Drugs Used to Treat Parkinson’s Disease

Parkinson’s Disease Parkinson’s Disease

• Parkinson’s diseaseParkinson’s disease – is a disorder caracterized by:

• Resting tremor• Skeletal muscle rigidity• Bradikinesia (poverty of

movement)

Parkinson’s Disease Parkinson’s Disease subtypessubtypes

• Idiopathic Parkinson’s diseaseIdiopathic Parkinson’s disease – Primary (unknown origin)

•ParkinsonismParkinsonism – Secondary (known origin) – drugs, stroke, trauma

•FamilialFamilial – (genetic origin)

Subclinical hypodopaminergic state Subclinical hypodopaminergic state - loss of 80-90% of DA neurons before symptoms present (roughly 20 years)DA neuronal loss not from Basal DA neuronal loss not from Basal Ganglia -Ganglia - loss of dopaminergic input to Striatum

Neuronal death observed in Substantia Nigra (Pars Compacta) and the Nigrastriatal bundle

A9 DA System

DA content decrease in extra pyramidal motor areas of basal ganglia

Caudate and putamen

Disrupted signaling between basal ganglia, cortex, and thalamus

Degeneration of neurons in substantia nigra pars compacta

Loss of dopaminergic input to striatum

CortexCortex

ThalamusThalamus

MidbrainMidbrain

Corpus striatum

Caudate nucleus

Putamen

Globus pallidus

Pathophysiology of PD Disease

Pathology of Parkinson’s Disease

Midbrain(substantia nigraMidbrain (substantia nigra)Midbrain (substantia nigra)

Substantia Nigra, Normal. Pigment Loss Is Seen In Parkinson's Disease

• 1 % Prevalence in Adult Population- Age 65 and Older

• As many as 10% aged 60 and older may have undiagnosed early stages of the disease

• Increased onset due to – Transitory Ischemic Attacks (TIA)– Brain Damage– Drug Abuse

• 1 ½ times more prevalent in women

Cardinal SymptomsCardinal Symptoms

BradykinesiaBradykinesia - Slowness and poverty of movementMuscle “Cogwheel” rigidity“Cogwheel” rigidity

Resting tremorResting tremor Abates during voluntary movement

Shuffling gaitShuffling gaitImpairment of postural balance

P o s tu re d is tu rb a n c e in P a rk in s o n ‘s d is e a s e

Secondary SymptomsSecondary Symptoms

DementiaVisuospatial deficits, impaired attention and executive functionAnxietySleep disturbancesSexual dysfunction Abnormal theromregulation

Sites of Action of Parkinson’s Disease Drugs

Drugs Treatment of Parkinson’s Disease

Drugs that replace dopamine (e.g. levodopa, usually used concomitantly with peripherally acting dopa decarboxylase inhibitor, e.g. Carbidopa, benserazide)

Drugs that mimic the action of dopamine (e.g. bromocriptine, pergolide, ropinirole) and others in development)

MAO-B inhibitors (e.g. selegiline)

Drugs that release dopamine (e.g. amantadine)

Acetylcholine antagonists (e.g. artane)COMT Inhibitors - Entacapone (Comtan®), Tolcapone (Tasmar®)

Pharmacotherapy of PDLevodopa preparations:

Carbidopa/levodopa

Sinemet®

Sinemet CR®

Parcopa™

Stalevo®

Dopamine agonistsApomorphine (Apokyn®)

Pramipexole (Mirapex®)

Ropinirole (Requip®)

Rotigitine (Neupro®)

Parlodel (Bromocriptine®)*

Pergolide (Permax®)*

Pharmacotherapy of PDNMDA Antagonists

Amantadine (Symmetryl®)

MAO-B Inhibitors

Selegeline (Eldepryl® or Deprenyl)

Zydis Selegeline (Zelapar®)

Rasagiline (Azilect®)

Carbidopa

Anticholinergic agents

Benztropine (Cogentin®)

Trihexyphenidyl (Artane®)

COMT Inhibitors

Entacapone (Comtan®)

Tolcapone (Tasmar®)

