05,FEB,2013 PARKINSON’S Disease PDM.MURALI KRISHNAM.PharmPRD-traineeGVK BIO
Parkinsonism is a progressive degenerative, extra pyramidal disorder of muscle movement, due to dysfunction in basal ganglia, comprising four cardinal features:- Brady kinesia or hypo kinesia. Muscle rigidity. Resting tremor. Impairment of postural balance leading to disturbances of gait, and falling. The secondary manifestations are mask-like face, difficulty in speech, slowing of mental process and dementia. 2
It is slowness in initiating and carrying out voluntary movements. It is called poverty and suppression of voluntary movements. It is caused partly by muscle rigidity and partly by inertia of the motor system, which means that motor activity is difficult to stop as well as to initiate. It is hard to start walking, and once in progress, the patient can not stop quickly. 5
• Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse.• Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse.• Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may also follow graded electrical potentials.
• Major neurotransmitters Amino acids: glutamate, aspartate, D-serine, γ-amino butyric acid (GABA), glycine Monoamines and other biogenic amines: dopamine (DA), nor epinephrine, epinephrine ,histamine, serotonin (5-HT) Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.
• Dopamine neurons are more widely distributed than those of other monoamines, residing in the midbrain substantia nigra and ventral tegmental area and in the periaqueductal gray, hypothalamus, olfactory bulb, and retina.• In the periphery, dopamine is found in the kidney where it functions to produce renal vasodilation, diuresis, and natriuresis.• Three dopamine systems are highly relevant to psychiatry: The nigrostriatal, mesocorticolimbic, and tuberohypophyseal system.
Tyrosine, a precursor to dopamine, is taken up into dopamine nerveterminals via a tyrosine transporter and converted into DOPA by the enzymetyrosine hydroxylase (TOH). DOPA is then converted into dopamine (DA) bythe enzyme DOPA decarboxylase (DDC). After synthesis, dopamine ispackaged into synaptic vesicles via the vesicular monoamine transporter(VMAT2) and stored there until its release into the synapse during
The degeneration of neurons occurs in substantia nigra pars compacta and the nigrostriatal tract that are dopaminergic and inhibit the activity of striatal GABA ergic neurons. This results in deficiency of dopamine in striatum which controls muscle tone and coordinates movements. Nerve fibers from cerebral cortex and thalamus secrete acetylcholine in the neostriatum causing excitatory effects that initiate and regulate gross intentional movements of the body. In Parkinson’s disease, due to deficiency of dopamine in striatum, an imbalance between dopaminergic (inhibitory) and cholinergic (excitatory) system occurs, leading to excessive excitatory actions of cholinergic neurons on striatal GABA ergic neurons. 10
Degeneration of neurones in the substantia nigra pars compacta Degeneration of nigrostriatal (dopaminergic) tract Results in deficiency of Dopamine in Striatum - >80%
Imbalance primarily between the excitatory neurotransmitter Acetylcholine and inhibitory neurotransmitter Dopamine in the Basal Ganglia
• Two enzymes that play major roles in the degradation of dopamine are monoamine oxidase and catechol O-methyltransferase (COMT).• MAO is located on the outer membrane of mitochondria.• Two MAO isozymes MAO-A : Which preferentially deaminates serotonin and norepinephrine. MAO-B : Which deaminates dopamine, histamine, and a broad spectrum of phenylethylamines. COMT is located in the cytoplasm and is widely distributed throughout the brain and peripheral tissues. It has a wide substrate specificity, catalyzing the transfer of methyl groups from S-adenosyl methionine to the m-hydroxyl group of most catechol compounds. The predominant metabolites of dopamine is Homovanillic acid (HVA)
Dopamine synthesized within neurons from common amino acid precursors (step 1) and taken up into synaptic vesicles via a vesicular monoamine transporter (step 2). Upon stimulation, vesicles within nerve terminals fuse with the presynaptic terminal and release the neurotransmitter into the synaptic cleft (step 3). Once released, the monoamines interact with postsynaptic receptors to alter the function of postsynaptic cells (step 4), and they may also act on presynaptic autoreceptors on the nerve terminal to suppress further release (step 5). In addition, released dopamine may be taken back up from the synaptic cleft into the nerve terminal by DAT Dopamine Transpoter(step 6), a process known as reuptake. Once monoamines are taken up, they may be subject to enzymatic degradation (step 7), or they may be protected from degradation by uptake into vesicles.
Dopamine transporter (DAT) exists presynaptically and is responsible for clearing excessdopamine out of the synapse. The vesicular monoamine transporter (VMAT2) takesdopamine up into synaptic vesicles for future neurotransmission. There is also apresynaptic dopamine-2 autoreceptor, which regulates release of dopamine from thepresynaptic neuron. In addition, there are several postsynaptic receptors. These includedopamine-1, dopamine-2, dopamine-3, dopamine-4, and dopamine-5 receptors. Thefunctions of the dopamine-2 receptors are best understood, because this is the primarybinding site for virtually all antipsychotic agents as well as for dopamine agonists usedto treat Parkinsons disease.
Presynaptic dopamine-2 autoreceptors are "gatekeepers" for dopamine. Thatis, when these gatekeeping receptors are not bound by dopamine (nodopamine in the gatekeepers hand), they open a molecular gate, allowingdopamine release (A). However, when dopamine binds to the gatekeepingreceptors (now the gatekeeper has dopamine in his hand), they close themolecular gate and prevent dopamine from being released (B).
In Parkinson’s disease dopaminergic inhibitory activity is reduced and cholinergic excitatory activity is increased. Therefore, therapy is aimed at restoring dopamine in the basal ganglia and antagonizing the excitatory effects of cholinergic neurons. Lahore Medical & Dental College 20
Drug therapy is aimed at restoring the balance between the dopaminergic and cholinergic components, which is achieved by: Increasing the central dopaminergic activity OR Decreasing the central cholinergic activity OR BOTH. Lahore Medical & Dental College 22
Drugs that replace dopamine (Dopamine precursor): Levodopa Dopa-decarboxylase inhibitors (Drugs which increase the central availability of Levodopa) Carbidopa, Benserazide. They act in the periphery as they do not enter brain. Drugs which increase release or inhibit reuptake of dopamine (also called dopamine facilitator) Amantadine. Lahore Medical & Dental College 23
MAO-B INHIBITORSThere are two forms of MAO, MAO-A and MAOB.MAO-B predominates in brain and blood platelets. MAO-A predominant in GI tract – oxidation of tyramine – cheese reactionMAO-B predominant in human brain- breakdown of dopamine , de amination of phenyl ethylamine.In Parkinsonian brain MAO-B inhibitors block the oxidative metabolism of dopamine in basal ganglia there by conserving the depleted dopamine supply and prolonging its action.
Selegiline. They prolong the action of dopamineSelegiline, in low doses, does not interfere with peripheral metabolism of dietary amines. Catecholamine accumulation and hypertension does not occur, while intracerebral degradation of dopamine is retarded. Administered with levodopa, it prolongs levodopa action, decreases motor fluctuations and decreases ‘wearing off’ effect. Adverse effects are – postural hypotension, nausea and accentuation of levodopa induced involuntary movements. Lahore Medical & Dental College 26
• Dopamine and Tyrosine Are Not Used for Parkinson Disease Therapy, Why? – Dopamine Doesnt Cross the Blood Brain Barrier – Huge amount of tyrosine decreases activity of rate limiting enzyme Tyrosine Hydroxylase
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