Drugs for Parkinson’s Drugs for Parkinson’s diseasedisease

Pathogenesis of Parkinson’s Pathogenesis of Parkinson’s diseasedisease

Parkinson’s disease (PD) is a Parkinson’s disease (PD) is a progressive disorder of movement progressive disorder of movement that occurs mainly in the elderly. The that occurs mainly in the elderly. The chief symptoms are:chief symptoms are:

H ypokinesiaH ypokinesia

R igidityR igidity

T remorsT remors

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Parkinson’s DiseaseParkinson’s Disease

A degenerative and progressive disorderA degenerative and progressive disorderAssociated with neurological consequences of Associated with neurological consequences of decreased dopamine levels produced by the decreased dopamine levels produced by the basal ganglia (substantia nigra)basal ganglia (substantia nigra)Dopamine is a neurotransmitter found in the Dopamine is a neurotransmitter found in the neural synapses in the brainneural synapses in the brainNormally, neurones from the SN supply Normally, neurones from the SN supply dopamine to the corpus striatum (controls dopamine to the corpus striatum (controls unconscious muscle control)unconscious muscle control)Initiates movement, speech and self-expressionInitiates movement, speech and self-expression

Balance, posture, muscle tone and involuntary Balance, posture, muscle tone and involuntary movement depends on the roles of dopamine movement depends on the roles of dopamine (inhibitory) and acetylcholine (Ach: excitatory)(inhibitory) and acetylcholine (Ach: excitatory)

Basis to exploit by drugs:Basis to exploit by drugs: Restore dopamine functionRestore dopamine function Inhibit Ach within corpus striatumInhibit Ach within corpus striatum

Consequences of dopamine Consequences of dopamine reductionsreductions

TremorsTremors – hands and head develop involuntary – hands and head develop involuntary movements when at rest; pin-rolling sign (finger movements when at rest; pin-rolling sign (finger and thumb)and thumb)Muscle rigidityMuscle rigidity – arthritis-like stiffness, difficulty – arthritis-like stiffness, difficulty in bending or moving limbs; poker facein bending or moving limbs; poker faceBradykinesiaBradykinesia – problems chewing, swallowing – problems chewing, swallowing or speaking; difficulty in initiating movements or speaking; difficulty in initiating movements and controlling fine movements; walking and controlling fine movements; walking becomes difficult (shuffle feet)becomes difficult (shuffle feet)Postural instabilityPostural instability – humped over – humped over appearance, prone to fallsappearance, prone to falls

Clinical PresentationClinical Presentation

Altered body image Altered body image (depression)(depression)Poor balancePoor balanceBradykinesia (slow movement)Bradykinesia (slow movement)Bradyphrenia (slowness of Bradyphrenia (slowness of thought)thought)ConstipationConstipationDribbling/droolingDribbling/droolingDyskinesias (involuntary Dyskinesias (involuntary movements)movements)Dysphagia (difficulty Dysphagia (difficulty swallowingswallowingDystonia (pain spasms)Dystonia (pain spasms)

Excessive sweating (impaired Excessive sweating (impaired thermoregulation)thermoregulation)Festinating gaitFestinating gaitHallucinations (visual)Hallucinations (visual)Postural hypotensionPostural hypotensionRestless leg syndrome (leg Restless leg syndrome (leg aches, tingle, or burn)aches, tingle, or burn)RigidityRigiditySleep disturbanceSleep disturbanceSlurring/slowing of speechSlurring/slowing of speechTremorTremor

CausesCauses

number of factors:number of factors: Environmental – toxinsEnvironmental – toxins Free Radicals – there is a increase in post-Free Radicals – there is a increase in post-

mortem brain sectionsmortem brain sections Aging – age related decline in dopamine Aging – age related decline in dopamine

productionproduction Genetic – genes encode for Genetic – genes encode for

--αα-synuclein-synuclein

-Carboxy terminal hydroxylase of parkin & -Carboxy terminal hydroxylase of parkin & ubiquitinubiquitin

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Action of MPTPAction of MPTP

1-methyl 4-phenyl 1,2,3,6-1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP) causes tetrahydropyridine (MPTP) causes irreversible destruction of nigrostriatal irreversible destruction of nigrostriatal dopaminergic neurons in various species, dopaminergic neurons in various species, and produces a PD-like state in primates.and produces a PD-like state in primates.

