Parkinsonism

Parkinson’s disease

Dr. Fatima

Lahore Medical & Dental College 2

Parkinson’s disease• Parkinsonism is a progressive

degenerative, extrapyramidal disorder of muscle movement, due to dysfunction in basal ganglia, comprising four cardinal features:-• Bradykinesia or hypokinesia.• Muscle rigidity.• Resting tremor. • Impairment of postural balance leading to

disturbances of gait, and falling. The secondary manifestations are mask-like face, siallorrhoea, difficulty in speech, slowing of mental process and dementia.


Bradykinesia:• It is slowness in initiating and

carrying out voluntary movements. It is called poverty and suppression of voluntary movements. It is caused partly by muscle rigidity and partly by inertia of the motor system, which means that motor activity is difficult to stop as well as to initiate. It is hard to start walking, and once in progress, the patient can not stop quickly.


Muscle rigidity:• Rigidity is due to increased muscle

tone. The rigidity affects the opposing muscles equally, flexors and extensors. Rigidity is detectable as an increased resistance in passive limb movement.


Tremors: • Tremors are defined as rhythmic

oscillatory movements caused by the opposing muscles around a joint. Tremors of Parkinsonism are slow. Hand tremors involve all the fingers and thumb (pill rolling tremor) which tend to diminish during voluntary activity. The “resting tremors” are present at rest and disappear (abate) during voluntary movements.


Dyskinesia: Abnormal involuntary movements

Chorea: It consists of irregular, unpredictable, involuntary muscle jerks that occur in different parts of the body and impaired voluntary activity.

Athetosis: Abnormal movements are slow and writhing in character

Dystonia: The abnormal movements are slow in character and are sustained so that they are regarded as abnormal postures

Tics: They are coordinated abnormal movements that tend to occur repetitively particularly about the face and head, especially in children


Etiology• The degeneration of neurons occurs in substantia

nigra pars compacta and the nigrostriatal tract that are dopaminergic and inhibit the activity of striatal GABA ergic neurons. This results in deficiency of dopamine in striatum which controls muscle tone and coordinates movements. Nerve fibers from cerebral cortex and thalamus secrete acetylcholine in the neostriatum causing excitatory effects that initiate and regulate gross intentional movements of the body. In Parkinson’s disease, due to deficiency of dopamine in striatum, an imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) system occurs, leading to excessive excitatory actions of cholinergic neurons on striatal GABA ergic neurons.


• Substantia Nigra:• The substantia nigra pars compacta is the

source dopaminergic neurons that travel through nigrostriatal tract to terminate in the striatum. These dopaminergic neurons from the substantia nigra fire tonically, to produce a sustained influence on motor activity.

• Striatum: • The striatum is connected to the substantia

nigra par reticulata by neurons that secrete the inhibitory transmitter GABA at their endings in the substantia nigra. In turn, cells of the substantia nigra send neurons back to the striatum, secreting the inhibitory transmitter dopamine at their endings. Nerve fibers from the cerebral cortex and thalamus secrete Acetylcholine in the neostriatum causing excitatory effects.


Strategy of Treatment• In Parkinson’s disease dopaminergic

inhibitory activity is reduced and cholinergic excitatory activity is increased. Therefore, therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory effects of cholinergic neurons.


Drugs used for Parkinsonian Disease:

• Drug therapy is aimed at restoring the balance between the dopaminergic and cholinergic components, which is achieved by:• Increasing the central dopaminergic

activity

OR• Decreasing the central cholinergic

activity

OR BOTH.


Drugs which increase dopaminergic activity.

• Drugs that replace dopamine (Dopamine precursor): • Levodopa

• Dopa-decarboxylase inhibitors (Drugs which increase the central availability of Levodopa)• Carbidopa, Benserazide. They act in the

periphery as they do not enter brain• Dopamine receptor agonists: They mimic the

action of dopamine at D2 or D3 receptors• Bromocriptine, Pergolide, Lisuride,

pramipexole.• Drugs which increase release or inhibit

reuptake of dopamine (also called dopamine facilitator)• Amantadine.


Drugs which increase dopaminergic activity.

