5. PARKINSON'S DISEASE.pptx

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1. PARKINSON’S DISEASE OLORO JOSEPH (DCM, BSc. MSc. Pharm, PhD Tox . Fellow)

2. References

3. A chronic progressive neuro-degenarative disease Affects the dopamine producing neurone of the basal ganglia at the area called substantia nigra Due to imbalance in two neurotransmitters Dopamine Acetylcholine Dopamine low, Ach high

4. Dopamine play inhibitory role on cholinergic neurons in the area ↓ sed dopamine → elevated conc. Of Ach elevated conc. Of Ach → unctrolled muscle contraction. PKD is characterized by; Tremors Muscular rigidity Bradykinesia (slowness in initiating and carrying out voluntary movements), and Postural and gait abnormalities.

5. Treatment aims Elevating activity of dopaminergic neurons Replacing dopamine Stimulating dopamine production Preventing dopamine breakdown Reducing activity of Ach Blocking receptors

6. Dopamine replacement Levodopa [lee- voe -DOE-pa] Is a metabolic precursor of dopamine MOA levodopa , is actively transported into the CNS and is converted to dopamine in the brain Large doses of levodopa are required, because much of the drug is decarboxylated to dopamine in the periphery.

7. Carbidopa [ kar -bi-DOE-pa] The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa a dopa decarboxylase inhibitor that does not cross the blood-brain barrier. Carbidopa diminishes the metabolism of levodopa in the gastrointestinal tract and peripheral tissues; thus, it increases the availability of levodopa to the CNS The addition of carbidopa lowers the dose of levodopa needed by four- to five-fold and, consequently, decreases the severity of the side effects arising from peripherally formed dopamine.

8. Actions: Levodopa decreases the rigidity, tremors, and other symptoms of parkinsonism. Therapeutic uses: Levodopa in combination with carbidopa is a potent and efficacious drug regimen currently available to treat Parkinson's disease. In approximately two-thirds of patients with Parkinson's disease, levodopaâ €“ carbidopa treatment substantially reduces the severity of the disease for the first few years of treatment. Patients then typically experience a decline in response during the third to fifth year of therapy.

9. PK Absorption and metabolism: The drug is absorbed rapidly from the small intestine (when empty of food). Levodopa has an extremely short half-life (1 to 2 hours), which causes fluctuations in plasma concentration. Ingestion of meals, particularly if high in protein, interferes with the transport of levodopa into the CNS. Large, neutral amino acids (for example, leucine and isoleucine ) compete with levodopa for absorption from the gut and for transport across the blood-brain barrier. Thus, levodopa should be taken on an empty stomach, typically 45 minutes before a meal. Withdrawal from the drug must be gradual.

10. Selegiline [ seh -LEDGE-ah- leen ] also called deprenyl [DE-pre- nill ], MOA Selectively inhibits MAO Type B (which metabolizes dopamine) at low to moderate doses Does not inhibit MAO Type A (which metabolizes norepinephrine and serotonin) By decreasing the metabolism of dopamine, selegiline increase dopamine levels in the brain

11. Administered orally Metabolized to M ethamphetamine and amphetamine, whose stimulating properties may produce insomnia if the drug is administered later than mid afternoon. Adverse effects severe hypertension.

12. Rasagiline [ ra -SA- gi - leen ] Irreversible and selective inhibitor of brain monoamine oxidase Type B. Has five times the potency of selegiline . Unlike selegiline , rasagiline is not metabolized to an amphetamine like substance.

13. Catechol -O- methyltransferase inhibitors methylation of levodopa by catechol -O- methyltransferase (COMT) to 3-O-methyldopa is a minor pathway for levodopa metabolism. when peripheral dopamine decarboxylase activity is inhibited by carbidopa , a significant concentration of 3-O-methyldopa is formed that competes with levodopa for active transport into the CNS

14. Entacapone [en-TA-ka-pone] or Tolcapone [TOLE-ka-pone] Are nitrocatechol derivatives that selectively and reversibly inhibit COMT Inhibits COMT → ↓ sed plasma con. of 3-O-methyldopa, increased central uptake of levodopa , and greater concentrations of brain dopamine Reduce the symptoms of “wearing-off ” phenomena seen in patients on levodopa – carbidopa

15. Pharmacokinetics: Administered orally Absorption occurs readily and is not influenced by food. Are extensively bound to plasma albumin (>98 percent), with limited volumes of distribution. Tolcapone but not entacapone penetrates the blood-brain barrier and inhibits COMT in the CNS. Tolcapone has a relatively long duration of action (probably due to its affinity for the enzyme) compared to entacapone , which requires more frequent dosing. Both drugs are extensively metabolized and eliminated in feces and urine. Dosage may need to be adjusted in patients with moderate or severe cirrhosis.

16. Adverse effects: Diarrhea Postural hypotension, Nausea & anorexia, Dyskinesias Hallucination Sleep disorders. Fulminating hepatic necrosis is associated with tolcapone use.

17. Dopamine-receptor agonists Include; Pramipexole & ropinirole Apormorphine & Rotigotine Amantadine

18. Pramipexole [ pra -mi-PEX-ole] and ropinirole [roe-PIN- i -role] are agonists at dopamine receptors. Apomorphine [A- po - mor - feen ] and rotigotine [ ro -TI-go-teen] are newer dopamine agonists available in injectable and transdermal delivery systems, respectively

19. Amantadine Amantadine has several effects on a number of neurotransmitters implicated in causing parkinsonism, including; Increasing the release of dopamine, Blockading cholinergic receptors, and Inhibiting the N-methyl-D- aspartate (NMDA) type of glutamate receptors. Current evidence supports an action at NMDA receptors as the primary action at therapeutic concentrations

20. Adverse effects Agitation Confusion Hallucinations At high doses, it may induce acute toxic psychosis. Orthostatic hypotension Urinary retention Peripheral edema Dry mouth also may occur.

21. Antimuscarinic agents Benztropine [BENZ- tro -peen] Trihexyphenidyl [tri-hex- ee FEN- i -dill] Procyclidine [pro-CY- cli - deen ] Biperiden [bi-PER- i den] MOA Blocks cholinergic transmission producing effects similar to augmentation of dopaminergic transmission

22. Adverse effects pupillary dilation, confusion, hallucination, sinus tachycardia, urinary retention, constipation, and dry mouth.