Antiparkinsonics Med chem lecture


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Lecture Notes for B. Pharm, Medicinal Chemistry of Purbanchal University Nepal regarding Antiparkinsonics

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Antiparkinsonics Med chem lecture

  1. 1. Antiparkinsonics (Parkinson has no cure as of 2014 Drugs only control symptoms)
  2. 2. DEFINITION Parkinson's disease is degenerative disorder of the CNS dopaminergic neurons which shows mainly motor and sometimes cognition (thinking) related symptoms. movement-related (motor) shaking, rigidity, slowness of movement and difficulty with walking Cognitive problems Dementia
  3. 3. Causes • Parkinson is caused due to imbalance of dopamine(DA) and acetylcholine (Ach) • Ach and DA need to be balanced for smooth movement. DA causes muscle relaxation while Ach causes contraction. • Reduction of DA, in the basal ganglia results in imbalance of those two and causes motor disorders • In some cases, at later stages of the disease reduction of Ach which is also involved in learning and attention leads to dementia
  4. 4. Classification • Anti-Cholinergic drugs: atropine, Benzhexol* Reduces acetylcholine effects (treatment for tremors in early stages) • Cholinesterase inhibitors: Rivastigmine Promotes acetylcholine effects (treatment for dementia in later stages) • Dopamine precursors: levodopa* Prodrug of dopamine • Dopamine decarboxylase inhibitors: Carbidopa, benserazide Inhibits peripheral metabolic degradation of dopamine • Catechol-O-methyl Tranferase (COMT) inhibitors: Entacapone inhibits COMT based metabolism of Levodopa • Dopamine agonist: bromocryptin, Amantadine Promotes dopamine effect in the brain.
  5. 5. Anticholinergics • Anticholinergic medicines block cholinergic nerve impulses that help control the muscles of the arms, legs and body by inhibiting binding of acetylcholine with it’s receptors • For normal motor or muscle control, the effects of acetylcholine and dopamine need to be balanced. In Parkinson dopamine levels decrease but Acetylcholine levels remain same. • Anticholinergic medicines decrease levels of acetylcholine to achieve a closer balance with dopamine levels.
  6. 6. Benzhexol (Trihexyphenidyl) • It is an antimuscarinic drug that blocks Ach effect on M1 receptor • In Parkinson DA and Ach levels are imbalanced that causes motor defects. DA lvls are reduced while Ach lvls remain constant. Benzhexol lowers Ach levels and maintains the balance • Trihexyphenidyl is used for the symptomatic treatment of Parkinson's disease in mono and combination therapy with L-Dopa • Also used to control drooling of children with cerebral palsy (cebebrum paralysis that effects movement) • In older patients with Parkinsonism it can increases chances of dementia since Ach is involved in cognition too
  7. 7. Cholinesterase inhibitors • Cholinesterase inhibitors are designed to increase levels of acetylcholine, a chemical messenger involved in memory, judgment and learning, traits which are lost in dementia stage of Parkinsonism which only occurs sometimes at a later stage • Cholinesterase inhibitors do not stop the destruction of dopaminergic nerve cells. Their ability to improve symptoms eventually declines as brain cell damage progresses.
  8. 8. Rivastigmine • It is a acetylcholinesterase/butyrylcholinesterase inhibitor used to treat dementia that sometimes occurs at later stage of Parkinson • It increases lvl of Ach by blocking it’s degradation from the enzyme acetyl/butyryl cholinesterase • This improves cognitive functions like memory and awareness • Side effects are mostly nausea and vomiting and at low doses it is generally safe • It can sometimes dangerously slow heartbeat in which case atropine (Ach blocker) is used
  9. 9. Which is more hydrophillic or less lipophillic ? How does brain get glucose from blood when glucose is not lipophillic at all?
