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Block 6
Lecture 1 - Anti-Parkinsons
16
Pharmacology
Graduate
04/18/2010
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Term

Levodopa

(L-DOPA)

 Definition
nMOST effective symptomatic treatment for PD*
nTransported across the BBB* by amino acid transporters
nL-DOPA has NO effect of its own*; both its therapeutic and adverse effects result from the decarboxylation of L-DOPA to dopamine
 
Pharmacokinetics:
nWhen administered orally, levodopa is absorbed mainly in the duodenum and the proximal bowel. PEAK serum levels are reached at 30 to 60 minutes (TIME)
nAbsorption of levodopa is reduced by large neutral amino acids and by the delayed gastric emptying
nExogenously administered levodopa is extensively metabolized peripherally* to dopamine by AADC and to 3-o-methyldopa by the enzyme COMT – hence PROBLEM!!!
 
Therapeutic effects of EARLY vs LATE stages of PD
nTherapeutic effects last about 2-5 years
nEARLY in the course of PD, L-DOPA therapy dramatically improves ALL the signs & symptoms of PD
nDuration of the therapeutic effect exceeds that of the plasma lifetime of L-DOPA mainly because in early PD the nigrostriatal dopamine system has “buffering capacity” i.e retains some capacity to convert L-DOPA to dopamine and store it for release when needed and there is supersensitization of receptors
nIn LATE PD, “buffering” capacity of nigrostriatal pathway is lost with time  because of continued neurodegeneration, patient’s motor symptoms fluctuate with each dose of L-DOPA
 
Problems with administering L-DOPA ALONE
nDosage considerations
–Typically the doses are HIGH: PO 500 mg to 1 g daily in two or more equally divided doses. Increased up to  a maximum of 8 g/d)
–Less than 1% of this dose reaches cerebral circulation because L-DOPA is decarboxylated by enzymes in the intestinal mucosa and other peripheral sites
nSide effects
–Dopamine produced by peripheral conversion of L-DOPA produces side effects such as nausea, vomiting, cardiovascular  effects

 

Administration of carbidopa along with L-DOPA circumvents both issues

Dose limiting Toxicities

These are side effects that occur most often with

HIGHER doses

nGI disturbances
–Nausea, vomiting
nCardiovascular effects
–Hypotension-direct effects of DA on peripheral dopamine receptors leading to vasodilation
–Cardiac arrythmias- caused by increased synthesis & release of norepinephrine in the peripheral sympathetic terminals
nCNS effects: Dyskinesia, day time sleepiness
Behavioral Side Effects
nHallucinations and confusion due to excess dopamine in the mesolimbic pathway
nMuch more common in the elderly (AGE) and in those with pre-existing problems with memory
n“Atypical" antipsychotic agents eg Clozapine, Quetiapine can effectively treat psychosis and do not cause or worsen parkinsonism
Other Side Effects
nMydriasis & precipitation of acute glaucoma: effects though to be due to increased formation of Norepinephrine in peripheral sympathetic terminals
CONTRAINDICATIONS***
nContraindicated in patients with***
–Psychosis
–Narrow angle glaucoma
–Peptic ulcer disease 
Drug Interactions
nAdministration of L-DOPA & nonspecific inhibitors of MAOs, such as phenelzine and tranylcypromine can precipitate life-threatening hypertensive crisis and hyperpyrexia
nNonspecific MAOIs should be
Term

Carbidopa

(Lodosyn)

 Definition
nInhibitor of peripheral amino acid decarboxylase (AAD)
nDoes NOT cross the BBB*
nIncreases the fraction of administered levodopa that remains unmetabolized and available to cross the BBB: therapeutic dose of L-DOPA can be reduced by about 80% when given with carbidopa
n Carbidopa also reduces the incidence of nausea, vomiting
Term

Carbidopa / Levodopa

(SINEMET)

 Definition
nCommonly available formulations
–10mg /100mg  (C/L)
–25/100 tabs
n2-3 tabs/day
–50/200 sustained release form
nIn most individuals a daily dose of 75 mg of carbidopa is necessary to prevent nausea***
–25/100 sinemet formulation is used more commonly
nIn individuals whose GI side effects are not reduced, supplemental carbidopa (Lodosyn) should be given by itself without increasing the dose of Sinemet*
Term
Motor complications with LONG term L-DOPA therapy
 Definition

Response Fluctuations (HypOkinetic Phenomenon)

