PARKINSON’S PARKINSON’S DISEASEDISEASE

ETIOLOGYETIOLOGY

1)1) Idiopathic Idiopathic

2)2) Exposure to Exposure to ::neurotoxin neurotoxin

Oxidative stress Oxidative stress Drugs Drugs

3)Genetic factors.3)Genetic factors.

����Pathology &Principal Pathology &Principal treatmenttreatment

1)1) The normally high The normally high concentration of dopamine in the concentration of dopamine in the basal ganglia is reduced and attempts basal ganglia is reduced and attempts to restore dopaminergic activity with to restore dopaminergic activity with levodopa and dopamine agonist.levodopa and dopamine agonist.

2)2) Restore the normal balance Restore the normal balance of cholinergic and dopaminergic of cholinergic and dopaminergic influences on the basal ganglia with influences on the basal ganglia with antimuscarinic drugs .antimuscarinic drugs .

DRUGS AFFECTING DRUGS AFFECTING DOPAMINERGIC DOPAMINERGIC

NEUROTRANSMISSIONNEUROTRANSMISSION

DrugsDrugs

LEVODOPALEVODOPA

Metabolic precursor of dopamineMetabolic precursor of dopamine PharmacokineticsPharmacokinetics Half –life= 1-2 hrsHalf –life= 1-2 hrs Rapidly absorbed from small intestine.Rapidly absorbed from small intestine. Food delay absorption.Food delay absorption. Certain amino acids from ingested food Certain amino acids from ingested food

compete for absorption & drug transport compete for absorption & drug transport from blood to brain.from blood to brain.

PharmacokineticsPharmacokinetics

Main metabolic products: HVA & DOPACMain metabolic products: HVA & DOPACOnly 1-3% of given dose enters the brainOnly 1-3% of given dose enters the brain. .

Given with dopa decarboxylase inhibitorGiven with dopa decarboxylase inhibitor ( (CARBIDOPACARBIDOPA .) .)Combination Called Combination Called SinemeSinemett

11 - -Reduce peripheral biotransformation of Reduce peripheral biotransformation of levodopalevodopa

22 - -Increase plasma level & half-life of levodopaIncrease plasma level & half-life of levodopa33 - -Reduce daily requirement of levodopa ) 75%(Reduce daily requirement of levodopa ) 75%(

Excreted by kidneysExcreted by kidneys

Clinical Benefits of Clinical Benefits of levodopalevodopa

Can ameliorate all of the clinical Can ameliorate all of the clinical symptoms of parkinsonismsymptoms of parkinsonism

It is mainly effective in relieving It is mainly effective in relieving bradykinesiabradykinesia

Other drugs can be added to Other drugs can be added to levodopalevodopa

Clinical considerationsClinical considerations “ “ON” and “OFF” PhenomenonON” and “OFF” Phenomenon

Tolerance to therapeutic responseTolerance to therapeutic response

It does not arrest disease progressIt does not arrest disease progress

Only effective in the first few yearsOnly effective in the first few years

Taking drug in divided doses to reduce gastric Taking drug in divided doses to reduce gastric symptoms.symptoms.

Sudden withdrawal causes severe akinetic state.Sudden withdrawal causes severe akinetic state.

Clinical ConsiderationClinical Consideration

Postural hypotension is common , so Postural hypotension is common , so patient should take care when he stand patient should take care when he stand upup..

Dyskinesias occur up to 80% Dyskinesias occur up to 80% ) uncontrollable muscle jerks() uncontrollable muscle jerks(

Adv. Effects of LevodopaAdv. Effects of Levodopa

1.1. G.I.T : Nausea, vomiting, and G.I.T : Nausea, vomiting, and anorexiaanorexia

2. Cardiovascular:2. Cardiovascular:

- Tachycardia- Tachycardia

- Ventricular extrasystoles- Ventricular extrasystoles

- Atrial fibrillation (rare)- Atrial fibrillation (rare)