• Inhibitors of COMT:• Entacapone,Tolcapone. They inhibit

Catechol-O-methyl transferase which inactivates dopamine. They prolong the action of dopamine.

• Dopamine receptor agonist:• Bromocriptine, Pergolide, Lisuride,

pramipexole. They mimic the actions of dopamine at D2 or D3 receptors

• MAO-B inhibitors: • Selegiline. They prolong the action of

dopamine.


Drugs affecting brain cholinergic system

• Central anticholinergics:• Trihexyphenidyl (Benzhexole),

• Procyclidine

• Biperiden

• Antihistamines:• Orphenadrine

• Promethazine


LEVODOPA• Levodopa crosses blood brain barrier. It is

the immediate precursor of dopamine. It is transported by a neutral aminoacid transporter into the brain. It is taken up by the surviving dopaminergic neurons, decarboxylated to dopamine, which is stored and released as a transmitter. The effect of levodopa may be due to an increased release of dopamine from surviving dopaminergic neurones because the effectiveness of levodopa decreases as the diseases advances. Part of the action of levodopa may be due to ‘flooding’ of the striatum with exogenous dopamine.


LEVODOPA• Pharmacokinetics• Levodopa, when given without a

decarboxylase inhibitor, about 70% of the dose is metabolized in the gut wall and liver, 27-29% goes to peripheral tissues to exert adverse effects and only 1-3% enters the brain. When levodopa is administered with Carbidopa, about 10% of the dose reaches the brain.


LEVODOPA• Levodopa is rapidly absorbed from small

intestine by the active transport process meant for aromatic amino acids. Bioavailability of levodopa is effected by:• Gastric pH: Increased pH decreases its

absorption• Gastric emptying: If slow (delayed), levodopa

is exposed to degenerative enzymes of gut wall and liver for longer time and availability is decreased

• Aminoacids present in the food compete for the same carrier for absorption. So absorption is less when taken with meals.

• Levodopa undergoes high first pass metabolism in the gastrointestinal mucosa and liver.


Periphery Brain 3-O-Methyldopa 3-OMD

COMT COMT

Blood Brain BarrierLevodopa Levodopa

Dopadecarboxylase

Dopamine Dopamine

COMT MAO-B

3-Methoxytyramine DOPAC

Homovanillic acidDOPAC-3,4-dihydroxyphenylacetic acid


Adverse effects At the initiation of therapy:• Nausea and vomiting in almost every patient. It is

due to action of dopamine on CTZ• Postural hypotension: it occurs in about 1/3 of

patients, more common in the patients receiving antihypertensives. This may be a central action. Dopamine and noradrenaline formed in brain decreases sympathetic outflow.

• Tachycardia and cardiac arrhythmias: They are due to - adrenergic actions of dopamine formed peripherally.

• Exacerbation of angina may occur especially in patients with pre-existing heart disease.

• Alteration of taste sensation.


• After prolonged therapy:

• Abnormal movements: Facial tics, grimacing, choreoathetoid movements of limbs, start appearing after a few months of use.

• Behavioral effects: Range from mild anxiety, nightmares to depression, mania, hallucinations or psychosis, excessive dopaminergic action in limbic system is probably responsible.

• Fluctuation in motor performances: After 25 years of therapy, the level of control of symptoms starts showing fluctuation. In some patients, the loss of response is seen just before the next dose which is termed ‘end of dose akinesia’ or ‘wearing-off reactions’. In other cases, the fluctuations in clinical response are unrelated to the timing of the dose, termed ‘on-off phenomenon’. In this the period of good therapeutic response alternates with the periods of loss of therapeutic response, all within few hours. With progressive degeneration of dopaminergic neurons the ability to regulate storage and release of dopamine may be largely lost. Then, dopamine is synthesized in the striatum on a moment to moment basis resulting in rapid fluctuations in the motor control


Interactions• Pyridoxine: It enhances peripheral Decarboxylation of

levodopa hence; less is available to cross brain• Drugs which block dopamine receptors: e.g.,

Phenothiazines, butyrophenones, metoclopramide, reverse the therapeutic effects of levodopa.

