Parkinson’s Disease

  • First described in modern medicine in “An Essay on the Shaking Palsy,” published in 1817 by a London physician named James Parkinson
  • Parkinson’s Disease is a neurological disease affecting over four million patients worldwide.
  • While it can affect individuals at any age, it is most common in the elderly.
  • The average age of onset is 55 years, although approximately 10 percent of cases affect those under age 40.

Parkinson’s Disease is characterized by the clinical picture of

  • Bradykinesia – Slowness in Initiation and Execution of Voluntary Movements
  • Rigidity – Increase Muscle Tone and Increase Resistance to Movement (Arms and Legs Stiff)
  • Tremor – Usually Tremor at Rest, When Person Sits, Arm Shakes, Tremor Stops When Person Attempts to Grab Something
  • Postural Instability – abnormal fixation of posture (stoop when standing), equilibrium, and righting reflex
  • Gait Disturbance – Shuffling Feet

Accompanied Autonomic Deficits Seen Later in Disease Process:

  • Orthostatic Hypotension,
  • Dementia
  • Dystonia
  • Ophthalmoplegia
  • Affective Disorders

Neurological basis of Parkinson’s Disease

  • Loss of Dopaminergic (DA) Cells Located in Basal Ganglia; most symptoms do not appear until striata DA levels decline by at least 70-80%. 
  • Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia
  • Though the cholinergic system is not primarily affected. its suppression (by anticholinergics) tends to restore balance.
  • The Dopaminergic Neurons in the Basal Ganglia are mainly affected.
  • GABA neuron has an inhibitory action on the substantia nigra. From substantia nigra, there is a dopaminergic feed back to striatum which gets lost giving signs and symptoms of Parkinson disease.
  • Drug-induced reversible parkinsonism due to neuroleptics, metoclopramide (dopaminergic blockers) is now fairly common
  • Two major strategies for the treatment of Parkinsonism are to increase brain dopaminergic activity or to decrease central cholinergic activity.

Anti Parkinson’s Disease Drugs

Drugs affecting brain dopaminergic system

Dopamine Precursor: Levodopa (l-dopa)

Peripheral decarboxylase inhibitors: Carbidopa, Benserazide

Dopaminergic Agonists: Non ergot derivatives: Ropinirole, Pramipexole, Ergot derivatives: Bromocriptine, Pergolide

MAO- B inhibitors: Selegiline, Rasagiline

Dopamine facilitator: Amantadine

COMT inhibitors: Entacapone, Tolcapone

Drugs affecting brain cholinergic system

Central anticholinergics: Trihexyphenidyl (Benzhexol), Procyclidine, Biperiden

Antihistaminics: Orphenadrine, Promethazine


  • Mechanism of Action: Converted to dopamine by decarboxylation primarily within the presynaptic terminals of dopaminergic neurons in the striatum. The dopamine produced is responsible for the therapeutic effectiveness of the drug in PD; after release, it is either transported back into dopaminergic terminals by the presynaptic uptake mechanism or metabolized by the actions of MAO and catechol-O-methyltransferase (COMT)
  • It is inactive by itself, but is the immediate precursor of the transmitter DA. More than 95% of an oral dose is decarboxylated in the peripheral tissues (mainly gut and liver).
  • About 1–2% of administered levodopa crosses to the brain, is taken up by the surviving dopaminergic neurones, converted to DA which is stored and released as a transmitter.
  • Concentrations of the drug in plasma usually peak between 0.5 and 2 hours after an oral dose.
  • The half-life in plasma is short (1 to 3 hours)
  • The rate and extent of absorption of levodopa depends on the rate of gastric emptying, the pH of gastric juice, and the length of time the drug is exposed to the degradative enzymes of the gastric and intestinal mucosa
  • Adverse Effects:
    At the initiation of therapy:
    • Nausea and vomiting à DA action on CTZ à tolerance gradually develops à Domperidone but not metoclopramide can be used for the treatment of this vomiting à because domperidone does not cross blood-brain barrier, but reaches CTZ.
    • The peripherally formed DA can cause tachycardia by acting on β adrenergic receptors.
    • Postural hypotension
    • Cardiac arrhythmias and angina
    • Alteration of taste sensation
  • After prolonged therapy:
    • Abnormal movements à (dyskinesias) Facial tics, grimacing, tongue thrusting, choreoathetoid movements of limbs à no tolerance to adverse effects.
    • Behavioral effects à mild anxiety, nightmares, etc. to severe depression, mania, hallucinations, mental confusion or frank psychosis.
    • Fluctuation in motor performance à ‘End of dose’ deterioration (wearing off) which is initially gradual, develops into rapid ‘switches’ or ‘on-off’ effect. With time ‘all or none’ response develops à reflection of progression of the disorder
    • On/off phenomenon
    • Embarrassingly disproportionate increase in sexual activity has also been noted.
    • Abrupt withdrawal of levodopa may precipitate neurolept malignant syndrome.


