Neuro: Schriefer Antiparkinson Agents

Front 1

What is Parkinson's Disease?

Back 1

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

know the symptoms!

Front 2

What are the signs and symptoms of PD due to?

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.

Front 3

What do individuals of PD have a deficiency of?

Back 3

Thus, individuals with PD have a deficiency of dopamine.

Front 4

Schematic Diagram of the basal ganglia

Back 4

Focus on the SNpc

- Resting tremor
- Loss of Inhibition
- Cholinergic Neurons act in deposition
- Cholenergic = stimulus
- Dopamine = inhibits

Front 5

PD and Dopamine receptors:

What is the cause of PD?

Back 5

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.

So you have a lose of Dopamine which inhibits movement so this is why you see tremor

Front 6

PD

wiki style

Back 6

a degenerative disorder of the central nervous system. The motor symptoms of Parkinson's disease result from the death of dopamine-generating cells in the substantia nigra, a region of the midbrain; the cause of this cell death is unknown. Early in the course of the disease, the most obvious symptoms are movement-related; these include shaking, rigidity, slowness of movement and difficulty with walking and gait. Later, cognitive and behavioural problems may arise, with dementia commonly occurring in the advanced stages of the disease.

Front 7

What are the main symptoms of PD?

Back 7

Tremor

Bradykinesia

Rigidity

Front 8

What kind of tremor will a PD pt have?

Back 8

Tremor – pill rolling contractions. Often present at rest but disappear during purposeful movement

Front 9

What is Bradykinesia?

Back 9

Bradykinesia – decreased spontaneous movement, loss of normal associated movement, slow initiation of movement

Front 10

What is Rigidity of PD due to?

Back 10

Rigidity – due to increased muscle tone

Front 11

What will a PD pt posture look like?

Back 11

Posture – progressive stooped position

Front 12

Are psychological changes associated with PD?

Back 12

Psychological changes such as depression and dementia

Front 13

What is the underlying MOA for PD pts?

Back 13

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

remember Cholinergic is stimulatory

Front 14

What are Parkinson varients?

Back 14

It has become apparent that what has been called Parkinson’s Disease is not a single disorder.

Symptoms vary and response to drugs vary.

Front 15

What is Parkinsonism?

Back 15

this is from wiki but read it****

neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability.[1] The underlying causes of parkinsonism are numerous, and diagnosis can be complex.[2] While the neurodegenerative condition Parkinson's disease (PD) is the most common cause of parkinsonism, a wide-range of other etiologies may lead to a similar set of symptoms, including some toxins, a few metabolic diseases, and a handful of non-PD neurological conditions.[3] Its most common cause is as a side effect of medications,

Front 16

What are the 2 ways we can pharmacologically intervene to treat PD?

Back 16

Decrease function of striatothalamic cholinergic pathway

Increase function of nigrostriatal dopaminergic pathway

Front 17

What is our first line tx for PD?

Back 17

Levodopa

Front 18

What is Levodopa?

Back 18

immediate precursor of dopamine which will cross the blood brain barrier

Front 19

What is the MOA of Levodopa?

Back 19

Pharmacological properties – MOA is the conversion of l-dopa to dopamine in CNS, thus increasing dopamine in the basal ganglia

Dopamine will not cross the BBB
BUT....L-dopa will --> once across the BBB converted into dopamine

Front 20

Diagram of L-dopa

Back 20

Front 21

What are the CNS changes due to Levodopa?

Back 21

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 22

What are the cardiovascular effects of Levodopa?

Back 22

Cardiovascular

Asymptomatic (usually) orthostatic hypotension

Dopamine stimulates both alpha and beta receptors

Cardiac stimulation

Front 23

What are the Endocrine effects of Levodopa?

Back 23

Endocrine

Dopamine important in regulation of anterior pituitary function

Prolactin secretion inhibited

Little change in growth hormone secretion

Front 24

What do you need to consider when taking Levodopa and Food?

Back 24

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

Front 25

Where is Ldopa metabolized?

