Antiparkinsonian drugs

Pharmacotherapeutic measures are aimed at compensating striatal dopamine deficiency or suppressing unopposed cholinergic activity. 

L-Dopa. Dopamine itself cannot penetrate the blood-brain barrier however, its natural precursor, L-dihydroxyphenylalanine (levo-dopa), is effective in replenishing striatal dopamine levels, because it is transported across the blood-brain barrier via an amino acid carrier and is subsequently decarboxy-lated by dopa decarboxylase, present in striatal tissue. Decarboxylation also takes place in peripheral organs where dopamine is not needed and is likely to cause undesirable effects (vomiting hypotension p.116). Extracerebral production of dopamine can be prevented by inhibitors of dopa decarboxylase (carbidopa, benserazide) that do not penetrate the blood-brain barrier, leaving intracerebral decarboxylation unaffected. 

Excessive elevation of brain dopamine levels may lead to undesirable reactions such as involuntary movements (dyskinesias) and mental disturbances. 

Dopamine receptor agonists. Striatal dopamine deficiency can be compensated by lysergic acid derivatives such as bromocriptine (p.116), lisuride, cabergoline, and pergolide and by the non-ergot compounds ropinirole and pramipexole. 

Inhibitors of monoamine oxidase-B (MAO ). Monoamine oxidase occurs in the form of two isozymes MAOa and MAOB. The corpus striatumis rich in MAOB. This isozyme can be inhibited by selegiline. Degradation of biogenic amines in peripheral organs is not affected because MAOa remains functional. 

Parkinson s disease (shaking palsy) and its syndromal forms are caused by a degeneration of nigrostriatal dopamine neurons. The resulting striatal dopamine deficiency leads to overactivity of choUnergic intemeurons and imbalance of striopallidal output pathways, manifested by poverty of movement (akinesia), muscle stiffness (rigidity), tremor at rest, postural instability, and gait disturbance. 

Pharmacotherapeutic measures are aimed at restoring dopaminergic function or suppressing choUnergic hyperactivity. 

Dopamine receptor agonists. Deficient dopaminergic transmission in the striatum can be compensated by ergot derivatives (bromocriptine p. 114], lisu-ride, cabergoline, and pergolide) and nonergot compounds (ropinirole, prami-pexole). These agonists stimulate dopamine receptors (D2, D3, and D sub-types), have lower clinical efficacy than levodopa, and share its main adverse effects. 

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NPA and its potential pro-drug, / -10,11-methylenedioxy-A/-propylnorapomor-phine, have been measured in monkey plasma. Samples were prepared by SPE on ODS-modified columns and the residue divided so that the electroactive catechol could be separated (nitrile-modified silica HPLC column) and detected at a GCE (+0.7 V vs Ag/AgCl). The pro-drug was analysed on an octyl-modified HPLC column with detection at 280 nm. The LoDs were 0.5 and lOpgL for NPA and the methylenedioxy derivative, respectively. The corresponding /V-methyl homo-logues were used as internal standards. 

As might be expected, methods for measuring exogenous levodopa, L-DOPA methyl ester (LDME) and the DOPA-decarboxylase inhibitor, carbidopa 

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Mercuri, NB, Bond, A and Bemardi, G (1997) Electrophysiological pharmacology of the autoreceptor mediated responses of dopaminergic cells to antiparkinsonian drugs. Trends Pharmacol. Sci. 18 232-235. 

Anticholinergic drugs can be effective for tremor and dystonic features in some patients but rarely show substantial benefit for bradykinesia or other disabilities. They can be used as monotherapy or in conjunction with other antiparkinsonian drugs. They differ little from each other in therapeutic potential or adverse effects. 

Domperidone is used in combination with antiparkinsonian drugs to counteract the nausea and vomiting caused by the latter. Since it does not readily cross the blood-brain barrier, it is not associated with extra-pyramidal effects and is less likely to cause dystonia than metoclopromide and phenothiazines. 

Trihexyphenidyl, an antiparkinsonian drug, possesses central and peripheral anticholinergic actions, as well as a direct relaxant effect on smooth muscle. It reduces muscle rigidity and general stiffness, and has a relatively minor effect on tremors. It is used in Parkinsonism in the form of monotherapy as well as in combination with levodopa. The most common synonyms are parkopan, parkinsan, and cyclodol. 

Anticholinergic drugs - atropine, hyoscine, scopolamine, antiparkinsonian drugs, antipsychotic drugs, antihistamines, antidepressants... 

Other cholinergic agonists have no therapeutic use. Muscarine (4.3) is an alkaloid of the mushroom Anumita muscaria muscarone (4.9) is its semisynthetic analog. Pilocarpine (2.2) is found in the leaves of a shrub and can be used to increase salivation or sweating. Arecoline (4.10) is also an alkaloid, and occurs in the betel nut that is used as a mild euphoriant in India and Southeast Asia. Finally, oxotremorine (4.11) is a synthetic experimental agent that produces tremors and is helpful in the study of antiparkinsonian drugs. 

It s use with anticholinergic antiparkinsonian drugs can lead symptoms similar to atropine poisoning. 

An accurate diagnosis is important because these symptoms may be mistaken for an exacerbation of the psychosis, prompting an escalation in dose when a decrease or an antiparkinsonian drug should be considered. At times, a therapeutic trial with an agent such as procyclidine, benztropine, or diphenhydramine can be diagnostic, because acute dystonic reactions usually respond in minutes to parenteral administration of these agents. 

More serious complications are uncommon with the addition of antiparkinsonian drugs. 

Studies in which antiparkinsonian medications were discontinued have significant methodological problems. One specific issue is that patients placed on prophylactic therapy, who then fail to develop symptoms when their antiparkinsonian medication is withdrawn, may never have developed EPS at all. Still, up to 70% of patients have been noted to exhibit EPS after discontinuation of their antiparkinsonian drug, indicating that these agents indeed provide long-term efficacy. 

There is also evidence of the prophylactic effect of antiparkinsonian drugs from a chart review study showing that they substantially prevented EPS ( 454). 

Risperidone Acute Clinical Trials. Hillert et al. (107) found risperidone to have both antipsychotic and antidepressive properties in 10 patients with schizoaffective disorder, depressed type. These investigators prescribed 2 to 10 mg/day for 6 weeks in an open-label pilot study, and found marked improvement in psychosis in all patients and clinically significant overall improvement in psychosis in 7 to 10 patients. Two patients required antiparkinsonian drugs otherwise risperidone was well tolerated by the group. 

In the pharmaceutical synthesis industry, piperidine is used in some drugs such as budipine (antiparkinsonian drug), raloxifene (used in the prevention of osteoporosis), minoxidil (an oral drug to treat high blood pressure). Minoxidil has the interesting side effect of hair growth and reverses hair loss. A two percent minoxidil solution can be used to treat this condition. 

Antiparkinsonian drugs possessing anticholinergic properties (e.g., trihexyphenidyl and ethopropazine)... 

Studies (42 14) showed that patients treated with antiparkinsonian drugs suffer from sleep attacks. These attacks were responsible for traffic accidents (45) modafinil can efficiently counterbalance this symptom in patients suffering from Parkinson s disease (46). 

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