antiparkinson drugs objectives description of parkinson's disease the neurotransmitter model...
TRANSCRIPT
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