Dr Keli Med III lectures

Outline
Overview Diagnosis Treatment

Physical Therapy Drug Therapy Surgery

New Research

Overview
Second most common human neurodegenerative disorder. Prevalence of 1 out 272 in U.S. Increases to 4 to 5% for ages 85 and over.

Degeneration of dopaminergic neurons in the substantia nigra.

Dopamine
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Phothophysiology Cont
Reduction of dopamine occurs in the basal ganglia Dopaminergic neurones inhibit the output of GABargic cells in the corpus striatum Treatment based on

Restoration of dopaminergic activity Balance of doprminergic and cholinergic

activity with antimuscarinic drugs

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Overview contd

Symptoms caused by insufficient dopamine. 3 main symptoms:

Tremors Rigidity Slowed motion (Bradykinesia) Postural instability

Other symptoms include:

Dementia, sleep disturbances, depression, etc.
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Overview contd
Common causes of chronic progressive parkinsonism. Exact causes still yet unknown.

Gene mutation

Toxins , unrecognised neurotoxin, oxidative

stress Trauma

Diagnosis
No definitive tests for PD. PET scans can aid to determine levels of dopamine. Difficult to diagnose, many symptoms shared with other disorders. Medical history and neurological tests are conducted to diagnose.

Usually, if two of the cardinal symptoms are

present.

Treatment Parkinsons Disease

No cure for PD. Treatment can be divided into two stages.

Early and Later stages

Early stage
Onset of symptoms, treated with physical therapy and

medications (Levodopa, dopamine agonists, etc)

Later stage
Usually after having received 5+ years of levodopa

treatment. Wearing-off and On/Off effect develops, other medication in conjunction levodopa is commenced. MAO-B and COMT (Catecohol o methyltransferase) inhibitors.

Treatment Physical Therapy

Regular exercise
Recommended throughout the life of disorder.
Helps maintain and improve mobility and strength. Physical exercise aids in rigidity relief, muscle

strength and flexibility, balance, etc. Caution is advised to avoid sudden movements or strenuous activities fall could result in serious injury.

Treatment Drug Therapy

Levodopa (L-DOPA)
Preferred medication to control major symptoms.
Usually administered at the early onset of disorder. Drug is well tolerated and side affects are limited.

Levodopa

Dopamine
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Levodopa

Precursor of dopamine, penetrates the BBB Its an isomer of dopa Dopa is precursor of dopamine and norepinephrine D2 receptors are located post synaptically in the striatal neurons and in the presynapsis of substatia nigra of the basal ganglia Dopaminergic drugs stimulate mostly D2 receptors
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Kinetics Levodopa
Absorption delayed by food certain amino acids Peak 1-2 hrs T1/2 1-3 hrs Main met is Homovallinic acid Only 1-3% enters the brain must be given in large amounts Given with a dopa decarboxylase inhibitor the plasma half life is longer

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Drug Therapy L-DOPA

L-DOPA is converted to Dopamine by enzyme DOPA decarboxylase (DDC).

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Drug Therapy L-DOPA

Used with Carbidopa, which blocks the early

conversion of L-DOPA into dopamine.

Carbidopa

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Drug Therapy L-DOPA

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Drug Therapy L-DOPA

L-DOPA can cross blood-brain barrier, when dopamine cannot. This led to the idea of using L-DOPA as treatment for PD. First used in the 1960s, with daily increase dosage program. L-DOPA used in combination with Carbidopa in 1967.

Increases potency of L-DOPA up to 4-fold.

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Drug therapy
Used early in treatment daily dose has to be reduced over time Causes selective denervation some patients become less responsive Effects diminsh 3-4yrs of therapy ?due to dissappearance of nigrostrial and strial nerve tissue Early use lowers mortality of Parkinsonism

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:Levodopa dose
Sinemet is a preparation containing Levodopa and carbidopa Sinemet 25mg/100mg one TID increase accordingly 30 min before meals Can be used with a dopa agonist Particularly relieves bradykinesia only 1/3 patients respond well

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Drug Therapy L-DOPA

Side effects include

Psychiatric symptoms; linked to depression
Nausea and vomiting ( stimulation of emetic

center in the brain stem) in absence of carbidopa in 80% case Rx antacids easy dosing, anti emetics phenothiazines should be avoided they reduce the antiperkinsonism effect

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Side effects
CVS Arrythmias incidence reduced in the presence of Carbidopa; Tarchycardias,ventricular extrasysytoles, rare AF due to peripheral catecholamines Hypotension, Hypertension in massive doses,in presence of MAO I

