Parkinson's Disease

Penyakit manulaContinuous Progressive Neurological Disease gangguan gerak yang semakin parah no cure?

EtiologyCerebral atherosclerosisViral encephalitisSide effects of several antipsychotic drugs (i.e., phenothiazides, butyrophenones, reserpine)Trauma

Faktor lingkungan dan neurotoxinsPesticides, herbicides, industrial chemicals - contain substances that inhibit complex I in the mitochondria

Major Symptoms :Bradykinesia- Slowness in Initiation and Execution of Voluntary MovementsRigidity - Increase Muscle Tone and Increase Resistance to Movement (Arms and Legs Stiff)Tremor - Usually Tremor at Rest, When Person Sits, Arm Shakes, Tremor Stops When Person Attempts to Grab SomethingPostural Instability - abnormal fixation of posture (stoop when standing), equilibrium, and righting reflexGait Disturbance - Shuffling Feet

Gangguan otonom pada stadium akhir:Orthostatic HypotensionDementiaDystoniaOphthalmoplegiaAffective Disorders

NeurochemistryLoss of Dopaminergic (DA) Cells Located in Basal Ganglia; Gejala baru tampak bila terjadi penurunan dopamin 70-80%.

Imbalance antara excitatory neurotransmitter Acetylcholine dan inhibitory neurotransmitter Dopamine di Ganglia BasalisAChDA

Drug TherapyTujuan keseimbangan Ganglia BasalisMengurangi aktifitas Cholinergic di Ganglia Basalis 1. Aktifasi reseptor Dopamine di Substantia Nigra umpan balik ke Cholinergic Cells di striatum Padamkan Cholinergic Cells terjadi keseimbangan 2. Antagonize Acetylcholine receptors

Meningkatkan aktifitas Dopamin

Neurotransmitter synthesis, storage and releaseNeurotransmitter reuptake and degradationReceptor activation or blockadeMechanisms of Drug Action

L-DOPASSRIMAOIAMPHETAMINE

Obat peningkat fungsi Dopamine Meningkatkan synthesis dopamine - l-DopaHambat katabolisme dopamine - selegilineRangsang pelepasan/ release dopamine - amphetamineRangsang reseptor dopamine (agonis)- bromocriptine & pramipexoleBlock reuptake dan rangsang pelepasan/ release dopamine - amantadine

Dopamine and Tyrosine tidak dipakai ?Dopamine tidak lolos the Blood Brain BarrierTyrosine berlebihan menurunkan aktifitas enzyme Tyrosine Hydroxylase

L Dopa Therapy for Parkinson DiseaseL Dopa

Dopamine Decarboxylase

Dopamine

L Dopa- PharmacokineticsL Dopa absorbsi per oral baikHanya ~1% yang melintasi Blood Brain Barrier ke CNSFirst Pass Effect tinggi L Dopa dimetabolisme oleh dopa decarboxylase di hati dan jaringan perifer menjadi dopaminSekresi utuh di urine atau terkonjugasi dengan glucoronyl sulfateSebagian besar L Dopa berubah di perifer menjadi NE dan EPI

Efek L Dopa pada Symptoms Parkinson DiseaseL Dopa cukup efektif hilangkan sebagian besar gejalaBradykinesia dan Rigidity cepat berkurangTremor berkurang pada terapi lanjutL Dopa kurang efektif hilangkan Postural Instability dan Shuffling Gait Neurotransmitters lain terlibat dalam Parkinson Disease

Effects of L Dopa on BehaviorL Dopa Partially Changes Mood by Elevating Mood, and L Dopa Increases Patient Sense of Well BeingSignificant Number of Patients Get Behavior Side Effects

Effects of L Dopa on Cardiovascular SystemBeta Adrenergic Cardiac Stimulation + Propranolol untuk melawan eso tsbHati-hati pada manula (ada kelainan kardiovascular) tachycardia, cardiac arrhythmias dan hypertensionIn Some Individuals, L Dopa produces Orthostatic HypotensionToleransi dalam beberapa minggu

Effects of L Dopa on Gastrointestinal SystemESO Gastrointestinal: Nausea, Vomiting, dan Anorexia serta Abdominal PainKemungkinan karena Stimulasi Chemoreceptor Trigger Zone (CTZ) di MedullaTolerance Develops in a Few Weeks to this Effect

GI cont.Kadang Diarrhea atau KonstipasiDapat aktifasi tukak lambungSolusi berikan dosis rendah dan naikkan dosis dengan pelan.Diminum bersamaan saat makan

Effects of L Dopa on Endocrine SystemL Dopa Conversion to DopamineCauses decrease in Prolactin from Stimulation of Dopamine Receptors in Tubularinfundibular System

Adverse Effects with L DopaMasalah utama: Denervation Supersensitivity of ReceptorsKerusakan neuron Dopaminergic jumlah reseptor post-sinap meningkatL Dopa Therapy meningkatkan Dopamine di celah sinap Tetapi karena reseptor dopamin jumlahnya terlalu banyak Denervation Supersensitivity

Denervation SupersensitivityTransmissi post-sinap meningkat gejala Parkinson menghilang mulai terjadi Tardive Dyskinesia

Adverse Effects of L DopaSome are Irreversible and Dose DependentLong Term Therapy tidak merusak Renal atau Liver

