Parkinson's Disease treatment

Question 1

Parkinson’s disease

Answer 1

• hypokinetic hypertonic syndrome, due to the idiopathic destruction of dopaminergic neurons in the striated body and is manifested by
  1) generalized hypertonia of the skeletal muscles,
  2) hypokinesia with loss of flexibility of voluntary movements and fine tremor of the extremities.

Question 2

At the level of the nigro-striatal tract

Answer 2

there is a dynamic balance between dopamine and
acetylcholine responsible for the normal, voluntary motor activity.
- Dopamine, acting on -> D2 receptors, -> exerts an inhibitory effect, and
- Αcetylcholine, acting on -> muscarinic receptors,
exerts an -> excitatory effect on GABA neurons through which the striatum controls the voluntary movements commanded by the cerebral cortex.
Imbalance of this system in the sense of a relative decrease in dopaminergic activity would be responsible for the onset of Parkinson’s disease or Parkinson’s syndromes

Question 3

The treatment of Parkinson’s disease involves

Answer 3

rebalancing the ratio of dopamine to acetylcholine, by increasing brain dopaminergic activity and decreasing cholinergic activity.
In fact, increasing dopaminergic activity is much more effective in treating Parkinson’s disease than decreasing cholinergic activity.
- The main treatment for Parkinson’s disease is to increase brain dopaminergic activity.
!!! Dopamine cannot be used because it does not cross the BBB

Question 4

To increase brain dopaminergic activity are used:

Answer 4

• Levodopa, a precursor to dopamine
• drugs that prevent the degradation of dopamine (inhibitors of MAO and COMT),
• direct agonist of dopaminergic receptors
• drugs that increase the synaptic release of dopamine.

Question 5

Levodopa

Answer 5

• a precursor of dopamine, which is converted to dopamine by the enzyme dopadecarboxylase.
• It is absorbed digestively and crosses the blood-brain barrier.
• Most of the levodopa administered is converted to dopamine, epinefrine and norepinefrine in the
  periphery and only a small part, approx. 1-2%, reaches the brain to increase the brain’s available dopamine.
• The formation of large amounts of catecholamines in the periphery causes levodopa to cause severe side effects.
• The combination of levodopa with carbidopa or benserazide, substances that inhibit dopadecarboxylase but do not cross theΒΒΒ, significantly reduces the risk of peripheral side effects and increases the proportion of levodopa that crosses the blood-brain barrier.

Question 6

Levodopa (in combination with carbidopa or benserazide)

Answer 6

corrects all pathological manifestations of Parkinson’s disease.
Hypertonia and hypokinesia can disappear, tremor
diminishes greatly and patients can even resume their professional activity.
- The effect is due to the increase in the availability of dopamine in the nigro-striatal tract, stimulating
dopaminergic receptors and resuming fine control of voluntary movements.
- The effect of levodopa is specifically antagonized by neuroleptic drugs.
After a few years of treatment,
the effect of levodopa gradually decreases and may even disappear, probably by continuing the destruction of brain dopaminergic neurons.

Question 7

Side effects

Answer 7

• are toxic.
• Peripherals - orthostatic hypotension, tachycardia, arrhythmias, increased myocardial oxygen consumption.
• central nervous system - nausea, vomiting, psychotic disorders, hallucinations or delusional ideas.

Question 8

contraindication of the drug

Answer 8

in heart, liver, kidney failure, psychotic patients.

Question 9

Selegiline

Answer 9

• MAO B inhibitor, enzyme responsible for dopamine metabolisation in the brain.
• By inhibiting MAO B, selegiline increases the availability of dopamine in the striatum
• antiparkinsonian effect.
  Selegiline potentiates the antiparkinsonian effect of levodopa; is well-tolerated with about the same side effects as levodopa but less intense.

Question 10

Rasagiline

Answer 10

also selectively inhibits MAO B and has, in principle, the same properties as selegiline

Question 11

Dopaminergic receptor agonists

Answer 11

Bromocriptine
Ropinirole and
pramipexole

Question 12

Bromocriptine

Answer 12

agonist of dopaminergic receptors, especially D2 receptors.
- It has levodopa-like antiparkinsonian properties, but of lower intensity.
- Side effects are also similar to levodopa, but less pronounced.
Bromocriptine is used less in the treatment of Parkinson’s disease; it is usually used in endocrinology to decrease prolactin secretion.

Question 13

Ropinirole and pramipexole

Answer 13

• are newer dopaminergic agonists.
• They are effective drugs, especially in mild and moderate forms of the disease, have a relatively long half-life.
• Their side effects are central and peripheral dopaminergic side effects, but without the peripheral
  adrenergic side effects

Question 14

COMT inhibitors are

Answer 14

relatively little used in the treatment of Parkinson’s disease.

Question 15

Entacapone

Answer 15

drug that inhibits COMT - an enzyme that metabolizes levodopa, without crossing the BBB and increases the availability of levodopa in the periphery
and thus promotes the penetration of the substance into the CNS

Question 16

Amantadine

Answer 16

probably has an antiparkinsonian effect by increasing the release of dopamine in the synaptic cleft.
The antiparkinsonian effect is less intense than the effect of levodopa, and the side effects are similar to levodopa, but less intense.
In addition to the antiparkinsonian effect, amantadine also has an antiviral effect.

Question 17

Drugs that block cerebral muscarinic receptors are used to block cholinergic
receptors, but their effectiveness is lower.

Answer 17

Anticholinergics used as antiparkinsonian drugs are drugs that block cerebral muscarinic receptors.
Their effectiveness is lower than in the case of levodopa. The main use of these drugs is the treatment of extrapyramidal manifestations produced by neuroleptic drugs.
The side effects of these drugs are those characteristic of atropine - constipation, dry mouth, tachycardia, worsening glaucoma, bladder favoring in patients with prostate adenoma, etc.
The most widely used anticholinergic drug in Parkinson’s disease is trihexyphenidyl.