Introduction A neurodegenerative disorder caused by progressive death of selected dopaminergic neurons in the CNS. The pathology of this disorder leads to deteriorating motor, autonimic, cognitive and psychiatric function. First described by James Parkinson in his classic 1817 monograph, "An Essay on the Shaking Palsy,“ A neurodegenerative disorder caused by progressive death of selected dopaminergic neurons in the CNS. The pathology of this disorder leads to deteriorating motor, autonimic, cognitive and psychiatric function. First described by James Parkinson in his classic 1817 monograph, "An Essay on the Shaking Palsy,“

Epidemiology Affects between 100 to 200 per 100,000 people over 40 Uncommon in people younger than 40 Incidence of the disease increases rapidly over 60 years, with a mean age at diagnosis of 70 years Affects between 100 to 200 per 100,000 people over 40 Uncommon in people younger than 40 Incidence of the disease increases rapidly over 60 years, with a mean age at diagnosis of 70 years

Pathophysiology

A.Dopaminergic cells originating in substantia nigra pars compacta and terminating in the caudate & putamen (nigrostriatal pathway ) are lost gradually during the course of the disease. 1.Patients initially become symptomatic after 70%-80% cell loss in these area. 2.Accounts for development of rigidity & akinesia 3.May contribute to cognitive symptoms. B.Factors contributing to autonomic dysfunction 1.Degeneration of the intermediolateral columns of spinal cord 2.Degeneration of the sympathetic and parasympathetic ganglia C.Loss of brainstem serotonergic & noradrenergic cells – contribute to depressive symptoms D.Formation of Lewy bodies 1.Found in cortex, brainstem and basal forebrain in individuals with preclinical and advance PD 2.Enclosed bodies containing eosinophils and cytosolic proteins 3.Nonspecific finding; may be unrelated to PD process A.Dopaminergic cells originating in substantia nigra pars compacta and terminating in the caudate & putamen (nigrostriatal pathway ) are lost gradually during the course of the disease. 1.Patients initially become symptomatic after 70%-80% cell loss in these area. 2.Accounts for development of rigidity & akinesia 3.May contribute to cognitive symptoms. B.Factors contributing to autonomic dysfunction 1.Degeneration of the intermediolateral columns of spinal cord 2.Degeneration of the sympathetic and parasympathetic ganglia C.Loss of brainstem serotonergic & noradrenergic cells – contribute to depressive symptoms D.Formation of Lewy bodies 1.Found in cortex, brainstem and basal forebrain in individuals with preclinical and advance PD 2.Enclosed bodies containing eosinophils and cytosolic proteins 3.Nonspecific finding; may be unrelated to PD process

Motor features of Parkinson disease Cardinal manifestations Craniofacial Musculoskeletal Gait Visual Cardinal manifestations Craniofacial Musculoskeletal Gait Visual

Cardinal manifestations 1.Tremor A.Coarse, slow “pill rolling” seen in upper extremities B.More prominent at rest C.Usually occurs in one arm at first, then spreads to the contralateral arm. 2.Bradykinesia A.Generalized slowness of motion B.Difficulty initiating movement C.Facial masking D.Decrease swallowing 3.Rigidity A.Cogwheeling B.Muscle stiffness, fatigue and weakness C.Resistance observed during passive motion a limb. 4.Postural instability A.Alterations in balance and equilibrium B.Contributes to falls & injuries 1.Tremor A.Coarse, slow “pill rolling” seen in upper extremities B.More prominent at rest C.Usually occurs in one arm at first, then spreads to the contralateral arm. 2.Bradykinesia A.Generalized slowness of motion B.Difficulty initiating movement C.Facial masking D.Decrease swallowing 3.Rigidity A.Cogwheeling B.Muscle stiffness, fatigue and weakness C.Resistance observed during passive motion a limb. 4.Postural instability A.Alterations in balance and equilibrium B.Contributes to falls & injuries

