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  • Many different areas within the brain are involved in a complex chain of decisions required for even the smallest muscular movement. For an action like walking, for example, the brain must first gather all the information it needs about your body position. For example, are you sitting, lying down, or already standing up? Where are your feet? Do you have your balance? Then, the brain must add in what it knows about where you will be going. For example, do your eyes tell your brain that you'll be crossing an open field of grass or a busy street? Do your feet detect that the ground is easy to walk on or that you could lose your balance because it is bumpy or slippery? Figure 1. Your brain and spinal cord - a message pathway that turns thought into motion. This information comes together in a central area of the brain, called the striatum, which controls many aspects of bodily motion. The striatum works with other areas of the brain, including a part called the substantia nigra, to send out the commands for balance and coordination. These commands go from the brain to the spinal cord through nerve networks to the muscles that will then help you to move (figure 1).
  • he entire nervous system is made up of individual units called nerve cells. Nerve cells actually serve as a "communication network" within your body. To communicate with each other, nerve cells use a variety of chemical messengers called neurotransmitters. Neurotransmitters carry messages between nerve cells by crossing the space between cells, called the synapse (figure 2
  • Neurotransmitters also allow the nervous system to communicate with the body's muscles and translate thought into motion. One especially important messenger is dopamine, which is manufactured in the substantia nigra. Dopamine is crucial to human movement and is the neurotransmitter that helps transmit messages to the striatum that both initiate and control your movement and balance. These dopamine messages make sure that muscles work smoothly, under precise control, and without unwanted movement. When a dopamine message is needed, a nerve cell that produces dopamine gathers packets within itself filled with dopamine particles. These packets carrying the dopamine move to the end of the nerve cell, open a "window," and release the dopamine particles into the synapse. The dopamine particles flow across the synapse and fit into special pockets on the outside of the neighboring, or receiving, nerve cell (figure 3). The receiving cell is now stimulated to send on the message, so it gathers its own packets of dopamine and passes along the message to the next nerve cell in the same way.
  • After the receiving cell has been stimulated to pass along the message, the pockets then release the dopamine back into the synapse. To fine-tune coordination of movement, these "used" dopamine particles, along with any excess dopamine that did not originally fit into a pocket on the receiving cell, are broken down by a chemical in the synapse called MAO-B (figure 4). This is an important step in the precise control of muscle movement. Too much or too little dopamine can disrupt the normal balance between the dopamine system and another neurotransmitter system, and interfere with smooth, continuous movement.
  • One way to illustrate how the muscle control process works is as follows: two buckets - one for the dopamine system and one for the acetylcholine system - balanced on either end of a seesaw (figure 5). This depicts the situation at rest when the dopamine and acetylcholine systems are balanced. When you decide to move, your brain understands the movement you want to make and it sends out a balance of dopamine and acetylcholine messages to keep that movement smooth.
  • N= Substantia Nigra E= Globus Pallidus externa, S= Subthalamic nucleus, I/R= Globus Pallidus interna T = Thalamus Step1: Dopamine is normally produced in the pars compacta of the substantia nigra which has projections to the striatum. Step2: In the striatum, dopamine normally has an excitatory effect on D1 receptors. Step 3: This results in an increased production of GABA in neurones that project to the Gpi. GABA is an inhibitory neurotransmitter and reduces the output of the Gpi. In Parkinson’s however, Step One is removed and therefore Steps 2 and 3 don’t follow. The result is an increased output from the Gpi. (see step 8) Step4: Dopamine also has an inhibitory effect on the neurones in the striatum that make up the indirect pathway. Step 5: Inhibition here results in decreased production of GABA in the neurones that project to the Gpe. Step 6: Reduced inhibition of the Gpe results in an increased production of GABA by the neurones of the Gpe that project to the subthalamic nucleus. This results in an increased inhibitory effect on the subthalamic nucleus. Step 7: The Subthalamic nucleus, which projects to the Gpi, therefore reduces production of the excitatory neurotransmitter glutamate. In Parkinson’s disease however, the reverse occurs. There is no inhibition at step 4, therefore there is increased inhibition of the Gpe. This results in reduced production of GABA by the Gpe and reduced inhibition of the Subthalamic nucleus. It therefore produces more Glutamate and has an increased stimulatory effect on the Gpi. Step 8: In the normal situation, inhibition by the direct pathway and reduced stimulation by the indirect pathway would result in little production of GABA by the Gpi. This would mean that there would be little inhibition of the ventrolateral thalamus to which it projects via the lenticular fasciculus and the ansa lenticularis. However, in Parkinson’s disease, there is reduced inhibition by the direct pathway and increased stimulation by the indirect pathway. The result is an increased output of GABA and increased inhibition of the ventrolateral thalamus. Step 9: The ventrolateral nucleii of the thalamus are excitatory to the cortex. In the Parkinson’s patient therefore, the excessive inhibition of the thalamus from the Gpi could result in reduced excitation of the cortex and the classic symptoms of Parkinson’s disease, i.e. Bradykinesia, rigidity and tremor.