TherapyTherapy

LevodopaLevodopa (L-dopa)Remains the most effective drug for PDUsed since the 1960sMust be actively transported across gut and blood brain barrierRapidly decarboxylated to dopamine in the peripheryPulsatile receptor stimulation (due to short half-life) implicated in possible long term motor complications

TherapyTherapy

LevodopaLevodopa (L-dopa)

Rapid oral absorption – 95% converted to DA in plasmaDA doesn’t cross BBB from plasma into CNS

Precursor L-dopa does cross BBB via active transport system (about 5%)

Most effective current treatment

Problems Associated with L-Problems Associated with L-DopaDopa

Decrease high levels of DA in periphery that can cause nausea

by inhibiting dopa decarboxylase which converts dopa to DA

CarbidopaCarbidopa, Benserazide, Benserazide – Peripheral decarboxylase inhibitorCarbidopa/ levodopa combo reduces the amount necessary for therapeutic level of L-Dopa by 75%

Problems Associated with L-Problems Associated with L-DopaDopa

Even with carbidopa, much of L-Dopa converted by COMT (in GI tract and Liver) to inactive metabolic by-product

Recent addition of peripheral COMT inhibitors to standard treatment – Talcapone and Entacapone

Increase the half-life and prolong the effects of L-Dopa

– A few cases of serious liver toxicity attributed to Talcapone (1998) – Entacapone too new to say (2000)

L-dopa L-dopa – side effects– side effectsBecose the peripheraly dopamine generation

Nausea, vomitingVasodilation

Effects arising from excessive central dopamine generation

Diskinetic involuntary movements (face, neck)Akatisia (restlessness)Psychological disturbance – hallucinations, confusion

Limitations to L-dopa Limitations to L-dopa TherapyTherapy

Becomes less effective as time goes on “on-off”/ “wearing off” effect

between 1-5 yrs patients on L-dopa therapy gradually become less responsiveResults in hypermovement, then hypomovement, then no movement (akinesia)Taking doses more often, or taking large doses results in dyskinesias (uncontrolled movements) and may result in psychiatric complications.

On-off effect possibly related to DA neurons inability to synthesize and store DA

DA Receptor AgonistsDA Receptor Agonists

Bind to postsynaptic striatal neurons

Possible use for early and late stages

Four currently available

Bromocriptine (1978) and Pergolide (1989)

Derived from lysergic acid, structurally similar to DA

– Marginally effective with numerous side effects

– Affinity for D2 receptors (Inhibitory)

DA Receptor AgonistsDA Receptor AgonistsPramipexole, and Ropinirole (1997)

Affinity for D2, D3 receptors (Inhibitory)Indicated for use in early onsetIncreased safety and efficacy over older agonists (although risk of sleep attacks)Long half lives may partially explain reduction in on-off effect

Side effects: hallucinations, insomnia, nausea, somnolence and dizziness.

Long term use of DA agonists results in increased sensitivity of DA receptors (sensitization)

DA ReDA ReleasersleasersAMANTADINE

Stimulate release og dopamine stored in nerve terminalsReduce reuptake of released dopamine intzo the presinaptic neuron

Well absorbed from the gutVariable but long half-lifeExcreted unchanged by the kidney

DA ReDA ReleasersleasersAMANTADINE

Side effects:– Ankle oedema– Postural hypotension– Insomnia or hallucinations – high

dose– Livedo reticularis (skin

vasoconstriction caused by local catecolamine release)

SELECTIVE MONOAMINE OXIDASE B SELECTIVE MONOAMINE OXIDASE B INHIBITORSINHIBITORS

SSELEGILINEELEGILINESelectively inhibits MAO-B (preferential affinity for DA neurons) – responseble for the intraneural degradationProlongs the duration of action of levodopa and reduses the levodopa dosage requirement bu 1/3Used in newly diagnosed, younger patientsAppears to slow disease progression and delay need for L-Dopa

SELECTIVE MONOAMINE OXIDASE B SELECTIVE MONOAMINE OXIDASE B INHIBITORSINHIBITORS

SSELEGILINEELEGILINECompletely absorbed from the gutHas a short half-lifeMetabolized to several by-products, including amphetamine and methamphetamineIn combo with L-Dopa, may result in increased morbidity after 5 yearsSide effects:

Transient nauseaDiyyisness, lightheadednessAgitation, confusion, hallucination (amphetamine metabolites)

CATECOL – O – METHYL CATECOL – O – METHYL TRANSFERASE INHIBITORSTRANSFERASE INHIBITORS

ENTACAPONEENTACAPONECOMT – responsable for break down of between 10-30% of levodopaInhibition of COMT in conjunction with a dopamine decarboxylase inhibitors – doubles the half-life of levodopaEntacapone does not cross the blood-brain barrierRapidely absorbed from the gutMetabolized in liver Has a short half-lifeSide effects: nausea, diarrhoea, halluciantion, dyskinesia

Muscarinic Receptor AntagonistsTRIHEXIPHENIDYL

ORPHENADRYLPROCYCLIDINE

Block central muscarinic receptors – restore the balance between cholinergic and dopaminergic activity by reducind the formerHave little effect on bradikinesiaLess effective than levodopa for treating tremor and rigidity

Muscarinic Receptor Antagonists

PharmacokineticsOral absorbtion is moderateMost of these drugs undergo extensive hepatic metabolism with intermediate to long half-lifeHigh lipid solubility ensures ready transfere across the blood-brain barrierSide effects: reduce saliva production, confusion (in elderly)

DRUGS USED IN SPASTICYTY DISORDERSSPASTICYTY– sustained muscle tone or tension which is often associated with an increase in stretch reflexesThe increase in muscle tone can arise from continued spinal reflex activity in the absence of inhibitory input from motor cortex – stroke or multiple sclerosisIs often associated with partial or complete loss of voluntary movement and can produce painful and deforming contracturePrimary site of action of drugs for sparticity are:

Spinal reflexesThe release of Ca’’ in the muscle fibers

DRUGS USED IN SPASTICYTY DISORDERS

DIAZEPAM Inhances spinal inhibitory pathways by facilitating GABA – mediated opening of Cl- channelsSides effects: sedation – inhibitori activity in higher centres

DRUGS USED IN SPASTICYTY DISORDERSBACLOFEN

Inhibits excitatory activity at mono - and polisynaptic reflexes at the spinal level Agonist at GABA –B receptorsReduces presynaptic Ca++ influx - reducing excitatory neurotransmitter releaseInhibition of the release of substance P – analgezic effect

DRUGS USED IN SPASTICYTY DISORDERSBACLOFEN - Pharmacokinetics

Absorbed rapidly from the gastro-intestinal tractIt has a short half-lifeIs eliminated largely in the urine in the unchanged formIt can be given by intratraheal injection if severe spasticity is resistant to oral therapy

Side effects: sedation, drowsiness, nausea, confusion, dizziness, headache, hallucination

DRUGS USED IN SPASTICYTY DISORDERSDANTROLENE -

Inhibits the release of Ca++ from sarcoplasmatic reticulum of skeletal muscle – impaire activations of the contractile apparatus and relaxes the muscleIn patients with spasticity may improve functional capacityUsed for the tratment of malignant hyperthermiaAdjuvant in neuroleptic malignant syndrom

DRUGS USED IN SPASTICYTY DISORDERSDANTROLENE – Pharmacokinetics

Well absorbed from the gut Can also be given intravenouslyIt is metabolised in the liverIt has a variable and unpredictable half life

Side effects: drowsiness, dizzines, weakness, malais, hepatitis, diarrhoea

DRUGS USED IN SPASTICYTY DISORDERSTIZANIDINE

It is an alfa 2 – adrenoceptor agonist - increase in excitatory amino acid and increase presynaptic inhibitory of motor neurons Inhibition is greatest in polysinaptic rather than monosynaptic pathwayInhibits the imidazoline receptorsIts action are both spinal and supraspinal It inhibits descending noradrenergic pathways but has anly 10% of antihypertensive activity of clonidine

DRUGS USED IN SPASTICYTY DISORDERSTIZANIDINE – Pharmacokinetics

Well absorbed from the gut Undergoes extensive first-pass methabolismIt has a short half life

Side effects: dry mounth, drowsiness, tiredness, dizziness