Parkinson's Disease

Question 1

Neurodegenerative Disorders of the CNS?

Answer 1

• Parkinson’s Disease
• Alzheimer’s Disease

Question 2

What are neurodegenerative diseases characterised by?

Answer 2

These are generally characterised by a progressive loss of selected
neurons in various parts of the brain → characteristic disorders of
movement, cognition or both

Question 3

Parkinson’s Disease?

Answer 3

Parkinson’s disease is a slowly progressive degenerative CNS disorder characterised by tremor, rigidity,
bradykinesia and postural disturbances.

Question 4

Parkinson’s Disease Aetiology?

Answer 4

in primary PD there is loss of dopamine-producing
neurons in the substantia nigra→a deficiency of dopamine in the
basal ganglia. The resulting imbalance in neurotransmitter activity -
too little dopamine and too much acetylcholine- is thought to
bring about most of the symptoms.

Question 5

Parkinson’s Disease Symptoms?

Answer 5

TRAP in the PARK

Tremor
Rigidity
Akinesia(Bradykinesia)
Postural Disturbances?

Question 6

Parkinson’s Disease and tremor symptom?

Answer 6

*A 4 - 8 Hz tremor of one hand; the tremor is maximal at
rest, diminishes during movement and is absent during
sleep.
* Due to involuntary skeletal muscle contractions. The tremor
may start in the upper extremity, spread to the ipsilateral
lower limb and then to the contralateral limb.

Question 7

Parkinson’s Disease and rigidity symptom?

Answer 7

*Due to muscles contracting continuously.
* E.g. contraction of facial muscles→the face becomes
mask-like and open mouthed with a wide eyed, unblinking
stare.

Question 8

Parkinson’s Disease and Bradykinesia symptom?

Answer 8

• Slowness and poverty of movement.
• Activities such as shaving, buttoning a shirt take longer and
  become increasingly difficult.
• Muscular movements performed with decreasing range of
  motion (hypokinesia).
• Patients find it difficult to initiate movements (akinesia), the
  gait becomes shuffling with short steps and the arm swing
  diminishes.

Question 9

Parkinson’s Disease and postural disturbances symptom?

Answer 9

• The posture becomes stooped.
• There is a loss of postural reflexes a tendency to fall forward (propulsion) or backward (retropulsion) when the
  center of gravity is displaced.

Question 10

Parkinson’s Disease Treatment strategy?

Answer 10

• Restoration of DA in the basal ganglia
• Inhibition of excitatory effects of↑cholinergic neurons
  stimulation
• Re-establishing the optimum DA/Ach balance

Question 11

Which neurotransmitters are the problem in Parkinson’s Disease?

Answer 11

Imbalance between the “low inhibitory” dopaminergic
neurones and “high excitatory” cholinergic neurones

Question 12

What is the relationship between dopamine and ACh?

Answer 12

It has been shown that dopamine inhibits the release of acetylcholine (ACh) from nerve terminals of caudate cholinergic interneurons, and the imbalance between dopaminergic and cholinergic system by 6-hydroxydopamine pretreatment leads to an increased ACh release.

Under dopamine depleted conditions, proper motor function is dependent on adequate levels of both acetylcholine and dopamine, the study concluded. Its findings suggest that progressive dopamine deficiency reduces the activity of striatal cholinergic interneurons, resulting in progressive motor difficulties.

Question 13

Agents modifying Dopaminergic system?

Answer 13

• DA precursor (Levodopa)
• DA receptor agonists (Bromocriptine, Ropinirole,
  Pergolide, Pramipexole, Apomorphine)
• Catechol-O-methyltransferase (COMT) inhibitors
  (Tolcapone, Entacapone)
• Monoamine Oxidase (MAO) type B inhibitors (Selegiline,
  Rasagiline)

Question 14

Anticholinergic agents?

Answer 14

• Trihexyphenidyl, Benztropine

Question 15

Drugs that facilitate stimulation of dopamine receptors?

Answer 15

BALSA: Bromocriptine, Amantadine, Levodopa

Bromocriptine
Amantadine
Levodopa

Question 16

Levoda MOA?

Answer 16

Levodopa is a dopamine precursor→facilitates the synthesis of
dopamine in the brain (DA does not cross the BBB)

Question 17

Levoda Function?

Answer 17

• Restores DA-ergic neurotransmission in neostriatum by enhancing
  synthesis of DA in surviving neurones of the substantia nigra
• Therapy is initiated with small doses and gradually increased.
• Therapy loses effectiveness after ≈ two years of use.

Question 18

Levoda Effect on drug-induced Parkinson’s Disease

Answer 18

• Has no effect on drug-induced Parkinsonism.

Question 19

Levoda Pharmacokinetics?