  • methylphenyltetrahydropyridine
  • methylphenyltetrahydopyridine
  • Antiparkinsons

    5. 9. CASE 1 <ul><li>F.B., 70 year old male, living in a nursing home was noticed to have episodes of crying spells and labile mood. He also had difficulty in initiating sleep and had night time awakenings. Caregivers noticed also progressive slowing down of movement associated with fine tremors of the hands at rest. Few days PTC there were noticeable rigidity & impairment of body movements. </li></ul>
    6. 10. PARKINSONISM <ul><li>Paralysis Agitans </li></ul><ul><li>“ SHAKING PALSY” </li></ul><ul><li>Tremors are present even at rest </li></ul><ul><li>Rigidity & impairment of voluntary movements </li></ul><ul><li>Postural tremor, intention tremors </li></ul>
    7. 11. The UK Parkinson's Disease Society Brain Bank Criteria For Clinical Diagnosis: <ul><li>Bradykinesia plus one of rigidity, tremor, or postural instability </li></ul><ul><li>At least three of rest tremor, progressive symptoms, unilateral onset, early response to levodopa, revodopa-induced dyskinesia </li></ul><ul><li>No identifiable cause for the parkinsonism. </li></ul>
    8. 12. Motor Symptoms: <ul><li>Tremor: </li></ul><ul><ul><li>70% of patients suffer resting tremor </li></ul></ul><ul><ul><li> pill rolling quality </li></ul></ul><ul><ul><li>can affect all of the limbs as well as the face, neck, head and jaw. </li></ul></ul><ul><li>Rigidity: </li></ul><ul><ul><li>increased tone or stiffness in the muscles </li></ul></ul><ul><ul><li>mask-like face and clog-like release of muscles. </li></ul></ul><ul><li>Bradykinesia </li></ul><ul><ul><li>difficulty initiating and continuing movement. </li></ul></ul>
    9. 13. <ul><li>Postural Instability </li></ul><ul><ul><li>Forward flexion of neck, hips, knees and elbows leads to poor balance . </li></ul></ul><ul><li>Gait disorders </li></ul><ul><ul><li>Shuffling, small steps described as festination, reduced arm swing and sudden freezing spells lead to problems walking </li></ul></ul><ul><li>Swallowing (dysphagia) and Speech disorders (dysarthria) </li></ul><ul><li>Handwriting: Micrographia </li></ul>
    10. 14. Nonmotor Symptoms: <ul><li>Depression: </li></ul><ul><ul><li>20-90% major depressive episode, reactive or endogenous </li></ul></ul><ul><li>Dementia: </li></ul><ul><ul><li>20% of patients will become demented (have impairments of 3 of the following in the presence of clear consciousness: language, memory, visuospatial skills, emotionality, personality and cognition </li></ul></ul>
    11. 15. <ul><li>Sleep disturbances: </li></ul><ul><ul><li>Problems with sleep fragmentation, sleep initiation, early morning awakening, excessive daytime somnolence and parasomnias . </li></ul></ul><ul><li>Sexual dysfunction </li></ul><ul><li>Ability to drive a car </li></ul><ul><li>Ability to gain employment </li></ul><ul><li>Constipation </li></ul>
