Pharmacology

Section 13.

Treatment of motor disorders

Treatment of Alzheimer’s

disease

Marta Jóźwiak-Bębenista

Department of Pharmacology

Medical University of Lodz

[e-mail]

Parkinson's Disease

»

PD belongs to a group

of conditions called

motor system

disorders

»

progressive neurologic

disorder that affects

neurons in the part of

the brain controlling

muscle movement.

»

1-2% of population

suffer from this

condition

normal, AD, PD,
PD+dementia

Symptoms of PD

P

P

rimary symptoms of

rimary symptoms of

PD

PD

:

:

»

Tremor

Tremor

»

Muscle rigidity

Muscle rigidity

(stiffness or inflexibility)

»

Bradykinesia

Bradykinesia (

slowing

slowing

of voluntary movement

of voluntary movement )

»

Postural and gait

Postural and gait

abnormalities

abnormalities

Causes of PD

»

DA-ergic neurons in

substantia nigra and corpus

striatum (nigrostriatal DA-

ergic tract) are destroyed

»

nigrostriatal DA-ergic tract -

part of the extrapyramidal

system, responsible for

motor control

»

80% of

80% of

DA-eric neurons

DA-eric neurons

are

are

damaged, the symptoms of

damaged, the symptoms of

Parkinson disease appear.

Parkinson disease appear.

Causes of PD

»

The

striatum

, is also

rich in

excitatory

cholinergic neurons

that counteract the

action of dopamine.

»

This is the

dopamine-

acetylocholine

balance

»

the dopaminergic

system inhibits the

acetylocholinergic

system.

DA

ACh

In Parkinson`s disease

dopaminergic neurons

degenerate in nigro-striatal

dopaminergic tract

and the

inhibitory influence of

dopamine on the striatum is

diminished, resulting in

increased activity

of

excitatory

cholinergic

neurons

.

Causes of PD

»

Parkinson's disease may result from a

combination of genetic and environmental

factors.

»

Certain toxins, diseases

(viral encephalitis,

small vascular lesions)

and drugs may also

cause symptoms similar to those of PD.
-

haloperidol

(Haldol)

-

chlorpromazine

(Thorazine)

-

metoclopramide

(Reglan)

-

prochlorperazine

(Compazine)

-

valproate

(Depacon)

Risk factors

•

Age

- PD usually affects people over the

age of 50

•

Genetic factors / Heredity

•

Sex

-

Men are more likely to develop

Parkinson's disease than women are.

•

Exposure to

pesticides and

herbicides

•

Reduced estrogen levels

•

Reduced folate levels

Treatment of PD

»

There is no cure for
PD, but a variety of
medications provide
dramatic relief from
the symptoms! 

»

The strategy of

treatment of PD rests

on:

.

1 dopamine levels in

nigro-striatal

dopaminergic tract

2. restoring the correct

dopamine-

acetylocholine balance

(through antagonizing

the excitatory effect of

cholinergic neurons)

Drugs used in PD

»

Drugs, which restore the dopamine levels in

nigro-striatal dopaminergic tract:



Levodopa (L-dopa) and carbidopa



COMT inhibitors



Dopamine agonists



Amantadine



Selegiline

»

Drugs, which restore the dopamine-

acetylocholine balance:



Anticholinergics

Levodopa

»

the most effective medication for

Parkinson`s disease. 

»

70-80% of treated Parkinson`s patients

are on levodopa therapy. 

»

Standard release preparations:
- levodopa/carbidopa (Sinemet or Atamet)
- levodopa/benserazide (Madopar)

»

Prolonged release preparations:
- levodopa/carbiopa (Sinemet CR)
- levodopa/benserazide (Madopar HBS)

Levodopa

»

Mechanism of actions:

dopamine doesn't cross

the BBB!

Levodopa – metabolic

precursor of DA easily
penetrate the BBB into
the CNS.

Levodop
a

Dopamine

DOPA-decarboxylase

DOPA decarboxylase

inhibitors

»

Levodopa combined with DOPA decarboxylase
inhibitors represent a significant improvement
in the treatment of PD.



Carbidopa



Benserazide

»

a smaller dose of levodopa is needed to treat
symptoms

»

nausea and vomiting often associated with
levodopa treatment are greatly reduced by the
presence of DOPA decrboxylase inhibitors. 

Levodopa

»

Actions:

Levodopa reduces akinesia and
rigidity, in smallest degree
decreases tremor.

»

Pharmacokinetics:

-

well absorbed upon oral

administration.

-

should be taken on empty

stomach, 45 minutes before a
meal. Foods inhibit the
absorption from the gut of
levodopa and it`s transport into
the CNS.