Back 25

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

Front 26

What can happen with long term exposure of ldopa and metabolism?

Back 26

metabolism may be increased with prolonged therapy

Front 27

What happens to the L-dopa metabolites?

Back 27

Metabolites excreted in urine

Front 28

What is Parcopa?

Back 28

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

Front 29

What are adverse SHORT term effects of L-dopa?

Back 29

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

Front 30

What are LONG term effects of L-dopa?

Back 30

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

Front 31

What is the difference between the LONG term efftects:

"On-Off" syndrome
&
"End of Dose"

Back 31

“On-Off” syndrome – oscillations in performance involving rapid changes from akinesia to dyskinesia (different from “end of dose”).

End of Dose: took drug a long time ago and have metabolized it all....so become frozen

Front 32

What are some important drug interactions you need to know fir L-dopa?

***Objective

Back 32

1. Pyridoxine
2. “Typical” antipsychotic drugs
3. MAO inhibitors
4. Anticholinergic drugs
5. Tricyclic antidepressants

Front 33

What do Pyridoxine (vitamin B6) interactions cause with l-dopa

Back 33

increases peripheral conversion of dopa to dopamine

Front 34

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

Back 34

MAO inhibitors increase the effects of dopa, may lead to hypertensive crises, inhibits metabolism of L-Dopa….used to treat depression

Front 35

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

Back 35

Tricyclic antidepressants – may aggravate hypotensive symptoms

Front 36

Next drug to treat PD

Back 36

Carbidopa

Front 37

What is Carbidopa

Back 37

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.

Front 38

What is the MOA for Carbidopa?

Back 38

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

so you increase the amount of drug to the brain

carbidopa --> DOES NOT cross the BBB

Front 39

What are the advantages of Carbidopa?

Back 39

Allows reduction in dopa dose

Nausea and vomiting are decreased

Cardiac side effects decreased

B6 Pyridoxine antagonism prevented

Front 40

Compare how available l-dopa and carbidopa are for tx.

Back 40

Front 41

which drug is more available in the CNS?

Back 41

Carbidopa

Front 42

What are the adverse side effects of Carbidopa?

Back 42

Increased central side effects of dopa

Early development of long term side effects possible

Activation of COMT pathway

Front 43

What is the COMT pathway?

Back 43

In the prefrontal cortex, however, there are very few dopamine transporter proteins, and dopamine is inactivated instead by reuptake via the norepinephrine transporter (NET), presumably on neighboring norepinephrine neurons, then enzymatic breakdown by catechol-O-methyl transferase (COMT) into 3-methoxytyramine

Front 44

What 2 drugs act as COMT inhibitors?

Back 44

Tolcapone
&
Entacapone


Pneumonic: (Remember Al Capone and Chicago Organized Mob)

Front 45

What is the MOA of COMT inhibitors?

Back 45

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

Front 46

What is the difference between Tolcapone and Entacapone?

Back 46

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

Front 47

diagram of how Capones work (COMT inhibitors)

Back 47

COMT --> depgrades dopamine in the synapase so Capones block COMT

Front 48

What are adverse effects of COMT inhibitors?

Back 48

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 49

What is the preferred drug due to side effects:

Tolcapone or Entacapone?

Back 49

Entacapone

Front 50

what are the clinical uses of the COMT inhibitors?

Back 50

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.

Front 51

What is Stalevo?

Back 51

A combination of carbidopa + l-dopa + entacapone is now available (Stalevo).

Front 52

End COMT inhibitors

Back 52

Begin Dopamine Agonists

Front 53

What are your dopamine agonists?

Back 53

Ergot compounds which possess dopaminergic activity.

Bromocryptine (bro moe krip’ teen – Parlodel) is the prototype.

Front 54

What is the MOA of dopamine agonist?

Back 54

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.

Front 55

Are dopamine agonists used much today?

Back 55

Not used too much anymore
LSD --> hallucinattions

Front 56

What are your Non-ergot DA Agonists

Back 56

Ropinirole
&
Pramipexole

Direct stimulation of DA receptors in striatum

Front 57

What is the 1st line choice for PD?

