Antiparkinson Drugs Flashcards
Dopamine Synthesis
Dopamine synthesis, like that of all catecholamines in the nervous system originates from the amino acid precursor tyrosine, which must be transported across the blood- brain barrier into the dopamine neuron.
Tyrosine, like other neutral amino acids such as phenylalanine and leucine, is transported by system L across the blood brain barrier in a Na+-independent manner.
Once tyrosine gains entry into the neuron the rate-limiting step in dopamine synthesis is the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-DOPA) by the enzyme tyrosine hydroxylase.
Note: The levels of tyrosine in the brain are relatively high and are above the Km for tyrosine hydroxylase; therefore, under normal conditions it is not feasible to increase dopamine synthesis significantly by increasing brain levels of tyrosine.
DOPA is subsequently converted to dopamine by aromatic L-amino acid decarboxylase (DOPA decarboxylase). This latter enzyme turns over so rapidly that DOPA levels in the brain are negligible under normal conditions. Because of the high activity of this enzyme and the low endogenous levels of DOPA normally present in the brain, it is possible to enhance dramatically the formation of dopamine by providing this enzyme with increased amounts of substrate.
Once synthesized, dopamine is sequestered in storage vesicles. The vesicular monoamine transporter 2 (VMAT2) is responsible for transporting dopamine into vesicles for subsequent release. VMAT2 is an antiporter of protons and monoamines that uses energy derived from an electrochemical proton gradient across the vesicle membranes.
Release of dopamine from nerve terminals occurs through exocytosis of presynaptic vesicles, a process triggered by depolarization leading to Ca2+ entry.
The actions of dopamine are terminated by reuptake into the nerve terminal or uptake into the postsynaptic cell. Metabolism occurs by the sequential actions of COMT, MAO and aldehyde dehydrogenase. In humans, HVA is the principal metabolite of dopamine.
Dopamine Receptors
The actions of dopamine in the brain are mediated by a family of dopamine receptors. D1 and D2 receptors are abundant in the striatum and are the most important receptor sites with regard to the causes and treatment of Parkinson’s disease.
D1 receptors activate adenylyl cyclase.
D2 receptors inhibit adenylyl cyclase, activate K+ currents and supress Ca2+ currents.
The benefits of dopaminergic antiparkinsonism drugs appear to depend mostly on stimulation of the D2 receptors, but D1-receptor stimulation may also be required for maximal benefit.
Levodopa
Mechanism of Action
Levodopa is the levorotatory stereoisomer of dopa. It is the metabolic precursor of dopamine (and norepinephrine).
Levodopa restores dopamine levels in the extrapyramidal centers. In patients with early disease, the number of residual dopaminergic neurons in the substantia nigra is adequate for conversion of levodopa to dopamine.
With time, the number of neurons decreases and there are fewer cells capable of taking up exogenously administered levodopa and converting it to dopamine for storage and release. Consequently, motor control fluctuation develops. Relief provided by levodopa is only symptomatic and lasts only while the drug is present in the body.
MECHANISM OF ACTION
Dopamine does not cross the blood-brain barrier, but its immediate precursor levodopa is transported into the CNS and is converted to dopamine in the brain.
Levodopa is transported into the brain by the facilitative L-transport system for neutral amino acids. The L-system is also involved in the transport of other L-neutral amino acids including phenylalanine, tyrosine, tryptophane, leucine, isoleucine, methionine, valine, and histadine. The reversal of the effects of levodopa by the ingestion of proteins containing these other amino acids is thought to occur at the blood-brain barrier by competitive inhibition.
A large fraction of levodopa is decarboxylated to dopamine by L-dopa decarboxylase in the periphery, resulting in peripheral side effects (nausea, vomiting, cardiac arrhythmias, hypotension).
Carbidopa
When levodopa is used it is generally given in combination with carbidopa. Carbidopa is a dopa decarboxylase inhibitor that does not cross the blood-brain barrier. Carbidopa decreases the metabolism of levodopa in the GI tract and peripheral tissues, thus increasing the availability of levodopa to the CNS.
