PHARMACOTHERAPY OF

PARKINSON’S DISEASE
Prepared by:
Miguelita Digal-Espinosa, M.D.
Parkinson Disease (PD): Prepared by:
Miguelita Digal-Espinosa, M.D.
 is a neurologic disorder characterized by
progressive loss of movement coordination.

 is a clinical syndrome of 4 Cardinal Features:

1) Bradykinesia
 slowness and poverty of movement.
2) Muscular rigidity
3) Resting tremor
 abating during voluntary movement
4) Impairment of postural balance
 leading to disturbances of gait and falling
= Idiopathic PD:
 the most common form of parkinsonism,

 described by James Parkinson in 1817

as paralysis agitans, or "shaking palsy”.

= Pathological Hallmark of PD:

 loss of the pigmented, dopaminergic neurons
of the substantia nigra, specifically the pars compacta,

 with the appearance of intracellular inclusions,

the “Lewy bodies”.
= In the brain, the neurons responsible for movement
coordination are located at the Striatum.

= Striatum receives information from 2 major sources:

1) Neocortex,  relays sensory information and

plans for future actions.

2) Substancia nigra  sends dopamine the

neurotransmitter that helps to
coordinate all of the inputs.
= Parkinson’s disease develops,
 when neurons connecting the substantia nigra,
(pars compacta of the caudate and putamen).

 that the striatal DA content is reduced > 80%.

 leading to striatal progressive degeneration.

= Dopaminergic neurons,
originating from the substantia nigra,
 normally exert inhibitory effect on GABA neurons
located in the striatum.
= Diminished Dopamine;
 results in increased GABA,
 causing increased Thalamic inhibition, and
 reduced excitatory inputs to the motor cortex.

= These Dopaminergic neurons,

 also exert inhibitory effects,
 on the excitatory cholinergic neurons in the striatum.

= Without sufficient levels of dopamine;

 the production of Ach is increased,
 that triggers a chain of abnormal signaling
leading to impaired mobility.
= The imbalance therefore between the inhibitory and
excitatory activities;

 leads to the manifestations of,

 the typical clinical symptoms of PD:

1. Resting tremors
2. Rigidity
3. Postural instability
4. Slowed movement
The treatment of Parkinson’s Disease:
 is aimed to replenish Dopamine.

Dopamine Synthesis, Metabolism, and DA Receptors:

= Dopamine synthesis:
> DA, a catecholamine,
 is synthesized in the terminals of dopaminergic
neurons from an amino acid Tyrosine
Dopamine synthesis:
= Inside the dopaminergic neurons,
the synthesis of Dopamine takes 2 steps:

1. Hydroxylation of Tyrosine;
 by tyrosine hydroxylase
to L-dopa(Levodopa).

2. Decarboxylation of Levodopa;
 by Aromatic L-amino acid
decarboxylase (AADC)

 to the Dopamine neurotransmitter.

DA Storage and Metabolism:
= Dopamine is stored in synaptic vesicles and
 released by physiologic stimuli into the synapse.

= Excess Dopamine in the synapse,

 is reuptaken into the pre-synaptic neuron or into glial cells,
 where dopamine is metabolized,
 by MAO and Catechol-O-methyltransferase (COMT);
 that converts Levodopa to 3-O-methyldopa, (3-O-MD).
 = Two types of MAO:
1) Type A

2) Type B – predominant in glial cells.

The Dopamine Receptors:

= Actions of DA in the Brain:

 are mediated by a family of DA-receptors.
= 2 Types of DA Receptors identified in the Brain:
1) D1 Receptors;
 stimulate the synthesis of cyclic AMP.

2) D2 receptors ;
 inhibit cyclic AMP synthesis
 suppress Ca++ ion currents
 activate receptor-operated K+ currents

= Genetic studies revealed five distinct DA receptors;

 D1 to D5.
 All the DA receptors are GPCRs.
Pharmacological Classification of DA Receptors:
= Class D1 and D5 Receptor proteins :
1) The D1 and D5 Receptor proteins,

 stimulate the formation of cyclic AMP

and phosphatidyl inositol hydrolysis.

2) Class D2, D3, and D4 Receptors;

 decrease cyclic AMP formation and
modulate K+ and Ca++ currents.
= Each of the 5 DA Receptor proteins
 has a distinct anatomical pattern of
expression in the brain.

