Drugs Used In Parkinsonism

Question 1

Neurodegerative disorders?

Answer 1

1. Parkinson’s disease (PD)
2. Alzheimer’s disease (AD)
3. Ischemic brain damage (stroke).
   - PD & AD are the most common examples of a group of chronic, slowly developing conditions

Question 2

Common aetiology of neurogenerative disorders?

Answer 2

They have a common etiology in that they are caused by the aggression of misfolded variants of normal physiological proteins.
- Therapeutic intervention is aimed at compensating for, rather than preventing or reversing neuronal loss.

Question 3

What is protein misfolding?

Answer 3

The formation of large insoluble aggregates by certain proteins, to adopt an abnormal confirmation
- These are normally removed by intracellular degradation pathways, which may be altered in neurodegenerative disorders

Question 4

Parkinsons disease?

Answer 4

• disease is a progressive motility disorder
• it occurs primarily due to loss of dopaminergic neurons running from substantia nigra to corpus striatum.
• these dopaminergic neurons are inhibitory neurons that act on D2 receptors of cholinergic neurons in the corpus striatum, thus loss of inhibition causes hyperactivity of these cholinergic neurons

Question 5

Symptoms of Parkinsons?

Answer 5

1. hypokinesia
   - voluntary movement is hard to initiate and to stop due to loss of dopaminergic neurons
2. tremor
   - at rest due to hyperactivity of cholinergic neurons
3. rigidity
   - increased resistance to voluntary movement
   - due to loss of dopaminergic neurons and hyperactivity of cholinergic neurons
4. dementia
   - decreased mental capacity due to loss of other types of neurons elsewhere in the CNS

Question 6

Classification of treatments?

Answer 6

1. DOPAMINE REPLENISHERS
2. D2 RECEPTOR AGONISTS

Question 7

Drug therapy of Parkinsons?

Answer 7

Drug therapy aims towards:
1. Augmentation of central dopaminergic function
2. Reduction of central cholinergic activity.
- On this basis, antiparkinsonism drugs are thus classified.

Question 8

Adjunctive therapy of Parkinsons?

Answer 8

Physical therapy to delay disability
Emotional support to lessens feelings of helplessness and inadequacy

Question 9

Dopaminergic agents?

Answer 9

1. Dopamine precursor (Levodopa)
2. Dopamine releasing agents (Amantandine)
3. Dopamine receptor agonists(Bromocriptine)
4. Inhibition of dopamine inactivation(selegilin)

Question 10

Levodopa?

Answer 10

• Levodopa, a metabolic precursor of DA, is the logical replacement therapy of parkinsonism, since the disease seems to be related to the deficiency of striatal DA.
• DA itself does not cross the BBB in adequate quantities and is not effective in treating the disease.
• Levodopa (L-DOPA, 1 dihydroxyphenalanine), however crosses the BBB and is converted to dopamine in the brain, replenishing the deficient neurotransmitter.
• The enzyme (dopa decarboxylase) is present in the brain as well as the plasma, therefore a significant fraction of an oral dose of L-DOPA is converted to DA in the plasma & cannot cross the BBB.
• A large amount of L-DOPA are required to provide clinically effective levels of dopamine in the brain.
• This is associated with many side effects and therefore Levodopa is seldom used alone

Question 11

Carbidopa?

Answer 11

• Carbidopa is a peripheral dopa decarboxylase inhibitor and retards the breakdown of L-DOPA and allows the L-DOPA dose to reach the BBB, producing higher DA levels.
• Carbidopa itself does not cross the BBB and hence does not interfere with the conversion of L-DOPA to DA.

Question 12

Therapeutic uses of dopaminergic agents?

Answer 12

1. Treatment of all types of parkinsonism except those associated with antipsychotic drug therapy
   - antipsychotic drug therapy counteract the effects of L-DOPA by blocking dopaminergic receptors on the neurons in the basal ganglia
2. Relief of pain associated with herpes zoster.

Question 13

Adverse reactions to dopaminergic agents?

Answer 13

1. GIT distress - Nausea, vomiting, anorexia, salivation
2. CVS – Tachycardia, palpitations, arrhythmias, orthostatic hypertension
3. CNS – Brady kinetic episodes (loss of symptoms control due to excessive L-DOPA levels in the body), muscle twitching, grinding of teeth

Question 14

Drug interactions of dopaminergic agents?