Sinemet is a preparation containing carbidopa and levodopa in fixed proportion (1:10 or 1:4).
Levodopa Pharmacokinetics and Uses
PHARMACOKINETICS
Levodopa is absorbed rapidly from the small intestine, but its absorption depends on the rate of gastric emptying and the pH of the gastric contents. Food delays the appearance of levodopa in the plasma. Moreover, certain amino acids from ingested food can compete with the drug for absorption from the gut and for transport from the blood to the brain.
Plasma half-life is usually between 1 and 3 hours. About 2/3 of the dose appears in urine as metabolites. The main metabolites are 3-methoxy-4-hydroxyphenylacetic acid (homovanillic acid, HVA) and dihydroxyphenylacetic acid (DOPAC).
Only about 1-3% of administered levodopa actually enters the brain unaltered, the remainder being metabolized extracerebrally, predominantly by decarboxylation to dopamine, which doesn’t penetrate the blood-brain barrier. This means that levodopa must be given in large amounts when it is used alone. However, when it is given in combination with a dopa decarboxylase inhibitor, such as carbidopa, that doesn’t penetrate the blood-brain barrier, the peripheral metabolism is reduced, plasma levels of levodopa are higher, plasma half-life is longer, and more dopa is available for entry into the brain. Concomitant administration of carbidopa may reduce the daily requirements of levodopa by 75%.
CLINICAL USES
Levodopa in combination with carbidopa is an efficacious drug regimen to treat Parkinson’s disease. In approximately 2/3 of patients with Parkinson’s disease, this treatment substantially reduces the severity of the symptoms in the first few years of treatment. Patients typically experience a decline in response during the 3rd to 5th year of therapy. Responsiveness to levodopa may ultimately be lost completely, perhaps because of the disappearance of dopaminergic nigrostriatal nerve terminals or some pathologic process directly involving the striatal dopamine receptors.
Levodopa does not stop the progression of Parkinson’s disease, but early initiation of levodopa therapy seems to lower the mortality rate due to the disease.
Levodopa Adverse Effects, Fluctuations in Response, Interactions and Contraindications
ADVERSE EFFECTS
GI effects
Anorexia, nausea and vomiting, due to stimulation of the emetic center.
CV effects
Tachycardia and ventricular extrasystoles, due to dopaminergic action on the heart. Postural hypotension is common, but tends to diminish with continuing treatment.
CNS Effects
Visual and auditory hallucinations and dyskinesia may occur. Mood changes, depression and anxiety, insomnia. These CNS effects are the opposite of parkinsonian symptoms and reflect the overactivity of dopamine at receptors in the basal ganglia.
FLUCTUATIONS IN RESPONSE
Certain fluctuations in clinical response to levodopa occur with increasing frequency as treatment continues. In some patients, these fluctuations are related to the timing of levodopa intake, and they are then referred to as wearing-off reactions or end-of-dose akinesia.
In other instances, fluctuations in clinical state are unrelated to the timing of doses (the on-off phenomenon). In the on-off phenomenon, off-periods of marked akinesia alternate over the course of a few hours with on-periods of improved mobility but often marked dyskinesia. The phenomenon is most likely to occur in patients who responded well to treatment initially. The exact mechanism is unknown. For patients with severe off-periods who are unresponsive to other measures apomorphine SC may provide temporary benefit (see below).
INTERACTIONS AND CONTRAINDICATIONS
Vitamin B6 is a cofactor for L-Dopa decarboxylase. Vitamin B6 increases peripheral metabolism of levodopa and decreases its effectiveness.
Concomitant administration of levodopa and nonspecific MAO inhibitors, such as phenelzine or tranylcypromine, may precipitate hypertensive crisis.
Levodopa should not be given to psychotic patients, as it may exacerbate the mental disturbance.
Contraindicated in patients with angle-closure glaucoma; those with chronic open- angle glaucoma may be given levodopa if intraocular pressure is well controlled and can be monitored.
