Nervous System- Anti-Parkinson Drugs By Schriefer

Front 1

Nervous System- Anti-Parkinson Drugs by Schriefer

Back 1

Nervous System- Anti-Parkinson Drugs by Schriefer

Front 2

Parkinson’s Disease (PD) signs and symptoms due to what

Back 2

The signs and symptoms of PD are due to the progressive degeneration of the inhibitory dopaminergic pathway projecting from the substantia nigra to the caudate nucleus. Thus, individuals with PD have a deficiency of dopamine.

A prevalent neurologic disorder characterized by progressive motor dysfunction due to tremor, rigidity, bradykinesia, and disturbance of posture.

Front 3

Which are the most important receptors in the cause and treatment of PD?

Back 3

D1 (increase cAMP) and D2 (decrease cAMP) receptors are abundant in the striatum and are the most important receptors in the cause and treatment of PD.

Front 4

Sx

Back 4

Tremor – pill rolling contractions. Often present at rest but disappear during purposeful movement
Bradykinesia – decreased spontaneous movement, loss of normal associated movement, slow initiation of movement
Rigidity – due to increased muscle tone
Posture – progressive stooped position
Psychological changes such as depression and dementia

Neurochemical defect:
Normal voluntary movement is controlled by a balance of dopaminergic and cholinergic nervous activity. In PD, there is a deficiency of dopamine, allowing cholinergic dominance.

Front 5

How can we pharmacologically intervene?

Back 5

Decrease function of striatothalamic cholinergic pathway

Increase function of nigrostriatal dopaminergic pathway

Front 6

Levodopa

why does it work?
other pharm properties

Back 6

immediate precursor of dopamine which will cross the blood brain barrier

Pharmacological properties: MOA is the conversion of l-dopa to dopamine in CNS, thus increasing dopamine in the basal ganglia
-No change in muscle tone or movement in normals. Bradykinesia and rigidity are reversed quickly; reversal of tremor requires continued therapy
-Changes in mood associated with PD are reversed; patients more alert and interested in environment. Dementia may not reverse

Front 7

CV, Endocrine

Back 7

Cardiovascular:
Asymptomatic (usually) orthostatic hypotension; Dopamine stimulates both alpha and beta receptors; Cardiac stimulation

Endocrine:
Dopamine important in regulation of anterior pituitary function
Prolactin secretion inhibited
Little change in growth hormone secretion

Front 8

pharmacokinetics of L-dopa

Back 8

Disposition:
Well absorbed orally but can be altered by
Rate of gastric emptying
pH of gastric fluids
Degradation by enzymes
Dietary protein

95% of l-dopa is metabolized in the periphery to dopamine; metabolism may be increased with prolonged therapy

Metabolites excreted in urine

Parcopa – orally dissolving, immediate release dopa + carbidopa mixture is now available.

Front 9

Adverse effects

early and long term effects

Back 9

Adverse effects:
Majority of patients treated with l-dopa develop side effects. Intensity and type vary at different stages of therapy

Early side effects
Dose dependent; tolerance may develop
GI – nausea, vomiting (80%)
CVS – orthostatic hypotension (30%), cardiac arrhythmias

Long term effects – severity correlates with the degree of clinical improvement, duration of therapy and dose. No tolerance develops.
-Abnormal involuntary movements (dyskinesia) (80% after 1 year). Reduction in dosage required
-Psychiatric and behavioral disturbances (15%)
-“On-Off” syndrome – oscillations in performance involving rapid changes from akinesia to dyskinesia (different from “end of dose”).

Front 10

Drug interactions

Back 10

Pyridoxine (vitamin B6) increases peripheral conversion of dopa to dopamine

“Typical” antipsychotic drugs are dopaminergic antagonists and thus counteract the effects of dopa

MAO inhibitors increase the effects of dopa, may lead to hypertensive crises

Anticholinergic drugs may slow gastric emptying time and decrease absorption of l-dopa

Tricyclic antidepressants – may aggravate hypotensive symptoms

Front 11

Carbidopa

what it does, what are the advantages?

Back 11

L-aromatic amino acid decarboxylase is responsible for the conversion of dopa to dopamine. Its activity causes 95% of a dose of dopa to be converted to dopamine before entering the CNS.
Carbidopa is an inhibitor of the peripheral decarboxylase and allows greater amounts of dopa to enter the CNS. Only available in combination with l-dopa (Sinemet).

Advantages:
Allows reduction in dopa dose
Nausea and vomiting are decreased
Cardiac side effects decreased
Pyridoxine antagonism prevented

Front 12

adverse effects

Back 12

Adverse effects – increased central side effects of dopa
Early development of long term side effects possible
Activation of COMT pathway

Slow release form (SINEMET CR) is available. New on the market is a formulation (Parcopa) which dissolves on the tongue. This may be useful since PD patients often have trouble swallowing.

Front 13

COMT Inhibitors

name them, and how they work

Back 13

Tolcapone (tol’ ca pone – Tasmar)
Entacapone (en ta’ ca pone – Comtan)
(Remember Al Capone and Chicago Organized Mob)

Pharmacological properties – drugs inhibit COMT, thereby increasing the duration of action of l-dopa and dopamine (COMT inactivates l-dopa and dopamine).

