parkinsonism overview
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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
REFERENCES:1. JOEL G HARDMAN,LEE E.LIMBIRD,editors.GOODMAN& GILMAN’S THE
PHARMACOLOGICAL BASIS OF THERAPEUTICS.11th
EDITION.USA:McGraw Hill;2006,p-336-344
2. MICHAEL J NEAL, MEDICAL PHARMACOLOGY AT A GLANCE,4TH
EDITION,UK: BLACKWELL;2002;P-58-59
3. Diagnosis and pharmacological management of Parkinson’s disease, A
national clinical guideline;JAN,2010; Scottish Intercollegiate Guidelines
Network,P-34-43
4. Parkinson's Disease;
http://www.nlm.nih.gov/medlineplus/parkinsonsdisease.html CITED ON
7/9/2014
5. DANIEL TRASY, PHARMACOLOGIC-TREATMENT-OF-PARKINSON-
DISEASE; Aug 2014. http://www.uptodate.com/contents/pharmacologic-
treatment-of-parkinson-disease CITED ON 7/9/2014
6. Parkinson's Disease Therapeutics: New Developments and Challenges Since the Introduction of Levodopa ; http://www.nature.com/npp/journal/v37/n1/fig_tab/npp2011212f1.htmlCITED ON 7/9/2014
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