Craniofacial Hypomimia (masked facial expression) Decreased eye blinking Speech disturbances (hypokinetic dysarthria, hypophonia) Dysphagia Sialorrhea

Musculoskeletal 1.Micrographia 2.Dystonia 3.Myoclonus 4.Stooped posture (camptocormia) 5.Kyphosis 6. Scoliosis 7.Difficulty turning in bed 1.Micrographia 2.Dystonia 3.Myoclonus 4.Stooped posture (camptocormia) 5.Kyphosis 6. Scoliosis 7.Difficulty turning in bed

NONMOTOR SYMPTOMS Cognitive dysfunction and dementia Psychosis and hallucinations Mood disorders including depression, anxiety Sleep disturbances Fatigue Olfactory dysfunction (Smell sensory) Pain and sensory disturbances Dermatologic findings (seborrhea) Cognitive dysfunction and dementia Psychosis and hallucinations Mood disorders including depression, anxiety Sleep disturbances Fatigue Olfactory dysfunction (Smell sensory) Pain and sensory disturbances Dermatologic findings (seborrhea)

STAGES Hoehn and Yahr Scale SymptomsStages Unilateral involvement only, minimal or no fx impairmentStage I: Bilateral involvement, without impairment of balanceStage II: Evidence of postural imbalance, some reduction in activities, capable of leading independent Stage III: Severely disabled, unable to walk and stand unassisted, markedly incapacitated Stage IV: Restricted to bed or wheelchair unless aidedStage V

Treatment The pharmacologic treatment of PD can be further divided into – Neuroprotective – Symptomatic therapy The pharmacologic treatment of PD can be further divided into – Neuroprotective – Symptomatic therapy

SYMPTOMATIC THERAPY The major drugs available for symptomatic therapy include 1.Levodopa 2.MAO B inhibitors 3.Dopamine agonists 4.COMT inhibitors 5.Anticholinergic agents 6.Amantadine The major drugs available for symptomatic therapy include 1.Levodopa 2.MAO B inhibitors 3.Dopamine agonists 4.COMT inhibitors 5.Anticholinergic agents 6.Amantadine

LEVODOPA Levodopa (L-dopa) is well established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD It is particularly effective for the management of akinetic symptoms and should be introduced when these become disabling and are uncontrolled by other antiparkinsonian drugs Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so Levodopa (L-dopa) is well established as the most effective drug for the symptomatic treatment of idiopathic or Lewy body PD It is particularly effective for the management of akinetic symptoms and should be introduced when these become disabling and are uncontrolled by other antiparkinsonian drugs Tremor and rigidity can also respond to levodopa therapy, but postural instability is less likely to do so

LEVODOPA Mechanism Levodopa is converted to dopamine by dopa decarboxylase for use in striatal neurons Role in Therapy useful for motor symptom in Stage II-V disease Mechanism Levodopa is converted to dopamine by dopa decarboxylase for use in striatal neurons Role in Therapy useful for motor symptom in Stage II-V disease

LEVODOPA Formulations Levodopa is combined with a peripheral decarboxylase inhibitor carbidopa Advantage of combination: 1.Carbidopa blocks its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension 2.Carbidopa increases amount of levodopa which can penetrate the CNS. Need app mg/day of carbidopa to effectively block the peripheral conversion of levodopa The combination drug carbidopa/levodopa (immediate-release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg Controlled release formulation has 70% bioavailability of immediate release: 25/100mg, 50/200 mg. Levodopa is combined with a peripheral decarboxylase inhibitor carbidopa Advantage of combination: 1.Carbidopa blocks its conversion to dopamine in the systemic circulation and liver (before it crosses the blood-brain barrier) in order to prevent nausea, vomiting, and orthostatic hypotension 2.Carbidopa increases amount of levodopa which can penetrate the CNS. Need app mg/day of carbidopa to effectively block the peripheral conversion of levodopa The combination drug carbidopa/levodopa (immediate-release Sinemet) is available in tablets of 10/100, 25/100, and 25/250 mg Controlled release formulation has 70% bioavailability of immediate release: 25/100mg, 50/200 mg.

