1. Drugs That Act On The Central Nervous System SAMUEL AGUAZIM( MD)

2. Drugs Used in Parkinson Disease Parkinsonism A neurological syndrome usually resulting from deficiency of the neurotransmitter dopamine as the consequence of degenerative, vascular, or inflammatory changes in the basal ganglia. Characterized by rhythmical muscular tremors, rigidity of movement, bradykinesia, droopy posture.

3. WHAT IS THE PATHOPHYSIOLOGY OF THIS DISEASE The disorder is thought to occur because of a loss of dopamine in the nigrostriatal pathway. The loss of dopamine disrupts the delicate balance between the cholinergic and dopaminergic systems within the striatum and basal ganglia.

4. Signs Remember RAFT R = rigidity of skeletal muscles A = akinesia (loss of voluntary movement) F = flat facies T = tremor at rest (not always)

5. CLASSIC FEATURES SHUFFLING GAIT STOOPING POSTURE DECREASED ARM SWING TURNING EN BLOC DYSPHONIA MOOD DISTURBANCES SLEEP DISTURBANCES MEMORY LOSS

6. Therapy for Parkinson Disease 1. dopamine replacement therapy 2. dopamine agonist therapy 3. anticholinergic therapy

7. What are the pharmacologic treatment options? Levodopa Carbidopa bromocriptine Pergolide Amantadine Selegiline Antimuscarinic agents

8. Secondary Parkinsonism Sometimes parkinsonism like symptoms follow after viral encephalitis or multiple vascular lesions. Phenothiazines and Haloperidol – action block dopamine receptors – may produce Parkinson's symptoms. Strictly not used in the patient’s with parkinsonism.

9. Can these drugs cure? No! pharmacologic treatments can only offer temporary relief; they neither reverse nor arrest the disease process The ultimate goal of treatment is to reestablish the balance between dopamine and acetylcholine in the brain.

10. Dopamine replacement therapy LEVODOPA (L-DOPA): metabolic precursor of dopamine enters the brain decarboxylation to dopamine Large doses of levodopa are required because much of the drug is decarboxylated to dopamine in the periphery. All this dopamine floating around peripherally causes side effects.

11. To achieve therapeutic brain levels, either: Large quantities to be given With a dopa decarboxylase inhibitor, such as Carbidopa Carbidopa does not penetrate BBB

12. Clinical Use :Levodopa Does not stop disease progression May reduce Parkinson's disease mortality rate Most effective in diminishing bradykinesia

13. Side Effects Dyskinesis Psychosis Hypotension Vomiting MC: Choreoathetosis

14. Contraindications Psychotic patients Angle-closure glaucoma Vit. B-6.- increases peripheral breakdown Careful management : CVS disease. Not with MAO (Monoamine oxidase inhibitor)– I such as phenelzine > HTN crisis.

15. Carbidopa Peripheral decarboxylase inhibitor which doesn't cross the BBB To decrease peripheral decarboxylation of L-dopa. Carbidopa leads to decreased side-effects and decreased dosage of L-dopa required.

17. Other Drugs Tolcapone and Entacapone are plasma catechol-o-methyltransferase (COMT) inhibitors that prolong the half life of levodopa. Initial Rx and adjunct to levodopa Side effect- dyskinesis, hypotension, hallucinations and diarrhea

18. Selegiline and rasagiline This drugs inhibit MAO-B slows the breakdown of dopamine thus, dopamine remains in the vicinity of its receptors on the cholinergic neurons for a longer period of time. Side effect: dyskinesis, psychosis and insomnia

19. Dopamine Agonist therapy Directly activate dopamine receptors Not requiring enzymatic activation Bromocriptine. Pergolide, pramipexole, ropinirole and rotigotine. Administration of dopamine agonists to stimulate these receptors should therefore restore the balance of inhibition and excitation in the basal ganglia.

20. Clinical Use :Bromocriptine Compared with Levodopa: Less incidence of response fluctuation and Dyskinesias It is the drug of choice to treat cases of hyperprolactinemia Adverse Effects GIT : nausea, vomiting Peptic ulceration with bleeding CVS : postural hypotension Behavioural : confusion, hallucinations, delusions

21. Amantadine Antiviral drug Mechanism of action: unclear Clinical Use Short-term benefits; less potent Levodopa Improves rigidity, tremor, bradykinesia Toxic effects: restlessness, agitation, confusion, peripheral edema and skin rash( livedo reticularis)

22. Anticholinergic therapy Trihexyphenidyl Benztropine Biperiden They reduce the activity of the uninhibited cholinergic neurons in the basal ganglia They are muscarinic antagonist and differ only in potency

23. Anticholinergics Clinical Use Improvement: rigidity/tremor Minor effect: bradykinesia

24. SIDE EFFECTS Dry mouth Constipation Urinary retention Confusion

25. DRUGS USED IN ALZHEIMER DISEASE IS THE MOST COMMON FORM OF DEMENTIA Alzheimer dementia 3 distinguishing features Accumulation of senile plaques Neurifibrillary tangles Loss of cortical neurons –cholinergic Drugs used—inhibition of acetyl choline esterace Donepezil, galantamine, rivastigmine & tacrine Galantamine competitive inhibitor Tacrine--hepatotoxic

26. N-methyl-D-aspartate NMDA receptor antagonist Antagonist of NMDA receptors are neuroprotective Memantine—slows the rate of memory loss Prevents loss of neurons