= D1 and D2 Receptor proteins;

 are abundant in the striatum.
 the most important receptor sites with regard
to the causes and treatment of PD.

= The D4 and D5 Receptor proteins are largely extrastriatal,

= While D3 Receptor expression;

 is low in the caudate and putamen
 but more abundant in the nucleus accumbens
and olfactory tubercle.
Drugs used in the Treatment of PD:

1. Levodopa, one of the commonly used drug.

= Since Dopamine cannot freely access the tightly

packed layer of endothelial cells in the BBB, while
= while Levodopa can gain access through the BBB
carried by amino acid transporter.

= The problem with Levodopa,

 is its peripheral metabolism.

= Levodopa gains access through the BBB,

 carried by an amino acid transporter.
= Thus Levodopa must be given with Carbidopa,
 which inhibits Dopamine decarboxylase and
 reduce the metabolism of Levodopa in the periphery.

= Levodopa gains access through the BBB,

 carried by an amino acid transporter.

= Inside the brain now, Levodopa;

 is efficiently converted to Dopamine,
 supplementing the depleted DA levels in the midbrain.
PK/PD Levodopa:
Levodopa (L-DOPA, LARODOPA, L-3,4-dihydroxyphenylalanine),
 the metabolic precursor of Dopamine,

= the single most effective agent in the treatment of PD.

= both its therapeutic and adverse effects

 result from the decarboxylation of Levo-dopa to DA.

= Orally, it is absorbed rapidly from the small bowel,

 by the transport system for aromatic amino acids.

= Plasma Drug concentrations;

 peak between 0.5 and 2 hours after an oral dose.

= The t1/2 in plasma is short  1-3 hours.

= The rate and extent of Absorption of Levodopa depends on the:
a) Rate of gastric emptying
b) pH of gastric juice
c) Exposure time the Drug to degradative enzymes
of the gastric and intestinal mucosa

= Its administration with high-protein meals,

 delays absorption and reduces peak plasma
concentrations,
 due to competition for absorption sites in small bowel.

= Levodopa Crosses the BBB ;

 mediated by a membrane transporter for
aromatic amino acids,

 and competition between dietary protein.

= In the brain, Levodopa is converted to DA ,
 by decarboxylation primarily within the presynaptic
terminals of dopaminergic neurons in the stratium.

= The DA produced;
 is now responsible for the therapeutic
effectiveness of the Drug in PD.

= After release, DA is either :

a) transported back into dopaminergic terminals by the
presynaptic uptake mechanism.
b) Or, metabolized by the actions of MAO and
catechol-O-methyltransferase (COMT).
Levodopa is almost always administered;
 in combination with a peripherally acting
 inhibitor of aromatic L-amino acid decarboxylase;
such as:

= Carbidopa or Benserazide,
 drugs that do not penetrate well into the CNS.

= Levodopa administered alone,

 is largely decarboxylated
 by enzymes in the intestinal mucosa
and other peripheral sites.

 less than 1% of the unchanged Levodopa;

reaches the cerebral circulation.
= DA release into the circulation,
by the peripheral conversion of Levodopa,
 produces undesirable effects, particularly nausea.

= Inhibition of peripheral decarboxylase markedly;

 markedly increases the fraction of Levodopa,
 that remains un-metabolized and available
to cross the BBB,
 and reduces the incidence of GI side effects.

= A daily dose of 75 mg Carbidopa,

 sufficient to prevent the development of nausea.
The "wearing off " Phenomenon :
= A principal limitation to the long-term use of Levodopa
 is the lose of its "buffering" capacity,

= the patient's Motor State;

 may fluctuate dramatically with each dose of Levodopa,
 described as “ motor complications “ of Levodopa.

= A common problem is the development of the

"wearing off" phenomenon .
= High doses of Levodopa are associated with
 early onset of Dyskinesias.
= Other Adverse Effects of Levodopa Treatment:
> Hallucinations and Confusion;
 especially in elderly patients, or
 in patients with preexisting cognitive dysfunction.

> Levodopa-induced Psychosis;

 Antipsychotic agents, like Phenothiazines,
are effective against levodopa-induced Psychosis,
 but may cause marked worsening of parkinsonism,
thro’ actions at the D2 DA receptors.