  1. Pyridoxine: Abolishes the therapeutic effect of levodopa (not combined with carbidopa) by enhancing its peripheral decarboxylation so that less of it remains available to cross to the brain.
  2. Antihypertensive drugs: postural hypotension caused by levodopa is accentuated

Dopamine Decarboxylase Inhibitors

  • These are the drugs that inhibit peripheral metabolism of levodopa by inhibiting enzyme Dopa decarboxylase
  • Do not cross blood brain barrier
  • Drugs included in this category are:
    • Carbidopa and Benserazide
  • Plasma t1/2 of levodopa is prolonged and its dose is reduced to 1/ 4th
  • Systemic conc. of DA is reduced, nausea and vomiting are not prominent – therapeutic doses of levodopa can be attained quickly
  • Cardiac complications are minimized
  • On-off effect is minimized since cerebral DA level are more sustained
  • Pyridoxine reversal of levodopa effect does not occur.
  • Degree of improvement may be higher

Problems not resolved or accentuated are—

1. Involuntary movements

2. Behavioural abnormalities

3. Excessive day time sleepiness in some patients.

4. Postural hypotension.


  • A D2 agonist
  • Bromocriptine is absorbed to a variable extent from the gastrointestinal tract;
  • Peak plasma levels are reached within 1-2 hours after an oral dose
  • It is excreted in the bile and feces.
  • The usual daily dose of bromocriptine in the treatment of parkinsonism is between 7.5 and 30 mg, depending on response and tolerance.
  • To minimize adverse effects, the dose is built up slowly over 2 or 3 months from a starting level of 1.25 mg twice daily after meals; the daily dose is then increased by 2.5 mg every 2 weeks depending on the response or the development of adverse reactions.


  • Ergot derivative
  • Directly stimulates both D1 and D2 receptors
  • Has been widely used for parkinsonism
  • Comparative studies suggest that it is more effective than bromocriptine in relieving the symptoms and signs of the disease, increasing “on-time” among response fluctuators, and permitting the levodopa dose to be reduced.
  • Because the use of pergolide has recently been associated with clinical or subclinical valvular heart disease in about one third of patients, one of the newer non-ergot agents is preferred when a dopamine agonist is required.


  • Preferential affinity for the D3 family of receptors
  • It is effective when used as monotherapy for mild parkinsonism
  • It is also helpful in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations
  • It may ameliorate affective symptoms


  • Nonergoline derivative
  • Relatively pure D2 receptor agonist that is effective as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa in patients with more advanced disease and response fluctuations
  • longer acting than levodopa, useful in the management of motor fluctuations and reducing frequency of on-off effects
  • also used for Restless leg syndrome.
  • It is introduced at 0.25 mg three times daily, and the total daily dose is then increased by 0.75 mg at weekly intervals until the fourth week and by 1.5 mg thereafter. In most instances, a dose of between 2 and 8 mg three times daily is necessary

COMT inhibitors: Entacapone, Tolcapone

  • As an adjuvants to levodopa-carbidopa for advanced PD
  • Inhibit enzyme Catechol-O-methyl transferasewhich is responsible for degradation of levodopa when peripheral Dopa decarboxylase is inhibited by Carbidopa.
  • It also inhibits COMT in brain, thereby increasing t1/2 of levodopa.
  • Entacapone has peripheral effect whereas Tolcapone has peripheral as well as central effect
  • Worsen the adverse effects of levodopa (nausea, vomiting, dyskinesias, etc.)
  • Not indicated early in the disease
  • Used to smoothen ‘wearing off’, increase ‘on’ time and decrease ‘off’ time in response fluctuators
  • Tolcapone: Hepatotoxic and rhabdomyolysis
  • Entacapone is not hepatotoxic

MAO-B inhibitors: Selegiline, Rasagiline

  • Selective, irreversible MAO-B inhibitor
  • Mild antiparkinsonian activity, decreases motor fluctuations and wearing off effects.
  • Permits reduction in dose of levodopa.
  • Clinical benefits are short lived (6 – 26 months)
  • Postural hypotension, nausea, accentuation of levodopa induced involuntary movements and psychosis
  • Interaction with tricyclic antidepressants and SSRIs.

Safinamide à new MAO-B inhibitor à used with levodopa/carbidopa in patients of PD experiencing ‘off’ episodes.


  • An antiviral agent, found to have anti-parkinsonism properties
  • It increases synaptic dopamine level by increasing presynaptic release and decreasing its reuptake.
  • It also possesses anticholinergic and antiglutaminergic (NMDA blocking) activity.
  • It is indicated forà dyskinesia associated with chronic levo-dopa therapy.
  • The plasma half-life is between 2 and 4 hours
  • Excreted unchanged in the urine
  • Amantadine is less potent than levodopa, and its benefits may be short-lived, often disappearing after only a few weeks of treatment. Nevertheless, during that time it may favorably influence the bradykinesia, rigidity, and tremor of parkinsonism
  • Number of undesirable central nervous system effects: restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations, and confusion
  • Livedo reticularis (bluish discolouration) and edema of ankles.
  • Amantadine should be used with caution in patients with a history of seizures or heart failure

Rotigotine transdermal patch à dopamine agonist à discontinued due to crystal formation on the patches.