MPTP MPP+MAO-B

MPP+ is taken up by the dopaminergic neurons, selective

in destroying nigrostriatal neurons. It inhibits

mitochondrial oxidation reactions, producing oxidative

stress.Selegiline

inhibit

Medication RationalMedication Rational

Replace depleted levels of dopamineReplace depleted levels of dopamine

Stimulate the nerve receptors enabling Stimulate the nerve receptors enabling neurotransmissionneurotransmission

Increase the effect of dopamine on nerve Increase the effect of dopamine on nerve receptors (agonist)receptors (agonist)

Counteract the imbalance of Ach and Counteract the imbalance of Ach and DopamineDopamine

The Drugs:The Drugs: Dopaminergic drugs (improving dopamine Dopaminergic drugs (improving dopamine

functioning)functioning)LevodopaLevodopa

Dopamine receptor agonists Dopamine receptor agonists

AmantadineAmantadine

Selective monoamine oxidase B inhibitorsSelective monoamine oxidase B inhibitors

Catechol-O-methyltransferase inhibitorsCatechol-O-methyltransferase inhibitors Antimuscarinic drugs (Ach inhibitors)Antimuscarinic drugs (Ach inhibitors)

Drugs Treatment of Parkinson’s Drugs Treatment of Parkinson’s DiseaseDisease

Dopamine precursor –Dopamine precursor –levodopalevodopa

Peripherally dopa decarboxylase inhibitor Peripherally dopa decarboxylase inhibitor ((carbidopacarbidopa))

COMT inhibitors ( COMT inhibitors ( entacapone, tolcaponeentacapone, tolcapone))

Drugs that mimic the action of dopamine Drugs that mimic the action of dopamine ( ( bromocriptinebromocriptine, , cabergoline, ropinirole, cabergoline, ropinirole, pramipexolepramipexole))

Drugs Treatment of Parkinson’s Drugs Treatment of Parkinson’s DiseaseDisease

MAO-B inhibitors (e.g. MAO-B inhibitors (e.g. selegilineselegiline))

Drugs that release dopamine (e.g. Drugs that release dopamine (e.g. amantadineamantadine))

Centrally acting antimuscarinic Centrally acting antimuscarinic drugs (e.g. drugs (e.g. trihexyphenidyl, trihexyphenidyl, procyclidine, orphenadrine, procyclidine, orphenadrine, benztropinebenztropine))

LevodopaLevodopa

Mechanism:Mechanism:(1) Because dopamine does not cross the (1) Because dopamine does not cross the

blood-brain barrier levodopa, the blood-brain barrier levodopa, the precursor of dopamine, is given instead.precursor of dopamine, is given instead.

(2) Levodopa is formed from L-tyrosine (2) Levodopa is formed from L-tyrosine and is an intermediate in the synthesis and is an intermediate in the synthesis of catecholamines.of catecholamines.

LevodopaLevodopa

Mechanism:Mechanism:(3) (3) Levodopa itself has minimal pharmacologic Levodopa itself has minimal pharmacologic

activity, in contrast to its decarboxylated activity, in contrast to its decarboxylated product, dopamine.product, dopamine.

(4) Levodopa is rapidly decarboxylated in the (4) Levodopa is rapidly decarboxylated in the gastrointestinal tract. Prior to the advent of gastrointestinal tract. Prior to the advent of decarboxylase inhibitors (carbidopa), large decarboxylase inhibitors (carbidopa), large oral doses of levodopa were required; thus, oral doses of levodopa were required; thus, toxicity from dopamine was a limiting factor. toxicity from dopamine was a limiting factor.

LevodopaLevodopa

PharmacokineticsPharmacokinetics::(1)(1) Levodopa is well absorbed from the small Levodopa is well absorbed from the small

bowel; however, 95% is rapidly bowel; however, 95% is rapidly decarboxylated in periphery.decarboxylated in periphery.

(2)(2) Peripheral Peripheral dopamine is metabolized dopamine is metabolized in the in the liver to dihydroxyphenylacetic acid liver to dihydroxyphenylacetic acid ((DOPACDOPAC) and homovanillic acid () and homovanillic acid (HVAHVA), ), which are then excreted in urine.which are then excreted in urine.