 “Atypical" antipsychotic Clozapine and Quetiapine ;

 most effective and best tolerated in patients
with advanced PD.
Drug Interactions and Adverse Effects:

= Peripheral decarboxylation of Levodopa and

release of DA into the circulation,
 may activate vascular DA receptors,
 and produce orthostatic hypotension.

= Administration of Levodopa with Nonspecific

Inhibitors of MAO;
 like, Phenelzine and Tranylcypromine ,
 markedly accentuates the actions of Levodopa,

 and may precipitate life-threatening hypertensive

crisis and hyperpyrexia;
= Non-specific MAO inhibitors
 be discontinued at least 14 days before
Levodopa is administered.

= This prohibition does not apply to the

MAO-B subtype-specific Inhibitors :
 Selegiline and Rasagiline (AZILECT),
 which can be administered safely in
combination with Levodopa.

= Abrupt withdrawal of Levodopa,

or other dopaminergic medications may precipitate;
 the Nuroleptic Malignant Syndrome :
of confusion, rigidity, and hyperthermia,
 a potentially lethal adverse effect.
= Dopamine is also susceptible to breakdown,
by COMT as well as MAO-B,
which converts Dopamine to:

 3-methoxytyramine (3-MT), and

 3,4dihydrophenylacetic acid(DOPAC)
= Another agent used in combination with, Levodopa and Carbidopa;
 is Entacapone,
 which inhibits peripheral COMT, and like Carbidopa;
 it prolongs the time that Levodopa is available to the brain.

= By decreasing the metabolism of Dopamine

 these drugs; (carbidopa, Levodopa, Entacapone)
 help to access the BBB, and

 can act both in the CNS and in the periphery.

SINEMET, ATAMET:
 most commonly prescribed Carbidopa/Levodopa
in the 25/100 form, three or more tablets daily
 provide acceptable inhibition of decarboxylase.

= Supplemental Carbidopa (LODOSYN)

 to minimize GI side effects, is at times beneficial.
= Carbidopa/Levodopa ( PARCOPA )
 an orally disintegrating tablet,
 for those with swallowing difficulty.

= Levodopa is not absorbed thro’ the oral mucosa,

 still has to reach the small intestines for absorption.
SINEMET CR :
 sustained-release formulation of
Carbidopa/Levodopa, in an erodable wax matrix .
 designed to maintain a stable plasma Levodopa levels.

= Treatment with Levodopa ;

 dramatic effect on all the signs and symptoms of PD.

= If treatment is started early;

 improvement in tremor, rigidity,
and bradykinesia is nearly complete.
= Dopamine depletion,
 leads to increased Ach release,
 which then activates muscarinic receptors,
responsible for smooth motor control.
= Overstimulation of these neurons by Ach,
 causes tremors and rigidity.

= The Anti-muscarinic agents, now come into play,

 by blocking the muscarinic Ach receptors
and cholinergic nerve activity.
= As the balance between Ach and Dopamine is restored,
by the anti-cholinergic agents, and
 the symptoms of PD may improve.
= Another useful drugs are the
Selective MAO-B Inhibitors:
 that selectively inhibits MAO-B and COMT.

Two Selective MAO-B inhibitors used for PD:

1) Selegiline (ELDEPRYL, EMSAM, ZELAPAR)
2) Rasagiline (AZILECT).
Selective MAO-B Inhibitors:
= Two isoenzymes of MAO (MAO-A and MAO-B)
 oxidize and inactivate monoamines
 present in the periphery of intestinal origin.

= Isoenzyme MAO-B;
 is the predominant in the striatum
 responsible for most of the oxidative
metabolism of DA in the brain.

= Two selective MAO-B inhibitors used for PD:

1) Selegiline (ELDEPRYL, EMSAM, ZELAPAR)
2) Rasagiline (AZILECT).
= In recommended doses,
both selective MAO-B inhibitors:
 selectively inactivate MAO-B through
 irreversible inhibition of the enzyme.