- Postural hypotension- Postural hypotension

- Hypertension- Hypertension

3. Dyskinesias ( with chronic 3. Dyskinesias ( with chronic treatment)treatment)

Side effects con’dSide effects con’d

4- Behavioral effects are more 4- Behavioral effects are more common in patients taking common in patients taking levodopa in combination with levodopa in combination with carbidopacarbidopa

- Depression- Depression- Anxiety- Anxiety- Agitation- Agitation- Confusion- Confusion- Hallucinations- Hallucinations

Adverse Effects ) cont.(Adverse Effects ) cont.(

55 - -Fluctuations in responseFluctuations in response66 - -MiscellaneousMiscellaneous

Mydriasis ) an attack of acute glaucoma(Mydriasis ) an attack of acute glaucoma(Hemolysis ) +v Coombs test (Hemolysis ) +v Coombs test (

GoutGoutAbnormal of smell or tasteAbnormal of smell or taste

Brownish discoloration of saliva, urine orBrownish discoloration of saliva, urine or vaginal secretionsvaginal secretionsPriapismPriapism

Levodopa- Drug Levodopa- Drug InteractionsInteractions

1.1. Pyridoxine- Enhances Pyridoxine- Enhances peripheral metabolism of peripheral metabolism of levodopalevodopa

2.2. Non selective MOAI –Non selective MOAI –Hypertensive crisesHypertensive crises

ContraindicationsContraindications

Psychotic patients Psychotic patients GlaucomaGlaucoma Cardiac patientsCardiac patients Peptic ulcerPeptic ulcer In patients with history of melanoma or In patients with history of melanoma or

undiagnosed skin lesions. undiagnosed skin lesions.

Advantages for the use of Advantages for the use of dopamine agonist in parkinsonismdopamine agonist in parkinsonism

11--They do not require metabolic They do not require metabolic conversion to an active productconversion to an active product..

22 - -Circulating plasma amino acids do not Circulating plasma amino acids do not compete with dopa agonist for absorption compete with dopa agonist for absorption or transportationor transportation..

33--They have long plasma half-life as They have long plasma half-life as compared to levodopacompared to levodopa

44 - -They do not undergo oxidative They do not undergo oxidative metabolism & no generation of free metabolism & no generation of free radicals & the associated oxidative stressradicals & the associated oxidative stress..

BROMOCRIPTINEBROMOCRIPTINE

A synthetic ergot derivativeA synthetic ergot derivative directly stimulate directly stimulate D D22 receptors receptors Used in hyperprolactinemiaUsed in hyperprolactinemia

Best for patientsBest for patients Who show akinesiaWho show akinesia With “ON” and “OFF” phenomenonWith “ON” and “OFF” phenomenon Who are refractory to levodopaWho are refractory to levodopa

Can be combined withCan be combined with Levodopa Levodopa AmantadineAmantadine AnticholinergicsAnticholinergics

Pharmacokinetics of Pharmacokinetics of BromocriptineBromocriptine

Given orallyGiven orally The dose must be built up slowlyThe dose must be built up slowly Plasma ½ life =12-16 hrsPlasma ½ life =12-16 hrs Excreted in bile & fecesExcreted in bile & feces

Clinical ConsiderationsClinical Considerations - Produces less dyskinesia than levodopa- Produces less dyskinesia than levodopa

- It has more psychiatric adverse effects- It has more psychiatric adverse effects

--

Adverse effects of Adverse effects of BromocriptineBromocriptine

G.I.T:G.I.T: nausea, vomiting and anorexia, nausea, vomiting and anorexia,G.I .T bleedingG.I .T bleeding

Cardiovascular:Cardiovascular:- Postural hypotension- Postural hypotension- Cardiac arrhythmias- Cardiac arrhythmias- Painless digital vasospasm- Painless digital vasospasm

CNS:CNS: Dyskinesia, Dyskinesia, Confusion,hallucination Confusion,hallucination and psychiatric disturbancesand psychiatric disturbances

Headache .Headache . MiscelleniousMiscellenious :Nasal congestion, :Nasal congestion,

erythromelalgiaerythromelalgia Rarely pulmonary fibrosis.Rarely pulmonary fibrosis.

