Antiparkinson Drugs

Objectives• Description of Parkinson's disease

• The neurotransmitter model

• Use of levodopa

• Agents which enhance dopaminergic activity

• Anticholinergic agents

• New approaches..

Antiparkinson Drugs

Description• Signs of the disease»muscular rigidity (cog-wheel)» bradykinesia» resting tremor (pill-rolling)» characteristic flexed posture and

shuffling gait» loss of normal associated movement» little spontaneous movement» slow initiation of voluntary movement..

Antiparkinson Drugs

Historical evidence - a great story - the first piece• Biogenic amines - amphetamine» originally given for excess sleepiness » found to relieve symptoms» Clue ==> enhanced biogenic amine

activity is a positive factor

• Atropine» given for excess salivation» anticholinergic agents relieved

symptoms » Clue ==> enhanced cholinergic activity

is a negative factor..

Antiparkinson Drugs

The second piece - drug-induced extra-pyramidal disorders

• Drugs which deplete dopamine (reserpine) or block receptors (antipsychotics: chlorpromazine, haloperidol, etc.) cause Parkinson effects

• A decrease in dopamine in the basal ganglia

• MPTP - may be related to cell damage caused by excitatory amino acids at NMDA receptors..

Antiparkinson Drugs

Neurotransmitter model

Motor cortex

Striatum

Substantia nigra

Thalamus

Comp. Retc.

Movement

Dopamine

ACh

Glutamate

GABA

GPi.

Motor cortex

Striatum

Substantia nigra

Thalamus

Comp. Retc.

Movement

Dopamine

ACh

Glutamate

GABA

GPi.

Disorder

Antiparkinson Drugs

Treatment approaches• Dopaminergic drugs» augment defective inhibitory systems: l-DOPA» probably involves D2 receptors

– D2 agonists: Pramipexole, Ropinirole and Bromocriptine, are used for effective treatment

– potent D2 blockers, butyrophenones (other anti-schizophrenic drugs), cause the syndrome

• Anticholinergic agents» may be used for mild cases » used as adjunctive therapy with dopaminergic

drugs» for drug-induced extrapyramidal effects

• Treatment does not reverse the disease process..

Antiparkinson Drugs

The dopamine picture

Rotigotine

Antiparkinson Drugs

The use of levodopa• Stimulating dopamine synthesis

• Therapy with levodopa

• Side/toxic effects

• Combination of a peripheral dopa-decarboxylase inhibitor - Carbidopa

• Interactions/precautions..

Antiparkinson Drugs

Rate-limiting step in dopamine synthesis

• Tyrosine hydroxylase is the rate-limiting step in the synthesis dopamine

• By-pass the bottleneck in the remaining healthy neurons by giving dopa to synthesize more dopamine..

Tyrosine DOPA

DopamineNorepinephrineEpinephrine

DOPAdecarboxylase

Tyrosinehydroxylase

Dopamineß-oxidase

( )

Why don't we administerdopamine?

Antiparkinson Drugs

Therapy with levodopa• Goal: low doses at small intervals - side-

effects are then reduced

• Improvement may take several weeks

» 70% respond well

» 90% obtain relief for 5 years– neuronal deterioration occurs

– levodopa can no longer be converted to dopamine

– new dopaminergic agonists are important agents

• Fluctuations in therapeutic response may occur..

Antiparkinson Drugs

Side/toxic effects• Gastrointestinal - nausea, vomiting

(Chemoreceptor Trigger Zone)

• Cardiovascular/autonomic» orthostatic hypotension in 30% -

tolerance occurs» ß-adrenergic stimulation of the heart in

patients with pre-existing problems

• Endocrine - growth hormone increases, prolactin decreases..

Antiparkinson Drugs

Side/toxic effects• Abnormal involuntary movements» choreiform or faciolingual problems» after 5-8 years, many patients have dose-

related dyskinesias (chorea, dystonia)

• Psychiatric/behavioral problems - about 15%» the dopamine hypothesis for schizophrenia» reports of increased compulsive behavior» cognitive defects may be related to decreased

cholinergic activity..