    12. 17. What causes Parkinson’s Disease? <ul><li>A viral cause: </li></ul><ul><li>In 1918 there was an outbreak of Encephalitis Lethargica and many sufferers developed postencephalitic Parkinsonism. </li></ul><ul><li>A toxic substance: </li></ul><ul><li>For instance, the illegal drug MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). </li></ul><ul><li>A genetic cause : </li></ul><ul><li>Research by the NHGRI (National Human Genome Research Institute) suggests that a mutated gene, which codes the alpha synuclein protein located on chromosome 4, has a role in familial parkinsonism. </li></ul><ul><li>Other causes: </li></ul><ul><li>Head injuries. </li></ul><ul><li>Oxidative stress. </li></ul><ul><li>Heavy metal ion exposure from fillings etc. </li></ul><ul><li>It is proposed that these factors cause the neurone's mechanisms for proteolysis to go awry leading to the formation of the characteristic Lewy bodies seen on autopsy of Parkinson’s patients. The cells then fail to function correctly and ultimately die. </li></ul>
    13. 18. PATHOGENESIS: <ul><li>Idiopathic </li></ul><ul><li>Genetic (<50 y/o) </li></ul><ul><li>Exposure to unrecognized neurotoxins </li></ul><ul><li>Oxidation reaction with generation of free radicals </li></ul><ul><li>Reduced level of dopamine in the basal ganglia </li></ul>
    14. 19. MOTOR SYMPTOMS: <ul><li>POSITIVE SYMPTOMS </li></ul><ul><li>Tremor </li></ul><ul><li>Chorea, </li></ul><ul><li>Athetosis </li></ul><ul><li>Ballismus </li></ul><ul><li>NEGATIVE SYMPTOMS </li></ul><ul><li>Bradykinesia </li></ul><ul><li>Akinesia </li></ul><ul><li>Loss of postural reflexes . </li></ul>
    15. 20. CHOREA <ul><li>Irregular, unpredictable involuntary jerks </li></ul><ul><li>Impaired voluntary activity </li></ul><ul><li>ballismus </li></ul>
    16. 21. TICS <ul><li>Sudden coordinated abnormal movements </li></ul><ul><li>Repetitive sniffing </li></ul><ul><li>shoulder shrugging </li></ul><ul><li>face & head movement </li></ul>
    17. 22. ATHETOSIS <ul><li>Slow & writhing movements </li></ul><ul><li>Abnormal postures (dystonia) </li></ul>
    18. 24. <ul><li>Pyramidal System : </li></ul><ul><ul><li>begins in the primary motor cortex </li></ul></ul><ul><ul><li>descends through the corticospinal and corticobulbar tracts </li></ul></ul><ul><ul><li>affects the lower motor neurons in the brain stem and spinal cord . </li></ul></ul>
    19. 25. <ul><li>Extrapyramidal System: </li></ul><ul><ul><li>basal ganglia and their cortical connection </li></ul></ul><ul><ul><li>basal ganglia are made up of the: </li></ul></ul><ul><ul><ul><li>Caudate Nucleus </li></ul></ul></ul><ul><ul><ul><li>Putamen (Striatum) </li></ul></ul></ul><ul><ul><ul><li>Globus Pallidus interna (Gpi) </li></ul></ul></ul><ul><ul><ul><li>Globus Pallidus externa (Gpe) </li></ul></ul></ul><ul><ul><ul><li>Subthalamic Nucleus </li></ul></ul></ul><ul><ul><ul><li>Substantia Nigra </li></ul></ul></ul><ul><ul><ul><li>Main Outputs: </li></ul></ul></ul><ul><ul><ul><li>Substantia Nigra </li></ul></ul></ul><ul><ul><ul><li>Globus pallidus interna </li></ul></ul></ul><ul><ul><ul><li>Both of which feed to the ventrolateral thalamus </li></ul></ul></ul>
    20. 26. <ul><li>The main Pathological feature of Parkinson’s disease is the loss of the dopaminergic nigrostriatal pathway </li></ul><ul><li>Dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the striatum are lost </li></ul><ul><li>80% of the Dopamine producing cells must be lost before symptoms begin to show </li></ul>
    22. 32. GOALS OF TREATMENT: <ul><li>Pharmacologic attempt to restore dopaminergic activity with levodopa and dopamine agonists </li></ul><ul><li>Restore normal balance of cholinergic & dopaminergic influences on the basal ganglia </li></ul>
    23. 33. PATHOPHYSIOLOGIC BASIS OF TREATMENT: <ul><li>Dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic cells in the corpus striatum are lost </li></ul>
