Agents used in the treatment of Parkinsonian disorders

History• Parkinson's disease is

named after James Parkinson. He was a British doctor who first described the disease in 1817.

• During the nineteen sixties, research scientists discovered chemical and other changes in the brains of people suffering from the disease. These discoveries led to medicines to treat Parkinson's disease. However, the cause of the disease is still a mystery.

Dr.James Parkinson

Parkinson’s disease

• These symptoms include shaking of the arm or leg on one side of the body. Other symptoms are a general slowness of movement, or severe difficulty in moving the arms and legs. Another is difficulty walking and keeping balance while standing or walking.

• Other signs observed in some people include restricted or decreased movement of the face. Also, victims of Parkinson's disease can feel sad or worried. Victims may swallow less often than normal. And, they may have difficulty forming words while talking

Parkinson’s disease

• Another common theory is that people with Parkinson's disease could pass it to their children. There are examples of many members of families having the disease leading to genetic inheritence.

Parkinson’s disease• Parkinsonian disorder

s are classified into both parkinson’s disease( PD) and syndrome. Parkinson’s syndrome is secondary to chronic cerebrovascular diseases, some diseases in CNS and antipsychotic drugs.

Parkinson’s disease

• The mode of treatment Parkinson's disease is a medical operation. One such operation is called a pallidotomy. It was used often in the past to treat the disease. However, it is used less often after the discovery of levodopa.

• More recently, improved technology has increased the chances of successful pallidotomies. The operation involves placing electrical devices directly on the brain. These devices target cells in the area that cause unwanted movements of the body. The most serious risk from this treatment is the possibility of the patient having a stroke.

Pathogensis of parkinsonian disorders

Motor neurons in anterior horn of spinal cord

Nigra

Caudatum

Dopaminergic neurons

Cholinergic neurons

Striatum(DA)

Putamen(Ach)

(--)

(+)

Neuronal injury and a loss of doparminergic neurons

Bradykinesia;muscular rigidity; resting tremor and an impairment of postural balance leading to disturbances of gait and falling

Dopaminomimetic drugs

Anticholinergic drugs

• PD are caused by both hypofunction of dopaminergic nerves( DA deficiency) and relative hyperfunction of cholinergic nerves in nigrostriatum with the manifestation of muscular rigidity.

Hypothesis of selective vulnerability

• Genetic and environment– Genetic predisposition plays an important r

ole in the etiology of neurodegenerative disorders.

– Infectious agents and environment toxins also have been proposed as etiologic agents for neurodegenerative disorders. For example , the epidemic of encephalitis lethargica often lead to PD.

• Excitotoxicity – Glutamate is used as a neurotransmitt

er by many different neural systems and is believed to mediate most excitatory synaptic transmission in the mammalian brain. Although glutamate is required for normal brain function, the presence of excessive amounts of glutamate can lead to excitotoxic cell death .

– The destructive effects of glutamate are mediated by glutamate receptors, particularly those of the N-methyl-D-aspartate(NMDA) type. Activated NMDA receptor-channels allow an influx of Ca 2+ , which in excess can activate a variety of potentially destructive processes.

• Oxidative stress – DA is converted by mona

mine oxidase(MAO) and aldehyde dehydrogenase to 3,4-dihydroxyphenylacetic acid(DOPAC),producing hydrogen peroxide (H2O2). In the presence of ferrous iron, H2O2 undergoes spontaneous conversion, forming a hydroxyl free radical

DA + O2 + H2O

DOPAC + NH3 + H2O2

H2O2 + Fe2+

•OH+OH- +Fe3+

Energy ,metabolism, and aging

• The capacity of neurons for oxidative metabolism declines progressively with age, perhaps in part because of a progressive accumulation of mutations in the mitochondrial genome.

Environmental

toxins

neuronalmetabolism

Free radical formation

Oxdative stressexcitotoxicity

aging

Selective vulnerabilityOf neuronal populations

DNA damage Lipid peroxidation

Protein damage

Cell death

Levodopa ( L-dopa)• Mechanism of action

– The metabolic precursor of dopamine. L-dopa is transformed to DA via decarboxylase in the brain and corrects DA deficiency in nigrostriatum.

• Pharmacokinetics– DA does not cross

BBB, thus L-dopa, the precursor of DA , is given instead.

• When administered orally, L-dopa is rapidly absorbed from the small bowel by an active transport system for aromatic amino acids.T1/2:1~3h.the rate and extent of absorption of L-dopa is dependent 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 administration of L-dopa with meals delays absorption and reduces peak plasma concentration.

• In the brain ,L-dopa is 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 terminal by the presynaptic uptake mechanism or metabolized by the action of MAO and COMT.

– In modern practice ,L-dopa is almost always administered in combination with a peripherally acting inhibitor of aromatic L-amino acid decarboxylase , such as carbidopa.

• If L-dopa is administered alone, the drug is largely decarboxylated by enzymes in the intestinal mucosa and other peripheral sites that are rich in MAO , so that relatively little unchanged drug reaches the cerebral circulation and probably less than 1% penetrates the CNS.

• In addition, dopamine release into the circulation by peripheral conversion of L- dopa produce undesirable effects, particularly nausea.

• Pharmacological effects– The effects on bradykinesia and rigidity are m

ore rapid and complete than effects on tremor.

– L-dopa is more effective for young and mild patients with PD than old and severe patients.

– L-dopa is ineffective for Parkinson’s syndrome induced by phenothiazide due to blockade of DA receptors in the brain by phenothiazides.

• Clinical uses– PD and Parkinson’s

syndrome caused by other causes except phenothiazides.

• Adverse reaction – Gastrointestinal reaction – Cardiovascular effects Cardiac arrhythmias,Exacerbation of A

ngina– Mental disturbance: hallucinations, co

nfusion,severe depression,mania or frank psychosis.

– Altered taste sensation– Facial tics,choreoathetoid movements.

– On –off phenomenon• In the late stages of PD, patients may fluctuate rapidly bet

ween being “off”, having no beneficial effects from their medications,and being” on” but with disabling dyskinesias.

Carbidopa• Carbidopa is an inhibitor of dopa decarb

oxylase. Because it is unable to penetrate BBB, it acts to reduce the peripheral conversion of L-dopa to DA. Carbidopa is used in combination with L-dopa to augment beneficial effects of L-dopa and reduce dose and adverse effects of L-dopa.

Amantadine• Amantadine may improve Parkinsonian

syndromes by stimulating the release of DA from dopaminergic nerve terminals and delaying its reuptake in the nigrostriatum.

• Amantadine is more effective than anticholinergic agents, however , is less effective than L-dopa in the treatment of Parkinsonian disorders.

• Amantadine is used alone to treat early Parkinson’s disease and in combination with L-dopa to treat various Parkinsonian disorders.

Anticholinergic agents

Trihexyphenidyl (artane)• Artane blocks cholinergic receptors in C

NS to reduce the function of cholinergic nerves in nigrostriatum.

• The effects on tremor is more pronounced than effects on bradykinesia and rigidity.

• Artane is used alone for mild patients, patients of discontinuation of L-dopa due to its adverse effects as well as Parkinson’s syndrom induced by phenothiazides. Artane combines with L-dopa to treat any Parkinsonian disorders.