NEURODEGENRATIVE DISEASES - ANTI-PARKINSON DRUGS, ALZHEIMER DISEASE,MULTIPLE SCLEROSIS, AMYOTROPHIC LATERAL SCLEROSIS

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Parkinsonism Neurological disorder of muscle movement, characterized by Tremor, Muscular rigidity, Bradykinesia(slowness ininitiating & carrying voluntary  movement) , Postural and gait abnormalities.


Etiology:

imbalance b/w Substantia nigra & Neostriatum...Loss of DOPAMINE results in increased production of Ach in NEOSTRIATUM & decrease Inhibitory effect of DOPAMINE(produce in SUBSTANTIA NIGRA) on Ach...

What is Neurodegenerative Disease? Alzheimer's disease (AD) and other dementias. Parkinson's disease (PD) and PD-related disorders. Prion disease. Motor neurone diseases (MND) Huntington's disease (HD) Spinocerebellar ataxia (SCA) Spinal muscular atrophy (SMA)


Levodopa

 metabolic precursor of DOPAMINE...only provide Symptomatic relief

MOA

Dopamine does not cross B.B.B..Levodopa actively transported into CNS .converted into Dopamine in Brain...

Carbidopa

 DOPA decarboxylase inhibitor...Θ metabolism of Levodopa in GIT & Peripheral tissue...increasing availability of DOPA in brain

T.E

 2/3rd of Patient in Parkinson disase reduce severity of disease..

P.K

levodopa 1-2 hr t1/2..ingestion of high protein(Amino ACIDS) may interfere in the transport of Levodopa...should be taken empty stomach

S.E 

Dyskinesia(Abnorma involuntary movement), Mydriasis, Blood Dyscrasias, +Ve Coomb‟s test, Hypertension, saliva and urine red color due to melanin pigment produced from catecholamine oxidation

Drug interactions

Pyridoxine (Vit B6) increases breakdown of Levodopa

MOAI & Levodopa coadministration causes Hypertensive crisis

Contraindicated in Glaucoma due to increase intraocular pressure

Antipsychotics contraindicated in Parkinson disease

Selegiline & Rasagiline= Selectively inhibit MOA type B which metabolize

DOPAMINE.. Selegiline also called Deprynyl...

Selegiline metabolized into Methamphetamine & Amphetamine..may produce insomnia

so administered afternoon in Depression Patient

Rasigiline have 5 times more potency of selegiline

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COMT INHIBITORS 

Entacapone & tolcapone..inhibit the Catechol-O- methylTransferase which convert Levodopa into 3-O-MethylDopa

3-O-MethylDopa compete with Levodopa for active transport into CNS...increased conc. Of levodopa...these drugs help to reduce “wearing off” phenomenon

P.K

 plasma binding 98%..Tolcapone enter in CNS & inhibit COMT in CNS, has long t1/2,

S.E

“Fulminating Hepatic Necrosis” caused by Tolcapone


DOPAMINE-RECEPTOR AGONIST

Bromocriptine 

 Derivative of Vasoconstrictive Ergotamine Alkaoid ,

Coadministration with Levodopa cause mental condition to worse,

S.E

 cause vasospasm not used in M.I, pulmonary & retroperitoneal fibrosis, worsen the ulcer

Apomorphine, Pramipexole, Ropinirole, Rotigotine= non-ergot dopamine agonist

Apomorphien & Rotigotine available in injectable and transdermal delievery sys..

Cimetidine inhibit renal tubular secretion of organic base increase t1/2 of Pramipexole

.Flouroquinolone antibiotics inhibit met. Of Ropinirole & increase AUC by 80% ...

Rotigotine treat Early Stage Parkinson‟s disease, O.D patch,

ANTIVIRAL

Amantadine= increase release of DOPAMINE, block cholinergic receptor, inhibit NMDA

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DRUG USED IN ALZHEIMER DISEASE

AcetylcholineEsterase Inhibitors=Galantamine, Tacrine, Rivastigmine, Donepzil

NMDA-Receptor anatagonist=Memantine drug.

MOA

Stimulation of Glutamate in CNS essential for making memories.. Binding of Glutamate to NMDA receptor..opening of Na+ & Ca++ channel...activate process damage neuron e.g Apoptosis

Memantine Block NMDA ...prevent neurodegeneration

DRUGS USED IN MULTIPLE SCLEROSIS

Autoimmune inflammatory demyelinating disease of CNS

Mitoxantrone 

cytotoxic anthrcycline...kill T-cells...modify the immune sys by destroying anti-inflammatory process that lead to myelin sheath damage & decrease axonal communication b/w cells

Fingolimod

first oral drug ...alters lymphocyte migration, resulting sequestration of lymphocytes in lymph nodes...decrease severity & frequency of M.S

Dalfampridine

 K+ channel blocker..improve walking speed...decrease relapse rate

Glatiramer

 synthetic polypeptide resemble myelin protein...act as “decoy” to kill T- cells


DRUGS USED IN AMYOTROPHIC LATERAL SCLEROSIS

Riluzole= block glutamate. Sodium channel, calcium channel, improve survival time




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