    24. 34. CASE 2 <ul><li>F.B., was brought to the clinic for evaluation , diagnosed to have Parkinson’s disease. </li></ul><ul><li>What is the goal in the management of this case? </li></ul><ul><li>What is the first line drug that can relieve the signs and symptoms of parkinsonism </li></ul>
    26. 36. LEVODOPA <ul><li>(-) -3-(3-4 dihydroxyphenyl) L- alanine </li></ul><ul><li>Immediate metabolic precursor of dopamine </li></ul><ul><li>Levorotatory stereoisomer of dopamine </li></ul><ul><li>D1 receptors stimulate adenylcyclase, located in the zona compacta of the substantia nigra </li></ul><ul><li>D2 receptors inhibit adenylcylase, located postsynaptically on striatal neurons &presynaptically in the substantia nigra </li></ul>
    27. 37. PHARMACOKINETICS: <ul><li>Rapidly absorbed from the SI </li></ul><ul><li>Food delays absorption </li></ul><ul><li>Amino acids in food compete with drug </li></ul><ul><li>Peak plasma concentration: 1-2 hrs </li></ul><ul><li>Plasma t ½ : 1-3 hrs </li></ul><ul><li>HVA, DOPAC (dihydroxyphenylacetic acid) are main metabolites </li></ul><ul><li>1-3% enters the brain </li></ul>
    28. 38. CLINICAL USE: <ul><li>Responsiveness may be lost secondary to disappearance of dopaminergic nigostriatal nerve terminals </li></ul><ul><li>Early use lowers mortality rate </li></ul><ul><li>Combined with Carbidopa & Benseraside </li></ul><ul><li>Sinemet – dopa preparation containing levodopa in fixed proportion (1:10 or 1:4) </li></ul><ul><li>Sinemet 25/100 TID </li></ul><ul><li>30 -60 minutes before meals </li></ul>
    29. 39. ADVERSE EFFECTS: <ul><li>Fluctuations in response </li></ul><ul><li>Misc: mydriasis, blood dyscrasias, hot flushes, gout, brownish discoloration of the urine, abnormal smell, priapism, transient elevations of transaminases & BUN </li></ul>
    30. 40. ADVERSE EFFECTS: <ul><li>GIT effects: vomiting (CTZ) </li></ul><ul><ul><li>Reduced by carbidopa </li></ul></ul><ul><ul><li>Phenothiazenes are contraindicated </li></ul></ul><ul><li>Cardiovascular: tachycardia, ventricular extrasystoles, atrial fibrillation </li></ul>
    31. 41. <ul><li>Dyskinesias </li></ul><ul><ul><li>Common in patients receiving carbidopa </li></ul></ul><ul><li>Behavioral effects: </li></ul><ul><ul><li>Common in patients receiving levodopa </li></ul></ul><ul><ul><li>controlled by clozapine, olanzapine, resperidone </li></ul></ul>
    32. 42. DRUG INTERACTIONS: <ul><li>Vitamin B6 enhance extracerebral metabolism of levodopa </li></ul><ul><ul><li>Prevented by decarboxylase inhibitors </li></ul></ul><ul><li>MAO – A inhibitors </li></ul><ul><ul><li>Hypertensive crisis </li></ul></ul>
    33. 43. CONTRAINDICATIONS: <ul><li>Psychoses </li></ul><ul><li>Angle closure glaucoma </li></ul><ul><li>Cardiac dysrhythmia </li></ul><ul><ul><li>Less incidence in combination with carbidopa </li></ul></ul><ul><li>PUD </li></ul><ul><li>Melanoma or suspicious undiagnosed skin lesions </li></ul>
    34. 44. CASE 3 <ul><li>F.B. Was maintained on low dose of Levodopa and was titrated until given the highest dose where he started to had palpitations and chest pain. </li></ul><ul><li>What is next step in your management? </li></ul>