• The antidopaminergic domperidone blocks levodopa induced vomiting without abolishing its effects because domperidone does not cross blood brain barrier. Reserpine abolishes levodopa actions by preventing the entry of dopamine into synaptic vesicles.

• Non-selective MAO inhibitors prevent degradation of peripherally synthesized dopamine

• Antihypertensives: Postural hypotension is accentuated • Anticholinergic drugs have additive antiparkinsonian

action, but retard the absorption of levodopa


Pharmacological actions:• CNS• Levodopa produces marked

symptomatic improvement in Parkinsonian patients. Hypokinesia and rigidity resolve first, later tremor as well. Secondary symptoms of posture, gait, facial expression and mood are gradually normalized.


• The effect of levodopa on behavior has been described as a “general alerting response”. In some patients it may progress to excitement.

• Two types of dopamine receptors, D1 and D2 were originally described. Later, three more (D3,D4,D5) have been identified.

• D1 like (D1,D5). They are excitatory. Act by increasing cAMP formation.

• D2 like (D2,D3,D4). They are inhibitory. Act by inhibiting adenylyl cyclase/opening K channels/depressing voltage sensitive Ca channels. Both D1 and D2 receptors are present in striatum .They respectively regulate the activity of two pathways having opposite effects on thalamic input to the motor cortex. Thus, stimulation of excitatory D1 as well as inhibitory D2 receptors in the striatum achieves the net effect of smoothening movements and reducing muscle tone.

• Dopamine receptor in substantia nigra pars compacta and in pituitary is also of D2 type.


• CVS:• Dopamine formed in periphery can cause

tachycardia by acting on beta receptors. Dopamine causes postural hypotension. This may be a central action. Dopamine and noradrenaline formed in brain decrease sympathetic outflow.

• CTZ: • Dopamine acts as an excitatory transmitter on

dopamine receptors in CTZ. Peripherally formed dopamine gains access to the CTZ and causes nausea and vomiting.


• Endocrine:• Dopamine acts on pituitary

mammotropes to inhibit prolactin release.and prolactin level in blood falls. Dopamine acts on somatotropes to increase growth hormone release but increased growth hormone levels are not noted in Parkinsonian patients.


PERIPHERAL DECARBOXYLASE INHIBITORS• Carbidopa and Benserazide are extracerebral

(peripheral) decarboxylase inhibitors. They do not inhibit conversion of levodopa to dopamine in brain. They increase the half-life of levodopa in the periphery and make more of it available to enter the brain. The benefits obtained are: • The plasma half-life of levodopa is prolonged

and dose is reduced to approximately ¼• Due to reduced systemic concentration of

dopamine, nausea and vomiting are not prominent

• Cardiac adverse effects are minimized• Pyridoxine reversal of levodopa effect does

not occur as the decarboxylase has been inhibited already

• ‘On-off’ effect is minimized since cerebral dopamine levels are more sustained.


DOPAMINERGIC AGONISTS• Bromocriptine: It acts as an agonist

on D2, but as partial agonist or antagonist on D1 receptors. It is used only in late cases of parkinsonism as a supplement to levodopa.

• Ropinirole and Pramipexole: They are selective D2/D3 receptor agonists. Their actions are similar to those of Bromocriptine but they are better tolerated with fewer gastrointestinal symptoms.


MAO-B INHIBITOR.• Selegiline (Deprenyl) : There are two forms of

MAO, MAO-A and MAO-B. Both are present in peripheral adrenergic structures and intestinal mucosa, while MAO-B predominates in brain and blood platelets. Selegiline, in low doses, does not interfere with peripheral metabolism of dietary amines. Catecholamine accumulation and hypertension does not occur, while intracerebral degradation of dopamine is retarded. Administered with levodopa, it prolongs levodopa action, decreases motor fluctuations and decreases ‘wearing off’ effect. Adverse effects are – postural hypotension, nausea and accentuation of levodopa induced involuntary movements.


COMT INHIBITORS:• When peripheral decarboxylation of

levodopa is blocked by Carbidopa, it is metabolized by COMT to 3-O-methyldopa. Blockade of this pathway by Entacapone prolongs the t1/2 of levodopa and allows a larger fraction of administered dose to cross to brain.

Education

Parkinsonism