestinal system by causing nausea and vomiting probably through dopaminergic stimulation of the chemoreceptor trigger zone (CTZ)is especially prominent at beginning of treatment ,consequently aspira-
tion in induction should be anticipated.
Concurent administration of carbidopa with levodopa result in increased peripheral availability of levodopa to enter the CNS,as a result of this combination theraphy the dose of levodopa can be reduced up to 75% while maintaining beneficial CNS effects,and at the same time reducing the likelihood of dose dependent side efects,resulting from too high plasma concentration of dopamine.
Carbidopa is inhibitor of the peripheral enzyme activity of dopa decarboxylase does not cross the blood brain barrier (BBB),administered alone carbidopa lacks pharmacologic activity.(3)
Levodopa and carbidopa are absorbed in the small intestines and thus must first traverse the stomach,making administration of tablets through a gastric tube suboptimal,or ineffective because patients with PD have delayed gastric emptying .As such a duodenal feeding is expected.(2).
Intravenous levodopa has been used succesfully in the perioperative period but without coadministration of a decarboxylase inhibitor (not yet available in intravenous form) cardiovascular side effects such as hypertension,hypotension and dysrhythmia can be anticipated.(2).
Bromocriptine are employed because their stimulating effects on dopamine receptors are used in patients not responding well to levodopa.(1)
Amantadine an antiviral drug produces symtomatic improvement in patients with PD presumably by facilitating the release of dopamine from intact dopaminergic terminals that remain in the negrostriatum of patient (Schwab et all 1977).(3)
Deprenyl, a highly selective inhibitor of Monoamino oxydase(MAO)(the mayor enzyme involved in oxidative metabolism of dopamine in the striatum).(2,3)
It inhibits the intracerebral metabolism of dopamine,thus maximizing the therapeutic efficacy of concomitanly administered levodopa.Deprenyl(selegiline) is itself metbolized to amphetamine derivatives which may exert a weak anti parlkinsonism response.
Anticholenergic drugs :(benzotropine ,cycrimine and trihexyphenedyl)
The presumed mechanism of action of anticholenergic drugs is the ability to blunt the effects of the excitatory neurotransmitter acetylcholine.
More than 50% of patients who respond to levodopa manifest additional beneficial effects when therapy is suplemented with anticholinergic drugs.(3)
Elderly patients receiving combination of levodopa and anticholenergic drugs are particularly vulnerable to development of psychiatric distiurbances.
Propranolol can suppress the fast frequency tremor which sometime occurs in PD patients. Metprosol is also used and may be safer betablockers in patients with asthma.
In patients with PD who become resistant to medical theraphy ,three other approaches are available including stereotactic surgery,tissue transplant and electroconvulsive theraphy.
Neuroblative procedure may be useful not only in these PD patients who are resistant to drugs theraphy but also can employed to treat tremor and rigidity in the younger group. Dyskinesias due to levodopa treatment have been treated by lesion in the ventralis intermedius nucleus (VIM) of the thalamus as well as in the ventralis oralis posterior(VOP).
The study of Kelly and Gillinghan regarding lesioning the thalamic ventralis oralis anterior(VOA) in 58 patients showed that 88% had no signs of rigidity after thalamotomy.
Recently lesions of the internal and external segments of globus pallidus(pallidotomy) have been used for resolution of PD symptoms that are resistant to medical treatment.(1)
Since many of the drugs used in PD and PS therapy have mark systemic effects ,drug interaction response are very important,in the preoperative evaluation,intraoperative management and post operative anesthetic care.
DRUGS INTERACTION TO LEVODOPA :
Drug Response
=========================================================
1.Tricyclic antidepressant Slow gastric emptying,enhance
degradation of levodopa to in-
active form in Gi tract.
2. Benzodiazepine Mechanism not clear,with 5 ca-
ses reported in deterioration of
PD after diazepam and chloor-
diazepoxide.
3. Beta blocker(propranolol) May antagonized beta adrenergic
effect of dopamine due to levo-
dopa intake.May enhance levodo-
pa response in patients witrh PD
and tremor. May increase levodo-
pa stimulation of growth hormon
secretion.
4.Clonidine Inhibits levodopa respons by sti
mulating central alpha adrener-
gic receptors.Seven patients had
exacerbation of PD.
5.Guanethidine Hypotensive efects of guanethi-
dine increased with levodopa in
2 patients.
6.Methyldopa Inhibits response to levodopa
and may cause an additive hypo-
tensive response.
7.MAO Inhibitors (MAOI) The degradation of dopamine in-
volves MAO hence MAO inhibitors
decreases dopamine breakdown.
and levodopa increases dopamine
concentration this will increases
nor epinephrine formation.
Hypertensive responses have been
reported with nialamide and phenel-
zine.The use of MAOI in patients on
levodopa can result in worsening of
akinesia and tremor.
A pavorable clinical response was no-
ted with levadopa and the MAOI
L-deprenal.
8.Papaverine PD worsened following papaverine
possibly due to dopamine receptors
blockade.
9.Phenylephrine Suggested that levodopa or its me-
tabolits involve competitive inhibi-
tor on alpha receptors since levo-
dopa produces mydriasis following
topical phenylephrine.
10.Pyridoxine Increases metabolism of levodopa
decreasing availability in brain.
Pyridoxine reverses improvement
with levodopa in PD.
11.Phenothiazine and Phenothiazine may block dopamine
butyrophenones receptors in the CNS
Extrapyramidal symptoms are well-
known side effects of penothiazine
Halopridol have the same effects.
12.Phenythoin Phenythoin controlled levodopa dys-
kinesias but also suppressed the-
rapeutic effect in controlling PD.
If phenythoin is to be used the dose
of levodopa should be increased.
13.Reserpine Implicated as a causal agent in PD
by depleting brain dopamine.
to be continued
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