Agents For Parkinson’S Disease

Front 1

Be aware of the prevalence of Parkinson’s Disease

Back 1

Parkinson’s Disease is a neurodegenerative disease that
affects about 6.3 M people worldwide. About 3 people/1,000 are affected in the USA. Prevalence is higher in certain populations (Amish in Northeast, genetic and others environmental,Males more than females (ex.Japan)

Front 2

Describe the signs and symptoms of PD.

Back 2

1) Bradykinesia
2) Muscle rigidity
3) Resting tremor
4) Impairment of postural balance
5) Loss of automatic movements (blinking, smiling, swinging arms when walking, etc)
6) Speech changes
7) Dementia.

Front 3

Describe Risk Factors for PD.

Back 3

Age: More common >50 YO
Genetics: Early Onset (<50 YO) can have 100% concordance rate in monozygotic twins;if any age is used 16%. Many genes implicated in early onset PD
Environmental Toxin exposure

Front 4

Describe the key brain morphologic changes in PD

Back 4

PD specifically affects dopamine-containing neurons in the Substantia Nigra region of the brain (diminished size)

Front 5

Treatments for PD

Back 5

Nonpharmacologic:Exercise,Therapy: (Physical, Occupational),Surgery
Pharmacologic
1. L-Dopa
2. Dopamine Agonists
3. MAO-B inhibitors
4. COMT inhibitors
5. Amantidine
6. Centrally acting anticholinergics

Front 6

levodopa

Back 6

the most effective treatment for PD. However,“On” and “Off” effects may cause physicians to delay use until absolutely necessary. Pro drug, Dopamine does not cross the BBB. Peripheral Dopamine can interact with chemoreceptor trigger zone. excess, levodopa will result in dystonia or dyskinesia, movements that can be as disabling as the “off” periods.

Front 7

levodopa/Carbidopa

Back 7

(Sinemet IR and CR;Parcopa ODT) Dopamine Agonists,Dopamine Agonists, Carbidopa increases brain bioavailability of levodopa by decreasing the peripheral conversion of levodopa to dopamine by inhibiting periheral l-amino acid decarboxylase (sometimes called DOPA decarboxylase) Carbidopa is renally excreted as either intact drug or metabolites

Front 8

levodopa/Carbidopa/Entacapone

Back 8

(Stalevo)Dopamine Agonists ,Dopamine Agonists, a peripheral COMT inhibitor. COMT breaks down Dopamine in the brain. Entacapone increases levodopa AUC by about 35% and increases T1/2 from ~1 to 2 hrs

Front 9

Apomorphine

Back 9

(Apokyn Pen injection)) non-selective dopamine agonist which activates both D1-like and D2-like receptors.a morphine derivative, but without narcotic effects,has effects at alpha adrenergic and 5-HT receptors.metabolized in liver (3 ways),severe N/V, may need trimethobenzamide (a D2 antagonist in CTZ) T1/2 is 30-60 min.

Front 10

Ropinirole

Back 10

(Requip) is a non-ergoline dopamine agonist, may be used as oral monotherapy or used in combination with levodopa to reduce
“off” effects. has activity at D3 receptors,relevance unknown .Metabolized primarily by CYP1A2. T1/2 is ~6 hrs. XL form is 1QD administration.

Front 11

Pramipexole

Back 11

(Mirapex) is a non-ergoline dopamine agonist may be used as oral monotherapy or used in combination with levodopa to reduce
“off” effects. has activity at D3 receptors,relevance unknown. T1/2 is ~8 hrs. ER form is 1QD; ~90% excreted by kidney as unchanged
drug.

Front 12

Rasagiline

Back 12

(Azilect) is an irreversible inhibitor of monoamine oxidase (MAO-B Selective Inhibitors) for early symptomatic treatment of PD. helping to delay use of levodopa. Adverse Effects of monotherapy with Rasagiline:Weight Loss,Orthostatic hypotension,Dry mouth, Dyskinesias (movement disorder).Hallucinations

Front 13

Selegiline

Back 13

(Atapryl, Carbex, Eldepryl, Zelapar) a selective irreversible MAO-B inhibitor, however in larger doses it loses its specificity and also inhibits MAO-A. has little benefit in PD when used alone.When used in combination with levodopa, adverse effects of levodopa are enhanced

Front 14

Benztropine

Back 14

anticholinergic, and antihistaminic effects. Anticholinergic agents improve rigidity and tremor in PD, little effect on bradykinesia (slowness of motion).
Indications: PD, drug-induced EPS (akinesia (inability to initiate movement) and akathisia (inability to remain motionless).
Adverse Effects:Peripheral: “Anti-SLUD” effects are common.
CNS: anxiety, restlessness, amnesia, euphoria, delirium, paranoia

Front 15

Amantadine

Back 15

(Symadine, Symmetrel)The drug has many effects in the brain, including release of dopamine and norepinephrine from nerve endings. It appears to be a weak NMDA receptor antagonist as well as an anticholinergic. Influenza A infection and prophylaxis .used in mild PD prior to levodopa,or as an adjunct to levodopa with dose-related fluctuations and dyskinesias.