Cardiac patients should be carefully monitored because of the possible development of arrhythmias.
Antipsychotic drugs are contraindicated in parkinsonian patients, since they block dopamine receptors and produce a parkinsonian syndrome themselves.
Patients with active peptic ulcer must be managed carefully, since GI bleeding has occasionally occurred with levodopa.
Levodopa is a precursor of skin melanin and may activate malignant melanoma; its use should be avoided in patients with a history of melanoma or with suspicious undiagnosed skin lesions.
DOPAMINE RECEPTOR AGONISTS
The enzymes responsible for synthesizing dopamine are depleted in the brains of PD patients; dopamine agonists may therefore have a beneficial effect additional to that of levodopa. Unlike levodopa, they don’t require enzymatic conversion for activity, therefore they do not depend on the functional capacities of the nigrostriatal neurons. There are a number of dopamine agonist with antiparkinsonism activity:
Ergot derivates (bromocriptine)
Nonergot derivatives (pramipexole, ropinirole, rotigotine & apomorphine)
Bromocriptine
ERGOT DOPAMINE AGONISTS
BROMOCRIPTINE
Bromocriptine, a D2 agonist, has been widely used to treat Parkinson’s disease and has also been used to treat certain endocrinologic disorders, especially hyperprolactinemia.
Pramipexole
NONERGOT DOPAMINE AGONISTS
Ropinirole
NONERGOT DOPAMINE AGONISTS
PRAMIPEXOLE & ROPINIROLE
Because these agents are well tolerated they are used increasingly as initial treatment for PD rather than as adjuncts to levodopa. Many experts favor dopamine agonists as initial therapy in younger patients with PD, and levodopa as initial therapy in older patients who may be more vulnerable to the adverse cognitive effects of the dopamine agonists.
Pramipexole has preferential affinity for D3 receptors. It is effective when used as monotherapy for mild parkinsonism. It is also effective in patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out response fluctuations.
Ropinirole is a relatively pure D2 receptor agonist. 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. Ropinirole is metabolized by cytochrome P450. Drugs metabolized by the liver may significantly reduce its clearance.
Rotigotine
NONERGOT DOPAMINE AGONISTS
Approved for the treatment of early stage Parkinson’s disease. Available in a transdermal formulation. It offers the convenience of once-daily use and the advantage of more stable plasma levels.
NONERGOT DOPAMINE AGONISTS
Adverse Effects
GI Effects
Anorexia, nausea and vomiting are especially common when a dopamine agonist is introduced and can be minimized by taking the medication with meals. Other adverse GI effects include constipation, dyspepsia, and symptoms of reflux esophagitis. Bleeding from peptic ulceration.
Cardiovascular Effects
Postural hypotension, Cardiac arrhythmias, Peripheral edema, Painless digital vasospasm is a complication of long-term treatment with the ergot derivatives.
Dyskinesias
Abnormal movements similar to those introduced by levodopa may occur. Treatment consists of reducing the total dose of dopaminergic drugs being taken.
Mental Disturbances
Confusion, hallucinations, delusions, and other psychiatric reactions are more common and severe than with levodopa. Such effects clear on withdrawal of the offending medication.
Miscellaneous Adverse Effects
Ergot dopamine agonists: Headache, nasal congestion, increased arousal, pulmonary infiltrates, pleural and retroperitoneal fibrosis, and erythromelalgia.
Pramipexole, ropinirole and rotigotine: can cause uncontrollable somnolence. This requires discontinuation of the medication.
CONTRAINDICATIONS
Dopamine agonists are contraindicated in patients with a history of psychotic illness or recent myocardial infarction. Best avoided in patients with peripheral vascular disease or peptic ulceration.
Apomorphine
APOMORPHINE
Nonergot dopaminergic agonist. FDA-approved as rescue therapy for the acute treatment of “off” episodes of akinesia in patients on dopaminergic therapy. Administered SC.
Apomorphine is highly emetogenic: pretreatment with the antiemetic trimethobenzamide is recommended. Oral domperidone is also effective in blocking emesis.
