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Parkinsonism

Parkinsonismis characterized by rigidity, bradykinesia, tremors and postural instability. It is usually idiopathic but can also occur by a wide variety of reasons. It may have genetic background. Idiopathic disorder may be due to exposure to some unrecognized or neurotoxin or to the occurrence of oxidation reactions with the generation of free radicals.

The normally high concentration of dopamine in the basal ganglia of the brain is reduced in Parkinsonism. Due to this, there occurs imbalance between the cholinergic and doparniriergic influences on the basal ganglia. Further dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum are lost.

Classification of Parkinsonism

I. Drugs acting through the dopaminergic system

i. Dopamine precursor: Levodopa (Ldopa)

ii. Dopamine metabolism inhibitors: a. MAO-B inhibitors: Selegiline, b. COMT inhibitors: Talcapone, entacapone

iii. Dopaminergic agonists: Bromocriptine, lisuride, pergolide, piribedil

iv. Drugs that facilitates dopaminergic transmission: Amantadine

v. Peripheral decarboxylase inhibitors: carbidopa, benserazide

II. Drugs acting through cholinergic system

i. Central anticholinergic: Trihexyphenidyl (benzhexol), procyclidine, biperiden

ii. Antihistaminics: promethazine, Orphenadrine,

Levodopa

It is [(-) -3-(3, 4-dihydroxyiphenyl) L-alanine]. Dopamine does not cross the blood—brain barrier while levodopa penetrates the brain. Levodopa is the immediate metabolic precursor of dopamine which is decarboxylated to dopamine in the brain. Dopaminergic antiparkinsonian drugs produce beneficial effects in patients of parkinsonism by stimulation of dopamine D2 receptors but dopamine D1 receptor stimulation may also be required for maximum benefit.

Levodopa is rapidly absorbed from the small intestine. Peak plasma concentration occurs between 1 and 2 hours after an oral dose arid the plasma half-life is usually between 1 and 3 hours. About two-thirds of the dose appears in the urine as metabolites (homovanillic acid and dihydroxyphenyl acetic acid). Unfortunately, only about 1—3% of the administered levodopa actually enters the brain unaltered, the remainder being metabolized extra-cerebrally, predominantly by decarboxylation to dopamine. Hence levodopa is always administered along with the dopa decarboxylase inhibitor which may reduce the daily requirements of levodopa by approximately 75%.

Levodopa can ameliorate all of the clinical features of parkinsonism but it is particularly effective in relieving bradykinesia and any disabilities resulting from it. It is given in combination with carbidopa. Dose: carbidopa 25 mg + levodopa 100 mg three times daily. Later on the dose of levodopa may have to be gradually increased to 250 mg.

Adverse effects: Anorexia, nausea, vomiting, dyskinesia (chorea, ballismus, athetosis, dystonia, myoclonus, tics and tremors), behavioural effects (depression, anxiety, agitation, insomnia, somnolence, confusion, delusions, hallucinations, nightmares, euphoria and other changes in mood or personality), mydriasis, blood dyscrasias, hot flushes, aggravation or precipitation of gout, abnormalities of smell and taste, brownish discoloration of saliva, urine or vaginal secretion, priapism, elevation of blood urea nitrogen and of serum transaminases, alkaline phosphatase and bilirubin.

Certain fluctuations in response to levodopa occur with increasing frequency as treatment continues. These fluctuations may be related to the timing of levodopa intake (weaning of reactions or end-of-dose akinesia) or unrelated to the timing of doses (on-off phenomenon). The exact mechanism of on-off phenomenon is not known. It is characterized by off periods of marked akinesia that alternate over the course of a few hours with on periods of improved motility. The situation can be handled by: (a) taking medication at more frequent interval; (b) reducing dietary intake of protein; (c) using controlled release formulations.

Levodopa should not be given along with pyridoxine (enhances extracellular metabolism of levodopa) and monoamine oxidase A inhibitors (precipitate hypertensive crisis).

Levodopa is contraindicated in psychotic patients (exacerbate the mental disturbance), in patients with angle-closure glaucoma and history of melanoma. It should be given carefully in patients with active peptic ulcer.

Dopomine Agonists

The enzymes responsible for synthesizing dopamine are depleted in the brains of parkinsonism patients. So dopamine agonists have a beneficial effect and an important role as first line therapy for Parkinson’s disease. They lower incidence of the response fluctuations and dyskinesia occurring with long-term levodopa therapy.

i. Bromocriptine is an ergot derivative. It is widely used in patients with parkinsonism in doses between 7.5 and 30 mg. Peak plasma levels are reached within 1—2 hours after an oral dose. It is excreted in the bile and faeces. It is a D2 agonist.

ii. Pergolide is another ergot derivative. It directly stimulates both D1 and receptors. The average dose is 3 mg daily. The doses of both drugs should be small in the beginning of the treatment and gradually increased to full dose in order to avoid adverse effects. When these drugs are used the dose of levodopa is gradually reduced to about half of the previously required dose.

