Block 5 - Movement Disorders Drugs

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Ways to treat Parkinson's Dz

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Increase dopamine available in synapse
-Increase dopamine synthesis
-Stablize dopamine in synapse
-Inhibit degreadation in glia

Direct agonist action on receptors

Decreases ACh - Anticholinergics

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Drugs used to Treat Parkinson's

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Levodopa (L-Dopa)
Carbidopa
Bromocriptine
Pergolide
Selegiline
Amantadine
Trihexyphenidyl

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Levodopa

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Parkinson's Dz Treatment
Mechanism: L-dopa crosses blood brain barrier and is converted to dopamine.

-Absorbed from small intestine. Excreted in urine. Only 3% actually gets to brain.

Toxic effects:
-Peripheral: GI symptoms (nausea, vomiting, anorexia), postural hypotension
-CNS: neurological issues (dyskinesias, chorea, facial ticks) and behavioral issues (insomnia, anxiety, confusion, psychosis)

Fluctuations in therapeutic response. "wearing off" phenomenon and "on-off" phenomenon

Drug Interactions
-Beta agonists cause cardiac stimulation
-Pyridoxine (vit B6) decrease efficacy of levodopa by increasing peripheral metabolism of dopa.
-Antipsychotic drugs decrease efficacy by decreasing dopamine levels
-MOA inhibitors - cause HTN crisis

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Carbidopa

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Parkinson's treatment
-Usually given with levodopa as Sinemet
Mechanism: Competitive inhibitor of preipheral dopa-decarboxylase
-Decreases metabolism of levodopa in gut and blood so lower total dose to get same total levodopa delivery to brain.

Advantages: increased half-life of levodopa; decreased peripheral side effects
Disadvantages: Increased CNS side effects

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Sinemet

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Carbidopa + Levodopa

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Amantadine

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Parkinson's Dz treatment
Mechanism: Increases synaptic concentration of dopamine
-Less efficacy, toxicity than levodopa
-Often given with levodopa

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Apomorphine hydrochloride (Apokyn)

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Potent non-selective dopamine agonist
-Used for temporary relief or rescue from off-periods of akinesia
-Injected subcutaneously
-Works in 10 min. lasts up to 2hr
-Pretreatment with antiemetic trimethobenzamide (prevent nausea)

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Anticholinergic Drugs

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Trihexyphenidyl, Benztropine, Biperiden, Orphenadrine, Procylcidine
Mechanism: muscarinic blockade restore imbalance of neurotransmitters
-May be used to counteract drug induced Parkinsonism (anti-psychotics)
-Less efficacy compared to levodopa
Toxicity: peripheral atropine-like effects, CNS (delirium, confusion)

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Trihexyphenidyl

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Anticholinergic drug

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Bromocriptine

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Ergot Alkaloids
Mechanism: Dopamine receptor agonist
-Used as additive therapy with levodopa for Parkinson's Dz
Toxicity: hypotension, nausea, hallucinations

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Pergolide

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Ergot Alkaloids
Mechanism: Dopamine receptor agonist
-Used as additive therapy with levodopa for Parkinson's Dz
Toxicity: hypotension, nausea, hallucinations

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Selegiline

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Treats Parkinson's Dz
Mechanism: monoamine oxidase B inhibitor --> blocks metabolism of dopamine in CNS so increased dopamine

Decreased incidence of dyskinesias, "on-off" fluctuations.
Prolongs the total # of years levodopa will be effective.

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COMT Inhibitors

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Entacapone, Tolcapone
Mechanism: Inhibit peripheral metabolism of levodopa. --> Increases available dopa

Entacapone preferred.
Tolcapone - potential hepatotoxicity

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Levodopa Clinical problems

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Limited effectiveness after 3-5 years of treatment.
Fluctuations in response as disease progresses.
Dyskinesias
Psychotic symptoms

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Anticholinergic Drugs Clinical problems

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Confusion
Memory impairment

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Trade Names to Know

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Sinemet: carbidopa/L-dopa
Parlodel: Bromocriptine
Permax: Pergolide
Symmetrel: Amantadine
Cogentin: Benztropine
Artane: Trihexyphenidyl
Eldepryl, Carbex: selegiline, deprenyl

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1. Describe the major anatomical pathways and neurotransmitter systems involved in control of motor function.