= Both agents have modest beneficial effects

on the symptoms of PD,
 through inhibition of DA breakdown
in the striatum.
= Unlike the non-specific inhibitors of MAO
( Phenelzine, Tranylcypromine, and Isocarboxazid),

= Selective MAO-B inhibitors:

 do not substantially inhibit peripheral metabolism
of catecholamines, thus;
> can be taken safely with Levodopa.
> do not exhibit the "cheese effect,"
 the potentially lethal potentiation of
catecholamine action observed
 when patients on nonspecific MAO inhibitors
 ingest indirectly acting sympathomimetic amines
such as the tyramine found in certain cheeses and wine.
Selegiline:
 used as symptomatic treatment for PD,
 well tolerated in younger patients with early or mild PD.

= In patients with more advanced PD

or with underlying cognitive impairment,
 selegiline may accentuate the adverse
motor and cognitive effects of levodopa therapy.

= Metabolites of Selegiline include

a) Amphetamine
b) Methamphetamine
 may cause anxiety, insomnia, and
other adverse symptoms.
Selegiline available in:
= Orally disintegrating tablet (ZELEPAR)
= Transdermal patch (EMSAM).

 both delivery routes are intended

to reduce hepatic first-pass metabolism
 and limit the formation of Amphetamine metabolites.

= Unlike Selegiline, Rasagiline;

does not give rise to undesirable Amphetamine metabolites.

= In randomized controlled clinical trials,

Rasagiline monotherapy;
 was effective in early PD, as adjunctive therapy
 significantly reduced levodopa-related
"wearing off" symptoms in advanced PD.
= In randomized controlled clinical trials,
Rasagiline monotherapy;

 was effective in early PD, as adjunctive therapy;

 significantly reduced levodopa-related

"wearing off" symptoms in advanced PD.
Catechol-O-Methyltransferase (COMT) Inhibitors:
= COMIT together with MAO,
 metabolizes Levodopa and DA.
= COMT, transfers a methyl group
 from the donor S-adenosyl-L-methionine,
 producing the inactive compounds:
a) 3-O-methyl DOPA (from levodopa) and
b) 3-methoxytyramine (from DA );
= Almost 99% of Oral Levodopa
 is metabolized and does not reach the brain.
 mostly converted by aromatic L-amino acid
decarboxylase (AADC),
 to DA,
 which causes nausea and hypotension.
= Addition of an AADC inhibitor, like Carbidopa,
 reduces the formation of DA,
 but increases the methylation of Levodopa
by COMT.

= The principal therapeutic action of COMT inhibitors;

 is to block this peripheral conversion of Levodopa
to 3-O-methyl DOPA,

 increasing both the plasma t1/2 of Levodopa,

 and, the fraction of each dose that reaches the CNS.
= Two COMT inhibitors, available for use in US;
Tolcapone (TASMAR) and Entacapone (COMTAN).
 both significantly reduced the "wearing off"
symptoms in patients under Levodopa/Carbidopa

 both drugs differ only in their PK properties and adverse effects:

= Tolcapone, a long duration of action,

 allow 2 to 3 times daily dosing,
 act as both central and peripheral inhibitors of COMT.

= In comparison to Entacapone,
 Tolcapone can penetrate the BBB,
 thus, can act both in the CNS and the periphery.
= Important adverse effect with Tolcapone,
 is hepatotoxicity.

= Up to 2% of the patients treated have,

 increased serum alanine aminotransferase
and aspartate transaminase.
 3 fatal cases of fulminant hepatic failure .
(a black box warning to the label.)
 used only in patients non-responsive to other
therapies and has to be monitored for hepatic injury.

= Entacapone :
 has not been associated with hepatotoxicity
 requires no special monitoring.
 available in fixed-dose combinations with
Levodopa/Carbidopa (STALEVO).
= Entacapone:
 has a short duration of action (2 hours)
 administered simultaneously with
each dose of Levodopa/Carbidopa.

= MOA of Entacapone;
 principally peripheral inhibition of COMT.
= Entacapone: has not been associated with hepatotoxicity
 requires no special monitoring.
 available in fixed-dose combinations with
Levodopa/Carbidopa (STALEVO).

= Adverse effects are similar to those of Levodopa/Carbidopa,

 nausea, orthostatic hypotension, vivid dreams,
confusion, and hallucinations.
= Important adverse effect with Tolcapone,
 is hepatotoxicity.