Contraindications to Contraindications to BromocriptineBromocriptine

History of psychiatric diseaseHistory of psychiatric disease

Myocardial infarctionMyocardial infarction

History of peptic ulcerHistory of peptic ulcer Peripheral vascular diseasePeripheral vascular disease

PERGOLIDEPERGOLIDE

Stimulates both D1 & D2 receptors.Stimulates both D1 & D2 receptors.

More potent than bromocriptineMore potent than bromocriptine

Dose must be built up slowly Dose must be built up slowly

Has the same side effects &Has the same side effects & contraindications of bromocriptinecontraindications of bromocriptine

NON ERGOT DOPAMINE AGONISTSNON ERGOT DOPAMINE AGONISTS

1) 1) PRAMIPEXOLEPRAMIPEXOLE

Widely used nowWidely used now

Ha a high affinity for the Ha a high affinity for the D3D3 receptors. receptors.

Is effective as monotherapy in mild case of Is effective as monotherapy in mild case of Parkinson’s diseaseParkinson’s disease

In advanced cases is given with levodopa In advanced cases is given with levodopa ) reducing the dose & fluctuation response ) reducing the dose & fluctuation response of levodopa(of levodopa(..

Has a neuroprotective effect ) antioxident Has a neuroprotective effect ) antioxident activity(activity(..

Rapidly absorbed & excreted mostly Rapidly absorbed & excreted mostly unchanged by the kidneysunchanged by the kidneys..

Renal insufficiency may necessitate dosage Renal insufficiency may necessitate dosage adjustmentadjustment..

2. Ropinirole:2. Ropinirole:

D2D2 receptor agonist receptor agonist

Effective as monotherapy in patients Effective as monotherapy in patients with mild diseasewith mild disease

Can be combined with levodopa to Can be combined with levodopa to smooth smooth its response and prevent its response and prevent fluctuations fluctuations in advanced diseasesin advanced diseases

It is metabolized by CYP1A2 hepatic It is metabolized by CYP1A2 hepatic enzymesenzymes

Adverse Effects of Adverse Effects of Pramipexole and RopinirolePramipexole and Ropinirole

Anorexia ,nAnorexia ,nausea ,vomiting and constipationausea ,vomiting and constipation

Excessive day time somnolence has been reported Excessive day time somnolence has been reported ( uncontrollable tendency to fall asleep that can ( uncontrollable tendency to fall asleep that can result in car accidentresult in car accident

Postural hypotensionPostural hypotension

Cardiac arrhythmiasCardiac arrhythmias

Peripheral edemaPeripheral edema

DyskinesiasDyskinesias

Mental DisturbanceMental DisturbanceAre more common & severe than with Are more common & severe than with

levodopalevodopa

AMANTADINEAMANTADINE Mode of action:Mode of action:1.1. Releases DA from CNS neuronsReleases DA from CNS neurons2.2. Inhibits the re-uptake of DAInhibits the re-uptake of DA3.3. Anticholinergic effectAnticholinergic effect4.4. It affects the bradykinesia more than It affects the bradykinesia more than

tremors.tremors.

Pharmacokinetics:Pharmacokinetics: - t ½ = 2-4 hrs- t ½ = 2-4 hrs

- excreted unchanged in urine- excreted unchanged in urine - absorbed orally- absorbed orally

Clinical considerationsClinical considerations1.1. less potent than levodopaless potent than levodopa2.2. effective only for a few weekseffective only for a few weeks3.3. can not be used alonecan not be used alone

Adverse effects:Adverse effects:- Depression, Agitation, Confusion- Depression, Agitation, Confusion- Insomnia- Insomnia- Psychosis ,Convulsions, C.H.F, urinary - Psychosis ,Convulsions, C.H.F, urinary retention, Postural hypotensionretention, Postural hypotension

- Ankle edema- Ankle edema - Livedo reticularis- Livedo reticularis

Contraindications:Contraindications: - History of seizures - History of seizures - History of C.H.F - History of C.H.F

- With - With antimuscarinic drugsantimuscarinic drugs

DEPRENYL (SELEGILINE)DEPRENYL (SELEGILINE) Used in patients who do not respond Used in patients who do not respond

well well to carbidopa-levodopa to carbidopa-levodopa combinationcombination

Mechanism of actionMechanism of action A) it traps free A) it traps free radicals radicals and and

other toxins that other toxins that degrade the neurons.degrade the neurons. B) As a MAO- B inhibitor ,it may B) As a MAO- B inhibitor ,it may

retard retard the the break-down and break-down and destruction of destruction of dopamine by dopamine by MAO-MAO-B ,thus freeing B ,thus freeing more DA to interact more DA to interact with its with its receptors in substantia nigra.receptors in substantia nigra.