»

Interactions:

›

Vit. B6

›

MAOIs

›

Antidepressants

›

Neuroleptics

›

Hypotensive drugs

Levodopa loses

therapeutic efficacy after

a long time of treatment.

This means that the

length of time that each

dose is effective begins

to decrease, leading to

more frequent doses.

Levodopa

»

The adverse side effects:

CNS:

- visual and auditory hallucinations,
- mood changes (depression, excitation).

With increased dosing and prolonged use of levodopa,

patients experience:
-

dyskinesias

(spontaneous, involuntary

movements) and

"on-off" periods

when the

medication will suddenly and unpredictably start

or stop working.
- insomnia and anxiety.

Peripheral:

- nausea, vomiting
- low blood pressure.

COMT inhibitors

»

represent a new
class of Parkinson's
medications

»

they must be taken
as an adjunct with
levodopa/carbidopa! 

Entacapone

(Comtan)

Tolcapone

(Tasmar)

COMT inhibitors

»

Side effects: diarrhea,

postural hypotension,

dyskinesias,

insomnia, nausea,

hallucinations,

anorexia,

constipation .

Tolcapone is

hepatotoxic

»

Interaction: MAOIs

»

Indication:

»

Tolcapone- reduces

the frequency of the

“on-off”periods

(motor fluctuations)

»

Entacapone-

secondary

medication; delays

wearing off by

prolonging

effectiveness of

levodopa (Stalevo)

Dopamine agonists

»

Agonists available in the

United States include:

› bromocriptine

(Parlodel)

› pergolide

(Permax)

»

New drugs:

› pramipexole

(Mirapex)

› ropinirole

(Requip)

»

They mimic the effects of

dopamine in the brain

»

The older used in

combination with levodopa

»

The side effects:

similar to those of levodopa,
although they are less likely
to cause involuntary
movements (dyskinesia) and
more likely to cause
hallucinations, confusion,
nausea or orthostatic
hypotension.

The

newer

used alone, as

the first-line; side effects
similar to bromocriptine
but they are milder.

Amantadine- Symmetrel

»

antiviral drug

»

Mechanism of actions:

enhences the syntesis and
release of DA and improve
Dopaminergic neurotransmission.

»

Actions:

»

less efficacious than levodopa

but it has fewer side effects

»

has little effect on tremor but is

more effective than the

anticholinergics against rigitidy

and bradykinesia

»

Side effects:

-

difficulty in concentrating

-

confusion, insomnia

-

nightmares, agitation

-

hallucinations 

-

leg swelling

-

mottled skin

for people in the latter

stages of Parkinson's

disease, if they have

problems with

dyskinesia induced by

levodopa

Selegiline- Deprenyl

»

selective IMAO-B

»

an adjunct to
levodopa therapy,

»

prevent the break
down of both
naturally occurring DA
and DA formed from
levodopa, resulting in
dopamine levels in

the brain

»

Side effects:

-

heartburn,

-

nausea,

-

dry mouth,

-

dizziness

-

risk for severe
hypertension (only at
high doses of drug)

has a mild antidepressant

effect

. 

- Eldepryl
- Atapryl
- Carbex

Anticholinergics

»

the main treatment for

Parkinson's disease

before the introduction

of levodopa.

»

Mechanism of actions:



the activity of Ach

»

Actions:

- used as secondary-

adjuvant medications.

- they help control

tremors in the early

stages of the disease. 

»

Adverse effects:

•

blurred vision, dry mouth,
urinary retention)

•

mental problems:

-

memory loss,

-

confusion

-

hallucinations.

»

They are not used long-
term due to their side
effects.

Biperiden HCL

(Akineton),

Benztropine mesylate

(Cogentin)

Procyclidine

(Kemadrin),

Trihexyphenidyl

(Artane)

Over the counter

medications

»

Free radicals or
reactive oxygen
species may be
harmful to cells and
lead to their death.

»

Antioxidants protect
nerve cells from
oxidative damage.

»

Neuroprotective
treatments may be
most helpful at an
early stage of PD.

Pharmacology

Section 13.

Treatment of Alzheimer’s

disease

Marta Jóźwiak-Bębenista

Department of Pharmacology

Medical University of Lodz

[e-mail]

Alzheimer’s disease

»

AD it is one of the

dementing disorders

,

which are a group of

brain diseases that result

in the loss of mental and

physical functions.

»

AD is a progressive

disease of the brain that

is characterized by

impairment of memory

and a disturbance in at

least one other thinking

function (for example,

language or perception

of reality).

Symptoms of AD

» Cognitive symptoms:

- memory loss
- disorientation
- confusion

- difficulty with reasoned thought

- loss of language skills.