There is a difference in these drugs in that tolcapone is highly lipid soluble and reaches CNS. Entacapone does not.

Clinical uses – adjunct to l-dopa in patients with stable PD and in patients with end of dose (“wearing off”) problems with l-dopa/carbidopa therapy.
A combination of carbidopa + l-dopa + entacapone is now available (Stalevo).

Front 14

adverse reactions

Back 14

Adverse reactions – diarrhea, bright yellow discoloration of urine, increased l-dopa side effects.

Increased amino-transferase activity (indication of hepatotoxicity) with tolcapone may require DC. Apparently not a problem with entacapone.

Front 15

Dopamine agonists (that don't have to be converted by these dying neurons)

Back 15

Ergot compounds which possess dopaminergic activity. Bromocryptine (bro moe krip’ teen – Parlodel) is the prototype.

Act by direct stimulation of dopamine receptor

Rapidly absorbed, effective levels reached quickly and persists 3-4 times longer than l-dopa

May prove useful as adjunct to l-dopa therapy and allow decrease in dopa dosage.

hallucinations!

Front 16

Non-ergot DA Agonists (which are more often used compared to the ergots)

Back 16

Ropinirole (ro pi ni role – Requip; D2) and pramipexole (pra mi pex’ ole – Mirapex; D3) – non-ergot DA agonists.

Direct stimulation of DA receptors in striatum

Pramipexole may also have a neuroprotective effect, slowing progression of PD

Used as initial therapy (without l-dopa) or as adjunctive therapy with l-dopa

Ropinorole and pramipexole have been approved for the treatment of restless leg syndrome. Other DA agonist may also be effective.

Front 17

Non-ergot DA Agonists adverse effects

Back 17

Adverse effects:
Nausea, dizziness, somnolence, headache, hallucinations, impulse control problems.
-Less dyskinesia and on-off syndrome.

Syncope or hypotension can occur early in treatment with ropinirole

Pramipexole (and pergolide) can cause sudden onset of sleep with no warning

Front 18

a non-ergot DA agonist recently approved for RESCUE treatment of PD patients with “off” episodes (freezing).

Back 18

Apomorphine (Apokyn)

Is given by SC injection
Adverse effects include vomiting, orthostatic hypotension and syncope.

Front 19

Amantadine (a man’ ta deen – Symmetrel)

what it does, adverse effects

Back 19

An antiviral agent found to be effective against PD.

Apparently acts by increasing dopamine release from intact dopaminergic neurons. Also blocks NMDA receptors.

Is effective quickly but for short time (6-8 weeks). Also used to control dyskinesias occurring with l-dopa therapy late in progression of disease.

Adverse effects – are mild and reversible and include:
-Hallucinations, confusion, and nightmares
-Insomnia, dizziness, lethergy, slurred speech
-Long term use may result in **livido reticularis

Front 20

Anticholinergic drugs used as adjunct to l-dopa therapy

Back 20

Pharmacological properties – these agents block the unopposed cholinergic effects in the basal ganglia of PD patients.

Trihexyphenidyl (Artane) and benztropine (Cogentin) are used

Decrease tremor
Little effect on rigidity and bradykinesia
Generally have little peripheral effect, but may reduce some autonomic symptoms

Front 21

Anticholinergic drugs adverse effects, CNS, peripheral

Back 21

Adverse reactions
CNS – confusion, delerium, somnolence, hallucinations

Peripheral – may produce cycloplegia, constipation, and urinary retention in certain patients

Front 22

MAO B Inhibitors.. name them, what does it do, adverse, other uses

Back 22

Selegiline (Eldepryl)
Rasagiline (Azilect)

Pharmacological properties – drugs specifically inhibits MAOB. This decreases catabolism of DA (dopamine breakdown).
Rasagiline may have neuroprotective effect

Adverse effects
-Nausea (10%), dizziness (7%), hallucinations, confusion, depression
-Insomnia if taken late in the day
-Dose must be kept low (10 mg/day or less) to retain specificity for MAOB, otherwise adverse reactions associated with non-specific MAOs occur (it would inhibit MAOA as well if there's too much dose)

Transdermal selegiline (Emsam) now available for the treatment of Depression.

Front 23

Functional impairment..how to tx

Back 23

dopamine agonists (preferred)

or

l-dopa w/ or w/o COMT inhibitor

Front 24

initial neuroprotection

Back 24

Rasagiline (preferred) or selegiline

Front 25

first, second, third line

Back 25

At the top: Rasagiline, a developing new drug (pot'l first line)

1. dopamine agonist
2. L-dopa (always with carbidopa)
3. COMT inhibitor
4. other stuff

Front 26

Huntington’s Disease (HD)

name a drug and what it helps, how it works

nevermind. no question about this.

Back 26

HD is a genetic disorder characterized by progressive chorea and dementia.

Tetrabenazine (Xenazine) recently approved for treatment of chorea associated with HD.

Acts by depleting CNS monoamines (DA)
Adverse rxns – hypotnesion, sedation, depression.