MAO-B INHIBITORSMAO-B INHIBITORS(SELEGILINE)(SELEGILINE)

Lacks the cheese reaction( dietary amines)Lacks the cheese reaction( dietary amines)

Reduces “ON” -“OFF” phenomena Reduces “ON” -“OFF” phenomena Enhances & prolongs the antiparkinsonism Enhances & prolongs the antiparkinsonism

effect of levodopa.effect of levodopa.

Reduces Neuronal damage by toxic free Reduces Neuronal damage by toxic free radicalsradicals

It retards DA metabolism allowing for It retards DA metabolism allowing for reduction of levodopa dosagereduction of levodopa dosage

Can be combined with other drugsCan be combined with other drugs1.1.

Adverse effects of Adverse effects of SelegilineSelegiline

Dependence upon chronic use (due to Dependence upon chronic use (due to methamphetamine methamphetamine metabolite )metabolite )

NauseaNausea

SedationSedation

Skin rashesSkin rashes

G.I.T irritationG.I.T irritation InsomniaInsomnia

ContraindicationsContraindications

Should not be taken withShould not be taken with::MeperidineMeperidine

Tricyclic antidepressantsTricyclic antidepressantsSerotonin reuptake inhibitorsSerotonin reuptake inhibitors

( (Risk of acute toxic interactionsRisk of acute toxic interactions))

ANTIMUSCARINIC AGENTSANTIMUSCARINIC AGENTS Benztropine Benztropine

Trihexyphenidyl Trihexyphenidyl ProcyclidineProcyclidine

Centrally acting antimuscarinic Centrally acting antimuscarinic drugs.drugs.

Block CNS muscarinic Block CNS muscarinic receptors receptors and reduce cholinergic and reduce cholinergic

transmission in Corpus Striatumtransmission in Corpus Striatum

CLINICAL CLINICAL CONSIDERATIONSCONSIDERATIONS

Starts with small doses- gradually Starts with small doses- gradually increase.increase.

Improve best tremor and rigidity Improve best tremor and rigidity with little effect on bradykinesia.with little effect on bradykinesia.

Can be combined with : levodopa Can be combined with : levodopa to Rx to Rx severe formssevere forms

**Withdrawal should be gradually to Withdrawal should be gradually to prevent acute exacerbation of prevent acute exacerbation of parkinsonismparkinsonism..

**Benztropine is used mainly in reserpine Benztropine is used mainly in reserpine induced parkinsonisminduced parkinsonism..

Side effects of antimuscarinic Side effects of antimuscarinic agentsagents

Peripheral: Peripheral: Dry mouth, Dry mouth, constipation, constipation, tachycardia, increased tachycardia, increased

intraocular intraocular pressure, blurred pressure, blurred vision, urinary retention,increased vision, urinary retention,increased skin temperatureskin temperature

CNS: CNS: Drowsiness, mental Drowsiness, mental slowness, delusions, mood changes, slowness, delusions, mood changes, confusion.confusion.

Side Effects ( cont.)Side Effects ( cont.)

Prolonged use of trihexyphenidyl produces Prolonged use of trihexyphenidyl produces involuntary movements & dependence involuntary movements & dependence

Contra-indications of Contra-indications of antimuscarinic agentsantimuscarinic agents

Prostatic HypertrophyProstatic Hypertrophy

Obstructive G.I.T disease( paralytic Obstructive G.I.T disease( paralytic ileus)ileus)

GlaucomaGlaucoma

Combination with TCA or certain Combination with TCA or certain antihistaminesantihistamines