LevodopaLevodopa

Pharmacologic effects:Pharmacologic effects:

The effects on bradykinesia and rigidity The effects on bradykinesia and rigidity are more rapid and complete than the are more rapid and complete than the effects on tremor. Other motor defects in effects on tremor. Other motor defects in PD improve. The psychological well-PD improve. The psychological well-being of patient is also improved.being of patient is also improved.

LevodopaLevodopa

Pharmacologic effects:Pharmacologic effects:

Tolerance to both Tolerance to both beneficial and adverse beneficial and adverse effectseffects occurs with time. Levodopa is occurs with time. Levodopa is most effective in the first 2-5 years of most effective in the first 2-5 years of treatment.treatment.

wearing off effectwearing off effect

On-off phenomenonOn-off phenomenon

LevodopaLevodopaAdverse effect:Adverse effect:

Principal adverse effects include:Principal adverse effects include:

(1)(1) Anorexia, nausea, and vomiting upon Anorexia, nausea, and vomiting upon initial administration, which often limit initial administration, which often limit the initial dosage.the initial dosage.

(2)(2) Cardiovascular effects, including Cardiovascular effects, including tachycardia, arrhythmias, and tachycardia, arrhythmias, and orthostatic hypotensionorthostatic hypotension..

LevodopaLevodopaAdverse effect:Adverse effect:

(3) Mental disturbances, including vivid (3) Mental disturbances, including vivid dreams, delusions, and hallucination.dreams, delusions, and hallucination.

(4) Hyperkinesia(4) Hyperkinesia

(5) On-off phenomena(5) On-off phenomena

LevodopaLevodopaAdverse effect:Adverse effect:

Sudden discontinuation can result in Sudden discontinuation can result in fever, rigidity, and confusion. The drug fever, rigidity, and confusion. The drug should be withdrawn gradually over 4 should be withdrawn gradually over 4 days.days.

LevodopaLevodopaDrug interactions:Drug interactions:

Vit B6 reduces the beneficial effects of Vit B6 reduces the beneficial effects of Levodopa by enhancing its extracerebral Levodopa by enhancing its extracerebral metabolism.metabolism.

Phenothiazines, reserpine, and Phenothiazines, reserpine, and butyrophenones antagonize the effects of butyrophenones antagonize the effects of levodopa because they lead to a junctional levodopa because they lead to a junctional blockade of dopamine action.blockade of dopamine action.

CarbidopaCarbidopa

Carbidopa is an inhibitor of dopa Carbidopa is an inhibitor of dopa decarboxylase. Because it is unable to decarboxylase. Because it is unable to penetrate the blood-brain barrier, it acts to penetrate the blood-brain barrier, it acts to reduce the peripheral conversion of reduce the peripheral conversion of levodopa to dopamine. As a result, when levodopa to dopamine. As a result, when carbidopa and levodopa are given carbidopa and levodopa are given concomitantly.concomitantly.

CarbidopaCarbidopa

Virtue:Virtue:

a. It can decrease the dosage of levodopa.a. It can decrease the dosage of levodopa.

b. It can reduce toxic side effects of b. It can reduce toxic side effects of levodopa.levodopa.

c. A shorter latency period precedes the c. A shorter latency period precedes the occurrence of beneficial effects.occurrence of beneficial effects.

SelegilineSelegiline

A selective inhibitor of MAO-B, A selective inhibitor of MAO-B, which which predominates in DA-containing regions of predominates in DA-containing regions of the CNS and lacks unwanted peripheral the CNS and lacks unwanted peripheral effects of non-selective MAO inhibitors.effects of non-selective MAO inhibitors.

It enhances and prolongs the It enhances and prolongs the antiparkinsonism effect of levodopa.antiparkinsonism effect of levodopa.

It may reduce mild on-off or wearing-off It may reduce mild on-off or wearing-off phenomena.phenomena.

SelegilineSelegiline

Long-term trials showed that the Long-term trials showed that the combination of selegiline and levodopa combination of selegiline and levodopa was more effective than levodopa along in was more effective than levodopa along in relieving symptoms and prolonging life.relieving symptoms and prolonging life.