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Side effects

Prolonged use/ poor timing can cause wearing-off effect the latter also known as end of dose effect
Leads to other motor complications, such as

dyskinesia in 80% cases

Include chorea, ballismus, athetosis, dystonia, myoclonus, tics, tremor At other times fluctuations are unrelated to timing of doses on and off effect

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Side effects
Behaviour variety of mental effects depression, anxiety, agitation, insomnia, somnolense, delusions, hallucinations night mares,due to high concetrations of levodopa in the brain Rx mental dx clozapine BM depression 6.254mg at bed increament as required olanzapine, quietipine, risperidone no BM depression less effective

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Miscellenous side effects

Mydriasis proceeding to glaucoma Positve coombs test with evidence of hemolysis Hot flushes agraavation or ppt of gout, abnormalities of smell Discoloration of body fluids Priapism, urea serum transaminases, ALP, Bilirubin
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Drug holidays
Upto 3-21 days Alleviates neurologic side effects, lowers required doses, on and off phenomenon Holidays pose a risk of perkinsonism complications aspiration pneumonia, DVT,PE, depression of immobility Not recommended effects are short lived

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Drug interactions
Pyridoxine B6 enhances extracerebral met of levodopa Rx include a peripheral decaboxylase inhibitor Not be taken with MOA I even within 2/52 of their discontinuation to avoid a hypertensive crisis C/I not to be given to psychotic patients, open angle glaucoma, GI bleeds, Melanoma

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Treatment Drug Therapy

Dopamine Agonists
Acts directly on the dopamine receptors.
Initially was used with L-DOPA. Today, sometimes prescribed before L-

DOPA, to delay wearing-off effect and other motor complications brought on by prolonged use of L-DOPA.

Pramipexole

Dopamine
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Dopamine agonists
Do not require enzymatic conversion No toxic met Do not compete for transport into blood and BBB May have less AE Lower incidence of drug fluctuations and dyskinesia of long term use Allows lower dose of Sinemet Alternatives to sinemet

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Drug Therapy - DOPA agonists

Triggers dopamine receptors in place of depleted dopamine neurotransmitters.

http://www.youtube.com/watch?v=dTdW8q9hukw&feature=related

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Bromocriptine D2 agonist Peaks 1-2 hrs oral adm, 7.5mg 30mg built over 2-3 months by 2.5 mg every 2 weeks Pergoline Egort derivative Stimulates D1D2 receptors Effective than Bromo Dose 3mg Od start at 0,05mg then increase weekly
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Pramipexole,
Pramipexole D3 receptor agonist Effective as monotheapy, permits reduction of levodopa, smoothens fluctutations May reduce mood disorders Dose 0.125mg TID, double weekly then by 0.75mg upto 0.5mg to 1.5mg TID caution in renal dx

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Ropinirole
A nonegoline drivative Pure D2 agonist Effective as monothearapy Dose 0,25mg TID then increase weekly at 0.75mg tiil week 4 then by 1,5mg may have interactions with drugs met by CYP1A2

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Drug Therapy DOPA agonists

Adverse side effects

GI N, Anorexia,V,C,bleeding form PU

esophegeal reflux Mental disturbances dizziness, hallucinations, confusion, dikinesia CVS hypotension, painless digital vasospams, arrrythmias, edema Sleep attacks Permax (pergolide) pulled after direct link to fibrosis of cardiac valves that can lead to death. Unavailable in U.S. since 2007.
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Other side effects dopamine agonists

Headache, increased arousal, pulmonary infiltrates, pleural and retroperitoneal fibrosis, athralgia, pain in the extremities

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Monoamine Oxidase B (MAOB) Inhibitors

Delays or reduces breakdown of dopamine by

MAO-B selective inhibitor Used as monotherapy or in conjunction with L-DOPA, it can reduce the dosage of L-DOPA by 15%.

Selegeline

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Mono amine oxidase enzymes

MAO A breaks down serotonin and norepinephrine MAO B metabolizes DOPAMINE

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Drug therapy MAO-B Inhibitors

MAO-B is an enzyme that metabolizes dopamine. From the breakdown of dopamine, hydrogen peroxide is produced, which the oxidative stress can damage dopaminergic neurons in the substantia nigra. (Possibly neuroprotective) MAO-B inhibitor delays or reduces the metabolism of dopamine.

