PHARMACOLOGY OF

ANTIPARKINSONIAN DRUGS

PRESENTED BY : DIPANJAN MANDALASSISTANT PROFESSOR

GURUNANAK INSTITUTE OF PHARMACEUTICAL SCIENCE AND TECHNOLOGY

• Neurological disease affecting over 4 million

patients worldwide, over 1.5 people in U.S.It can

affect individuals at any age, it is the most

common in elderly .The average age of onset is

55 years, although approx. 10 % of causes affect

those under age 40.

PARKINSONISM:

DEFINITION:

• Parkinson’s disease (neurodegenerative disorder ) is

a disease of basal ganglia and is characterized by

combination of bradykinesia, poverty of

movement ,rigidity and tremor.

• The primary deficit in parkinsonism is the

neurons that extent from substantial nigra (present

in basal ganglia) degenerate.

CLINICAL SYNDROME

• 1)Bradykinesia (slowness and

poverty of movement)

• 2)Muscular rigidity (involves

increased muscular resistance to

passive range of motion . Postural

instability may lead to falls).

• 3)Resting tremor (Tremor is

present most commonly in the

hands, often begins unilaterally.

The resting tremor is absent

during sleep)

• 4)Impairment of postural balance

leading to disturbances of gait

and falling.

• The cause of Parkinson’s disease is unknown and to endogenous or environmental neurotoxin has been discovered.

• The possibilities are :

Oxidative stress and apoptosis

Aging

Drug induced (metoclopromide , reserpine )

Genetic predisposition

Imbalance between Dopamine ( inhibitory) and acetylcholine (excitatory)

Increase Ach concentration and decrease Dopamine concentration

MPTP LIKE TOXIN

A chemical 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causesdegeneration of nigrostriatal tract.MPTP acts indirectly via a metabolite, 1-methyl-4-phenylpyridine (MPP+),which is formed by action of MAO-B.

Oxidation of dopamine by MAO-B and aldehyde dehydrogenase generateshydroxy free radicals in presence of ferrous ion. These free radicals arequenched by glutathione and other protective mechanisms.

AEITIOLOGY

free radicals generated during its formation by

MAO-B may destroy energy electron transport

chain in mitochondria or damage the cell

membrane.

Production of free radicals by the metabolism of dopamine. Dopamine is converted by monamine oxidase (MAO) and aldehyde dehydrogenase (AD) 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 (the Fenton reaction).

Dopaminergic neurons (color) originating in the substantia nigra normally inhibit theGABAergic output from the striatum, whereas cholinergic neurons (gray) exert an excitatory effect. In parkinsonism, there is a selective loss of dopaminergic neurons (dashed, color).

MANAGEMENT (CLASSIFICATION OF DRUGS)

1.DRUG AFFECTING BRAIN DOPAMINERGIC SYSTEM

• a)Dopamine Precursor: levodopa

• b)Dopaminergic agonist: bromocriptine(D2),lisuride

,pergolide(D1+D2),apomorphine (D4),ropinirole (D2+D3)

• c)Peripheral decarboxylase inhibitor:

carbidopa,benserazide

• d)Selective MAO-B inhibitor: seligiline

• e)COMT inhibitor: entacapene

2.DRUG AFFECTING BRAIN CHOLINERGIC SYSTEM

a) Anticholinergic : orphenadrine,benzhexole, bentropine, procyclidine

b) Faciliated dopeminergic transmission: amantadinec)Antihistamine: promaethagine

GENERAL MECHANISM OF ACTION OF DRUG

LEVODOPA : Prevent dopamine deficiency,dopamine does

not cross BBB

CARBIDOPA: Diminish metabolism of levodopa in GIT and

Increase availability to CNS

SELIGILINE : Inhibit MAO-B ,↓dopamine metabolism

ENTACAPONE: COMT metabolizes both levodopa and

dopamine

AMANTADINE: Block muscarinic receptor

DOPAMINERGIC AGONIST: bind with dopamine receptor

D1: STRIATUM,NEOCORTEX D3: HYPOTHALAMUSD2:STRIATUM, SnPC , PITUITARY D4: MEDULLA, FRONTAL CORTEX

Metabolism of levodopa (L-DOPA). AD, aldehyde dehydrogenase; COMT, catechol-O-methyltransferase; DbH, dopamine bhydroxylase; AAD, aromatic L-amino acid decarboxylase; MAO, monoamine oxidase.