–End of dose deterioration (‘‘wearing off’’)
–Unpredictable ‘‘on/off’’ (yo-yoing)
–Early morning hypokinesia or akinesia
–Short duration ‘‘off’’ period freezing
–Short duration ‘‘on’’ period freezing
nManagement of hypokinetic phenomena
–‘‘Off’’ period freezing can be improved by
nIncreasing levodopa dose frequency
n Administration of controlled released levodopa preparations (SINEMET CR)
n ‘‘On’’ period freezing is very difficult to treat

 

Involuntary Movements (HypERkinetic Phenomenon)

–Peak dose dyskinesia
–Diphasic dyskinesia
–Off period dystonia
–Early morning dystonia
–Biphasic dystonia
nManagement of the hyperkinetic phenomena
–Initially, dyskinesias arise as a result of high levodopa dosage and can be reduced or ameliorated by the dose reduction. However, as the disease advances, they can occur regularly at the time of peak plasma levels of levodopa (peak dose dyskinesia). Switch or add on  dopamine receptor agonists
–Early morning dystonias can be alleviated by increasing the dose of           L-DOPA or controlled release preparation in the nights
–Cholinergic antagonists can also relieve dystonia (this is the QUICKEST way to relieve it!)*
Term
Dopamine Receptor Agonists
 Definition

Alternative to L-DOPA

 

Advantages 

– Enzymatic conversion is not required for activity
– Do not depend on the functional capacities of the nigrostriatal neurons
– Have substantially LONGER durations of action (8-12 hrs) than L-DOPA &  are useful in the management of dose-related fluctuations in motor state

 

Disadvantages

Hallucinations and hypotension are much more common than with L-DOPA*

Place in PD Therapy

Increasingly used as INITIAL* treatment for PD rather

than as adjuncts to L-DOPA

Why?

(1)Belief that because of their longer duration of action, DA agonists may be less likely than L-DOPA to induce wearing off  or on/off effects
(2) Concern that levodopa may contribute to oxidative stress, thereby accelerating loss of dopaminergic neurons

Clinical trials with DA agonist pramiprexole show less incidence on/ off effects and less degeneration of dopaminergic neruons

nDA agonists are used as initial therapy in younger (AGE) patients with PD either alone or as an adjunct
nL-DOPA as the initial treatment in older (AGE) patients who may be more vulnerable to the adverse cognitive defects

 

– Enzymatic conversion is not required for activity
– Do not depend on the functional capacities of the nigrostriatal neurons
– Have substantially LONGER durations of action (8-12 hrs) than L-DOPA &  are useful in the management of dose-related fluctuations in motor state

 

The main difference between the ergot and non-ergot DA agonists is

–Speed of titration

nTherapeutic effects can be achieved FASTER with the     newer DA agonists

–Extent of their side effects

nCNS side effects such as hallucinations &  peripheral side effect such as hypotension, nausea etc are common to BOTH types of agonists but the extent of these side effects vary.

Ergot Alkaloid Derivatives

First generation DA agonists (not used as much)

nBromocriptine (Parlodel)

–Strong agonist at D2 family of receptors & partial agonist at D1 receptor

nPergolide (Permax)

nAgonist at BOTH D1 and D2 receptor families

Newer ergot derivative:

nCabergoline, specific to  D2 receptor, long half–life (60-100 hrs), single dose

 

 

Term
Bromocriptine & Pergolide
 Definition

NONspecific Dopamine Receptor agonists

Ergot Alkaloids (FIRST generation 

 

nInitial treatment with these drugs causes profound hypotension
–Should be initiated at low dosage
nOften induce nausea and fatigue with initial treatment
–Symptoms usually are transient
–Requires slow upward adjustment of the dose over a period of weeks to months (TIME)
nLONG-term use of pergolide associated with significant  damage to cardiac valves. The drug is being slowly phased out of the market.
Term

Ropinirole (REQUIP)

Pramipexole (MIRAPEX)

 Definition

SELECTIVE Dopamine receptor agonists

 

Mechanism of Action

–Both drugs act selectively at D2 family of receptors (especially D2 & D3)*
–Little or no activity at D1 family of receptors

 

