Pharma 3: Treatment Of Parkinsons

Question 1

Levodopa

Precursor of:

Answer 1

Precursor of dopamine which crosses BBB

Dopamine is peripheral product of levodopa

Question 2

LEVODOPA

T1/2 and consequence on dose

Answer 2

T1/2 very short (1-2hrs)—> fluctuations in plasma concentration

There4 need large doses

Question 3

LEVODOPA

Adverse effects

Answer 3

1. Dyskinesia ie involuntary movements result from:OVERACTIVITY of dopamine on receptors of basal ganglia
2. “On-off)” effects due to t1/2–>fluctuations in plasma concentrations
3. N/V + anorexia due to stimulation of CHEMORECEPTOR ZONE OF MEDULLA
4. Tachycardia due to dopaminergic effects on heart
5. Behavioral changes eg, confusion + hallucinations similar to schizophrenia due to increased dopamine activity in brain

Question 4

How do you optimize levodopa treatment

Answer 4

Combining it with drugs that enhance central effects and MINIMIZE PERIPHERAL EFFECTS.

Question 5

Dopa decarboxylase inhibitors MOA

Answer 5

They decrease dopa metabolism peripherally and its metabolism in GI leading to fewer side effects by inhibiting dopa decarboxylase

Question 6

Dopa decarboxylase inhibitors

Answer 6

Carbidopa

Benserazide

Question 7

Result of taking levodopa with Carbidopa/Benserazide

Answer 7

1. Minimize PERIPHERAL SE ONLY (arrhythmia, nausea) ie Dyskinesia still present
2. Use dopa at lower dose (80%less)

Question 8

Carbidopa/Benserazide adminstration

Answer 8

Orally with levodopa

Question 9

Peripherally acting dopamine ANTAGONIST

Answer 9

DOMPERIDONE

Question 10

Domperidone MOA

Answer 10

Peripheral Dopamine antagonist that does NOT cross bbb but can act on the chemoreceptor trigger zone (outside bbb) to prevent Nausea + anorexia

Question 11

Domperidone useful for

Answer 11

1. Nausea
2. Headache
3. Dizziness
4. Dry mouth

Question 12

MAO-B inhibitor

Answer 12

SELEGILINE

Question 13

Selegiline MOA

Answer 13

Selectively blocks MAO-B to selectively inhibit dopamine metabolism in brain

Question 14

Effect of Selegiline

Answer 14

Reduces motor complications of Levodopa

Question 15

SELEGILINE administration

Answer 15

Orally with levodopa-carbidopa

Question 16

Selegiline metabolism

Answer 16

Metabolized into amphetamine and methamphetamine—>cause insomnia if taken later than mid afternoon

Question 17

Selegiline can possibly

Answer 17

Neuroprotective ie slow progression of newly diagnosed patients

Question 18

COMT inhibitor

Answer 18

Entacapone

Tolcapone

Question 19

Entacapone/Tolcapone

MOA

Answer 19

When peripheral dopamine decarboxylase is inhibited by CARBIDOPA, a byproduct; 3-0methyldopa is formed. 3-0-methyldopa competes with levodopa for actuve transport into CNS.

Nutshell: levodopa+carbidpoa—

Question 20

Entacapone/tolcapone

Effect

Answer 20

Reduce symptoms of “waring off” in patients taking levodopa-carnidopa

Question 21

Entacapone/tolcapone

Administration

Answer 21

Orally

With levodopa-carbidopa +/- selegiline

Question 22

Entacapone/tolcapone

Adverse effects

Answer 22

1. Postural hypotension
2. Nausea
3. Anorexia
4. Dyskinesia
5. Hallucinations
6. Sleep disorders

“Similar to levodopa-carbidopa”

Question 23

Levodopa’s effect on dopaminergic neurotransmisison

Answer 23

Enhances it by enhancing synthesis of dopamine in surviving substansia nigra cells

Question 24

Pros of DOPAMINE RECEPTOR AGONISTS

Answer 24

1. Duration of action > levodopa
2. Can be used as a single agent early in disease or with levodopa/carbidpoa in later stages
3. Effective in early treatment of motor symptoms of pd
4. Controls motor fluctuations associated with levodopa (newer drugs are at less risk of causing motor dyskinesia)

Question 25

Pramipexole + Ropinirole

MOA

Answer 25

Potent agonists of D2 receptors

Question 26

Pramipexole and Ropinirole

Administration

Answer 26

Added to levodopa if levodopa ineffective or to prevent on off fluctuations

Question 27

Pramipexole and Ropinirole

Adverse effects

Answer 27

Less likely to cause dyskinesia

*CAN CAUSE:

1. Hallucinations
2. Confusion
3. SWELLING OF ANKLES
4. COMPULSIVE BEHAVIOR eg uncontrolled shopping and eating

Question 28

Rotigotine

MOA

Answer 28

Dopamine receptor agonist

Question 29

Rotigotine

Administration

Answer 29

Once daily transdermal patch changed every 24 hrs

Question 30

Rotigotine

Side effects

Answer 30

Mild skin irritation that can be avoided by rotating the sites of adhering the patch

Question 31

Apomorphine

MOA

Answer 31

Dopamine receptor agonist

Question 32

Apomorphine administration

Answer 32

Self injectable (up to five times a day)

AS A RESCUE for advanced pd or sever “off” episodes

Question 33

Apomorphine side effects

Answer 33

N/V

Question 34

Amantadine MOA

Answer 34

Increases dopamine release AND blocks cholinergic receptors

Question 35

Amantadine administered

Answer 35

1. Prescribed alone for short term relief of mild ie early pd
2. • Carbidopa/levodopa during late stages to control the dykinesias caused by carbidopa/levodopa

“Less effacious than levodopa or ropinirole ie only for mild reflief”

Question 36

Amantidine adverse effects

Answer 36

1. Purple mottling of skin
2. Ankle swelling
3. Restlessness
4. Agitation
5. Confusion
6. Hallucinations
7. At high dose—> acute toxic psychosis

Question 37

MUSCARINIC ACETYLCHOLINE RECEPTOR ANTAGONIST

Answer 37

Atropine

Benztropine—> less peripheral effects than atropine

Question 38

Atropine, Benztropine

Therapeutic use

Answer 38

Less than levodopa

Reduce tremor more than rigidity and bradykinesia

+SIDE EFFECTS

There4 used in pts on antipsychotic drugs, which are dopamine antagonists

Question 39

Benztropine

Side effects

Answer 39

1. Dry mouth
2. Constipation
3. Impaired vision
4. Urinary retention