1.  Parkinson’s disease is a neurodegenerative disorder first described by Dr James Parkinson, a London physician, in 1817. The underlying cause is loss of dopaminergic neurons in the substantia nigra.  Parkinson’s disease is a disorder of the extrapyramidal system, a complex neuronal network that helps regulate movement. When extrapyramidal function is disrupted, dyskinesias (disorder of movement) result.

2. Proper functioning of the striatum requires a balance between 2 neurotransmitters: dopamine and acetylcholine The symptoms of parkinsonism result from disruption of neurotransmission within the striatum.

3.  Dopamine is an inhibitory neurotransmitter; acetycholine is excitatory. The neurons that release dopamine inhibit neurons that release γ-aminobutyric acid (GABA). In contrast, the neurons that release acetylcholine excite the neurons that release GABA.  Movement is normal when the inhibitory influence of dopamine and the excitatory influence of actylcholine are in balance.

4.  In parkinson’s, there is an imbalance between dopamine and acetylcholine in the striatum.. In the absence of dopamine, the excitatory influence of acetylcholine becomes unopposed, causing excessive stimulation of the neurons that release GABA.  Overactivity of these GABAergic neurons contributes to the movement disorders seen in parkinson’s disease.

5.  Therapy must be directed at restoring the functional balance between dopamine and acetylcholine. To restore this balance, 2 types of drugs are used:  1. Agents that directly release dopamine, or indirectly activate dopamine receptors (dopaminergic drugs).  2. Agents that block actylcholine receptors (anticholinergic drugs).

6.  Levodopa  Levodopa is the drug of choice for parkinsonism.  With initial treatment, about 75% of patients experience a 50% reduction in severity of symptoms. Full therapeutic response may take several months to develop.  In contrast to the dramatic improvement seen during initial therapy, long-term therapy with levodopa has been disappointing. Although symptoms may be well controlled during the first 2 years of treatment, by the end of 5 years the patient’s ability to function may deteriorate to pretreatment levels. This probably reflects progression of the disease and not development of tolerence to levodopa.

7.  Levodopa reduce symptoms of parkinsonism by promoting synthesis of dopamine in the striatum. Levodopa enters the brain and converted to dopamine in the few dopaminergic nerve terminals that remain in the striatum. By this way levodopa helps restore a proper balance between dopamine and acetylcholine. The conversion of levodopa to dopamine is catalyzed by the enzyme decarboxylase that remove a carboxyl group from levodopa. The activity of decarboxylase is enhanced by pyridoxine.

8.  Why is parkinsonism treated with levodopa and not with dopamine itself. Dopamine cannot be employed for 2 reasons.  1. dopamine cannot cross the blood brain barrier.  2. dopamine has such a short half life in the blood that would be impractical to use even if it could cross the blood brain barrier.

9.  Levodopa is administered orally and undergoes rapid absorption from the small intestine.  Only a small fraction of each dose of levodopa reaches the brain. The majority is metabolized in the periphery, primarily by decarboxylase enzymes, and to a lesser extent, by catechol-O-methyl transferase (COMT).

10.  Peripheral decarboxylases convert levodopa into dopamine, an active metabolite. In contrast, COMT converts levodopa into an inactive metabolite.  Decarboxylases work faster in the presence of pyridoxine.  Because of peripheral metabolism, less than 2% of each dose enters the brain.

11.  1. Nausea and vomiting, due to activation of dopamine receptors in the chemoreceptor trigger zone.  2. Dyskinesia: About 80% of those treated develop involuntary movements(head bobbing, tics, grimacing) within the first year of therapy.  3. Cardiovascular effects.  a. Postural hypotension is common early in treatment. The mechanism of this paradoxical effect is not known.  b. dysrrhythmias due to activation of beta1 receptors in the heart by dopamine.  4. Psychosis:

12.  1. Traditional antipsychotic drugs, block receptors for dopamine in the striatum. As a result these agents will decrease therapeutic effects of levodopa.  2. Monoamine oxidase inhibitors. Levodopa can cause a hypertensive crisis if administered to an individual taking MAO inhibitor.  3. Pyridoxine. Vitamin B6 stimulates decarboxylase activity. By accelerating decarboxylation of levodopa in the periphery, pyridoxine can decrease the amount of levodopa that reaches the CNS. As a result, therapeutic effects of levodopa are reduced.

13.  Carbidopa is used to enhance the effects of levodopa. Carbidopa has no therapeutic effects of its own, and therefore is always used in conjunction with levodopa.  Carbidopa enhances the actions of levodopa by inhibiting decarboxylases in the periphery, and thereby makes more levodopa available to the CNS.  Carbidopa does not prevent the conversion of levodopa to dopamine by decarboxylases within the brain because carbidopa is unable to cross the blood brain barrier.

14.  1- in the absence of carbidopa, about 98% of levodopa is lost in the periphery (decarboxylases in the GIT and peripheral tissues convert it to dopamine), leaving only 2% available to the brain.  2-. By increasing the fraction of levodopa available for actions within the CNS, carbidopa allows the dosage of levodopa to be reduced by about 75%.  For example, in order to provide 2.5 mg of dopamine to the brain, we must administer 125 mg of levodopa if carbidopa is absent, but only 25 mg if carbidopa is present.

15.  3. By reducing production of dopamine in the periphery, carbidopa reduces cardiovascular responses to levodop[a and also reduces nausea and vomiting.  4. By causing direct inhibition of decarboxylase, carbidopa obviates stimulation of decarboxylase by pyridoxine. As a result, carbidopa eliminates concern about decreasing the effects of levodopa through inadvertent use of vitamin preparations that contain pyridoxine.

16.  Selegiline is a selective inhibitor of type B monoamine oxidase (MAO-B), the enzyme that inactivates dopamine in the striatum. Another form of MAO, known as MAO-A, inactivates NE and serotonin.  Selegiline appears to benefit patients with parkinsonism by suppressing destruction of dopamine derived from levodopa. Thus selegiline can prolong the effects of levodopa.

17.  Bromocriptine is a dopamine agonist, bind to dopamine receptors and thereby cause receptor activation. Beneficial effects in parkinson’s disease is believed to result from binding to the D2 receptors in the striatum. Responses are inferior to those of levodopa. Although bromocriptine can be used as monotherapy, the drug is usually employed as an adjunct to levodopa.

18.  1. Nausea, occurring in over 50% of patients.  2. Psychotic reactions.  3. Like levodopa, bromocriptine can cause dyskinesias and postural hypotension.

19.   Originally developed as an antiviral agent, amantadine is also effective in parkinsonism.  The drug relieves symptoms by promoting release of dopamine from remaining dopaminergic terminals in the striatum.  Responses develop rapidly, often within 2 to 3 days, but are less profound than those seen with levodopa. Furthermore, responses may begin to diminish within 3 to 6 months  Amantadine may be employed alone in the early stages of parkinsonism and in combination with levodopa.

20.  The centrally acting agents are just as effective as the older agents (Atropine and related drugs), and have the advantage of producing fewer anticholinergic effects in the periphery.

21.  Excessive stimulation of striatal cholinergic receptors contributes to the symptoms of parkinsonism. The centrally acting anticholinergic drugs help control symptoms by blocking access of acetylcholine to these receptors.  These drugs may be employed alone or in combination with levodopa for the treatment of parkinsonism.  The anticholinergic drugs are often preferred agents for treating mild parkinsonism in younger patients, and their use avoids exposing the patient to the more serious adverse effects of levodopa. Anticholinergic drugs are generally avoided in the elderly because of the risk of severe CNS effects.

22. Thank you