1.

To describe the following diseases:

a. Parkinsonism
b. Huntington’s Disease
2. To explain the causes of such diseases.
3. To determine signs and symptoms of the listed diseases.
4. To relate causes and signs and symptoms of diseases with
the type of pharmacological treatment to be
implemented.
5. To discuss the pharmocokinetics and pharmacodynamics
of selected drugs for parkinsonism
6. To associate drug mechanism to its adverse effects.
Acetylcholine - the acetic acid ester of choline, which is a
neurotransmitter at cholinergic synapses in the central,
sympathetic, and parasympathetic nervous system
Akinesia - loss or inability to initiate movement
Bradykinesia - abnormal slowness of movement
Catechol – O – methyltransferase – enzyme that
metabolize dopamine to 3-methyldopa (peripherally) or
3- methoxypyramine (brain)
Dopamine - A monoamine neurotransmitter formed in the
brain by the decarboxylation of dopa and controls
secretion of GABA
Dopamine agonist – drugs capable of binding and
activating dopamine receptors
DOPA decarboxylase – converts L-DOPA to its
active form dopamine
GABA - neurotransmitter that slows down the
activity of nerve cells in the brain
Glutamate - an excitatory neurotransmitter; a salt of
glutamic acid
Hypokinesia - decreased amplitude, slowness, loss
of movement
Hyperkinesia - excessive, abnormal, involuntary
movements
L – Amino Acid Transporter – a protein carrier
responsible for the active transport of levodopa
through the blood brain barrier
Postural Instability - loss of balance that causes
someone to feel unsteady
Tremor - a shaking or vibrating movement
• A chronic progressive degenerative disorder of
the central nervous system which has the
hallmark of loss of pigmented, dopaminergic
neurons of the substantianigra pars compacta.
(Goodman and Gilman)
• Characterized by a combination of rigidity,
bradykinesia, tremor and postural instability
that can occur for a variety of reasons but is
usually idiopathic. (Katzung)
Dopamine Synthesis

3,4-dihydroxyphenylalanine
 Dopamine Metabolism

monoamine
oxidase (MAO)
monoamine
oxidase (MAO)

Aldehyde dehydrogenase

3,4dihydroxyphenylace
tic acid

COMT- catechol-O-methyl tranferase

 Homovanillic acid (HVA)-the principal metabolite of DA
 Metabolized by catechol-O-methyltransferase
(COMT) from DOPAC.
 indicators of DA turnover; represent dopaminergic
activity
 Functional Circuitry between
Cortex, Basal Ganglia and Thalamus

E
• It has 3 cardinal
features:
1. Bradykinesia
2. Muscular rigidity
3. Resting tremor
 The Alpha Synuclein

A protein found in the

brain and some to enteric
nervous system.

It is functionally part of the

vesicle formation at the
presynaptic terminal

When these protein

becomes aggregated,
formation of the “lewy
bodies” results.
Lewy Body
Hypothesis of Parkinsons
Disease Timeline
 Epidemiology

• Protective factors against parkinsonism:

