Problems With Long Term Therapy

Published Date: 02 Nov 2017

INTRODUCTION

Levodopa is the most effective therapy available for parkinson’s disease and most patients will eventually be commenced on it1. Levodopa is the immediate metabolic precursor of dopamine, it penetrates the blood brain barrier where it is decarboxylated to dopamine2. Dopamine does not cross the blood brain barrier and when given into the peripheral circulation it has no therapeutic effect on parkinson’s disease2. Levodopa is the first-line treatment for parkinson’s disease and it is combined with a dopa decarboxylase inhibitor, either carbidopa or benserazide which decreases the dose required by about 10-fold and reduces the peripheral side effects3. If levodopa is given alone, it is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites so that relatively small unchanged drug gets to the cerebral circulation and about less than 1% crosses the central nervous system7. Levodopa is a metabolic precursor of dopamine, it restores dopaminergic neurotransmission in the corpus striatum by enhancing the synthesis of dopamine in the surviving neurons of the substantia nigra5. Treatment with levodopa can have a dramatic effect on all the signs and symptoms of parkinson’s disease. Levodopa with a selective extracerebral decarboxylase inhibitor is the most efficient therapy for most patients with parkinson’s disease4.

MECHANISM OF ACTION

Levodopa is the immediate precursor of dopamine and can penetrate the brain4. Since parkinson’s disease is due to insufficient dopamine in specific regions of the brain, attempts are made to replenish the dopamine deficiency5.Dopamine does not cross the blood brain barrier but levodopa is actively transported into the central nervous system and is converted to dopamine in the brain. A large dose of levodopa is required because most of the drug is decarboxylated to dopamine in the periphery, leading to side effects that include cardiac arrhythmias, hypotension, nausea and vomiting5.

ACTION

Levodopa reduces the tremors, rigidity and other symptoms of Parkinson’s disease5.

PHARMACOKINETIC

It is absorbed rapidly from the small intestine and its absorption depends on the PH of the gastric contents and the rate of gastric emptying2. The appearance of levodopa in the plasma is delayed by ingestion of food. Peak plasma concentration of levodopa a is usually obtained between one and two hours after an oral administration and the plasma half-life is usually between one and three hours, this varies among individuals. Within eight hours of oral administration approximately two thirds of the drug is present in the urine as metabolites, the main metabolite products being 3-methoxy-4-hydroxylphenyl acetic acid and dihydroxyphenylacetic acid. Only approximately 1-3% of the levodopa administered is able to enter the brain unaltered3.

Levodopa is broadly distributed to most body tissues, but not to the central nervous because of widespread metabolism in the periphery11. It is not bound to plasma proteins. Levodopa penetrates the blood-brain barrier by active but saturable transport system for large neural amino acids11. In the presence of carbidopa, levodopa is mainly metabolised to amino acids, and to a less extent, to catecholamine derivatives. All metabolites are excreted renally11.After an oral dose of levodopa approximately 50% is recorded in the urine11.

THERAPEUTIC USES

The best results of levodopa therapy are achieved within the first few years of therapy2. Levodopa when combined with carbidopa is an efficient and potent drug regimen currently available for the treatment of Parkinson’s disease5. Levodopa-carbidopa therapy substantially decrease the severity of parkinsonism for the first few years of treatment in about two-thirds of patients with the disease. During the third to fifth year of treatment patients typically experience a decrease in response5, that is there is a gradual decline in the effectiveness of levodopa3. It is possible that the loss of levodopa efficacy portrays the natural progression of the disease, although other contributory factors may be receptor downregulation and other compensatory mechanisms3. There is no proof that levodopa can actually speed up the neurodegenerative process through the excessive production of dopamine. Generally, levodopa increases the life expectancy of patients with Parkinson’s disease, possibly through improved motor function3.

PROBLEMS WITH LONG TERM THERAPY

Following five years therapy, approximately fifty percent of patients will have lost ground. There will be a gradual recurrence of parkinsonian akinesia in some patients4. There will also be a second form of deterioration which is the shortening of duration of action of each dose of levodopa. Various

SIDE EFFECTS/ADVERSE EFFECTS

Dry mouth, palpitations, nausea, vomiting, taste disturbances, anorexia, hypotension, insomnia, psychosis, arrhythmias, fatigue, confusion, dizziness, depression, euphoria, anxiety, chorea and dyskinesia 6.

Adverse effects are common, and usually result from an extensive stimulation of dopamine receptors4. Stimulation of the chemoreceptor zone in the area postrema is the cause of nausea and vomitng4. This can be reduced by domperidone a peripherally acting dopamine antagonist. In treatment using levodopa psychiatric side-effects are the most frequent limiting factor such as hallucinations, vivid dreams, confusion and psychotic states4. Dyskinesia is an important adverse effect that in the early stages of parkinson’s disease, commonly shows overtreatment and respond to simple dose reduction (or fractionation). Postural hypotension occurs but is usually asymptomatic4. Different dyskinesias may appear and after a while, many patients begin to experience increasingly severe and fast oscillations in mobility and dyskinesias – the 'on-off effect' 4

ROPINIROLE

INTRODUCTION

Ropinirole is a nonergoline derivative and is a relatively pure D2 receptor agonist that is efficient 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 fluctuations2. It is one of the newer ergot drugs4 and is an agonist at dopamine receptors5. Ropinirole is started at 0.25mg three times daily, and the complete daily dose is then increased by 0.75mg at weekly intervals until the fourth week and by 1.5mg thereafter. In most cases, a dose of between 2mg and 8mg three times daily is necessary. Ropinirole is metabolised by CYP1A2.2

Ropinirole is better tolerated and does not portray the fluctuations in efficiency associated with levodopa3. Sometimes they cause hallucinations and somnolence. Suggestions from recent evidence is that they may predispose to compulsive behaviours, such as over-eating, sexual excess, and excessive gambling3. Ropinirole have selective activity at D2 class sites (mainly at the D2 and D3 receptor)7. Ropinirole do not exacerbate peripheral vasospasm and do not cause fibrosis unlike the ergotamine derivatives5.