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Dose, side effects MAO Inhibitors

5mg with BF and 5mg at lunch to avoid insomnia C/I not with Meperidine, TA, SRIs Side effects of L-DOPA may be enhanced by selegeline. Nausea and dizziness Rasagiline A MAO I More potent than selegiline May be neuroprotective

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Catechol o Methyltransferase
Involved with Levodopa met It increases levels of 3- O methyl dopa which is associated with poor therapeutic response to Levodopa 3-OMD competes with levodopa for active carrier mechanism that controls its transport across the intestinal mucosa and the BBB

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Treatment Drug Therapy

Catechol O-Methyl Transferase (COMT) Inhibitors (Tolcapone, entacapone less hepatotoxic)

Mainly used in combination with L-DOPA, it

increases the half-life of L-DOPA. Delays wearing-off effect of L-DOPA , response fluctuations,and other motor complications such as dyskinesia
Tolcapone(Tasmar )

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Drug therapy COMT Inhibitors

COMT catalyses methylation of L-DOPA. Addition of COMT inhibitor along with LDOPA and carbidopa prolongs the half-life of L-DOPA and increases the amount in the CNS.

This increases on time for L-DOPA.

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Tolcapone Entacapone
Rapid absorption Tolcapone has central and peripheral effects, Entacapone peripheral T1/2 2hrs Tolcapone more potent prolonged action dose 100mg TID Entacapone 200mg with each dose of Levodopa

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COMT I AE

Tasmar are hepatotoxic. N,Diarrhea and sleep disturbances Relate to increased levodopa exposure dyskinesia confusion rx lower the dose by 30% after 48 hrs Abdominal pain,orthostatic hypotension, sleep disturbances, orange discoloration of urine Tolcapone associated with liver enzymes requires monitoring and consent before administration
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Treatment Drug Therapy Amantadine

Amantadine
Antiviral agent.

MOA May pontetiate doperminergic function by influencing synthesis, release, or reuptake of dopermine and release of dopermine form peripheral stores

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Amatadine Kinetics Use

Peaks at 1-4hrs on oral adm T1/2 2-4 hrs Use

Known to aid in reducing dyskinesia., rigidity,tremor Effects are shortlived less potent than Levodopa Dose 100mg BID or TID

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Amantadine AE
Restlessness, depression, irritability, insomnia, agitation,excitement, hallucination confusion Over dose acute psychosis Sometimes Livedo retiularis Edema which responds to diuretics Headache, HF,hypotension,Anorexia, N,constipation, dry mouth Not be given in HF, seizures

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Acetylcholine blocking drugs Anticholinergics

Improve tremors and stiffness no effects on

bradykinesia Includes benztropine, biperiden, orphenadrine, procyclidine, trihexyphenidyl Cause drowsiness, mental slowness ,constipation, restlessneslltion,dry mouth, N,V, poor vision, arrythmias, Withdrawal should be slow C/I not given in prostatic hyperplasia, obstructive GI disease, angle closure glaucoma, with TA , adverse effects are ppt
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Livedo reticularis

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Treatment - Surgery
Before commerciality of levodopa, surgical treatment (Thalamotomy or pallidotomy) were preferred. Early surgeries were successful with tremors, but failed to relieve other symptoms. Means of last resort due to high risk of potential complications.

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Surgical procedures Perkinsonism

Recent advances in neurosurgical procedures allow for better treatment. Include stimulation of the thalamus relieves tremor Stimulation of the subthalamic nuclei, globus pallidus internus C/I in atypical Perkinsonism

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Surgery

Deep Brain Stimulation

Brain pacemaker, sends electrical impulses to

brain to stimulate the subthalamic nucleus. Improves motor functions and reduce motor complications. Complications include: brain hemorrhage, seizures, death.

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New Researches

Nicotine
Intake of nicotine has shown to slow the

degeneration of neurons. Acts similar to levodopa.

Melatonin
Serotonin derivative that helps insomnia. Also shown to cause a reduction in

production of neurodegenerative radicals.

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Homework Problems
Which medicinal treatment is generally started for younger patients with mild symptoms in early-stage treatment? 2. Levodopa is used with which drug and why? 3. Describe wearing-off and on-off effect.
1.

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References
Davie, C. A. A review of Parkinsons disease, British Medical Bulletin, 86 (2008): 109-127 Munchau, A., Bhatia, K P. Pharmacological treatment of Parkinsons disease, Postgrad Med J, 76 (2000): 602-610 Rao, Shobha A., Hoffman, Laura A., Shakil, Amer. Parkinsons Disease: Diagnosis and Treatment., American Family Physician, 74 (2006): 2046-2054 Singh, N., Pillay, V., Choonara, Y. E. Advances in the treatment of Parkinsons disease, Progress in Neurobiology, 81 (2007): 29-44

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