Long Term TherapyBehavioral Disturbances in 20 to 25% of PopulationTrouble in Thinking (Cognitive Effects)L Dopa Can Induce:PsychosisConfusionHallucinationAnxietyDelusionSome Individuals develop Hypomania = Inappropriate Sexual Behavior; "Dirty Old Man", "Flashers"

TreatmentMengurangi DosisDrug Holiday (Stop All Medication for 3-21 Days and Then Slowly Reinitiate Gradually)

"On/off" Effect"On/off" Effect mirip saklar lampuMendadak kambuh (30 menit sampai beberapa jam) kemudian membaik lagiBiasanya timbul setelah pengobatan 2 tahun atau lebihBerhubungan dengan Denervation Hypersensitivity

Drug Interactions with L DopaVitamin B6 - Vitamin B6 Is a Cofactor for Decarboxylation of L Dopa; Vitamin B6 Enhances Conversion of L Dopa to Dopamine in Periphery Making it less Readily for Use in the CNSL Dopa Is co-administered with Carbidopa

Drug Interactions contCarbidopa = Antagonistic to Peripheral L Dopa Decarboxylation, Doesn't Cross Blood Brain BarrierBy co-administering Carbidopa, will decrease metabolism of L Dopa in GI Tract and Peripheral Tissues thereby increasing L Dopa conc into CNS; meaning we can decrease L Dopa dose and also control the dose of L Dopa to a greater degree.

Drug Interactions contAntipsychotic Drugs - Antipsychotic Drugs Block Dopamine ReceptorReserpine -Reserpine Depletes Dopamine StorageAnticholinergics - Used Synergistically with L Dopa as an Antiparkinson Agent, but Anticholinergics Act to decrease L Dopa absorption since Anticholinergics have an effect on gastric emptying time which delays crossing of GI Membrane by L Dopa

Drug Interactions contNonspecific MAO Inhibitors - Interfere with L Dopa Breakdown and exaggerate the CNS effects the Nonspecific MAO Inhibitors Can Precipitate Hypertensive Crisis by the tyramine-cheese effect (Tyramine Is Found in Cheese, Coffee, Beer, Pickles, Chocolate, and Herring), when given to a person taking a MAO Inhibitor Tyramine Is not broken down therefore producing a tremendous release of Norepinephrine)

Other Drugs for Treating Parkinson DiseaseBefore Using Other Drugs, First Use L Dopa until Dosage of L Dopa Starts Becoming too high for the Patient; L Dopa's Therapeutic and Toxicity Index Figures become too close

Bromocriptine (Ergotamine derivative) Dopamine Receptor Agonis

Pramipexole is a nonergot dopamine agonist with high relative in vitro specificity and full intrinsic activity at the D2 subfamily of dopamine receptors, binding with higher affinity to D3 than to D2 or D4 receptor subtypes. precise mechanism of action is unknown, although it is believed to be related to its ability to stimulate dopamine receptors in the striatum.

Amantadine for Treating Parkinson DiseaseAmantadine Effective as in the Treatment of Influenza, however has significant Antiparkinson Action; it appears to Enhance Synthesis, Release, or Reuptake of Dopamine from the Surviving Nigral Neurons

Deprenyl ( Selegiline) for Treating Parkinson DiseaseDeprenyl Selectively Inhibits Monoamine Oxidase B Which Metabolizes Dopamine, but Does Not Inhibit Monoamine Oxidase a Which Metabolizes Norepinephrine and Serotonin

The Protective Effects of SelegilineAlthough the factors responsible for the loss of nigrostriatal dopaminergic neurons in Parkinson's disease are not understood, the findings from neurochemical studies have suggested that the surviving striatal dopamine neurons accelerate the synthesis of dopamine, thus enhancing the formation of H202 according to the following scheme.

Amphetamine for Treating Parkinson DiseaseAmphetamine Has Been Used Adjunctively in the Treatment of Some Parkinsonian Patients it Is Thought That, by Releasing Dopamine and Norepinephrine from Storage Granules, Amphetamine Makes Patients More Mobile and More Motivated

Catechol-O-methyltransferase (COMT) inhibitorsTolcapone (Tasmar) and Entacapone (Comtan) are two well-studied COMT inhibitors.Increases the duration of effect of levodopa doseCan increase peak levels of levodopaShould be taken with carbidopa/levodopa (not effective used alone)Can be most beneficial in treating "wearing off" responsesCan reduce carbidopa/levodopa dose by 20-30%

Antimuscarinic Agents for Treating Parkinson DiseaseThe Antimuscarinic Agents Are Much less Efficacious than Levodopa, and These Drugs Play Only an Adjuvant Role in Antiparkinson Therapy the Actions of Atropine, Scopolamine, Benztropine, Trihexyphenidyl, and Biperiden Are Similar

Drugs used to treat other Neurodegenerative disordersHuntingtons disease-D2 antagonists and diazepamAlzheimers disease- cholinesterase inhibitors (donepezil and tacrine)

Alzheimers diseaseProgressive dementiaAffects memory, cognition, emotion and physical functionLoss of cholinergic (and other types) neurons in the cortex and limbic structures of the brain including hippocampus, amygdala and basal forebrainCortical atrophy, neurofibrillary tangles and plaques containing -amyloid protein

L-DOPASSRIMAOIAMPHETAMINE

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