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Dopaminergic neurons project from the substantia nigra to the corpus striatum, and convey inhibitory signals to GABAergic neurons located there. Stimulatory striatal cholinergic neurons also act on GABAergic neurons in the striatum.

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2. Discuss current hypotheses about the etiology and pathophysiology of Parkinson’s disease.

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In Parkinson’s disease, striatal dopamine levels are reduced. A current theory describing the etiology of this disease is that striatal neurons may be sensitive to free radicals generated in the glia. Enzymatic dopamine oxidation in the glia (by monoamine oxidase) may contribute to the generation of radicals. The reaction generates hydrogen peroxide, which is normally detoxified by glutathione but which in the presence of iron can undergo the Fenton reaction, resulting in hydroxyl free radicals (see figure on p. 515). Since there is a lot of iron in dopaminergic neurons (it is a cofactor for tyrosine hydroxylase), there is a lot of potential for free radicals to be generated.

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Understand how the “Balance Hypothesis of Striatal Function” predicts management and side effects of all extra-pyramidal movement disorders.

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a. Voluntary movement is controlled by a balance between inhibitory nigrostriatal dopaminergic and stimulatory striatal cholinergic neurons acting on striatal GABAergic neurons. In normal tissue dopaminergic and cholinergic signaling are in balance.

b. In Parkinson’s Disease, this balance is disturbed by degeneration of dopaminergic neurons. Therapies for PD are therefore aimed at restoring the balance between dopaminergic and cholinergic signaling. Most of these therapies are directed towards enhancing dopamine levels. Anti-cholinergic agents can also restore the balance, but are not as effective as dopamine enhancing agents. As can be predicted by this hypothesis, drugs that suppress dopamine levels can induce Parkinsonism.

c. In contrast to PD, Huntington’s disease is the result of loss of GABAergic neurons (and some cholinergic neurons). Therefore the problem is not dopamine signaling (there are regular dopamine levels), but rather GABA signaling (see figure on p. 516). Therapies that work for PD will not be effective for HD.

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4. Describe the rationale for the use of levodopa in Parkinson’s disease and the rationale for its use in combination with peripheral L-amino acid decarboxylase inhibitor. Discuss how the drug combination alters levodopa’s therapeutic and adverse effect profiles.

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a. Levodopa is a precursor of dopamine that is able to cross the blood brain barrier. In the striatum it is converted to dopamine and increases dopamine levels. However, when given alone only 1-3% of the levodopa will enter the brain unaltered because most of it is metabolized to dopamine in the periphery.

b. Carbidopa can be given to increase the amount of levodopa that is delivered to the brain. Carbidopa inhibits peripheral dopa-decarboxylase, the enzyme that metabolizes dopa to dopamine. The result is that you need a lower total dose to get the same total levodopa delivery to the brain.

c. Side effects of levodopa include peripheral and CNS toxicities. Peripheral toxicities include GI symptoms (nausea, vomiting, anorexia), and cardiovascular symptoms (postural hypotension). CNS effects include neurological symptoms (dyskinesias) and behavioral symptoms (insomnia, anxiety, 15% suffer confusion, psychosis). Combination therapy with carbidopa decreases the peripheral side effects of levodopa, but increases the CNS side effects.

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5. Discuss the adverse effect profile of levodopa and how it is altered by combination with carbidopa.

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a. Side effects of levodopa include peripheral and CNS toxicities. Peripheral toxicities include GI symptoms (nausea, vomiting, anorexia), and cardiovascular symptoms (postural hypotension). CNS effects include neurological symptoms (dyskinesias) and behavioral symptoms (insomnia, anxiety, 15% suffer confusion, psychosis). Combination therapy with carbidopa decreases the peripheral side effects of levodopa, but increases the CNS side effects. Because of the increase in CNS side effects, a lower dose of levodopa should be used when giving the combination therapy.