a. Cigarette smoking
b. Coffee
c. Anti-inflammatory drug use
d. High serum uric acid levels
• Dopamine does not cross the blood-brain
barrier and if given into the peripheral
circulation has no therapeutic effect in
parkinsonism.
• However, Levodopa, the immediate metabolic
precursor of dopamine, does enter the brain via
L-amino acid transporter (LAT) where is it
decarboxylated to dopamine.
• Dopa is the amino acid precursor of dopamine
and norepinephrine
• Form: Tablet
• Dose: 25 mg carbidopa + 100 mg levodopa
("25/100" tablet), 3x daily and gradually
increased (25 mg carbidopa + 250 mg
levodopa), 3-4x daily
• Taken 30-60 minutes before meals
• Mechanism of Action: acting as exogenous
supplementation of dopamine
• Absorption: rapidly absorbed from the small intestine but
its absorption depends on the rate of gastric emptying,
and pH of gatric content.
• Distribution: both drugs widely distributed; 1-3% of
levodopa enters CNS.
• Metabolism:
>plasma concentration peaks between 1-2 hours after
oral dose.
> it undergoes first-pass hepatic metabolism.
> Main metabolic products: Homovanillic acid (HVA) and
dihydroxyphenylacetic acid (DOPAC)
• Elimination:
> Half life is between 1-3 hours.
> 2/3 of the dose appears in the urine within 8 hours
Levodopa and Carbidopa
• Gastrointestinal Effects
> When levodopa is taken alone:
80% suffers from nausea, anorexia and vomiting
> This can be minimized if the drug is:
1. taken in divided doses
2. taken with or immediately after meals
3. antacids taken 30-60 minutes before
levodopa
> When Levodopa is taken with Carbidopa, less than
20% of cases are recorded for having GI problems
• Cardiovascular Effects
>Tachycardia, Ventricular extrasystoles and
rarely, Atrial Fibrillation.
> Incidence of these cardiac arrhythmias is
low and may be even reduced if taken with
carbidopa.
> Postural Hypotension is common.
> Hypertension may also occur.
 Adverse effects of Levodopa

• Behavioral Effects
> Anxiety
> Agitation > Somnolence
> Insomnia > Confusion
> Nightmares > Euphoria
> Delusion > Hallucination
• Reduce or withdraw the medication
• Atypical antipsychotic agents like clozapine,
olanzapine, quetiapine and risperidone may be
used.
 Adverse effects of Levodopa

• Dyskinesias and Response Fluctuations

>Dyskinesias happen in 80% of patients taking levodopa
for more than 10 years.
•
>Choreoathetosis of face and distal extremities is the most
common presentation.
 LEVODOPA

• Response Fluctuations occur with increasing

frequency as treatment continues.
- Response related to timing of drug
(wearing-off reactions / end-of-dose akinesia)
- Response unrelated to timing of drug
(on –off phenomenon)

> Patients with off periods, subcutaneous

apomorphine provides temporary benefits.
 Adverse effects of Levodopa

• Miscellaneous Adverse Effects

>Mydriasis that may lead to acute glaucoma

 Blood dyscrasias
 Positive Coomb’s test
 Hot flushes
 Gout
 Brown saliva, urine and vaginal secretions
 Mild elevations of BUN, serum transaminases,
alkaline phosphatases and bilirubin
Mydriasis and Glaucoma
 Drug Holidays

• Discontinuance of the drug for 3-

21 days may temporarily improve
responsiveness to levodopa and
alleviate some of its adverse
effects

• Carries the risks of aspiration

pneumonia, venous thrombosis,
pulmonary embolism and
depression
 Drug interactions

• Do not take Levodopa

with Pyridoxine (Vit.
B6)
 Drug interactions

• Do not take with

Monoamine Oxidase A
inhibitors or within 2
weeks of their
discontinuance.
 Contraindications
• Levodopa should not be given to:

•
 Levodopa

- Needs special
attention to be given
among:
1. Patients with active
peptic ulcer
2. Patients with history
of melanoma or
suspicious
undiagnosed skin
lesions
For first-line therapy
 Can be added to Carbidopa-
Levadopa doses

 Old DA - ergot derivatives

 Bromocriptine(Parlodel)
 Pergolide (Permax)

 Non-ergot derivatives -
supercedes old DA
 Pramipexole (Mirpex)
 Ropinorole (Requip)
Dopamine Receptor Agonist
Binds directly and selectively to
Dopamine receptors

Duration of action is longer than

levadopa.(8-24 hrs)

Does not require enzymatic

conversion

Does not compete with active

transport

More limited adverse effects

 NEW DOPAMINE AGONIST OLD DOPAMINE AGONIST
-Non-ergot derivatives -ergot derivatives

ROPINOROLE (REQUIP)
- Indirect Pathway(D2) BROMOCRIPTINE
(PARLODEL)
-scavenge H202
- indirect Pathway(D2)
-metabolized by CYP1A2

D4 D3 D2 D1 D5

PERGOLIDE (PERMAX)
- Indiret Pathway(D2)
-Direct Pathway(D1)

PRAMIPEXOLE (MIRPEX)
- Indirect Path.(D3)
- scavenge H2O2
 ROTIGOTINE
– - (2007) Skin patch, it supposedly provides more continous
dopaminergic stimulation than oral medications.