5-HT3 receptor antagonists are contraindicated because the combination can cause profound hypotension and loss of consciousness.
Other adverse effects of apomorphine include QT prolongation, dyskinesias, drowsiness, sweating, hypotension and bruising at the injection site.
Selegiline
MONOAMINE OXIDASE INHIBITORS
SELEGILINE (Deprenyl)
Selectively and irreversibly inhibits MAO-B (which selectively metabolizes dopamine). Selegiline retards the breakdown of dopamine in the brain; consequently it enhances the effect of levodopa and allows the dose of levodopa to be reduced. Unlike nonselective MAOIs, selegiline has little potential for causing hypertensive crises.
Selegiline’s effect on PD symptoms is modest when given alone. Selegiline is mainly used as adjunctive therapy for patients with a declining or fluctuating response to levodopa.
Selegiline is metabolized to methamphetamine and amphetamine whose stimulating properties may produce insomnia if the drug is taken later than midafternoon.
RASAGILINE
Used for early symptomatic treatment and also as adjunctive therapy to prolong effects of levodopa-carbidopa in patients with advanced disease.
Tolcapone and Entacapone
CATECHOL-O-METHYLTRANSFERASE INHIBITORS
TOLCAPONE & ENTACAPONE
Both MAO and COMT are responsible for the catabolism of levodopa as well as dopamine.
Inhibition of dopa decarboxylase leads to compensatory activation of other pathways of levodopa metabolism, especially catechol-O-methyltransferase (COMT), and this increases plasma levels of 3-O-methyldopa (3-O-MD). 3-O-MD competes with levodopa for a carrier that governs its transport across the intestinal mucosa and the blood-brain barrier.
Inhibition of COMT by tolcapone and entacapone leads to decreased metabolism of levodopa, decreased plasma levels of 3-O-methyldopa, increased uptake of levodopa and higher concentrations of dopamine in the brain. The COMT inhibitors are useful as levodopa extenders. They are ineffective when given alone, but they may prolong and potentiate levodopa effect when given with a dose of levodopa.
These agents may be helpful in patients receiving levodopa who have developed response fluctuations –leading to smoother response, more prolonged “on-time” and the option of reducing the total daily levodopa dose.
The pharmacologic effects of tolcapone and entacapone are similar and both are rapidly absorbed, bound to plasma proteins and metabolized prior to excretion. However, tolcapone has both central and peripheral effects, whereas the effect of entacapone is only peripheral.
Entacapone is generally preferred because it has not been associated with hepatotoxicity.
Entacapone is also available as fixed-dose combinations with levodopa/carbidopa. Use of this preparation simplifies the drug regimen and requires consumption of fewer tablets.
ADVERSE EFFECTS
Adverse effects of the COMT inhibitors relate in part to increased levodopa exposure and include dyskinesias, nausea and confusion. Other side effects include diarrhea, abdominal pain, orthostatic hypotension, sleep disturbances, and an orange discoloration of the urine.
Fulminating hepatic necrosis is associated with the use of tolcapone. Accordingly, its use in the US requires signed patient consent (as provided in the product labelling) plus monitoring of liver function tests every 2 weeks. No such toxicity has been reported for entacapone.
Amantadine
The antiviral drug amantadine has antiparkinsonian actions. It appears to increase synthesis, release or re-uptake of dopamine from the surviving neurons.
It is less efficacious than levodopa and tolerance develops more readily, but it has fewer side effects.
The drug may cause restlesness, agitation, confusion and hallucinations, and at high doses it may induce acute toxic psychosis.
Livedo reticularis sometimes occurs in patients taking amantadine and usually clears within a month after withdrawing the drug. Other dermatologic reactions have been described. Peripheral edema is not accompanied by signs of cardiac, hepatic or renal disease and responds to diuretics.
Other adverse reactions include headache, heart failure, orthostatic hypotension, urinary retention and gastrointestinal disturbances.
Amantadine should be used with caution in patients with a history of seizures or heart failure.