Back 57

Ropinirole
and
Pramipexole

Front 58

What do the Non-ergot DA agonists do?

Back 58

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

Produce less dyskinesia and lower incidence of repsonse fluctuation

Front 59

Diagram of Dopamine Agonists

Back 59

Front 60

Adverse effects
Non-ergot DA agonists

Back 60

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 can cause sudden onset of sleep with no warning

Front 61

Non-ergot DA agonists

Use***EXAM!!!!!!!!!!!

Back 61

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

Front 62

What is another use of Ropinorole and Pramipexole?

Back 62

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

Front 63

What if your PD pt just froze?

CANNOT MOVE.....what drug can you give him/her?

Back 63

Apomorphine


An old drug with a new use. Apomorphine is a non-ergot DA agonist recently approved for rescue treatment of PD patients with “off” episodes (freezing).

Is given by SC injection

Adverse effects include vomiting, orthostatic hypotension and syncope.

Front 64

This is an ANTIVIRAL drug found to be effective against PD.

Back 64

Amantadine

Front 65

Amantadine An antiviral agent found to be effective against PD.

MOA?

Back 65

Apparently acts by increasing dopamine release from intact dopaminergic neurons. Also blocks NMDA receptors (glutamate receptor).

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.

Front 66

What is the disadvantage of Amantadine?

Back 66

Limitation of amantadine --> only works a month or 2 and then has limited value

Front 67

picture of Amantadine

Back 67

Front 68

What are the adverse effects of Amatadine?

Back 68

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 69

What is Livido reticularis?

Back 69

Livido reticularies -> see white streaks --> vasocontriction --> localized vasoconstriction and get discoloration of the skin

Front 70

What is a drug that effects mainly the tremor of PD?

Back 70

Anticholinergic drugs - used as adjunct to l-dopa therapy

Front 71

Anticholinergic drug MOA

Back 71

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

Front 72

What are your Anticholinergic drugs

Back 72

Trihexyphenidyl
&
Benztropine

Front 73

Trihexyphenidyl and benztropine
what is main use?

Back 73

Decrease tremor

Little effect on rigidity and bradykinesia

Generally have little peripheral effect, but may reduce some autonomic symptoms

Front 74

Trihexyphenidyl and benztropine

Adverse reactions

Back 74

CNS – confusion, delerium, somnolence, hallucinations

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

Front 75

When do you see PD?

Back 75

Generally older pts have this disease

Most are in 50s and 60s who develop

Don’t see symotopms till see 80% of nerves die

Front 76

What are MAO B Inhibitors

Back 76

Selegiline
&
Rasagiline

Front 77

MOA of for the MAO-B inhibitors

Back 77

Pharmacological properties – drugs specifically inhibits MAOB. This decreases catabolism of DA

Front 78

What is a benefit of Rasagiline?

Back 78

Rasagiline may have neuroprotective effect. Slows progression of the disease

Front 79

MAO B inhibitors
Adverse effects

Back 79

Nausea (10%), dizziness (7%), hallucinations, confusion, depression

Insomnia if taken late in the day (take early in 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.

Potential for hypertensive crisis

Front 80

MAO-B picture

Back 80

Front 81

What MAOB inhibitor can be used as transdermal patch for the tx of depression?

Back 81

selegiline

Front 82

GOAL of Rx for PD

Back 82

No cure of underlying pathology (although gene therapy is being tested)

Drug + physiotherapy + exercise + psychological support → provide maximal symptomatic relief and permits a near normal lifespan.

Front 83

Management of PD pic

Back 83

Front 84

What is Huntington's Disease?

Back 84

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

Front 85

What is the Tx for Huntington's Disease?

Back 85

Tetrabenazine

Front 86

What does Tetrabenazine do?

Back 86

Acts by depleting CNS monoamines (DA)

Front 87

Adverse effects of Tetrabenazine

Back 87

Adverse rxns – hypotnesion, sedation, depression.

Front 88

make sure you understand this shit......

Back 88