Dosing Initial: 25/100 mg two to three times daily with meals Avoid high fat meals which can interfere with abs. of levodopa in GI tract Total daily dose of carbidopa/levodopa can be titrated carefully upward over several weeks to a full tablet of 25/100 mg three times daily as tolerated If pt fails to respond to >1000 mg levodopa reconsider PD diagnosis Initial: 25/100 mg two to three times daily with meals Avoid high fat meals which can interfere with abs. of levodopa in GI tract Total daily dose of carbidopa/levodopa can be titrated carefully upward over several weeks to a full tablet of 25/100 mg three times daily as tolerated If pt fails to respond to >1000 mg levodopa reconsider PD diagnosis

Adverse effects Nausea, somnolence, dizziness, and headache are among the more common side effects that may accompany treatment with levodopa, but they are not likely to be serious in most patients More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, and psychosis Levodopa may also induce a mild to moderate elevation in serum homocysteine levels which in turn may be associated with an increased risk of hip fractures in elderly patients Nausea, somnolence, dizziness, and headache are among the more common side effects that may accompany treatment with levodopa, but they are not likely to be serious in most patients More serious adverse reactions to levodopa (mainly in older patients) may include confusion, hallucinations, delusions, agitation, and psychosis Levodopa may also induce a mild to moderate elevation in serum homocysteine levels which in turn may be associated with an increased risk of hip fractures in elderly patients

Adverse effects Motor fluctuations – Occur in at least 50 percent of patients after 5 to 10 years of treatment – Called (the wearing-off phenomenon): involuntary movements known as dyskinesia, abnormal postures of the extremities and trunk known as dystonia – Occur in at least 50 percent of patients after 5 to 10 years of treatment – Called (the wearing-off phenomenon): involuntary movements known as dyskinesia, abnormal postures of the extremities and trunk known as dystonia

MAO B INHIBITORS Selegiline Mechanism – Selegiline irreversibly and selectively inhibits monoamine oxidase (MAO) type B inhibitor the oxidative metabolism of dopamine Role in Therapy – Is modestly effective as symptomatic treatment for PD and may have neuroprotective properties (preclinical disease) – Adjunctive treatment in Stage I-IV. May use lower doses of levodopa and dopamine agonist. Mechanism – Selegiline irreversibly and selectively inhibits monoamine oxidase (MAO) type B inhibitor the oxidative metabolism of dopamine Role in Therapy – Is modestly effective as symptomatic treatment for PD and may have neuroprotective properties (preclinical disease) – Adjunctive treatment in Stage I-IV. May use lower doses of levodopa and dopamine agonist.

Selegiline Dosing 10 mg per day ; 5 mg qam and 5mg at lunch – Metabolized by liver to …. (to avoid insomnia) Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis in the absence of dietary restrictions 10 mg per day ; 5 mg qam and 5mg at lunch – Metabolized by liver to …. (to avoid insomnia) Doses higher than 10 mg daily are of no additional benefit and may result in nonselective MAO inhibition, thereby placing the patient at risk of hypertensive crisis in the absence of dietary restrictions

Selegiline Adverse effects Nausea and headache Amphetamine metabolites of selegiline can cause insomnia Augment levodopa toxicities Potential food-drug interaction (tyramine) Potential drug-drug interaction (SSRI) Nausea and headache Amphetamine metabolites of selegiline can cause insomnia Augment levodopa toxicities Potential food-drug interaction (tyramine) Potential drug-drug interaction (SSRI)

DOPAMINE AGONISTS mechanisms 1.Bromocriptine 1.Ropinirole 2.Pramipexole 1.Bromocriptine 1.Ropinirole 2.Pramipexole D1&D2 receptors Agonist D2 receptor Agonist