Important adverse effects are anorexia, nausea, vomiting, dyspepsia, postural hypotension, dyskinesia, confusion, delusions, hallucinations, headache, nasal congestion and erythromelagia. They are contraindicated in patients with history of psychotic illness and recent myocardial infarction. They are best avoided in patients with peripheral vascular disease or peptic ulceration.

iii. Non-ergot dopamine agonists: Pramipexole and ropinirole are newer non-ergot dopamine agonists. Due to non-ergoline structure, adverse effects such as erythromelagia, vasospasm and pleural or retroperitoneal fibrosis are unlikely to occur.

Pramipexole acts on D3 receptors preferentially. It may ameliorate effective symptoms of parkinsonism by its ability to scavenge hydrogen peroxide and enhance neurotropic activity in mesencephalic dopaminergic cultures. On oral administration, it is rapidly absorbed and peak plasma concentration occurs approximately in 2 hours. It is excreted largely in the urine. It may be used as monotherapy for mild parkinsonism as well as an adjunct to levodopa therapy to reduce and to smooth response fluctuations. It is given in doses of 0.5—1.5 mg three times daily. Treatment is started with 0.125 mg three times daily and the dose is gradually increased depending on response and tolerance.

Ropinirole is a relatively pure D2 receptor agonist. It may be used as monotherapy in mild parkinsonism as well as an adjunct to levodopa therapy. It is given initially on doses of 0.25 mg three times daily. The dose is gradually increased up to 2—8 mg three times daily depending upon the response. The drug is neutralized in the liver.

The adverse effects of both the drugs are postural hypotension, fatigue, somnolence or insomnia, peripheral edema, nausea, constipation, dyskinesia and confusion.

Monoamine Oxidase Inhibitors

i. Seligiline (deprenyl) is a selective inhibitor of monoamine oxidase B. So it retards the breakdown of dopamine and enhances and prolongs the antiparkinsonian effect of levodopa. It is, therefore, indicated as adjunctive therapy for patients with a declining or fluctuating response to levodopa. Dose: 5 mg with breakfast and 5 mg with lunch. It should not be given to patients receiving meperidine, tricycic agents or serotonin uptake inhibitors because of the risk of acute toxic interactions. Its neuroprotective effect may be due to its metabolite desmethylseligiline. It is believed to slow down disease progression.

ii. Rasagiline: It is another monoamine oxidase B inhibitor. It is more potent than seligiline in preventing MPTP-induced parkinsonism.

Catechol-O-Methyltransferase Inhibitors

Tolcapone and entacopone are selective COMT inhibitors. They prolong the duration of levodopa by diminishing its peripheral metabolism. Clearance of levodopa is decreased and relative bioavailability of levodopa is thus increased. They are useful in patients of parkinsonism receiving levodopa who have developed response fluctuations. They will, thus, lead to smooth response, more prolonged “on time” and the option of reducing total daily dose of levodopa. Out of the two, entacopone is preferred because it does not cause hepatotoxicity.

Entacopone is rapidly absorbed, bound to plasma proteins and metabolized prior to excretion. It has peripheral effect only. It is given in doses of 200mg along with each dose of levodopa, i.e. 4—6 times daily. Adverse effects are dyskinesia, nausea, vomiting, confusion, diarrhea, abdominal pain, orthostatic hypotension, sleep disturbance and an orange discolouration of urine.

Amantadine

Amantadine is an antiviral drug. Its antiparkinsonian effect may be due to its ability to potentiate dopaminergic function by influencing the synthesis, release or uptake of dopamine. Peak plasma concentration occurs within 1—4 hours after an oral dose and its plasma half-life is between 2 and 4 hours. Most of the drug is excreted unchanged in urine.

Amantadine reduces bradykinesia, rigidity and tremor of parkinsonism. Disadvantages of the drug are that its desired effect disappears within a few weeks of treatment.

Common adverse effects are restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations and confusion. It may also cause headache, congestive heart failure, postural hypotension, urinary retention and gastrointestinal disturbances. Overdose may produce an acute toxic psychosis and convulsions. Livedo reticularis sometimes occurs. It is due to local release of catecholamines resulting in vasoconstriction.

Acetyicholine Blocking Drugs

Centrally acting antimuscarinic preparations are used in the treatment of parkinsonism. They may improve tremor and rigidity but have little effect on bradykinesia. Some of the commonly used drugs are:

i. Benztropine mesylate: 1—6 mg/day

ii. Procyclidine: 7.5—30 mg/day

iii. Biperidine: 2—12 mg/day

iv. Trihexyphenydyl: 6—20 mg/day

Orphenadrine: 150—400 mg/day.