    35. 45. PERIPHERAL DOPAMINE DECARBOXYLASE INHIBITORS (PDI) <ul><li>Carbidopa , Benseraside </li></ul><ul><li>Does not penetrate the BBB </li></ul><ul><li>Reduce the peripheral metabolism of levodopa </li></ul><ul><li>Increase plasma levels of levodopa </li></ul><ul><li>Prolongs the plasma half life of levodopa </li></ul><ul><li>Increase available amounts of dopa for entry into the brain </li></ul><ul><li>Reduce the daily requirement of levodopa by 75% </li></ul>
    36. 47. CASE 4 <ul><li>F.B. After 1 year of taking Levodopa develop rigidity and bradykinesia with worsening of the tremors. </li></ul><ul><li>What treatment option should F.B. receive? </li></ul>
    37. 48. DOPAMINE AGONISTS <ul><li>Do not require enzymatic conversion for an active metabolite </li></ul><ul><li>No potential toxic metabolites </li></ul><ul><li>Do not compete with other substances for an active transport </li></ul><ul><li>First line in parkinsonism </li></ul><ul><li>End of dose akinesia to levodopa </li></ul><ul><li>On & off phenomenon refractory to levodopa </li></ul>
    38. 50. ERGOT ALKALOIDS: <ul><li>BROMOCRIPTINE (Parlodel) </li></ul><ul><ul><li>D2 agonists </li></ul></ul><ul><ul><li>Endocrinologic disorders (hyperprolactinemia) </li></ul></ul><ul><ul><li>Absorbed variably in GIT </li></ul></ul><ul><ul><li>Peak plasma levels: 1-2 hrs </li></ul></ul>
    39. 51. ERGOT ALKALOID: <ul><li>PERGOLIDE </li></ul><ul><ul><li>Stimulates both D1 and D2 </li></ul></ul><ul><ul><li>More effective than bromocriptine </li></ul></ul><ul><ul><li>Associated with clinical or subclinical valvular heart disease </li></ul></ul>
    40. 52. CLINICAL USE: <ul><li>BROMOCRIPTINE: </li></ul><ul><ul><li>7.5 mg & 30 mg </li></ul></ul><ul><ul><li>1. 25 mg BID after meals X 2-3 months and increase 2.5 mg q 2 wks </li></ul></ul><ul><ul><li>PERGOLIDE: </li></ul></ul><ul><ul><li>- 3 mg daily </li></ul></ul><ul><ul><li>- 0.05 mg starter dose </li></ul></ul>
    41. 53. NON-ERGOT DOPAMINE AGONISTS: <ul><li>PRAMIPEXOLE </li></ul><ul><ul><li>Preferential affinity to D3 </li></ul></ul><ul><ul><li>Monotherapy is effective </li></ul></ul><ul><ul><li>Neuroprotective (H scavenger) </li></ul></ul><ul><ul><li>Enhance neurotrophic activity </li></ul></ul><ul><ul><li>Rapidly absorbed </li></ul></ul><ul><ul><li>Peak plasma concentration: 2 hrs </li></ul></ul><ul><ul><li>0.125 mg TID then doubled after 1 wk </li></ul></ul><ul><ul><li>Increments of 0.75 mg at weekly intervals </li></ul></ul>
    42. 54. NON-ERGOT ALKALOIDS: <ul><li>ROPINIROLE </li></ul><ul><ul><li>Pure D2 receptor agonists </li></ul></ul><ul><ul><li>0.25 mg TID then total daily dose is increased by 0.75 mg at weekly intervals until the 4 th wk & increased by 1.5 mg thereafter </li></ul></ul>
    43. 55. ADVERSE EFFECTS: <ul><li>GIT: anorexia, nausea, vomiting, bleeding PUD, reflux esophagitis </li></ul><ul><li>Cardiovascular: postural hypotension, painless digital vasospasm </li></ul><ul><li>Dyskinesias </li></ul><ul><li>Mental disturbances </li></ul><ul><li>Misc: erythromelalgia </li></ul>
    44. 56. CONTRAINDICATIONS: <ul><li>History of psychotic illness </li></ul><ul><li>Recent myocardial infarction </li></ul><ul><li>Peripheral vascular disease </li></ul><ul><li>Peptic ulceration </li></ul>
    45. 57. APOMORPHINE <ul><li>Apokyn </li></ul><ul><li>Potent dopamine agonist </li></ul><ul><li>Temporary relief of off-periods of akinesia </li></ul><ul><li>Rapidly taken by blood and brain (10 minutes) and persists for 2 hours </li></ul><ul><li>Nausea – trimethobenzamide </li></ul><ul><li>Dyskinesias, drowsiness, sweating, hypotension, bruising at injection site </li></ul>