Most patients benefit initially from treatment with levodopa, but views are different as to whether the later development of dyskinesias and unpredictable 'on-off' effects are caused by the cumulative dose of levodopa or merely reflect progression of the disease4. As a result, younger patients in particular are usually given a dopamine agonist as initial therapy sometimes together with (selegiline)4. This strategy may slow the development of dyskinesias, although only 50% of patients show any beneficial response to monotherapy with dopamine agonist (ropinirole )4.

Compliance in parkinson’s disease can be difficult and ropinirole have recently become available in once daily oral preparations2.

THERAPEUTIC INDICATION

It is used for the treatment of Parkinson’s disease, either used alone or as adjunct to co-beneldopa or co-careldopa, moderate to severe restless legs syndrome6.

MECHANISM OF ACTION

Ropinirole is a non ergoline D2/D3 dopamine agonist which stimulates striatal dopamine receptors11.

PHARMACOKINETIC

The bioavailability of ropinirole is about 50% (36% to 57%) and a high fat meal decreases the rate of absorption of ropinirole11.

Plasma protein binding of ropinirole is low (10-40%). Ropinirole being highly lipophilic exhibits a large volume of distribution (about 7 l/kg).11

Ropinirole is mainly cleared by the cytochrome P450 enzyme, CYP1A2, and its metabolites are mostly excreted in the urine11.

Ropinirole is cleared from the systemic circulation with an average elimination half-life of about 6 hours. Following single and repeated oral administration no change in the oral clearance of ropinirole is observed11.

SIDE EFFECTS/ADVERSE EFFECTS

Constipation, hypotension, syncope, dyspepsia, nausea, vomiting, peripheral oedema, abdominal

pain, drowsiness,insomnia, hallucinations, dizziness, confusion, dyskinesia, nervousness6.

Dyskinesia are less frequent compared to the use of levodopa5. Abnormal movements similar to those introduced by levodopa may occur and are overturned by decreasing the complete dose of the ropinirole being taken2.

Hallucinations, delusion, confusion and other psychiatric reactions are other complications of ropinirole treatment

Anorexia and nausea and vomiting may occur when ropinirole is administered and can be minimized by taking ropinirole with food. Dyspepsia,constipation, and symptoms of reflux oesophagitis may also occur.

PARKINSON’S DISEASE (PD)

Parkinson’s is a neurodegenerative disease of the brain10. It happens with the same incidence in men and women and the mean age of onset of symptoms is approximately 65years, though in a small percentage (about 5-10%) of patients symptoms may firstpresent after 40 years of age. parkinson’s disease is a neurologic disorder in which drug therapy plays a central role8. It is a chronic, progressive disorder of motor function mainly of middle to late life. The diagnosis is made in people with progressive L-DOPA-responsive signs of parkinsonism (rigidity, bradykinesia and tremor) in the absence of a toxic or other known underlying aetiology9.

Parkinson’s disease is caused by a failure of dopamine transmission due to degeneration of dopaminergic cells1. The choice of the strategy for therapy is determined by the characteristics of the patient and the nature of the symptoms1. Levodopa based therapy is very efficient although its associated with side effects in the longer term1. Dopamine agonists (ropinirole) are of particular use in early parkinson’s disease as they ease symptoms and delay motor complications1.

AETIOLOGY

The cause of parkinson’s disease is not known and no environmental or endogenous neurotoxin has been discovered4. The possibility that such a chemical exists has been suggested by the findings (those attempting to make pethidine)in California drug addicts that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) leads to degeneration of the nigrostriatal tract and Parkinson;s disease4. MPTP acts indirectly through a metabolite, 1-methyl-4-phenylpyridine (MPP+), which is formed by the action of MAOB .4 A lot of theories have been put forward regarding the origin of parkinson’s disease. Genetic predisposition and environmental factors have been implicated most often.

PATHOPHYSIOLOGY

Parkinson’s disease is a disorder of the extrapyramidal system of the brain concerning the basal ganglia8.The extrapyramidal system is concerned with maintaining posture and muscle tone and with regulating voluntary smooth motor activity. In PD, dopamine is progressively lost in the nigrostriatal tracts, and acetylcholine is relatively increased8. The pathological feature of parkinson’s disease is Lewy bodies, or intraneuronal inclusion bodies within the dopaminergic cells of the substantial nigra8. Generally, it is believed that a 70% to 80% loss of nigral neurons must occur before PD becomes clinically identifiable. Recent facts suggests that a substantial preclinical or latent phase of PD exists (roughly 5 to 20 years) before this critical threshold of nigral cell loss takes place8.

The imbalance between dopamine and acetylcholine is mainly responsible for the manifestations of the disease, and drug treatment is aimed toward correcting this imbalance8.