PHARMACOLOGY 3rd stage
Anti Parkinson drugs :-Parkinson's disease is a progressive neurological disorder of motor movements characterized by tremor ; rigidity and bradykinesia ;it is caused by degeneration of the substantia nigra in the mid brain ,and consequent loss of dopamine –containing neurons .
In extra pyramidal pathway ,we have two balance systems are important one depend on Acetylcholine and the other depend on dopamine .
In Parkinson's disease ;there is degenerative loss of dopaminergic neurons and the symptoms and signs of the disease are due to dopamine depletion .
Certain drugs also produce the features of Parkinson's disease most commonly Trifluoperazine ;Haloperidol ;Chlorpromazine (anti psychotic drugs ) act by block dopamine receptors ;so the general term parkinsonism is used to cover both the disease and the drugs –induce the state .
To restore dopaminergic / cholinergic balance either :-
1)Reduce cholinergic activity by central acting antimuscarinic drugs ;this is most effective in treatment of tremor and rigidity ,and less effective in treatment of bradykinesia .
2)Enhance of dopaminergic activity either by :-
a- replenish neuronal dopamine by supplying Levo-dopa (natural precursor of dopamine ), administration of dopamine itself is ineffective as it doesn’t cross the blood brain barrier and because its rapid metabolism in the gut ,blood and liver by monoamine oxidase and catechol-o-methyl transferase (MAO & COMT ).
b- Inhibit metabolism of dopamine and prolong its action by Selegiline .
c- Giving dopamine agonist e.g. Bromocriptine .
d- Release of dopamine from nerve endings and inhibits its reuptake by Amantadine .
e- Inhibit the COMT by Tolcapone .
Both approaches are effective in therapy and usefully be combined .
Dopamine doesn’t cross BBB, but its precursor (L-dopa ) is rapidly transported into CNS and converted to dopamine by dopa decarboxylase in the brain .
Large doses of L-dopa are needed because much of the drug is decarboxylated in the peripheral tissue to dopamine and result in peripheral side effects ,include nausea ,vomiting ,postural hypotension, and even cardiac arrhythmia .
So that ; only 1-5% of an oral dose of L-dopa reaches the brain .
Can overcome these side effects by using (decarboxylase inhibitor ) ,which is don’t enter the BBB, so that they prevent only the extra cerebral metabolism of Levo-dopa including (Carbidopa and Benserazide ) these two drugs are given in combination with L-dopa .
This combination produce the same brain concentration with L-dopa alone ; but only 25% of dose of L-dopa is required which is smoothes the action of L-dopa and reduces the incidence of adverse effects .
Pharmacokinetic :-
L-dopa is absorbed rapidly from small intestine especially when it is empty . It has short plasma half life (1-2 h) .It causes fluctuation in plasma level and this is called (on-off phenomena) .
Adverse effects :-
1- Peripheral effects :-
a) nausea ,anorexia, and vomiting .
b) tachycardia ,cardiac arrhythmia and hypotension .
c) mydriasis due to adrenergic action on irris .
d) blood dyscresia with positive coomb's test .
e) brown discoloration of saliva and urine ;because dopamine stimulates the secretion
2- Central effects :- include visual and auditory hallucination with abnormal involuntary movements with depression and anxiety .
Interactions :-
1)With vitamin B6 lead to increase the peripheral breakdown of L-dopa .
2) MAOIs might cause hypertensive crisis .
3) contraindication in psychotic patients or those taking antipsychotic drugs .
4) contraindication in patients with glaucoma because it increase the I.O.P.
4) contraindication in patients with cardiac disease .
Bromocriptine :- It is D2 receptor agonist ,also it has a week alpha –adrenoceptor antagonist ;commonly used in combination with L- dopa ,rapidly absorbed from gut ;has more half life than L-dopa ,so it has smoother action than L-dopa .
Side effects :- nausea; vomiting ,hypotension ,dizziness and prolong use lead to pleural effusion and retroperitoneal fibrosis .
Amantadine :-
It is an antiviral drug used for treatment of flu. It act to enhance synthesis ;release and prevent re-uptake of dopamine ; it has little effect on tremor, but more effective against rigidity and bradykinesia .
Tolcapone :-
Inhibitor of the COMT lead to decrease the concentration of metabolite and increase the central uptake of L- dopa and greater concentration in the brain .
Antimuscarinic drugs:-
Act by block Ach. receptors centrally in the CNS .e.g. benzhexol ,orphenadrine ;procyclidine .they produce improvement in tremor ;rigidity ;sialorrhoea,muscluler stiffness ,but little in hypokinesia .