DOPAMINE AGONISTS Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD section on Dopamine agonists Advantages 1.Unlike levodopa-carbidopa, these drugs are direct agonists that do not require metabolic conversion do not compete with amino acids for transport across the gut or into the brain do not depend upon neuronal uptake and release 2.Longer duration of action Injectable apomorphine has been approved by the United States FDA for treatment of motor fluctuations in PD section on Dopamine agonists Advantages 1.Unlike levodopa-carbidopa, these drugs are direct agonists that do not require metabolic conversion do not compete with amino acids for transport across the gut or into the brain do not depend upon neuronal uptake and release 2.Longer duration of action

DOPAMINE AGONISTS Role of Therapy Monotherapy in early disease (younger pt) to delay the time to start levodopa. Less effective monotherapy for sever stages >stage 3 Monotherapy in early disease (younger pt) to delay the time to start levodopa. Less effective monotherapy for sever stages >stage 3

DOPAMINE AGONISTS Dosing Bromocriptine – Is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day. – Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used. Pramipexole – Is usually started at mg three times a day. – The dose should be increased gradually by mg per dose every five to seven days. – Most patients can be managed on total daily doses of 1.5 to 4.5 mg. Ropinirole – Is usually started at 0.25 mg three times a day. – The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg. – After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. – Benefit most commonly occurs in the dosage range of 12 to 16 mg per day. Bromocriptine – Is usually started at 1.25 mg twice a day; the dose is increased at two to four week intervals by 2.5 mg a day. – Most patients can be managed on 20 to 40 mg daily in three to four divided doses, although total daily doses as high as 90 mg can be used. Pramipexole – Is usually started at mg three times a day. – The dose should be increased gradually by mg per dose every five to seven days. – Most patients can be managed on total daily doses of 1.5 to 4.5 mg. Ropinirole – Is usually started at 0.25 mg three times a day. – The dose should be increased gradually by 0.25 mg per dose each week for four weeks to a total daily dose of 3 mg. – After week four, the ropinirole dose may be increased weekly by 1.5 mg a day up to a maximum total daily dose of 24 mg. – Benefit most commonly occurs in the dosage range of 12 to 16 mg per day.

DOPAMINE AGONISTS Adverse effects Poorly tolerated by about 30% due to – Allergy – Palpitation – Sinus tachycardia – Agitation Edema (hands, feet, face) Plural effusion Poorly tolerated by about 30% due to – Allergy – Palpitation – Sinus tachycardia – Agitation Edema (hands, feet, face) Plural effusion

COMT INHIBITORS Mechanism – Inhibits the enzyme catechol-O-methyl transeferase that converts levodopa to 3-O- methyldopa and converts dopamine to 3- methooxytyramine Drugs – Tolcapone 100mg,200mg – Entacapone 200mg – Carbidopoa/levodopa/entacapone Mechanism – Inhibits the enzyme catechol-O-methyl transeferase that converts levodopa to 3-O- methyldopa and converts dopamine to 3- methooxytyramine Drugs – Tolcapone 100mg,200mg – Entacapone 200mg – Carbidopoa/levodopa/entacapone

COMT INHIBITORS Role in therapy: – They are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa. – These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods. Role in therapy: – They are ineffective when given alone, but they may prolong and potentiate the levodopa effect when given with a dose of levodopa. – These medications are mainly used to treat patients with motor fluctuations who are experiencing end-of-dose wearing "off" periods.

