How do Parkinson’s drugs work?
Parkinson’s disease (PD) is a progressive condition of the nervous system where the brain hormone (neurotransmitter) known as dopamine is lower than normal. The treatment of Parkinson’s disease mainly revolves around an increase in the level of the neurotransmitter dopamine or its effects. Excess of acetylcholine levels, another neurotransmitter, is seen prominently in drug-induced Parkinson’s disease. Therefore drugs known as centrally acting anticholinergic agents (drugs that block the effects of acetylcholine as a neurotransmitter in brain) are used to manage this form of Parkinson’s disease.
Types of Parkinson’s Drugs
Drugs which increase brain dopamine levels are :
- Precursors of dopamine: levodopa
- Drugs inhibiting peripheral conversion of levodopa to dopamine: benserazide and carbidopa
- Drugs acting as agonist for dopaminergic receptors: ropinirole, pramiprexole, bromocriptine, piribedil, rotigotine, pergolide, lisuride, and apomorphine.
- Drugs inhibiting metabolism of dopamine :
– Mono Amine Oxidase-B (MAO-B) inhibitors: selegeline and rasagiline
– Catechol-O-Methyl Transferase (COMT) inhibitors: tolcapone and entacapone
- Facilitators of dopamine: amantadine
Drugs which decrease brain cholinergic activity include :
- Centrally acting anticholinergic drugs: trihexyphenydyl, biperiden, procyclidine, promethazine and orphenadrine.
Drugs to Increase Dopamine
Levodopa : Dopamine Precursor
How does it work?
Levodopa is a dopamine precursor which is converted to dopamine in the body by the action of the decarboxylase enzyme. It is more effective than any other antiParkinson’s drugs and it relieves all the prominent symptoms of Parkinson’s disease like rigidity, hypokinesia and tremors. Rigidity and hypokinesia are the first symptoms to ease and improvement in tremors usually follows thereafter. Secondary features like facial expression, speech and self care also show significant improvement.
More than 95% of oral dose of levodopa undergoes decarboxylation (enzymatic alteration) to form dopamine before reaching the brain. Dopamine formed outside the brain therefore cannot reach the brain to produce the beneficial effects. Only 1 to 2% of the oral dose of levodopa is able to cross the blood brain barrier to reach the brain, and get converted to dopamine to produce its effects. To increase the amount of levodopa reaching the brain, the drug is almost always used in combination with drugs like carbidopa that inhibits the enzymatic conversion of levodopa outside of the brain.
Adverse effects of levodopa can be categorized as early (immediate) and late adverse effects. Early adverse effects are mainly related its peripheral conversion to dopamine – conversion outside of the brain. The dopamine formed outside the brain can cause significant adverse effects as listed below.
- cardiovascular side effects :
– postural hypotension
– fluctuation in blood pressure
– disturbances in the rhythm of heart
– worsening of ischemic heart disease
- gastrointestinal side effects :
– anorexia (loss of appetite)
Side effects with long term use includes :
- abnormal involuntary muscle movements like :
– facial grimacing
– athetoid movements
– tongue thrusting
- behavioral side effects like :
– mood elation (mania)
– sleep disturbances
Fluctuations in response to levodopa following long term use (more than 2 years) manifests as “wearing off phenomena” and “on-off effect”. This usually indicates the progression of Parkinson’s disease. “Wearing off phenomena” is the appearance of Parkinson’s symptoms before the next scheduled dose of levodopa. Development of “on-off effect” is characterized by fluctuations in the response to lebodopa and can show periods of complete relief of the Parkinson’s symptoms and full Parkinson’s symptoms unrelated to timing of dose. These fluctuations may be reduced by increasing the frequency of administration of levodopa or adding adjuvant drugs to the therapy.
Use of levodopa is contraindicated in patients with psychosis, and acute congestive glaucoma. It should be used with caution in patients with cardiac arrhythmias, bleeding peptic ulcers and those with history of melanoma.
Drugs to Block Levodopa Break Down
How does it work?
Benserazide and carbidopa are inhibitors of the enzyme decarboxylase. This enzyme converts levodopa to dopamine. Since hese drugs cannot cross the blood-brain barrier, the blocking of levodopa-to-dopamine conversion is therefore limited to the tissues outside the brain. Conversion of levodopa to dopamine within the brain continues as normal. Therefore this class of drugs are known as as peripheral decarboxylase inhibitors.
When used in combination with levodopa, peripheral decarboxylase inhibitors provide significant advantages over just levodopa on its own. The advantages of the combination therapy include reduction in most of the peripheral side effects of levodopa, increase in the duration of action of levodopa (which helps in reducing frequency of administration of levodopa) and in reducing the dose of levodopa.
Fixed dose combinations contain specific doses of carbidopa and levodopa or benserazide and levodopa as a single tablet. These fixed combinations produce milder early side effects (like nausea, vomiting, heart rhythm disturbance etc) and “on-off effect”. However incidence of late side effects (like involuntary movements and behavioral abnormalities) and postural hypotension are similar to levodopa.
Drugs that Mimic Dopamine
How does it work?