Answer 19

• Levodopa is well-absorbed from the small intestine. Much of it is
  inactivated by MAO in the small intestine.
• 95% of the drug is converted (by dopa decarboxylase) to DA in
  peripheral tissue; < 1% enters the brain.
• Ingestion of high protein meals interferes with transport of L-Dopa
  into the CNS
• It should be taken on an empty stomach (atleast 30 mins before
  meals)
• Plasma concentrations fluctuate (may cause fluctuations in motor
  responses → loss of normal mobility, tremors, cramps, immobility)

Question 20

Levodopa adverse effects?

Answer 20

LEVODOPA

Lethargy
Euphoria/Excessive sleep
Vomit
Orthostatic Hypotension
Dellusion/Dyskinesia
On-off phenomenon
Priapsim
Atheosis

Question 21

Which drugs increase the efficacy of levodopa?

Answer 21

1. Carbidopa
2. Selegiline
3. Rasagiline
4. Domperidone

Question 22

COMT Inhibitors?

Answer 22

1. Entacapone
2. Tolcapone

Question 23

Entacapone MOA?

Answer 23

selective reversible COMT inhibitor;
prevents metabolism of L-Dopa to 3-O-methyldopa (a
metabolite that competes with L-Dopa for active transport
into the CNS) → ↓plasma concentration of 3-O-
methyldopa, ↑ central uptake of L-Dopa and ↑
concentrations of DA in the brain; SE: GI upsets, postural
hypotension, hallucinations, sleep disorders.

Question 24

Tolcapone MOA?

Answer 24

associated with hepatic necrosis

Question 25

COMT Inhibitors?

Answer 25

Entacapone
Benzarazide

Question 26

Orphenadrine MOA?

Answer 26

MOA: dopamine receptor agonist.
Bromocriptine has many adverse effects (caution in MI or
peripheral vascular disease). It is also very expensive; used only
for cases that cannot be effectively treated with levodopa.

Question 27

Orphenadrine adverse effects?

Answer 27

‣Nausea, dizziness, drowsiness and postural hypotension
occur during the first months of use.
‣Dyskinesia, hallucinations, confusion and behavioural
aberrations occur at higher doses over longer periods.
‣Peptic ulcers may be exacerbated.
‣Dementia and depression are also common.

Question 28

Amantadine MOA?

Answer 28

releases dopamine from its stores and inhibits the re-
uptake of dopamine from the synaptic cleft.

Question 29

Amantadine?

Answer 29

An anti-viral agent with moderate anti-Parkinson activity.
* Useful as monotherapy for early, mild parkinsonism; however
loses effectiveness after several months.
* Can be used in combination with levodopa.

Question 30

Amantadine Adverse Effects?

Answer 30

Adverse Effects
‣Discolouration of the skin, especially the legs and oedema of
the ankles.
‣Psychotic episodes, convulsions and nausea may occur at
high dosages.

Question 31

Drugs that antagonise acetylcholine at muscarinic receptors MOA?

Answer 31

MOA: competitive antagonists of acetylcholine at muscarinic receptors.
These drugs cross the blood brain barrier because they are lipophilic.

Question 32

Drugs that antagonise acetylcholine at muscarinic receptors?

Answer 32

1. Biperiden
2. Orphenadrine
   3.Trihexyphenidyl/Benztropin
   4.

Question 33

Biperiden I?

Answer 33

I: Parkinsonism, the injection can be used for rapid control of drug-
induced acute dystonic reactions.

Question 34

Biperiden MOA?

Answer 34

competitive antagonists of acetylcholine at muscarinic receptors.
These drugs cross the blood brain barrier because they are lipophilic.

Question 35

Biperiden A/E?

Answer 35

‣Pronounced drowsiness.
‣Anticholinergic side effects such as retention of urine, visual
disturbances, aggravation of glaucoma.
‣Postural hypotension, euphoria and aberrations of co-ordination (iv).

Question 36

Trihexyphenidyl/Benztropin MOA?

Answer 36

competitive antagonists of acetylcholine at muscarinic receptors.
These drugs cross the blood brain barrier because they are lipophilic.

Question 37

Trihexyphenidyl/Benztropin Function

Answer 37

Used for both idiopathic and drug-induced Parkinsonism.
It relieves tremors due to the disease.
Large doses induce a feeling of mental well-being and it is
sometimes abused for this reason.

Question 38

Trihexyphenidyl/Benztropin A/E?

Answer 38

‣Parasympatholytic side-effects: dry mouth, blurred vision,
dizziness and nausea occur at the beginning of therapy.
‣Constipation and retention of urine particularly in the
elderly.
‣Tachycardia and drowsiness.

Question 39

Trihexyphenidyl/Benztropin CI?

Answer 39

‣Prostatic hypertrophy:
anticholinergics aggravate
retention of urine associated with prostatic hypertrophy.
‣Glaucoma: these drugs increase intra-ocular pressure
and exacerbate glaucoma.
‣GI obstruction