Antiparkinson Drugs

Addition of carbidopa• Much of the l-dopa is converted to

dopamine in the periphery which doesn't cross the blood-brain-barrier>>

Tyrosine DOPA

DopamineNorepinephrineEpinephrine

DOPAdecarboxylase

Tyrosinehydroxylase

Dopamineß-oxidase

Carbidopa

Antiparkinson Drugs

Addition of carbidopa• Without carbidopa, large doses are

administered to obtain small amounts in the CNS which are converted to the necessary dopamine

• With cabidopa, smaller overall doses are effective» half-life is 60-90 min.» daily amount is divided into 3-6 doses to

reduce side effects

• Prevention of peripheral conversion allows for lower doses>>

Antiparkinson Drugs

Addition of carbidopaBrain

Metabolismin the GI

tract

Peripheraltissues

(toxicity)

30% 1-3%100%

70% 27-29%Levodopaalone

Gut

Blood

Brain

Metabolismin the GI

tract

100% 60%

Peripheraltissues(toxicity)

10%

50%40%

Levodopawith

carbidopa

BloodGut

Antiparkinson Drugs

Cost/benefit ratio to the combination• Advantages» Can reduce the effective dose of

levodopa by 75%» Nausea and vomiting are reduced» Effective dose levels are achieved more

rapidly» Control is more even - diurnal variation

is reduced» Per cent of patients helped is greater..

Antiparkinson Drugs

Benefit/cost ratio to the combination

• Disadvantages» Orthostatic hypotension is not helped» Involuntary movements may occur

earlier, be more severe, and last longer» Adverse mental effects occur earlier

• Combination of levodopa and carbidopa is SINEMET..

Antiparkinson Drugs

Interactions/precautions• Acute psychosis, psychoneurosis

• Caution with other adrenergic agents in asthma or emphysema

• MAO-A inhibitors» act primarily on norepinephrine and

serotonin» effects of dopamine (converted to

norepinephrine) may be exaggerated or unpredictable - hypertension, hyperpyrexia..

Antiparkinson Drugs

Peripheral enhancers of dopaminergic activity• COMT inhibitors (similar approach

to Carbidopa)» Entacapone (COMTAN) prevents the

conversion of dopa to 3-O-methyl DOPA peripherally– thereby prolonging its half-life and

enhancing entry into the CNS– other COMT-metabolized drugs will have

an increased duration of activity» a useful adjunct especially in patients

with an "end of dose" fluctuating response to treatment >>

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Antiparkinson Drugs

Peripheral enhancers of dopaminergic activity

entacapone

carbidopa

3-O-MD

COMT

L-DOPA

AAD

DOPAC

MAO

3MT

Perphery Brain

DA

L-DOPAAAD

COMT

DA

COMT: catechol-O-methyltransferaseAAD: aromatic L-amino acid decarboxylaseDOPAC: 3,4-dihydroxyphenylacetic acid3MT: 3-methoxytyramine3-O-MD: 3-O-methylDOPA

Antiparkinson Drugs

Peripheral enhancers of dopaminergic activity• Tolcapone (TASMAR), a similar

more potent agent is more hepatotoxic is reserved for patients not responding to entacapone

• There is now a combination product available» Stalevo is a combination of levodopa,

carbidopa and entacapone

QuickTime™ and aTIFF (LZW) decompressor

are needed to see this picture.

Antiparkinson Drugs

Central enhancers of dopaminergic activity• Dopaminergic agonists» Pramipexole (MIRAPEX) and Ropinirole

(REQUIP) are agonists at D2 and D3 receptors– may be used as initial treatment, fewer on/off issues,

longer duration of action, less likely to induce dyskinesias (movement difficulties)

– can reach therapeutic levels more rapidly– reduces levodopa requirement and smoothes the

response– Both drugs have been approved for “restless leg

syndrome”..

Antiparkinson Drugs

Central enhancers of dopaminergic activity• Dopaminergic agonists» Rotigotine (NEUPRO) is a D3/D2/D1 dopamine

agonist

» Used in a once daily patch

• Side effects include irritation at the site of application

– CNS - dizziness, headache, somnolence– GI - nausea, vomiting– poor impulse control - pathologic gambling,

excessive shopping, binge eating or hypersexuality (previously reported with levodopa)..

Antiparkinson Drugs

Central enhancers of dopaminergic activity• These have largely replaced

Bromocriptine (PARLODEL) - D2 agonist (ergot derivative)..

• DOPA induction of free radicals may contribute to cell death; agonists do not change the course of the disease..