COMT INHIBITORS Dosing The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately; up to 600 mg/day The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day (1600mg/day) The starting dose of tolcapone is 100 mg three times daily; the clinical effect is evident immediately; up to 600 mg/day The dose of entacapone is one 200 mg tablet with each dose of levodopa, up to a maximum of eight doses per day (1600mg/day)

COMT INHIBITORS Adverse effects Tolcapone 1.The most common side effects of tolcapone are due to increased dopaminergic stimulation and include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone. 2.Diarrhea that is poorly responsive to antidiarrheal medications appears in approximately 5 percent of patients. 3.An orange discoloration of the urine is a common but benign adverse event. 4.Elevations in liver enzymes may rarely occur. Entacapone are similar to tolcapone ADR, although entacapone has thus far not been associated with hepatotoxicity Tolcapone 1.The most common side effects of tolcapone are due to increased dopaminergic stimulation and include dyskinesia, hallucinations, confusion, nausea, and orthostatic hypotension. The adverse effects are managed by lowering the dose of levodopa either before or after the addition of tolcapone. 2.Diarrhea that is poorly responsive to antidiarrheal medications appears in approximately 5 percent of patients. 3.An orange discoloration of the urine is a common but benign adverse event. 4.Elevations in liver enzymes may rarely occur. Entacapone are similar to tolcapone ADR, although entacapone has thus far not been associated with hepatotoxicity

ANTICHOLINERGICS Mechanism – Antagonize muscarinic cholinergic receptors in the striatum Role of therapy – Used to control tremor Drugs – Trihexyphenidyl – Benztropine Mechanism – Antagonize muscarinic cholinergic receptors in the striatum Role of therapy – Used to control tremor Drugs – Trihexyphenidyl – Benztropine

ANTICHOLINERGICS Dosing Trihexyphenidyl The starting dose of trihexyphenidyl is 0.5 to 1 mg twice daily, with a gradual increase to 2 mg three times daily. Benztropine Traditionally used in the management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2 mg twice daily. Trihexyphenidyl The starting dose of trihexyphenidyl is 0.5 to 1 mg twice daily, with a gradual increase to 2 mg three times daily. Benztropine Traditionally used in the management of antipsychotic drug-induced parkinsonism; the usual dose is 0.5 to 2 mg twice daily.

ANTICHOLINERGIC Adverse effects Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Caution is advised in patients with known prostatic hypertrophy or closed-angle glaucoma. Discontinuation of anticholinergic drugs should be performed gradually to avoid withdrawal symptoms that may manifest as an acute exacerbation of parkinsonism, even in those in whom the clinical response has not seemed significant. Peripheral antimuscarinic side effects include dry mouth, blurred vision, constipation, nausea, urinary retention, impaired sweating, and tachycardia. Caution is advised in patients with known prostatic hypertrophy or closed-angle glaucoma. Discontinuation of anticholinergic drugs should be performed gradually to avoid withdrawal symptoms that may manifest as an acute exacerbation of parkinsonism, even in those in whom the clinical response has not seemed significant.

AMANTADINE Mechanism – Blocks presynapatic dopamine reuptake; causes release of dopamine from storage sites – Synergistic effects with levodopa and dopamine agonists Role of therapy – Improves bradykinaseia, tremor, and rigidity, in pateints with Stages I-IV disease Mechanism – Blocks presynapatic dopamine reuptake; causes release of dopamine from storage sites – Synergistic effects with levodopa and dopamine agonists Role of therapy – Improves bradykinaseia, tremor, and rigidity, in pateints with Stages I-IV disease

AMANTADINE Dosing The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects. It is excreted unchanged in the urine and should be used with caution in the presence of renal failure. Adverse effects — Peripheral side effects include ankle edema, which are rarely severe enough to limit treatment. Confusion, hallucinations, and nightmares occur infrequently, but unpredictably, even after long periods of use without side effects. These effects are more likely when amantadine is used together with other antiparkinsonian drugs in older patients. The dose of amantadine in early PD is 200 to 300 mg daily; there is no evidence that larger doses are of additional benefit. The main advantage of this agent is a low incidence of side effects. It is excreted unchanged in the urine and should be used with caution in the presence of renal failure. Adverse effects — Peripheral side effects include ankle edema, which are rarely severe enough to limit treatment. Confusion, hallucinations, and nightmares occur infrequently, but unpredictably, even after long periods of use without side effects. These effects are more likely when amantadine is used together with other antiparkinsonian drugs in older patients.