  10. 10. Dopamine precursor • External DA can’t cross BBB but the prodrug L- dopa can. L-Dopa is dopamine with acid group to create an amino acid functional group. The blood brain barrier has Amino Acid Transporter which allows penetration of L-dopa, even though L- Dopa is less lipophillic than DA • In the brain it gets metabolized into dopamine by the enzyme DOPA decarboxylase. • Thus, L-DOPA is used to increase dopamine concentrations in the brain which is lowered in Parkinson
  11. 11. • It is most preferred and safest drug in Parkinson • Metabolism outside the brain can lower the efficacy of L-Dopa • Thus L-Dopa is given with carbidopa which blocks Dopamine decarboxylase mediated peripheral metabolism and allows high dose of L-Dopa to penetrate brain. Carbidopa itself doesn’t penetrate the brain.
  12. 12. Carbidopa • It is a Dopamine decarboxylase inhibitors. • It’s purpose is to increase efficacy of L-Dopa by preventing it’s peripheral metabolic degradation and thus allowing more L-Dopa to penetrate the brain • While Dopamine decarboxylase exists both inside and outside the brain, Carbidopa only blocks metabolism outside the brain cause it can’t penetrate the brain.
  13. 13. Entacapone • It is a Catechol-O-methyl Tranferase (COMT) inhibitors • Entacapone prevents COMT from metabolizing L-DOPA into inactive metabolite 3-methoxy-4-hydroxy-L-phenylalanine (3-OMD) in the periphery. • Thus more L-Dopa can penetrate the brain • It itself doesn’t cross BBB
  14. 14. Amatidine • It promotes Dopamine release and prevents reuptake of dopamine in the CNS • Exact MOA is not known. It promotes dopamine, noradrenaline and serotonine and blocks monoamine oxidase A and NMDA receptors, • It has amine group with pKa of 10.8. Although mostly protonated in the blood, the unique cage structure provides a very high lipophilicity for good penetration into brain and also prevents metabolism such that it is excreted from kidney in unchanged form
  15. 15. Benzhexol
  16. 16. Levodopa
  17. 17. Thank you
  18. 18. Review • In Parkinson neurons that make Dopamine die • Thus need to supplement dopamine externally • But Dopamine can’t penetrate the brain (body makes dopamine in brain itself) • Thus given in prodrug form- levodopa
  19. 19. • Dopamine used for motor functions • Acetylcholine used for motor and cognitive functions • A balance of DA and Ach is needed for proper movement
  20. 20. • Levodopa has an amino group and penetrate the brain utilizing the amino acid transporters in the BBB • After getting inside brain, it is metabolized into dopa which eventually forms dopamine • This is a good strategy but it has metabolic problem
  21. 21. • There are 3 enzymes that want to degrade the levodopa outside brain thus limiting it’s therapy They are • Dopamine decarboxylase • COMT • MOA (mono amine oxidase)-B
  22. 22. • The solution is to co-administer Levodopa with drugs that block those enzymes • Dopamine decarboxylase- Carbidopa • COMT - Entacapone • MOA (mono amine oxidase)-B :Selegiline • Thus more Levodapa can enter the brain
  23. 23. Acetylcholine based therapy are also useful • 1) AntiCholinergics: lower Ach levels prevent tremors (as balance is reached with preexisting lowered DA lvls) • 2) Cholinergics: Increasing Ach levels controls dementia • (Lowering Ach levels might have lead to dementia as Ach is needed for cognitive function. Thus better to go with levodopa based therapy) • Dementia is a cognitive (thinking capacity)defect which sometimes (not always)occurs in Parkinson at later stage
  24. 24. Especial Topic Deep Brain Stimulation A drugless therapeutic wonder for Parkinson, Alzheimer, Depression and Dystonia
  25. 25. • Imagine curing UNCURABLE DISEASES not with drugs but just a piece of lead rod nailed into your brain! (remember brain feels no pain as it has no pain receptors) • The lead rod insulated except at the tip and delivers electrical stimulation to only a targeted area in brain • It doesn’t shock the patient or harm other brain areas • DBS is FDA approved for Parkinson and in Phase 3 clinical trial for Alzheimer
  26. 26. Incredible outcome in Parkinson and Dystonia Youtube- Andres Lozano- Parkinson's, depression and the switch that might turn them off