Dopamine agonists act like dopamine directly on the receptors on which dopamine normally exerts its action (dopaminergic receptors). Dopamine agonists thereby relieve the symptoms of Parkinson’s disease like levodopa. As dopamine agonists do not require functional dopaminergic (dopamine-secreting) neurons to exert its effects, unlike levodopa, dopamine agonists are effective in the treatment of advanced stages of Parkinson’s disease even when majority of the dopaminergic neurons have undergone degeneration. These drugs are also helpful in controlling and smoothening the “wearing off phenomena” and “on-off effect”. Dopamine agonists may be used as monotherapy in early stages or as a part of combination therapy in late stages.
- Ropinirole and pramipexole are used as monotherapy in early Parkinson’s disease, and as supplemental drugs to levodopa in advanced Parkinson’s disease.
- Bromocriptine is mainly useful as a supplemental drug in advanced stage of Parkinson’s disease, but it is rarely used at present due to availability of better drugs.
- Piribedil is not available in the US. Several antiparkinson’s drugs have been withdrawn from the US markets.
- Rotigotine which was available as once-daily transdermal patch to treat the Parkinson’s disease has been withdrawn due to problems related to absorption.
- Pergolide was discontinued in US due to higher incidence of cardiac toxicity while lisuride was withdrawn due lower efficacy compared to other available dopamine agonists.
Dopamine agonists are better tolerated and are as effective as levodopa to provide symptomatic relief in early Parkinson’s disease. Therapeutic effect of these drugs usually appears in about 2 to 4 weeks after the treatment initiation.
Side effects of commonly used dopamine agonists (ropinirole and pramipexole) are similar to levodopa but of lesser severity than levodopa.
Apomorphine is a dopamine agonist which may be of use in emergency rescue management of off-periods in Parkinson’s disease patients. It is given by subcutaneous injection and it has very fast onset of action. It is can cause severe vomiting and hence it almost mandatory to be administered with antiemetic drugs (like trimethobenzamide). It can also be used along with levodopa therapy.
Drugs to Block Dopamine Break Down
How does it work?
These drugs inhibit the enzymes which are responsible for breaking down of dopamine. Hence they prolong the duration of dopamine that is present in the brain. These drugs are also helpful in reducing fluctuations like “wearing off phenomena” and “on-off effect”. The two class of drugs that block dopamine break down are MAO-B inhibitors and COMT inhibitors.
Rasagiline and selegeline are reversible inhibitors of MAO-B which is responsible for metabolizing dopamine. These drugs are particularly useful as monotherapy in the early stages of Parkinson’s disease and as adjuvant with levodopa therapy to enhance the effects of levodopa in advanced Parkinson’s disease. Additionally both the drugs are believed to have some protective effect on dopaminergic neurons and thereby slowing the disease progression. MAO-B inhibitors are contraindicated in patients taking drugs like meperidine, tramadol, and non-selective MAO inhibitors. Side effects of these drugs include vomiting, dry mouth, rash, abnormal dreams, anorexia, arthralgia, postural hypotension, psychosis and confusion.
Tolcapone and entacapone inhibit enzyme COMT which also degrades dopamine like MAO. COMT inhibitors are useful adjunct medications to levodopa therapy. COMT inhibitors provide smoother response and prolonged on-time with levodopa therapy. It also helps in reducing total daily dose requirement of levodopa. Tolcapone is highly toxic to liver and hence it has been withdrawn in some countries. Side effects of entacapone include prominent diarrhoea and yellowish discolouration of urine. Other side effects of COMT inhibitors result from increased levels levodopa.
Drugs to Promote Dopamine
How does it work?
Amantadine is primarily an anti-influenza drug which has antiparkinson effects. It has been found to increase synthesis and release of dopamine in brain. It loses its efficacy on long term usage. Its use is restricted only for mild cases and as short courses along with levodopa.
Patient tolerance is fairly good but it produces mild confusion, dizziness, ankle edema, nightmares and insomnia.
Drugs to Decrease Acetylcholine
Centrally acting anticholinergic drugs
How does it work?
Centrally acting anticholinergic drugs have higher anticholinergic activity in the brain compared to outside the brain (peripheral tissues). These drugs relieve Parkinson’s symptoms by reducing relative overactivity of acetylcholine in the brain. Anticholinergic drugs are highly effective in relieving tremors and to a lesser extent rigidity but offers minimal improvement of hypokinesia. These are the only group of drugs which are effective in treatment and prevention of drug-induced Parkinsonism (like antipsychotic drug-induced). These drugs may be given along with antipsychotic drugs to prevent development of drug-induced Parkinsonism. Central anticholinergic drugs may be also used in combination with levodopa therapy in Parkinson’s disease.
- Trihexipheydyl is the most common drug to be used. It is available as 2mg tablet and it can be given up to 10mg per day.
- Procyclidine is available in 5 and 10mg tablet, and can be given up to 20mg per day.
- Biperiden is available both as tablets and injections and it can be given up to 10mg per day.
- Promethazine and orphenadrine are antihistaminic drugs having aonticholinergic activity in brain.
- Promethazine and orphenadrine may be given up to 75mg and 300mg per day, respectively for Parkinson’s disease.
Anticholinergic drug use can cause dryness of mouth, blurring of vision, urinary retention and constipation as side effects. Anticholinergic drugs are contraindicated in patients with glaucoma.