Front 16

Amantadine Pharmacokinetics ,

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Dosed twice daily as monotherapy; titrated up to twice daily for use in combination. ~90% excreted in urine; acidification of urine increases CL.

Front 17

Amantadine Adverse Effects:

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CNS: restlessness, depression, insomnia, irritability, agitation, hallucinations, confusion
Peripheral: edema, heart failure, postural hypotension, urinary retention, constipation, dry mouth, livedo reticularis

Front 18

Amantadine Pharmacodynamic Interactions

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• Increased nervousness, irritability, insomnia when taken with stimulants and bupropion
• Anticholinergics: increased adverse effects

Front 19

Long-term use of levodopa

Back 19

In early PD, the duration of the beneficial effects may outlast the plasma concentrations, suggesting Substantia Nigra neurons are still able to store and release dopamine .Long-term use may result in loss of this “buffering” capacity as more nerves are lost resulting in dramatic swings in the patient’s motor function between doses

Front 20

levodopa Pharmacokinetics:

Back 20

T1/2 1-2 hr. ER dosed every 4-8 hrs.

Front 21

levodopa Adverse Effects

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• Dystonia, Dyskinesia, Hyperkinesia
• Orthostatic Hypotension
• Hallucinations (particularly in elderly) • Confusion
• N/V/D
• Cardiac arrythmias

Front 22

Bromocriptine

Back 22

an ergoline derivative, potent agonist at dopamine D2 receptors[2] and various serotonin receptors. It also inhibits the release of glutamate, by reversing the glutamate GLT-1 transporter.

Front 23

Pergolide

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is an ergoline-based dopamine receptor agonist used in some countries for the treatment of Parkinson's disease

Front 24

5-HT1 receptors

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mediate inhibitory neurotransmission,

Front 25

Ergoline

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used clinically for the purpose of vasoconstriction (5-HT1 receptor agonists—ergotamine) the most famous ergoline derivative is the psychedelic drug LSD.

Front 26

5-HT1A

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decrease blood pressure and heart rate via a central mechanism, by inducing peripheral vasodilation

Front 27

5-HT1B

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induces presynaptic inhibition, vascular effects, such as pulmonary vasoconstriction, in the frontal cortex inhibiting the release of dopamine, In the striatum and the basal ganglia inhibiting the release of serotonin

Front 28

5-HT1D

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acts on the central nervous system, and affects locomotion and anxiety. It also induces vascular vasoconstriction in the brain.

Front 29

Glutamate

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excitatory neurotransmitter, NMDA receptor, bind glutamate and are activated. is involved in cognitive functions like learning and memory in the brain.

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NMDA receptor

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activation of an NMDA receptor increases the concentration of Ca2+ in the cell. The Ca2+ can in turn function as a second messenger in various signaling pathways

Front 31

excitotoxicity.

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Glutamate transporters rapidly remove glutamate from the extracellular space In brain injury or disease, they can work in reverse,This process causes calcium ions to enter cells via NMDA receptor channels, leading to neuronal damage and eventual cell death,

Front 32

MAO-A

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deaminates norepinephrine (noradrenaline), epinephrine (adrenaline), serotonin, and dopamine

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MAO-B

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preferentially degrades benzylamine and phenylethylamine.[1] Like MAOA, it also degrades dopamine.

Front 34

5-HT2B

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CNS: presynaptic inhibition, behavioural effects[3]
Vascular: pulmonary vasoconstriction[
regulate serotonin release via the serotonin transporter
can also lead to pathological proliferation of cardiac valves fibroblasts

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Dopamine receptor D1

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modulate dopamine receptor D2-mediated events
mediate some behavioral responses

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H1

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modulate circadian cycle
itching
systemic vasodilatation
bronchoconstriction (asthma)

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H2

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speed up sinus rhythm
Stimulation of gastric acid secretion
Smooth muscle relaxation
Inhibit antibody synthesis, T-cell proliferation and cytokine production

Front 38

Phenylethylamine

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psychoactive drug and stimulant effects
weight loss-related