= Up to 2% of the patients treated have,

 increased serum alanine aminotransferase
and aspartate transaminase.
 3 fatal cases of fulminant hepatic failure .
(a black box warning to the label.)
 used only in patients non-responsive to other
therapies and has to be monitored for hepatic injury.
= Because PD is a progressive disease,
 in time the number of dopaminergic neurons
decreases and,
 fewer are capable of synthesizing Dopamine.

= Some drugs have been developed,

 to mimic Dopamine, and
 directly stimulate Dopamine receptors in the brain.

= Some drugs that belong to this class include:

> Bromocriptine > Rotigotine
> Ropinirole > Apomorphine
> Pramipexole
Dopamine-Receptor Agonists:
= Drugs that are direct agonists of striatal DA Receptors,
 as an alternative to Levodopa.

= Offers several Potential Advantages:

1. Enzymatic conversion of these Drugs,
is not required for activity,
2. They do not depend on the functional capacities
of the nigrostriatal neurons.
3. Durations of action is longer than that of Levodopa;
4. Used in the management of dose-related fluctuations
in motor state, to prevent motor complications.
5. Have the potential to modify the course of PD;
 by reducing endogenous release of DA, and
 the need for exogenous Levodopa,
 thereby reducing free radical formation
Ropinirole (REQUIP) and Pramipexole (MIRAPEX).
 The 2 oral DA receptor Agonists for treatment of PD:

= Duration of action of DA agonists is 8-24 hours

 longer than levodopa (6-8 hours),
 effective in patients who have developed
on/off phenomena.

= Ropinirole (REQUIP XL), O.D. sustained release

 more convenient and reduce adverse effects
related to intermittent dosing.
= among these Drugs include:
> Benztropine > Procyclidine
> Bepiredine > Trihexyphenidyl
Amantadine:
 is another drug in the management of PD.
 Amantadine does not belong to the class
of anti-PD drugs; its MOA is not fully understood,

 but Amantadine is believed to:

a) Prevents DA reuptake, alter DA release in striatum.
b) Facilitates presynaptic DA release.
c) Has anticholinergic properties
d) Blocks Glutamate NMDA receptors.
 but Amantadine is believed to:
a) Prevents DA reuptake, alter DA release in striatum.
b) Facilitates presynaptic DA release.
c) Has anticholinergic properties
d) Blocks Glutamate NMDA receptors.

Amantadine (SYMMETREL):
= an antiviral agent used for the prophylaxis and
treatment of influenza A,
Apomorphine (APOKYN):
 a dopaminergic agonist.

= can be given subcutaneous

= high affinity for D4 receptors;
= moderate affinity for D2, D3, D5 , and
adrenergic 1D, 2B, and 2C Receptors.
= low affinity for D1 receptors.

= has FDA-approval as a "rescue therapy"

 for the acute intermittent treatment of
"off" episodes in patients with fluctuating
response to dopaminergic therapy.
= Side effects of Apomorphine;
 are the same as for the oral DA agonists;
 plus its highly emetogenic,
requires pre- and post-treatment anti-emetic therapy.

= Oral Trimethobenzamide (TIGAN),

 at a dose of 300 mg three times daily,

 should be started 3 days prior to

the initial dose of Apomorphine, and
continued during the first 2 months of therapy.
= Concomitant use of Apomorphine with:
 Antiemetic drugs of the 5-HT3 Antagonist class
 is contraindicated ;
 due to profound Hypotension and Loss of consciousness.

= Potentially serious side effects of Apomorphine;

a) QT prolongation
b) Injection-site reactions
c) Development of a pattern of abuse like;
 increasingly frequent dosing leading to:
= Hallucinations
= Dyskinesia
= Abnormal behavior
= Thus, Apomorphine is appropriate;
 only when other measures, such as
a) Oral DA agonists, or
b) COMT inhibitors
 have failed to control the "off" episodes.

= Apomorphine should be initiated with

 a 2-mg test dose
 patient should be monitored carefully.
 If tolerated, can be titrated slowly up to a
maximum dosage of 6 mg.
PROGNOSIS:
= Progressive loss of DA containing neurons,
 is a feature of normal aging, however

 however, most aged population

do not lose 70-80% of their dopaminergic neurons,
 required to cause symptomatic PD.

= Without treatment, PD progresses;

 over 5-10 years to a rigid, akinetic state,
when patients are incapable to carry ADLs.