» Behavioral symptoms:

- agitation/anxiety
- delusions/hallucinations
- depression
- insomnia
- wandering

The severity of the symptoms increases

over time.

The onset of AD is usually very slow and

gradual.

Causes of AD

»

Neuropathologic causes:

- beta-amyloid protein (amyloid plaques)

- degeneration of cholinergic neurons
- atrophy of NA,DA,5-HTergic neurons

- Large amount
patologic proteins:
apolipoprotein E,
presenilins
- Inflammation.
- traumatic head
injuries earlier in life.

Causes of AD

»

Abnormalities in the

brain's

neurotransmitters,

»

ACh is a critical

neurotransmitter in

the process of

forming memories.

»

ACh is abundant in

the nerve cells of the

hippocampus and

cerebral cortex, the

regions that are

devastated by AD.

• Age (10 % of
people over
age 65 and 50
% of those
over 85 have
AD)

• Genetic
factors

Treatment of AD

»

There is no

treatment that will

stop or reverse the

symptoms of AD.

»

The used drugs

attempt to slow the

progression of the

disease.

»

These drugs

work to

maintain levels of

neurotransmitters in

the brain!

»

To increase the

activity of cholinergic

system we use:

1.

acetylocholine

precursors

(lecithin,

choline)

2.

ACh-esterase

inhibitors

(acetylcholinesterase,

an enzyme responsible

for the destruction of

acetylcholine)

»

Tacrine

(Cognex),

»

Donepezil

(Aricept),

»

Rivastigmine

(Exelon),

»

Galantamine

(Razadyne, Reminyl)

Treatment of AD

»

Side effects of

tacrine:

»

abdominal cramps

»

nausea

»

polyuria

»

diarrhea

»

hepatotoxic

»

The newer

anticholinesterase

inhibitors: donepezil,

rivastigmine,

galantamine are better

tolerated.

»

The main side effects

are nausea, vomitimg,

diarrhea.

»

The newer

anticholinesterase

inhibitors have proved

beneficial in improving

memory, and have

fewer side effects.

The newer drugs are
not effective for
everyone, and their
effectiveness is limited
to the early and middle
stages of AD.

Treatment of AD

Memantine (Namenda)

»

approved to treat moderate to severe
AD,

»

It`s effects are independent of
acetylcholine and acetylcholinesterase.

»

by blocking the NMDA receptors and the
effects of glutamate, memantine may
protect nerve cells from excess
stimulation by glutamate.

Treatment of AD

»

It is possible to reduce

some of the common

emotional and

behavioral symptoms

associated with AD.

»

Tranquilizers- reduce

agitation, anxiety,

unpredictable behavior.

»

Benzodiazepines-

improve sleeping

patterns

»

Antidepressants - treat

depression.

Other drugs:

»

selegiline

»

antioxidants (vit. E,

koenzym Q10)

»

anti-inflammatory

drugs: indometacin

(NSAIDs)

Huntington`s disease

Huntington's disease (HD) =

Huntington disease =

Huntington's chorea = chorea

maior

»

movement disorder associated with
defects in the basal ganglia

»

inherited

neurological disorder

»

appears during adult life

»

one out of every 10,000 Americans has
HD

Pathophysiology of HD

Imbalance of dopamine, acetylcholine,

GABA

and perhaps other neurotransmitter

in the basal ganglia.

»

overactivity in dopaminergic

nigrostriatal pathways

1.

increased responsiveness of

postsynaptic dopamine receptors

2.

deficiency of a neurotransmitter that

normally antagonizes dopamine.

Pathophysiology of HD

»

GABA

and

glutamic acid decarboxylase

are

reduced in the basal ganglia of patients with HD.

»

Ach

and

choline acetyltransferase

are reduced in

the basal ganglia of patients with HD.

Theses deficiencies reduce the inhibitory influence

on the nigrostriatal dopaminergic neurons and

lead to the dopamainergic hyperactivity

associated with Huntington`s disease

The symptoms of HD are

suppressed by drugs that

block dopaminergic

receptors and worsened

by drugs that increase

basal ganglia

dopaminergic activity.

Treatment of HD

Drugs that deplete central
dopamine stores by blocking
entry into the neuronal
storage vesicles:



reserpine

(small doses of

0.25 mg daily; no longer

used in the UK)



tetrabenazine

The adverse effects:
hypotension, depression,
sedation, gastrointestinal

disturbances.

Drugs that block the
dopaminergic

receptors:

»

phenothiazines

(e.g.

Perphenazine)

»

butyrophenones

(e.g. Haloperidol)

The adverse effects:
restlessness,

parkinsonism.

Reduction basal ganglia dopaminergic activity

Treatment of HD

»

enhance central GABA or Ach
activity

no consistently beneficial response