Apomorphine can be given subcutaneously for temporary relief of off-periods. However, it cause troublesome nausea.

Central Anticholinergics

  • certain H1 antihistaminics have significant central anticholinergic proper
  • Act by reducing unbalanced cholinergic activity in striatum
  • Produce 10 – 25 % improvement in clinical features
  • Sialorrhoea is controlled by their peripheral action.
  • Tremor is more benefited than rigidity
  • Overall efficacy is less than levodopa
  • Used in mild cases OR in patients in whom levodopa is contraindicated
  • Anticholinergics are the only drugs effective in drug (phenothiazine) induced parkinsonism
  • Trihexyphenidyl It is the most commonly used drug. 2–10 mg/day.

‘Drug holiday’ (withdrawal of levodopa for 4–21 days) to reestablish striatal sensitivity to DA by increasing dopaminergic receptor population is no longer practiced.

RA in Parkinson drugs

  1. Need for new drugs:
    1. Current therapies do not prevent neuro-degeneration.
    2. The motor and behavioral s/e of levodopa decrease the QOL of patients.
  1. Recent advances in current t/t.
  • Orally disintegrating selegiline:
    • Bypasses the FPM. Therefore achieves Tmax faster. Also Cmax is 4 times higher than IR.
    • Lower dose is given (1.25 to 2.5 mg).
    • Also selegiline is metabolized to amphetamine which is a/w s/e; this is prevented by ODT.
    • Approved in 2006 as add on to Levodopa in patients who show deterioration in therapeutic response.
  • Rotigotine transdermal patch: 2,4,6 mg TDP. The primary outcome parameter was the change in baseline score of UPDRS II and III. a/w application site reaction, somnolesence etc. Approved in 2007 by EMEA for all stages of PD while in 2007 was approved by USFDA for mild PD.
  • Sustained release ropirinole: Advantage is OD dosing a/c/t TDS of the IR preparation. Approved in 2008 by USFDA.
  • Safinamide: March 2017 à (MAO-B) inhibitor.
    • inhibits the calcium, sodium channels, inhibits glutamate secretion and inhibits the MAO-B reversibly.
    • add on the dopamine agonist in early PD and add on the levodopa in PD with motor dysfunction
  • Duodopa (Levodopa 20 mg/mL and Carbidopa 5 mg/mL gel).  (Jan 2015)
  • Supplied in 100 mL cassettes. The cassette is attached to an external pump which is connected to a percutaneous endoscopic gastrostomy tube which releases the gel in the proximal jejunum.
  • Duopa is supplied as a solution for enteral infusion.
  • Duopa is administered over a 16-hour infusion period. The maximum recommended daily dose of Duopa is 2000 mg of levodopa (i.e., one cassette per day) administered over 16 hours.
  • Prior to initiating Duopa, convert patients from all forms of levodopa to oral immediate-release carbidopa-levodopa tablets. Titrate total daily dose based on clinical response for the patient.
  • Improvement in motor fluctuation in 96% and dyskinesia in 95%. But was a/w technical problems in 63%.
  • Drawbacks: Surgical intervention necessary, device malfunction can occur. Inconvenient
  • Alternative to DBS to treat motor fluctuations and dyskinesia.
  • Extended release formulation of Carbidopa/levodopa. (2015)
  • Increased time spent in the ON phase a/c/t IR formulation.

Pimavanserin (April 2016) à atypical antipsychotic.

  • specifically indicated for the treatment of hallucinations and delusions associated with Parkinson’s disease.
  • the effect of pimavanserin could be mediated through a combination of inverse agonist and antagonist activity at serotonin 5-HT2A receptors and to a lesser extent at serotonin 5-HT2C receptors.
  • s/e à peripheral edema, confusional state
  • New drugs in pipeline
  • A2a antagonists: A2a receptors are co-llocated with D2 receptors in the striatal neurons. Inhibition of these receptors is a/w decreased activity of the striatopallidal pathway.
  • Istradefylline: redcued the OFF time significantly a/c/t placebo.
  • Preladenant: Decreased time spent on OFF period when preladenant was added to levodopa. Phase 3 is on-going

Neuroprotective agents: Agents that have been tried are: Cogane, Ubiquinone, Ultra-pure creatine, Pioglitazone.

  • Pioglitazone: Furthest along development. Inhibits the neuro-inflammation involving reactive microglia, activation of genes involved in cellular bioenergertics and inhibition of MAO-B.
  • Stem cell therapy: Aims at modifying neuronal action to relieve symptoms.
  • AAV2/GAD: glutamic acid decarboxylase: increases synthesis of GABA
  • AAV2/AADC: aromatic acid decarboxylase: increases synthesis of dopamine
  • Drugs for Levodopa induced dyskinesia: Targets. mGluR5 antagonist. Fipamizole: Selective alpha 2 receptor antagonist.
  • Drugs for Parkinsons dementia: Rivastigmine is approved. Capsule: 2006 and transdermal patch: 2013.

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