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CCOMT- inhibitors OMT- inhibitors (entacapone)(entacapone)

MoA: inhibits the breakdown of levodopaMoA: inhibits the breakdown of levodopa

Pharmacokinetics: variability of absorption, extensive Pharmacokinetics: variability of absorption, extensive first-pass metabolism, short half-lifefirst-pass metabolism, short half-life

Adverse effects: dyskinesias, hallucinationsAdverse effects: dyskinesias, hallucinations

AmantadineAmantadine

Therapeutic uses and mechanism of Therapeutic uses and mechanism of actionaction

Amantadine is an antiviral agent used in Amantadine is an antiviral agent used in the prophylaxis of influenza Athe prophylaxis of influenza A22 . .

It improve parkinsonian symptoms by It improve parkinsonian symptoms by stimulating the release of DA stimulating the release of DA from from dopaminergic nerve terminals in the dopaminergic nerve terminals in the nigrostriatum and nigrostriatum and delaying DA reuptakedelaying DA reuptake..

Anticholinergic agentsAnticholinergic agents

Mechanism:Mechanism:Since the deficiency of dopamine in the Since the deficiency of dopamine in the

striatum augments the excitatory cholinergic striatum augments the excitatory cholinergic system in the striatum, the blockade of this system in the striatum, the blockade of this system by anticholinergic agents helps to system by anticholinergic agents helps to alleviate the motor dysfunction.alleviate the motor dysfunction.

Improvement in the parkinsonian Improvement in the parkinsonian tremortremor is is more pronounced than improvement in more pronounced than improvement in bradykinesia and rigidity.bradykinesia and rigidity.

Therapeutic uses: Therapeutic uses: Although not as effectives as levodopa, it Although not as effectives as levodopa, it

may have an additive therapeutic effect at may have an additive therapeutic effect at any stage of the disease when taken any stage of the disease when taken concurrently.concurrently.

Adverse effects:Adverse effects:Mental confusion and hallucinations.Mental confusion and hallucinations.It can occur as can peripheral atropine-like It can occur as can peripheral atropine-like

toxicity (e.g. cycloplegia, urinary retention, toxicity (e.g. cycloplegia, urinary retention, constipation)constipation)

Huntington’s ChoreaHuntington’s Chorea

Inherited autosomal dominant disorderInherited autosomal dominant disorder

Error in huntingtin geneError in huntingtin gene

Synthesis of huntingtin protein (repeats of Synthesis of huntingtin protein (repeats of polyglutamine cause excitotoxicity and polyglutamine cause excitotoxicity and apoptosis in cortex and striatum)apoptosis in cortex and striatum)

Degeneration of GABAergic neurons in the Degeneration of GABAergic neurons in the striatumstriatum

Huntington’s Chorea

Huntington’s ChoreaHuntington’s Chorea

Dance like movements of limbsDance like movements of limbs

Rhythmic movements of tongue and faceRhythmic movements of tongue and face

DementiaDementia

Progressive brain degenerationProgressive brain degeneration

Huntington’s ChoreaHuntington’s Chorea

TxTx

ChlorpromazineChlorpromazine

HaloperidolHaloperidol

OlanzapineOlanzapine

Alzheimer’s diseaseAlzheimer’s disease

Progressive memory lossProgressive memory loss

Disordered cognitive functionsDisordered cognitive functions

Reduced verbal fluencyReduced verbal fluency

Bedridden as disease progressesBedridden as disease progresses

Complications of immobilityComplications of immobility

Alzheimer’s diseaseAlzheimer’s disease

Amyloid plaque Amyloid plaque (extracellular deposits of (extracellular deposits of ββ-amyloid protein)-amyloid protein)

Intraneuronal Intraneuronal neurofibrillary tangles neurofibrillary tangles (aggregates of highly phosphorylated (aggregates of highly phosphorylated neuronal protein)neuronal protein)

Loss of cholinergic neurons Loss of cholinergic neurons in brain in brain (originates from nucleus basalis in (originates from nucleus basalis in forebrain and project to frontal cortex and forebrain and project to frontal cortex and hippocampus)hippocampus)