Characteristics

nInitiated more quickly, achieving therapeutically useful doses in a week or less (TIME)
nSide effects: Hallucinations, Somnolence*
nPramipexole is excreted unchanged:         adjust dose in patients with renal insufficiency
nRopinirole is metabolized by CYP1A2: adjust dose in presence of drugs that are metabolized by the same enzymes
Term
Apomorphine (APOKYN)
 Definition
nDA agonist that can be administered by SUBCUTANEOUS injection***
nHIGH affinity for D4 receptors*; moderate affinity for other D2 family receptors, and adrenergic alpha receptors
nApproved for use as a "rescue therapy" for the acute intermittent treatment of "off" episodes in patients with a fluctuating response to DA therapy

nHIGH potential to cause nausea & vomiting*

–Requires pretreatment with antiemetic trimethobenzamide (start 3 days prior to the first dose of apokyn and continue for first 2 months of treatment)
nDo not combine apomorphine with ondansetron (5-HT3 antagonist)
–Causes profound hypotension and loss of consciousness
Term

Trimethobenzoprine

 

 Definition

Antiemetic

Used as a pretreatment to treat the Nausea and Vomiting SEs of Apomorphine

(start 3 days prior to the first dose of apokyn and continue for first 2 months of treatment)
Term

Ondansetron

 

 Definition
nDo not combine apomorphine with ondansetron (5-HT3 antagonist)
–Causes profound hypotension and loss of consciousness
Term
COMT Inhibitors
 Definition

Tolcapone (TASMAR)

Entacapone (COMTAN)

MOA

nBlock peripheral conversion L-DOPA to 3-O-methyl DOPA
– Increasing the fraction of L-DOPA that reaches the CNS
nTolcapone also inhibits COMT in the CNS

Place in PD therapy

nADJUNCT to Sinemet treatment
nBoth Entacapone & Tolcapone reduce the clinical symptoms of "wearing off" in patients treated with SINEMET
nThe two drugs differ with regards to their pharmacokinetics & adverse effects

 
Term
Tolcapone
 Definition
nLONG duration of action (2-3 times/day)
nActs by BOTH central and peripheral inhibition of COMT
nNausea, orthostatic hypotension, confusion and hallucinations
nIncidence of hepatotoxicity*** in about 2% of patients
nIs used only in patients who have NOT responded to other therapies and with appropriate monitoring for hepatotoxicity
Term
Entacapone
 Definition
nSHORTER duration of action (2 hrs)
n Administered simultaneously with each dose of Sinemet. Available as fixed dose combination (Stalevo)
nTherapeutic effect is due to peripheral inhibition of COMT (ONLY) - Hence, NO CROSSING OF BBB!!!***
nNo incidence of hepatotoxicity and requires no special monitoring
Term

Selegiline

(ELDEPRYL)

 Definition

MAO-B Inhibitor

MOA

nAt doses of 10 mg/day or less, selegiline is a selective inhibitor of MAO-B, leading to irreversible inhibition of the enzyme
–Does not inhibit peripheral metabolism of catecholamines; thus it can be combined safely with levodopa
–Does not cause hypertensive crisis like the nonselective MAOIs

Place in PD Therapy

nUsed for symptomatic treatment of PD, although its benefits are modest
nMay have neuroprotective effects
nWell tolerated in patients with early or mild PD

Side Effects

nIn patients with late or advanced PD it increases the adverse motor and cognitive effects of L-DOPA therapy
nSelegiline is metabolized into amphetamine and methamphetamine, which may cause anxiety, insomnia, and other adverse symptoms
nSeveral drug interactions . Use with caution
Term

Trihexyphenidyl (ARTANE)

Benztropine (COGENTIN)

Diphenydramine hydrochloride (BENADRYL)

 Definition

Muscarinic Antagonists

Use

nUsed widely prior to L-DOPA discovery
nModest antiparkinsonian activity that is useful in the treatment of early PD or as an adjunct to dopamimetic therapy

Side Effects

nSedation and mental confusion
nBlurred vision through cycloplegia
–CAUTIOUS use in narrow-angle glaucoma*
nConstipation
nUrinary retention
Term

Amantadine

(SYMMETREL)

 Definition

Developed for use as an antiviral agent for

prophylaxis and treatment of influenza

nMechanism in PD:
–Blocks NMDA glutamate receptors to block excitotoxicity

–Alters dopamine release in the striatum and also has anticholinergic properties

Place in PD

nEffects in PD are modest, used as INITIAL therapy of MILD PD
nMay be helpful as an adjunct in patients on levodopa with dose-related fluctuations and dyskinesias
nDose of 100 mg twice a day and is well tolerated

Side Effects

nDizziness
nLethargy
nSleep disturbance
nAnticholinergic effects
nNausea & vomiting: mild and reversible
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