PARKINSON'S DISEASE-TREATMENTS
Prelude:-
We have already seen the idiopathic PD is incurable as its structure of inhibitory and excitatory irregularities in the midbrain is more complicated.
The general assumption is there is increased direct stimulation of the midbrain by the cerebral cortex through glutamate excitatory pathway with the result of increased inhibition of the thalamus through the inhibitory GABA pathway. This leads to a decreased thalamic stimulation to the cortex. In the middle of this, there are many complicated dopaminergic pathways irregularities that happened in the basal ganglia with the loss of dopaminergic nerve networks which leads to Parkinson's Disease.
Treatments:-
I.A table of commonly used medicines with some details:-
1.Carbidopa/Levodopa:-
25 /100mgs 2 to 3 times a day, to yield 200/ 1200 mg levodopa daily range.
C/L SR:-
50/ 200 mg.2 times/day.A daily range of 200 /1200 mg.
Bioavailability is 75% of the standard form
2.Pergolide:-
0.05 mg once daily with a daily range of 0.75 to 5 mg/day
3.Bromocriptine:-
1.25 mg twice a day.
A daily useful range is 3.75 to 40 mg. daily.
4.Selegiline:-
5 mg twice a day
A daily range of 2.5 to 10 mg.
5.Amantadine (Antiviral):-
100 mg twice a day.
A daily range of 200 mg.
6.Trihexyphenidyl HCl:-(Anticholinergic)
1 mg twice a day
A daily useful range is 2 to 15 mg.
II.A Comprehensive Study of Treatments
Classic PD is having many symptoms like hypercholinergic effects associated with impaired dopaminergic effects and extrapyramidal side effects like bradykinesia, akinesia, dyskinesia, etc.Hence all the effects should be antagonized to yield a comfortable relief.
The drugs are classified as follows:-
1.Anticholinergics (for tremors)
2.The precursor of Dopamine (Carbidopa/Levodopa)
3.Direct Dopamine agonists such as Bromocryptine, and Pergolide
4.Indirect Dopamine agonists such as i.By decrease dopamine reuptake (Amantadine)
ii.By decrease dopamine metabolism(Selegiline)
Also, there are associated symptoms like depression, action tremor, which can be treated as follows:-
1.Tricyclic Antidepressants can be used as they also have mild anticholinergic and dopaminergic effects.
2.Beta-blockers like nonselective propranolol is useful to control the action tremor as it is highly fat-soluble and can pass easily the blood-brain barrier.
3.Benzodiazepines and Primidone are also very well effective in solving the action tremor.
4.Antihistamines such as Diphenhydramine a common ingredient in the cough suppressant syrups is have a value in controlling the action tremor by its mild anticholinergic effects.
General Principles of The Treatments:-
As a rule treatment of PD should be stared with a low dose with a slow gradual increase.The response should be within a few days.If not with the doctor's advice try with another class of medicine.
If an additional drug is added then reduce the dose of the first medicine to minimize the side effects.
Drug therapy should never be discontinued suddenly because sudden withdrawal may relapse the symptoms with exacerbation.
When the therapy started the following unwanted effects should be watched and corrected by dosage adjustments or a change in drug recipe.
Dyskinesias are the facial symptoms with irregular jerky movements.
On-Off effects are the sudden changes in mobility from no symptoms to full PD symptoms in a matter of minutes.
End dose effects usually occur at the latter part of the dosing interval can be improved by shortening the dosing interval.
Drug holiday Prolonged and continued use of dopamine direct agonists like levodopa may desensitize the dopaminergic receptor network at the midbrain(neostriatum -substantia nigra network)and a drug holiday gap can resensitize the striatal nigra dopamine receptors.But risk and care should be exercised under the doctor's supervision when a holiday is imposed.
Individual Drugs
Anticholinergic and antihistaminic Drugs
They are used mostly for tremors, rigidity, and kinetic irregularities.Resting tremors are more responding to anticholinergics.They have no effects on postural irregularities.
These drugs are acting by decreasing the excitatory acetylcholine inflow to the basal ganglia in the midbrain.
Caution should be taken when using these medicines in patients with GI and urinary tract obstructions, narrow-angle glaucoma, or severe cardiovascular defects.
Alcohol and other CNS depressants should be avoided.
Side effects
Peripheral side effects such as dry mouth(chewing gum may be helpful), decreased sweating(beware of summer), urinary retention, constipation, increased intraocular tension.
CNS side effects are dizziness, delirium, disorientation, anxiety, agitation,
hallucination, and impaired memory.
Cardiovascular side effects are hypotension,and orthostatic hypotension.
Drug Interactions
Anticholinergic action will be dangerously potentiated by the concurrent use of antihistamines and phenothiazines.
Anticholinergics will interfere with digoxin metabolism and increase its plasma levels.
1)Dopamine Precursor (Levodopa/Carbidopa)-Sinemet
In this combination, only levodopa is the active medicine, and carbidopa is only to prevent levodopa to be converted into dopamine before it enters into the blood-brain barrier.
Dopamine cannot enter into the blood-brain barrier which is necessary for the purpose of action.Levodopa can enter but if administered alone it will be rapidly decarboxylated to dopamine which cannot enter into CNS and produce many unwanted peripheral effects. To prevent this carbidopa is included which is a dopa decarboxylase inhibitor and prevents the conversion of levodopa into dopamine at the periphery.
Levodopa after entering into the CNS will be converted to dopamine by the enzyme dopa decarboxylase to produce the dopaminergic effect.
The dose of carbidopa should be at least 100 mg/day depending on the conditions.
If the patient is still complaining about the peripheral effects plain carbidopa can be given with a doctor's supervision.
Precautions
1.In narrow-angle glaucoma
2.Malignant melanoma
Side effects
1.Anorexia, nausea and vomiting
2.Postural hypotension, tachycardia
3.Dystonia
4.Confusion,depression and psychoses.
5.Hemolytic anemia,leucopenia, and rarely agranulocytosis.
Drug Interactions
1.Antacids
2.Hydantoin
3.Methionine
4.Metoclopramide
5.MAOIs and Furazolidone
6.Papaverine
7.Food will interfere with the absorption.Hence a protein-free food is advisable.
2.Direct Acting Dopaminergic Agents
1.Bromocriptine.
It is directly stimulating the dopamine receptors at the neostriatum and substantia nigra at the midbrain.It can be used as adjunct with L-dopa therapy if the patient is decreasing response to it and also to patients who cannot tolerate levodopa in higher doses.
Initially start with 1/2 tablet twice daily which is later increased to one twice daily.
Side effects
1.First dose effects may cause sudden cardiac collapse (Careful with MIs, and arrhythmias)
2.CNS effects similar to levodopa
3.Lung effects
2.Pergolide
Similar to bromocryptine but stimulating more towards the excitatory D-1 receptors while bromocriptine to inhibitory D-2 receptors and hence this medicine is more potent.
3.Indirect-Acting Dopamine Agonists.
Selegiline
The mechanism of action is selegiline inhibit selectively the MAO-B which is responsible for metabolizing dopamine in the CNS.
2.Amantadine
The mechanism is this antiviral drug decrease the presynaptic reuptake and increase the synthesis of dopamine.
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