= Death frequently results from complications of

immobility, like:
a) Aspiration pneumonia
b) Pulmonary embolism
PROGNOSIS:
= Availability of effective pharmacological treatment
 radically altered the prognosis of PD.
 In most cases, good functional mobility
can be maintained for many years with PT.

= Life expectancy of adequately treated patients

 is increased substantially, but
 but, overall mortality remains higher than
that of the general population.
= As mentioned, aside from the prominent feature of PD,
 Dopaminergic neuron loss,
 is the most prominent feature of PD.

= PD affects a wide range of other brain structures,

 Brainstem, Hippocampus, and Cerebral cortex
 responsible for the "non-motor" features of PD:
a) sleep disorders
b) depression
c) memory impairment
 which usually prevails and be the sources of disability
as the motor features improved with treatment.
= Disorders other than Idiopathic PD
may also produce Parkinsonism, like :
a) Stroke
b) Intoxication with DA-receptor antagonist
c) Some relatively rare neurodegenerative disorders

= Drugs that may cause Parkinsonism:

a) Antipsychotics such as: Haloperidol and Thorazine
b) Anti-emetics such as: Prochloperazine and
Metoclopramide
= It is important to distinguish between Idiopathic PD
and other causes of Parkinsonism,

 because parkinsonism arising from other causes,

 are usually refractory to all forms of treatment.

Neural Mechanism of Parkinsonism:
= The BG regulates the flow of information,
 from Cerebral cortex to the motor neurons
of the spinal cord.
= Neostriatum, the principal input structure of BG,
 receives excitatory glutamatergic input
from many areas of the Cortex.
= Most neurons within the striatum;
 are projection neurons that innervate
other basal ganglia structures.
= An important small subgroup of striatal neurons,
 consists of interneurons that connect neurons
within striatum but do not project
beyond its borders.
= Acetylcholine (ACh) and Neuropeptides;
 the transmitters by these striatal interneurons.
Summary of Side effects:
= Both Pramipexole and Ropinirole may produce:

a) Hallucinosis or Confusion;
similar to that observed with Levodopa.

b) Nausea and Orthostatic Hypotension;

 thus both should be initiated at low dose, then
titrated slowly to minimize these side effects.

c) Fatigue and Somnolence

 for both DA agonists and Levodopa as well.
Summary of Side effects:

= All Dopamine agonists, may cause:

> Nausea > Orthostatic hypotension
> Mental disturbances > Daytime sleepiness

= Bromocriptine,
 has been associated with pulmonary and cardiac fibrosis.

= Drugs that block muscarinic receptors,

 generally produce anticholinergic side effects, such as:
> Constipation > Urinary retention,
> Dry mouth > Blurred vision.
Pharmacological treatment of PD, therefore:
a) Should be tailored to the individual patient.

b) Drug therapy is not obligatory in early PD;

 patients can be managed for a time with,
 exercise and lifestyle interventions.

c) For mild symptoms, MAO-B inhibitors, amantadine,

or (in younger patients) Anticholinergics are reasonable.

d) In most patients, a dopaminergic drug,

either Levodopa or a DA agonist, is eventually required.
Neuroprotective Treatments for PD:

= Treatment that modifies the progressive

degeneration that underlies PD,
 rather than simply controlling the symptoms.

= Current research strategies are:

 based on the disease mechanisms like:
a) energy metabolism
b) oxidative stress
c) environmental triggers
d) excitotoxicity
 based on discoveries related to the genetics of PD.
Genetics and Environmental Factors:
PD, AD, and ALS:
= mostly sporadic without clear pattern of inheritance.
= each with well-recognized genetic forms.

= In PD :
 there are both dominant (-synuclein, LRRK2)
and recessive (parkin, DJ-1, PINK1) gene mutations
 that may give rise to PD

= One toxin, N-methyl-4-phenyl-1,2,3,6-tetra-

hydropyridine (MPTP),
 can induce a condition closely resembling PD.

= Recent linking of pesticide exposure with PD

Selective Vulnerability:

= A striking feature of neurodegenerative disorders .

 is the specificity of the disease processes
for particular types of neurons.

= In PD :
 extensive destruction of the dopaminergic
neurons of the substancia nigra,

 whereas neurons in the cortex and many other

areas of the brain are unaffected.
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