2008- recalled in US because of crystal formation on patches

✔ ✔
Cardiac Arrhythmias
are indications of
✔ ✔ discontinuing
treatment

✔
Serious cardiac
problems may arise
✔ from ergot derivatives
✔
Miscellaneous Adverse Effects:
 Given via subcutaneous injection to provide temporary
relief of “off ” periods of akinesia (Rescue)
 Rapid but Short period of effectiveness (10min- 2 h)
 Binds with D1 and D2 receptors
NAUSEA is often troublesome, especially at the
initiation of apomorphine treatment; accordingly,
pretreatment with the antiemetic trimethobenzamide
(300 mg three times daily) for 3 days.
 Contraindications:

a. History of psychotic illness

b. Recent myocardial infarction
c. Active peptic ulcer
d. Peripheral vascular disease
 Monoamine Oxidase Inhibitors

• 2 types of Monoamine
Oxidase:
1. Monoamine Oxidase
A – metabolizes NE,
serotonin, and
dopamine
2. Monoamine
Oxidase B –
metabolizes Dopamine
selectively
 Selegiline Rasagiline

Form Tablet / capsule tablet

5 mg with breakfast; 5 mg 1 mg/d

Dose
with lunch Adjunct therapy = .5 – 1 mg/d

Selective irreversible
Inhibitor of monoamine
Mechanism of Action inhibitor of monoamine
oxidase B
oxidase B

Insomnia, less
Flu-like symptoms, nausea,
Adverse Effects antiparkisonism effect
headache
when given alone
 Pharmacokinetics
Selegiline Rasagiline
Rapidly absorbed from the Rapidly absorbed following
Absorption gastrointestinal tract oral administration

Plasma protein binding – Plasma protein binding – 88-

Distribution 85% 94%

Via CYP 2B6 and CYP 3A4

Complete biotransformation
Metabolism isozymes and to a minor
in the liver prior to excretion
extent, CYP2A6

Urine (Primarily)
Urine (Primarily)
Excretion Half life – 1.2 to 2 hours
Feces (Secondarily)
Half life – 3 hours
 Drug interactions

• Do not take Selegiline or Rasagiline with:

>Meperidine
>Tramadol
> Methadone
>Propoxyphene
>Cyclobenzaprine
> St. John’s wort
• Avoid over-the-counter cold preparations
Serotonin Syndrome
 Contraindications

• Selegiline and Rasagiline should not be

given to:
1. Patients taking Tricyclic antidepressant
and SSRI
2. Patients taking Monoamine oxidase
inhibitors (non selective)
 Inhibition of L-aromatic amino
acid decarboxylase is associated
with compensatory activation of
COMT.
*

**Adjunctive therapy in patients

treated with levodopa especially
for patients who developed
response fluctuations
1. Tolcapone (TASMAR)
2. Entacapone (COMTAN)

COMT inhibitors prolong the

action of levadopa by
diminishing metabolism.

Levadopa clearance:
DECREASED
Levadopa Bioavailability:
INCREASED
Adverse Effects:
Related to increased plasma
concentrations of levadopa these
include:
– Dyskinesias
– Nausea
– confusion

Tolcapone has been associated with

death from acute hepatic failure.
Patient consent is needed with LFT
test. No such toxicity has been
reported with Entacapone.
 Talcopone Entacapone

Form Tablet / capsule Tablet/ capsule

Dose 100-200 mg; 3x/day 200 mg; 5x/ day

Mechanism of Action COMT Inhibitor COMT Inhibitor

(Peripheral/ Brain) (Peripheral)

Adverse Effects Liver Toxicity No Liver Toxicity

Dyskinesia, nausea, Dyskinesia, nausea, confusion,
confusion, orange urine orange urine
 Antiviral drug with anti-Parkinsonian properties.
 Mechanism of action is unclear
 Potentiates dopaminergic function by modifying synthesis,
release, or reuptake of dopamine.