GENERAL PHARMACOLOGICAL ACTION

ON CNS: hypokinesia, dementia, speechand facial expression

ON CVS: tachycardia , increase BP

ON CTZ: nausea , vomitting

ON ENDOCRINE : ↓prolactin ,↑GH release

ADVERSE EFFECT:

Anorexia , hypotension, brown colour saliva and urine,

anxiety, mood chnages, sedation , constipation, urinary

retension, sleep disturbances,hepatic necrosis, dry mouth

NEW RESEARCH WORK ON

PARKINSON’S DISEASE

TOPOGRAPHIC PATTERN OF CORTICAL THINNING WITH CONSIDERATION OF MOTOR

LATERALITY IN PARKINSON DISEASE

03 September 2014

Kim JS, Yang J-J, Lee J-M, Youn J, Kim J-M, Cho JW

The asymmetry of Parkinson’s disease (PD) may contribute to the unilateral appearance of parkinsonism, as

well as its cerebral morphological changes. However, previous studies have not considered that cerebral

involvement would probably be asymmetric. Our study aimed to identify whether one-sided symptom

dominance has an influence on cortical thinning patterns in early-stage, non-demented PD patients from

cortical thickness analyses and cortical thinning patterns are associated with motor functions.

Methods We used cortical thickness analysis in64 non-demented right-handed subjects: 21 PD patients

with left-sided disease onset (LPD), 21 PD patients with right-sided disease onset (RPD) and 22 control

subjects. We modeled local cortical thickness as a linear association with each motor symptom.

Results We identified three clusters exhibiting significant cortical thinning(p< 0.01 RFT corrected)in the

LPD group compared with the control group: a cluster including the right primary sensory, motor cortex

and paracentral lobule, as well as another two clusters in bilateral parahippocampal gyri. In the RPD group,

there was only one cluster that exhibited significant cortical thinning compared with the control group,

located in the left lingual gyrus. There were no significant correlations between cortical thinning clusters

and motor severity, any of the motor subscales including tremor, rigidity, bradykinesia and axial

impairment.

Conclusions Our right-handed PD population revealed that significant thinning of motor-related cortical

areas in contralateral hemisphere to symptomatic side in LPD, but not in RPD group. Our results support

that neuroprotective effect of enhanced physical activity by handedness on contralateral motor cortex.

DIETARY FAT INTAKE AND RISK FOR PARKINSON'S DISEASE

03 September 2014

Dong J, Beard JD, Umbach DM, Park Y, Huang X, Blair A, Kamel F, Chen H

Previous epidemiological studies have generated inconsistent results regarding the

associations between dietary fat intakes and risk for Parkinson's disease (PD). We therefore

prospectively examined these associations in the National Institutes of Health–American

Association of Retired Persons (NIH-AARP) Diet and Health Study.

A 124-item food frequency questionnaire was administered at baseline in1995 to 1996, and

PD diagnosis was self-reported at the follow-up survey in 2004 to 2006. A total of 1,087 cases

with a PD diagnosis between 2000 and 2006 and 299,617 controls were included in the

analyses.

Overall, intakes of fats and other macronutrients were not associated with PD risk. However,

we found a weak positive association between n-6 polyunsaturated fatty acids (PUFA) and the

risk for PD. After adjusting for potential confounders, the odds ratio (OR) and 95%

confidence interval (CI) between extreme quintiles of n-6 PUFA intake was 1.23 (95% CI =

1.02-1.49, P for trend = 0.02). A similar association was observed for the intake of linoleic

acid. Results were similar among men and among women.

Our study suggests that fat intake in general is not related to the risk for PD. The weak

positive association between intake of n-6 PUFA and PD risk needs further investigation.

EARLY-ONSET PARKINSON'S DISEASE DUE TO PINK1 P.Q456X MUTATION - CLINICAL

AND FUNCTIONAL STUDY

03 September 2014

Siuda J, Jasinka-Myga B, Boczarska-Jedynak M, Opala G, Fiesel FC, Moussaud-Lamodière EL,

Scarffe LA, Dawson VL, Ross OA, Springer W, Dawson TM, Wszolek

Background Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset

Parkinson's disease (EOPD). The clinical phenotype of families that have this PINK1-associated disease

may present with different symptoms, including typical PD. The loss of the PINK1 protein may lead to

mitochondrial dysfunction, which causes dopaminergic neuron death.

Methods The clinical phenotypes of a large Polish family with EOPD and an

identified PINK1 homozygous nonsense mutation were assessed. Ubiquitination and degradation of

mitochondrial parkin substrates as well as mitochondrial bioenergetics were investigated as direct

functional readouts for PINK1's kinase activity in biopsied dermal fibroblasts.

Results A four-generation family was genealogically evaluated. Genetic screening identified two affected

subjects who were both homozygous carriers of the pathogenic PINK1 p.Q456X substitution. Both patients

presented with dystonia and gait disorders at symptom onset. Seven heterozygous mutation carriers

remained unaffected. Functional studies revealed that the PINK1 p.Q456X protein is non-functional in

activating the downstream ubiquitin ligase parkin and priming the ubiquitination of its substrates, and that

the RNA levels of PINK1 were significantly reduced.

Conclusions The PINK1 p.Q456X mutation leads to a decrease in mRNA and a loss of protein function.

The foot dystonia and gait disorders seen at disease onset in affected members of our family, which were

accompanied by parkinsonism had a similar clinical presentation to what has been described in previous

reports of PINK1 mutation carriers.

THANK YOU

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