    46. 58. MONOAMINE OXIDASE INHIBITORS <ul><li>MAO – A: metabolizes NE & serotonin </li></ul><ul><li>MAO – B: metabolizes dopamine </li></ul>
    47. 59. SELEGILINE ( Deprenyl) <ul><li>Selective irreversible inhibitor of </li></ul><ul><li>MAO-B (normal doses) </li></ul><ul><li>Inhibits MAO-A (higher doses) </li></ul><ul><li>Retards breakdown of dopamine </li></ul><ul><li>Prolongs & enhances the effect of levodopa </li></ul><ul><li>Adjunct in fluctuating response to levodopa </li></ul>
    48. 60. SELEGELINE <ul><li>5 mg with breakfast & lunch </li></ul><ul><li>Cause insomnia when taken later during the day </li></ul><ul><li>Not to be taken with meperidine, TCAs, SSRIs </li></ul><ul><li>Increase adverse effects of levodopa </li></ul><ul><li>METABOLITES: amphetamine & metamphetamine </li></ul>
    49. 61. DRUG INTERACTION: <ul><li>Stupor, rigidity, agitation, and hyperthermia - MEPERIDINE </li></ul>
    50. 62. RASAGILINE <ul><li>MAO-B inhibitor </li></ul><ul><li>Potent than selegiline in preventing MAO-B toxins induced parkinsonism (MPTP) </li></ul><ul><li>Combination with levodopa – HPN crisis </li></ul>
    51. 63. CATHECO-O-METHYLTRANSFERASE INHIBITORS: <ul><li>Compensatory activation pathways of levodopa metabolism after dopa decarboxylase inhibition </li></ul><ul><li>Increase 3- O- methyldopa (3OMD)  poor therapeutic response to levodopa </li></ul><ul><ul><li>Competes with levodopa for an active carrier mechanism in the intestinal mucosa & BBB </li></ul></ul>
    52. 64. CATHECOL-O-METHYLTRANSFERASE INHIBITORS: ( SELECTIVE) <ul><li>TOLCAPONE- central & peripheral metabolism </li></ul><ul><li>ENTACAPONE </li></ul><ul><ul><li>peripheral metabolism </li></ul></ul><ul><ul><li>Prolongs the duration of levodopa by decreasing its peripheral metabolism </li></ul></ul><ul><ul><li>Helpful in patients receiving levodopa who have fluctuations </li></ul></ul><ul><ul><li>t ½ = 2 hrs </li></ul></ul>
    53. 65. STALEVO <ul><li>Combination of levodopa with both carbidopa and entacapone </li></ul><ul><li>Simplifies drug regimen </li></ul><ul><li>Requires consumption of a lesser number of tablets </li></ul>
    54. 67. SIDE EFFECTS: <ul><li>Postural hypotension </li></ul><ul><li>Fatigue </li></ul><ul><li>Somnolence </li></ul><ul><li>Peripheral edema </li></ul><ul><li>Nausea </li></ul><ul><li>Constipation </li></ul><ul><li>Dyskinesias </li></ul><ul><li>Confusion </li></ul>
    55. 68. AMANTADINE <ul><li>Antiviral agent </li></ul><ul><li>Potentiates dopaminergic function by influencing the synthesis, release, reuptake of dopamine </li></ul><ul><li>PHARMACOKINETICS: </li></ul><ul><li>peak plasma concentration: 1-4 hrs after oral dose </li></ul><ul><li>Plasma t ½ = 2-4 hrs </li></ul>
    56. 70. CLINICAL USE: <ul><li>Less potent than levodopa and benefits are short-lived </li></ul><ul><li>100 mg BID-TID </li></ul><ul><li>ADVERSE REACTIONS: </li></ul><ul><li>Restlessness, depression, irritability, insomnia, agitation, excitement, hallucinations & confusion </li></ul><ul><li>Livedo reticularis – clears within a month after drug withdrawal </li></ul>
    57. 72. CONTRAINDICATIONS: <ul><li>History of seizures </li></ul><ul><li>Heart failure </li></ul>