Treatment is started with a low dose of one of the above drugs. The dose is then gradually increased until benefits occur or adverse effects appear. Important adverse effects are drowsiness, mental slowness, inattention, restlessness, confusion, agitation, delusions, hallucinations and mood changes. Other adverse effects are dryness of the mouth, blurring of vision, mydriasis, urinary retention, nausea and vomiting, constipation, tachycardia, tachypnea, increased intraocular pressure, palpitations and cardiac arrhythmias. Dyskinesia may occur rarely. These drugs should be withdrawn gradually. These drugs are contraindicated in patients with prostatic hyperplasia, pyloric stenosis, paralytic ileus and angle-closure glaucoma.

Drug-induced parkinsonism

Following drugs induce parkinsonism:

i. Reserpine and tetrabenazine: Due to depletion of biogenic monoamines from their storage sites.

ii. Haloperidol and phenothiazines: Due to their ability to block dopamine receptors. These drugs produce parkinsonism syndrome usually within three months of starting therapy with them. The syndrome clears over a few weeks or months after withdrawal. It may be treated with antimuscarinic drugs, if necessary. However, levodopa is of no help if neuroleptics are continued.

iii. MPTP: It is 1-mthyl-4-phenyl-1, 2, 3, 6- tetrahydropyridine. It is nephridine analogue. It is a protoxin. In the body, it is converted by MAO B to N-methyl-4- phenylpyridinium (MPPj. MPP is selectively taken up by cells in substantia nigra through an active mechanism normally responsible for dopamine reuptake. MPP inhibits mitochondrial complex, thereby inhibiting oxidative phosphorylation. This probably leads to cell death and thus to striatal dopamine depletion and parkinsonism.

Recognition of the effects of MPTP suggests:

• Spontaneously occurring Parkinson’s disease may result from exposure to an environmental toxin that is similarly selective to its target—no such toxin has been identified.

• A successful means of producing an experimental model of Parkinson’s disease in animal, especially non-human primates.

Points for Dental Students

  • Most of antiparkinson drugs cause xerostomia which is aggravated by antimuscarinic drugs used to treat parkinsonism.
  • It may increase the incidence of dental caries, pain in swallowing and difficulty in speech.
  • 2. Xerostomia is also increased with concurrent use of antihistaminics, tricyclic antidepressants and dicyclomine. This point is to be kept in mind by dentists while prescribing these drugs to patients of parkinsonism during dental procedures.
  • 3. Oral tremors provide difficulty during prosthetic restoration.
  • 4. Patients with parkinsonism always suffer with orthostatic hvpotension. So to avoid instant fall and injury, they should be asked to change the position in dental chair slowly.
  • 5. Use of adrenaline containing local anaesthetic in Parkinson’s patients on levodopa may precipitate cardiac arrhythmias due to peripheral conversion of levodopa to dopamine which stimulates the receptors of the heart.

TO REMEMBER

1. Parkinsonism (paralysis agitance) is characterized by rigidity, bradykinesia, tremor and postural instability. It is due to imbalance between cholinergic and dopaminergic influences on the basal ganglia and loss of dopaminergic neurons in the substantia nigra.

2.  Levodopa, immediate metabolic precursor of dopamine, is the drug of choice in the treatment of parkinsonism.

3.  It is always given with carbidopa (dopa decarboxylase inhibitor) which may reduce the daily requirement of levodopa by reducing its peripheral metabolism.

4.  Dopamine agonists are used as first line therapy for parkinsonism. They are ergot derivatives (bromocriptine and pergolide) as well as non-ergot dopamine agonists (pramipexole and ropinirol).

5.  Selegiline (deprenyl) and rasogiline are selective inhibitor of monoamine oxidase B. They prolong the antiparkinsonian effect of levodopa by reducing the breakdown of dopamine.

6.  Tolcapone and entacopone are selective catechol-O-methyltransferase inhibitors. They also prolong the duration of levodopa by diminishing its peripheral metabolism.

7.  Amantadine has antiparkinsonian effect due to its ability to potentiate dopaminergic function by influencing synthesis, release or output of dopamine.

8.  Centrally acting antimuscarinic preparations (benzotropine, mesylate, procyclidine, biperidine, trihexyphenydyl and orphenadrine) are used to improve tremor and rigidity in parkinsonism.

9. Parkinsonism may be precipitated by certain drugs such as reserpine, tetrabenazine, haloperidol, phenothiazine and MPTP.

About Dr. Muna

Dr. Muna Taqi is a Dental surgeon from India who has more than 10 years of experience in the field of Oral & Maxillofacial surgery, Endodontics, & Pedodontics. She has worked in multinational medical corporates in Middle East and is also a consultant dental surgeon for many. She has authored many articles for medical journals & websites and is a consultant dental expert for Healthdrip.

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