Antiparkinson Drugs

Central enhancers of dopaminergic activity

• Amantidine» antiviral agent - NMDA -antagonist» the exact mechanism in PD is unknown» usual CNS dopaminergic side-effects,

psychosis..

Antiparkinson Drugs

Central enhancers of dopaminergic activity• Deprenyl/selegiline - an MAO-B

inhibitor - affects predominately dopamine at the doses used» preserves dopamine in the basal

ganglia» allows for lower doses of l-dopa and

more even drug effect» probably does not slow the disease

progression as originally thought..

Antiparkinson Drugs

Enhancers of dopaminergic activity• Rasagiline (AZILECT) - another MAO-B

inhibitor that is completing clinical trials» may not be as selective for dopamine, as there

are major precautions against use with antidepressants that raise serotonin - serotonin syndrome (tachycardia, hypertension, hyperthermia, muscular rigidity)

» should not be used with meperidine, propoxyphene, tramaol, methadone, mirtazapine, cyclobenzaprine, dextromethorphan and St. John’s Wort because their breakdown is slowed

» should not be used with sympathomimetics..

Antiparkinson Drugs

Central enhancers of dopaminergic activity• About MAO-B inhibitors» early thoughts were that they were

neuroprotective and slow the advancement of PD

» this was later dispelled, particularly because selegiline is metabolized to amphetamine derivatives that may be neurotoxic

» Rasagiline may have neuroprotective and anti-apoptotic effects on dopaminergic neurons

» distinctive benefits remain to be seen..

Antiparkinson Drugs

Central enhancers of dopaminergic activity• Apomorphine has been introduced in

advanced Parkinson patients with significant “off” periods

• A specific dopamine agonist at the CTZ causing nausea

• Other typical dopaminergic side effects occur» orthostatic hypotension» confusion and other CNS effects..

Antiparkinson Drugs

Anticholinergic agents

• Historical background - the use of atropine

• Effective anticholinergic agents» trihexyphenidyl (ARTANE)»benztropine

(atropine/diphenhydramine)»others: antihistamines,

phenothiazines..

Striatum

Substantia nigra

Comp. Retc.

Dopamine

ACh

GPi.

Antiparkinson Drugs

Anticholinergic agents

• Only approach for drug-induced Parkinson effects>>

Striatum

Substantia nigra

Comp. Retc.

Dopamine

ACh

GPi.

BenztropineTrihexyphenidyl

Antiparkinson Drugs

Anticholinergic agents• Effectiveness - 25%» begun with small doses until side-

effects are too severe»may be used with dopaminergic agents

• Side/toxic effects» dry mouth, failure to accommodate» constipation, urinary retention» heat stroke (no sweating)» elderly: delirium, confusion

• Precautions/interactions» glaucoma, prostatic hypertrophy..

Antiparkinson Drugs

New approaches• Lesions/microstimulators » a return to an older approach, now more

precise for relieving tremor and rigidity

• Tissue implants» adrenal medullary tissue» fetal brain tissue - MPTP patients..

Antiparkinson Drugs

Review of Rotigotine therapy

Rotigotine

Antiparkinson Drugs

Initial therapy - NEJM ‘05, Treatment Guidelines ‘07• First-line dopaminergic agents» Carbidopa plus levodopa» Carbidopa plus levodopa plus entacapone» Dopamine agonists

– Non-ergot: pramipexole, ropinirole, rotigotine

– Ergot: pergolide

• Second-line agents» Anticholinergic: trihexyphenidyl, benztropine» Selective MAO-B antagoinist - selegiline» NMDA antagonist: amantadine..

Antiparkinson Drugs

Considerations on management

• Effectiveness of levodopa diminishes with time

• Adverse l-DOPA effects increase• Some suggest avoiding treatment until

symptoms or disability affect lifestyle• Suggest using dopamine agonists instead

of levodopa in younger patients..

Antiparkinson Drugs

Considerations on management

• With disease progression, begin dopaminergic therapy» levodopa/carbidopa/entacapone and an

agonist» a peripheral COMT inhibitor can be added as

levodopa control is difficult or wanes» consider adding selegiline as control becomes

more difficult» apomorphine may be added to deal with “off”

drug periods in advanced patients..

Antiparkinson Drugs

Costs