    58. 73. ACETYLCHOLINE BLOCKING AGENTS: <ul><li>Improve tremor & rigidity of parkinsonism but have little effect in bradykinesia </li></ul><ul><li>Benztropine mesylate </li></ul><ul><li>Biperiden </li></ul><ul><li>Orphenadrine </li></ul><ul><li>Procyclidine </li></ul><ul><li>Trihexyphenidyl </li></ul>
    59. 74. ADVERSE EFFECTS: <ul><li>CNS </li></ul><ul><li>Mydriasis, urinary retention, constipation, tachycardia, tachypnea, increase IOP, palpitations, cardiac arrythmias </li></ul><ul><li>Acute suppurative parotitis </li></ul><ul><li>Dryness of the mouth </li></ul>
    60. 75. CONTRAINDICATIONS: <ul><li>Prostatic hyperplasia </li></ul><ul><li>Obstructive GI diseases </li></ul><ul><li>Angle closure glaucoma </li></ul>
    61. 76. <ul><li>The net result of all of these medications is the balancing out of the acetylcholine/dopamine balance and an improvement in movement </li></ul>
    62. 78. SURGICAL PROCEDURES: <ul><li>Thalamotomy – conspicous tremor </li></ul><ul><li>Posteroventral pallidotomy or deep-brain stimulation </li></ul>
    63. 79. NEURONAL DEATH <ul><li>EXCITOTOXICITY </li></ul><ul><li>Environmental chemicals may contribute to neurodegenerative disorders </li></ul><ul><li>Can occur with excessive glutamate and kainic acids </li></ul><ul><li>Results from sustained rise in intracellular Ca </li></ul>
    64. 80. NEURONAL DEATH <ul><li>APOPTOSIS </li></ul><ul><li>Cell is systematically dismantled & shrunken remnants are removed by macrophages without causing inflammation </li></ul>
    65. 81. NEURONAL DEATH <ul><li>OXIDATIVE STRESS </li></ul><ul><li>Result of excessive production of oxygen and hydroxyl free radicals and hydrogen peroxide </li></ul>
    66. 82. ISCHAEMIC BRAIN DAMAGE <ul><li>Interruption of blood supply to the brain </li></ul><ul><li>Cerebral edema & inflammation </li></ul><ul><li>TREATMENT: </li></ul><ul><li>Calcium & Na channel blockers </li></ul><ul><ul><li>Nimodipine, fosphenytoin </li></ul></ul><ul><li>NMDA receptor antagonists </li></ul><ul><ul><li>Selfotel, eliprodil, dexrtromethorphan </li></ul></ul><ul><li>Glutamate inhibitors </li></ul><ul><ul><li>Adenosine, lobeluzole </li></ul></ul><ul><li>GABA agonists </li></ul><ul><ul><li>Clormethiazole </li></ul></ul><ul><li>Radical scavengers </li></ul><ul><ul><li>tirilazad </li></ul></ul>
    67. 83. CLINICAL SCENARIO <ul><li>A.D. 70 year old female living in a nursing home, has gradual onset of difficulty in recalling what time she has taken her snack but easily recalls the first ball she had in high school. </li></ul>
    68. 84. ALZHEIMER’S DISEASE <ul><li>Loss of intellectual ability with age </li></ul><ul><li>Dementia that does not have antecedent cause </li></ul><ul><li>Associated with brain shrinkage, localized loss of neurons in the hippocampus & basal forebrain </li></ul><ul><li>Amyloid plaques, neurofibrillary tangles in the hippocampus </li></ul><ul><li>Loss of cholinergic neurons </li></ul>
    70. 87. PATHOPHYSIOLOGY: <ul><li>Decrease in ACETYLCHOLINE </li></ul><ul><li>CHOLINERGIC DEFICIENCY SYNDROME </li></ul><ul><li>Decrease in markers of cholinergic neuron activity </li></ul><ul><li>Changes in brain glutamate, dopamine, norepinephrine, serotonin and somatostatin activity </li></ul><ul><li>Cholinergic and other neurons die or are destroyed </li></ul>
    71. 88. PATHOPHYSIOLOGY: <ul><li>Abnormal neuronal lipoprotein processing </li></ul><ul><li>Familial form is associated with abnormal lipoprotein - APOLIPOPROTEIN E4 </li></ul>