Answer 14

1. Antipsychotics reduce effects of L-DOPA.
2. Effects are potentiated by propranolol, methyldopa and anticholinergics.
3. Enhances the CVS effects of sympathomimetic drugs, ephedrine, adrenaline and amphetamines.
4. Diabetic control with oral hypoglycaemic drugs may be adversely effected by L-DOPA.
5. Tricyclics, MAOI’s concurrently used with L-DOPA can result in tachycardia and hypertension

Question 15

Dopamine releasing agents?

Answer 15

Amantandine – mode of action is not completely understood, but it causes release of DA from presynaptic nerve endings

Question 16

Dopamine receptor agonists?

Answer 16

Bromocriptine is a newer drug to treat
parkinsonism, a dopamine agonist acting directly on the post synaptic DA receptors
- It is used as an adjunct to L-DOPA, to provide additional therapeutic control in patients maintained on L-DOPA.

Question 17

Inhibition of dopamine inactivation?

Answer 17

Selegiline irreversibly inhibits MAO-B enzyme in the nerve endings in the brain, thereby increasing the levels of intraneuronal levels of
dopamine.
- Further, it facilitates dopamine release and interferes with dopamine reuptake into nerve endings
- It has been used as an adjuvant treatment, but there indications that in mild cases, it can slow the progression of disease.

Question 18

Old Parkinsons treatment?

Answer 18

Belladonna alkaloids (Atropine & scopalamine)
were the treatment for parkinsonism for a long
Time. They have now been largely replaced by
synthetic drugs with a more selective central
anticholinergic activity.

Question 19

Anticholinergic/antihistaminic agents?

Answer 19

Although they are less effective than levodopa, the central acting anticholinergics can be used in all forms of parkinsonism.
They are commonly used in the mild stages of the disease and appear to be most effective in relieving rigidity and tremour

Question 20

Mode of action of anticholinergic/antihistaminic agents?

Answer 20

1. They exhibit a postsynaptic blocking effect on central cholinergic excitatory pathways, which in parkinsonism become predominant especially
   due to the lack of functional dopamine in the corpus striatum.
2. Central anticholinergics also retard the reuptake of dopamine into the presynaptic nerve endings, thereby blocking its inactivation.

Question 21

Therapeutic uses of?

Answer 21

1. Sole or adjunctive agents in the treatment of parkinsonism, especially rigidity.
2. Prevention and relief of extrapyrimidal reactions resulting from antipsychotic drug therapy

Question 22

Adverse reactions to Anticholinergic/antihistaminic agents?

Answer 22

1. Common adverse reactions include: Dry mouth, blurred vision urinary hesitancy, dizziness, nausea.
2. Severe adverse effects include:
   Confusion, delirium, hallucinations, depression, memory loss, orthostatic hypotension, tachycardia, increased IOP, mydriasis

Question 23

Contraindications of Anticholinergic/antihistaminic agents?

Answer 23

1. Acute narrow angle glaucoma
2. Pyloric and duodenal obstruction
3. Prostatic hypotrophy

Question 24

Drug interactions of Anticholinergic/antihistaminic agents?

Answer 24

1. Agents with anticholinergic activity
2. Potentiation of sedation with other CNS depressants
3. Absorption of levodopa may be reduced, and delay in gastric emptying and thereby increase gastric degradation of levodopa.

Question 25

Choice of drug depends on?

Answer 25

the severity of disease and ability of the patient to tolerate adverse effects of the medication.

Question 26

In early and mild cases?

Answer 26

anticholinergic drug therapy. Treatment starts with small doses of trihexyphenidril (Artane) or Diphenhydramine, later the patient may be switched to a more potent drug like benztropine

Question 27

In advanced disease?

Answer 27

Amantadine is added to anticholinergic therapy. This however increases the risk of drug induced mental disturbances.
The combination of levodopa and carbidopa (sinemet) is considered the most effective for advanced cases.
If necessary levodopa/carbidopa maybe combined with amantandine and an anticholinergic drug

Question 28

Drug management of Parkinsonsism?

Answer 28

Patients who become less responsive to all these drugs on long term treatment may improve with the addition of bromocriptine.
The current status of selegiline is that it provides modest symptomatic relief in parkinsonism