 Therapeutic Effectiveness –
 Less effective than levodopa, but lesser adverse effects
 Therapeutic benefits are short-lived.
 100 mg 2/3x a day
 Well tolerated
 Antimuscarinic drugs
- Used widely before the discovery of
levodopa
- ATROPINE: is the prototype
- Blocks the action of Ach at
muscarinic receptors
- Improves tremor and rigidity but
have little effect on bradykinesia
Acetylcholine-blocking drugs
Acetylcholine-blocking drugs
These drugs are poorly
tolerated by the elderly.

Acute suppurative
parotitis sometimes
occur due to dryness of
the mouth
 Antimuscarinic drugs

- Improves tremor and rigidity but

have little effect on bradykinesia

- Antimuscarinic drugs ┼ levodopa

provide more effective therapy.
Some drugs with antimuscarinic properties
used in parkinsonism
 Benztropine
Biperiden Orphenadrine
Mesylate
Form Tablet Tablet Tablet/ Liquid

Dose 1-6 mg 2-12 mg 150-400 mg

Specific mode of
action is unknown,
Binds and inhibits
Thought to act by but it is thought that
both histamine H1
competitively these agents partially
receptors and
antagonizing block central
NMDA receptors. It
acetylcholine (striatal) cholinergic
Mode of Action restores the motor
receptors in corpus receptors, thereby
disturbances induced
striatum to restore helping to balance
by neuroleptics, in
neuromuscular cholinergic and
particular the
balance. dopaminergic
hyperkinesia.
activity in the basal
ganglia
headache, vision
Tachycardia, Visual changes, Constipation, try
hallucination, narrow sleeplessness, mouth, blurred
Adverse Effect
angle glaucoma, trembling of the vision, trouble
finger numbness hands and dry breathing
mouth.
Treatment starts with low dose
-Dosage gradually increased until
benefit occurs or adverse effect limit
increments
- If patient do not respond to one
drug, a trial with another class is used
Thalamotomy/ Posteroventral pallidotomy
-Deep Brain Stimulation

• Contraindicated in
patient with
Atypical
Parkinsonism
Dementia
Failure to respond to
dopaminergic
medication
-Antioxidants
-Antiapoptotic agents
-Glutamate antagonist
 Gene Therapy

Adeno Associated Virus Type 2

2. AADC (Aromatic Acid
Decarboxylase)

Putamen

To increase metabolism of
levodopa to dopamine
4 Dopamine Pathways
Therapy for nonmotor manifestations

Cognitive decline

-Rivastigmine (1.5-6
mg twice daily)
-Memantine (5-10
mg daily)
-Donepezil (5-10 mg
daily)
 Affective disorder
- Antidepressants or anxiolitic agents
 Excessive Daytime Sleepiness
-Mandafinil (100-400mg in the morning)
• -deplete biogenic
monoamines from • Block dopamine
their storage sites receptors
 Loss of neurons
I from the striatum

GABA

Dopamine
E
E
I

E
 Deplete amine transmitters (esp
Mechanism of
Dopamine);
Action Reversibly inhibits VMAT2

Effects Reduce chorea severity

Absorption Intestinal tract; 75%

Brain; Protein Bound: 82-85%; 59-68%

Distribution (metabolites)
Liver; alpha-hydroxytetrabenazine, beta-
Metabolism hydroxytetrabenazine
Half-Life: 7 hr (A); 5 hr (B)
Excretion 75% urine; 7-16% feces

Adverse Effects Hypotention, Sedation, Depression

Mechanism of Deplete amine transmiters;
Action Inhibits VMAT2 & VMAT1

Effects Reduce chorea severity

Absorption Bioavailability: 30-40%

Distribution Protein binding: 96%

Liver; trimethylbenzoic acid, methyl

Metabolism reserpate (inactive)
Half-Life: 50-100 hr
Excretion Excretion: Feces 60%; urine 12%
Hypotention, Sedation, Depression,
Adverse Effects Diarrhea