    72. 89. AMYLOID PLAQUES <ul><li>β AMYLOID PROTEIN – by product of neuronal death </li></ul>
    73. 90. NEUROFIBRILLARY TANGLES: <ul><li>More abundant in AD </li></ul><ul><li> tangles =  severity of cognitive impairment </li></ul>
    76. 94. CHOLINESTERASE INHIBITORS: <ul><li>TACRINE- central inhibitor </li></ul><ul><li>DONEZEPIL(Aricept) – not hepatotoxic, selective inhibitor </li></ul><ul><li>RIVASTIGMINE (Excelon) </li></ul><ul><li>GALANTHAMINE (Reminyl) </li></ul><ul><li>For mild to moderate Alzheimer’s disease </li></ul>
    77. 95. TACRINE <ul><li>Tetrahydroaminoacridine, THA </li></ul><ul><li>Long acting anticholinesterase & muscarinic modulator </li></ul><ul><li>Orally active </li></ul><ul><li>Duration of action: 6-8 hrs </li></ul><ul><li>Blocks both acetylcholinesterase & butyrylcholinesterase </li></ul><ul><li>Inhibitory effects on M1, M2 & muscarinic cholinoceptors </li></ul>
    78. 96. <ul><li>Increases the release of acetylcholine from cholinergic nerve endings </li></ul><ul><li>Inhibit MAO </li></ul><ul><li>Decrease the release of GABA </li></ul><ul><li>Increase the release of NE, dopamine, serotonin from nerve endings </li></ul>
    79. 97. DONAZEPIL, RIVASTIGMINE, GALANTAMINE <ul><li>Newer cholinesterase inhibitors with adequate penetration to the CNS </li></ul><ul><li>Indirect cholinomimetic effects than tacrine </li></ul>
    80. 98. ADVERSE EFFECTS: <ul><li>Nausea and vomiting </li></ul><ul><li>Hepatotoxicity is increased with tacrine </li></ul><ul><li>Should be used with caution: ketoconazole, quinidine </li></ul>
    82. 100. TARGACEPT <ul><li>Neuronal nicotinic receptors (NNRs), serve as key regulators of nervous system function. </li></ul><ul><li>When the natural neurotransmitter acetylcholine, or a drug that mimics acetylcholine, binds to an NNR, the NNR normalizes chemical signaling, allowing neurons to communicate properly (neuromodulation) </li></ul><ul><li>.&quot; </li></ul>
    83. 101. <ul><li>results in increased signaling when the nervous system is understimulated and decreased signaling when the nervous system is overstimulated </li></ul><ul><li>nervous system's &quot;volume knob </li></ul>
    85. 104. MEMANTINE (Ebixa) <ul><li>Binds to NMDA receptor channels </li></ul><ul><li>Produces a noncompetitive blockade </li></ul><ul><li>Prevents the effect of excess glutamate leaking out from the damaged brain cells </li></ul><ul><li>Treatment of moderate to severe form of Alzheimer’s disease </li></ul>
    86. 105. TREATMENT: <ul><li>INHIBITING NEURODEGENERATION </li></ul><ul><li>Anti-inflammatory drugs </li></ul><ul><ul><li>Ibuprofen, indomethacin </li></ul></ul><ul><li>Metal chelating agent </li></ul><ul><ul><li>Clioquinol </li></ul></ul>
    87. 106. THANK YOU !!!
    88. 107. POST –TEST: <ul><li>Tacrine </li></ul><ul><li>Targacept </li></ul><ul><li>Rivastigmine </li></ul><ul><li>Memantadine </li></ul><ul><li>Donazepil </li></ul><ul><li>NMDA glutamate receptor inhibitor </li></ul><ul><li>Neuronal Nicotinic Receptors </li></ul><ul><li>Cholinesterase inhbitor </li></ul>
    89. 108. <ul><li>6. SELEGILINE </li></ul><ul><li>7. TOLCAPONE </li></ul><ul><li>8. ROPINOROLE </li></ul><ul><li>9. BENSERASIDE </li></ul><ul><li>10. BIPERIDEN </li></ul><ul><li>MAOI </li></ul><ul><li>COMT INHIBITOR </li></ul><ul><li>DOPAMINE AGONIST </li></ul><ul><li>ACH BLOCKING AGENT </li></ul><ul><li>DOPA DECARB INHIBITOR </li></ul>