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6. Differentiate the two major classes of direct DA receptor agonists, and indicate how they are used therapeutically and any significant differences in their adverse effects.

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a. The Ergot alkaloids, Bromocriptine and Pergolide, are direct dopamine agonists. They provide additive therapeutic effects when given with levodopa. Their adverse effects include hypotension, nausea, and hallucinations.

b. The newer non-ergot Dopamine agonists are Pramipexole and Ropinirole. Their effects are similar to older agonists. They are sometimes used alone, particularly earlier in the disease course before levodopa therapy is initiated. Pramipexole has been associated with compulsive gambling in a small number of patients.

c. Apomorphine is an additional dopamine agonist that is used for temporary relief or “rescue” from off-periods of akinesia. It is injected subcutaneously, with rapid uptake and clinical benefit within 10 minutes. A side effect is nausea and vomiting, which can be prevented by pretreatment with an antiemetic.

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7. Compare and contrast the adverse effect profile of ergot and non-ergot dopamine agonists.

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a. The ergot alkaloids have side effects including hypotension, nausea, and hallucinations. Pramipexole, a non-ergot alkaloid, has been associated with compulsive gambling in a small number of patients. It is now used for treatment of restless leg syndrome.

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8. Describe the molecular mechanism of action of each primary drug.

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a. Levodopa: is converted to dopamine in the striatum, it results in increased dopamine concentration at its site of action.

b.Carbidopa: inhibition of peripheral dopa-decarboxylase (competitive inhibition), results in decreased peripheral metabolism of levodopa, increased half-life of levodopa, and increased levels of levodopa delivered to the brain.

c. Sinemet: carbidopa + levodopa, 1:4 or 1:10 ratio
i. Combination increases the effectiveness of levodopa therapy.

d. Amantadine: increases the synaptic concentration of dopamine (is not an agonist, rather it stabilizes dopamine in the synapse).
i. Need to know tradename – Symmetrel

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10. Discuss drugs that can cause Parkinsonism and other movement disorders, and how these drug-induced disorders can be treated.

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a. Drugs that suppress dopamine, such as the antipsychotic haloperidol, can cause Parkinsonism. Drugs that increase cholinergic signaling can also produce Parkinson-like symptoms.
b. Exposure to the dopamine neurotoxin MPTP causes a syndrome indistinguishable from Parkinson’s disease. MPTP is a contaminant that can result from sloppy synthesis of MPPP, a street analog of the opioid meperidine (Demerol).
c. Drug-induced Parkinsonism is often treated by the ergot alkaloids.

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11. Describe Huntington’s Chorea and discuss drugs available for its treatment and their effectiveness.

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a. Huntington’s disease is an autosomal dominant inherited disorder characterized by the gradual onset of motor incoordination and cognitive decline in midlife. Symptoms include either a movement disorder manifested by brief, jerklike movements of the extremities, trunk, face, and neck (chorea) or personality changes, or both.
b. Therapy for Huntington disease involves symptomatic treatment only.
c. Pharmacological therapy for the movement disorder of HD is usually only indicated in those with large-amplitude chorea causing frequent falls and injury. Therapy includes dopamine-depleting agents such as tetrabenazine and reserpine.
d. Treatment is needed for patients who are depressed, irritable, paranoid, excessively anxious, or psychotic.
i. Depression can be treated effectively with standard antidepressant drugs, with the caveat that drugs with substantial anticholinergic profiles can exacerbate chorea.
ii. Fluoxetine is effective treatment for both the depression and the irritability manifest in symptomatic HD.
iii. Carbamazepine also has been found to be effective for depression.
iv. Paranoia, delusional states, and psychosis usually require treatment with antipsychotic drugs, but the doses required are often lower than what you would use when treating primary psychiatric disorders.