Parkinson'sDisease Drugs

8/13/2019 Parkinson'sDisease Drugs

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Dr Keli Med III lectures


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Outline

Overview

Diagnosis

Treatment

Physical Therapy

Drug Therapy

Surgery

New Research

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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 corpusstriatum

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.5


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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

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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 arepresent.

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TreatmentParkinsons

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 levodopatreatment.

Wearing-off and On/Off effect develops, othermedication in conjunction levodopa is commenced.

MAO-B and COMT (Catecohol o methyltransferase)inhibitors.8


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TreatmentPhysical

Therapy Regular exercise

Recommended throughout the life of disorder.

Helps maintain and improve mobility and strength.

Physical exercise aids in rigidity relief, musclestrength and flexibility, balance, etc.

Caution is advised to avoid sudden movements or

strenuous activitiesfall could result in serious

injury.

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Levodopa

Precursor of dopamine, penetrates theBBB

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 basalganglia

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 TherapyL-DOPA

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Drug TherapyL-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 increasedosage 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 TherapyL-DOPA

Side effects include

Psychiatric symptoms; linked to depression

Nausea and vomiting ( stimulation of emetic

center in the brain stem) in absence of carbidopain 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 knownas 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 oflevodopa in the brain

Rx mental dx clozapine BM depression

6.254mg at bed increament as requiredolanzapine, 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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TreatmentDrug 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

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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.

28http://www.youtube.com/watch?v=dTdW8q9hukw&feature=related
http://www.youtube.com/watch?v=dTdW8q9hukw&feature=relatedhttp://www.youtube.com/watch?v=dTdW8q9hukw&feature=related


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Bromocriptine

D2 agonist

Peaks 1-2 hrs oral adm, 7.5mg30mg

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 thenby 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 TherapyDOPA

agonistsAdverse 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 2007.32


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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 by15%.

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 therapyMAO-B

Inhibitors MAO-B is an enzyme that metabolizes

dopamine.

From the breakdown of dopamine,

hydrogen peroxide is produced, which theoxidative 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


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Dose, side effects MAO

Inhibitors

5mg with BF and 5mg at lunch to avoidinsomnia

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 neuroprotective38

C t h l


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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 intestinalmucosa and the BBB

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Catechol O-Methyl Transferase (COMT)

Inhibitors (Tolcapone, entacapone

less hepatotoxic)

Mainly used in combination with L-DOPA, itincreases the half-life of L-DOPA.

Delays wearing-off effect of L-DOPA ,

response fluctuations,and other motor

complications such as dyskinesia

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Tolcapone(Tasmar)

D th COMT


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Drug therapyCOMT

Inhibitors COMT catalyses methylation of L-DOPA.

Addition of COMT inhibitor along with L-

DOPA and carbidopa prolongs the half-life

of L-DOPA and increases the amount inthe CNS.

This increases on time for L-DOPA.

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COMT I AE Tasmarare 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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T t t D Th


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Amantadine Amantadine

Antiviral agent.

MOA

May pontetiate doperminergic

function by influencing synthesis,

release, or reuptake of dopermine

and release of dopermine formperipheral 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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A t l h li bl ki


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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 ppt47


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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 withtremors, but failed to relieve other symptoms.

Means of last resort due to high risk of

potential complications.

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S rgical proced res


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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 motorcomplications.

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 inproduction of neurodegenerative radicals.

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Documents

Parkinson'sDisease Drugs