Alzheimer’s disease TxAlzheimer’s disease Tx

AnticholinesterasesAnticholinesterases Tacrine (hepatotoxic)Tacrine (hepatotoxic) DonepezilDonepezil RivastigmineRivastigmine GalantamineGalantamine

NMDA antagonistNMDA antagonist MemantineMemantine

NootropicsNootropics PiracetamPiracetam

Anti-oxidantsAnti-oxidants Vit. A, C, Vit. A, C, Zinc, SeleniumZinc, Selenium

MiscellaneousMiscellaneous StatinsStatins IbuprofenIbuprofen

Multiple SclerosisMultiple SclerosisDemylenationDemylenation in brain, spinal cord, optic in brain, spinal cord, optic nervesnerves

autoimmuneautoimmune

Weakness, numbness, Weakness, numbness, spastic paraparesisspastic paraparesis, , diplopia, sphincter disturbancesdiplopia, sphincter disturbances

TxTx Interferon beta-1bInterferon beta-1b NatalizumabNatalizumab Baclofen, Diazepam (for spasticity)Baclofen, Diazepam (for spasticity)

Amyotropic Lateral sclerosisAmyotropic Lateral sclerosis

Neurodegenerative dis. of motor neuronsNeurodegenerative dis. of motor neurons

Muscle wasting and atrophyMuscle wasting and atrophy

Defective superoxide dismutase Defective superoxide dismutase (defective (defective scavenging of superoxide free radicals)scavenging of superoxide free radicals)

Defective glutamate uptake Defective glutamate uptake (excitotoxicity)(excitotoxicity)

Spontaneous twitching of motor unitsSpontaneous twitching of motor units

Difficulty in chewing & swallowingDifficulty in chewing & swallowing

Respiratory failure & death within 5 yrsRespiratory failure & death within 5 yrs

Tx – Tx – RiluzoleRiluzole (↓es glutamate release) (↓es glutamate release)

PsychostimulantsPsychostimulantsAmphetamineAmphetamine & & MethylphenidateMethylphenidate

(release NA & DA in brain) -(release NA & DA in brain) -ADHDADHD

ModafinilModafinil- -

inc inc alertnessalertness & keep awake & keep awake

Caffeine- Caffeine-

Migraine, allay fatigue, apnoea in premature Migraine, allay fatigue, apnoea in premature infantsinfants

MCQsMCQs

Q1. In parkinsonism, Carbidopa acts as:Q1. In parkinsonism, Carbidopa acts as:

A.A.Dopamine agonistDopamine agonist

B.B.Dopamine precursorDopamine precursor

C.C.Peripheral decarboxylase inhibitorPeripheral decarboxylase inhibitor

D.D.Dopamine reuptake blockerDopamine reuptake blocker

Ans- CAns- C

Q2. In parkinsonism, Entacapone acts as:Q2. In parkinsonism, Entacapone acts as:

A.A.Dopamine agonistDopamine agonist

B.B.Dopamine precursorDopamine precursor

C.C.COMT inhibitorCOMT inhibitor

D.D.Dopamine reuptake blockerDopamine reuptake blocker

Ans- CAns- C

Q 3.Which one of the following clinical Q 3.Which one of the following clinical features of parkinsonism is benefited more features of parkinsonism is benefited more by central anticholinergic drugs?by central anticholinergic drugs?

A.A.Hypokinesia Hypokinesia

B.B.RigidityRigidity

C.C.TremorsTremors

D.D.Festinating gaitFestinating gait

Ans CAns C

Q 4.Which one of the following clinical Q 4.Which one of the following clinical features of parkinsonism is resolved features of parkinsonism is resolved first by levodopa?first by levodopa?

A.A.Hypokinesia Hypokinesia

B.B.RigidityRigidity

C.C.TremorsTremors

D.D.Festinating gaitFestinating gait

Ans A and BAns A and B

Q5. Tolcapone is withdrawn due toQ5. Tolcapone is withdrawn due to

A.A.CadiotoxicityCadiotoxicity

B.B.NephrotoxicityNephrotoxicity

C.C.CarcinogenecityCarcinogenecity

D.D.HepatotoxicityHepatotoxicity

Ans DAns D

Thank youThank you

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