NEURO DEGENERATIVE DISEASES

Introduction to Neuro Degenerative Diseases, Neurodegenerative diseases, Parkinson Disease, Alzhimer’s Disease, Newer Drugs
Presented by
K. THANMAYA DIVYA
Department of Pharmacology

1. 1 NEURO DEGENERATIVE DISEASES A Seminar as a part of curricular requirement for I year M. Pharm I semester Presented by K. THANMAYA DIVYA (Reg . No. L812IS00102) Under the guidance/Mentorship of Mr. A. Sudheer Kumar., M.Pharm . Associate Professor Dept. of Pharmacology

2. 2 Contents Neurodegenerative diseases Parkinson Disease Pathophysiology Pharmacological Therapy Adverse Effects Contraindications Alzhimer’s Disease Pathophysiology Pharmacological Therapy Adverse Effects Contraindications Newer Drugs References

3. 3 Neurodegenerative Diseases Neurodegenration refers to the progressive loss of structure and function of neurons, which may ultimately involve cell death. Many neurodegenerative diseases such as  Amyotrophic Lateral Sclerosis Alzheimer’s disease Huntington’s disease Multiple sclerosis Parkinson’s disease Prion disease

4. 4 PARKINSON DISEASE It is a chronic progressive neurological disease in which decreased dopamine production in the substantia nigra occurs. SYMPTOMS Tremor of resting muscles Rigidity Bradykinesia (slowness of movement) Impaired balance and Shuffling gait—called also paralysis agitans

5. 5 Pathophysiology NORMAL PARKINSON

6. 6 Dopamine Acetyl choline Dopamine Acetyl choline

7. 7 Dopamine Replacement Therapy Levodopa (L-DOPA) COMT Inhibitors Entacapone Tolcapone MAO-B Inhibitors Rasagaline Selegeline Peripheral decarboxylase Inhibitors Carbidopa Dopaminergic agonists Bromocriptine Ropinirole NMDA receptor antagonist Amantidine Pharmacological Therapy Drugs affecting brain dopaminergic neurons

8. 8 Drugs affecting brain cholinergic neurons Centrally acting anticholinergic drugs Benztropine Benzhexol Procyclidine Biperiden Antihistaminics (with anticholinergic activity) Promethazine Diphenhydramine Orphenadrine

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10. 10 Levodopa Dopamine Precursor Levodopa is converted to dopamine in striatum which interacts with D2 receptors in basal ganglia. Without carbidopa , roughly 97% of L- DOPA is decarboxylated in the periphery.

11. 11 Pharmacokinetics On oral administration, levodopa is rapidly absorbed from small intestine by active transport system. Rate of absorption is dependent on gastric ph and food with high amount of amino acids in the stomach. levodopa is taken 30-60 minutes before meals and with little or no protein. Adverse effects: GIT – Nausea, Vomiting and anorexia. CVS- Postural hypotension, Tachycardia, palpitation and cardiac arrhythmias Mental changes – Insomnia, hallucinations, delusions, euphoria and nightmares on/off phenomena Dyskinesia and Taste alteration

12. 12 Peripheral decarboxylase inhibitors Carbidopa and Benserazide Levodopa is always given in combination with carbidopa / benserazide . Levodopa + Carbidopa (4:1or 10:1 ratio) Levodopa + Benserazide (4:1) Advantages Cardiac complications are minimized Pyridoxine reversal of Levodopa effect does not occur The ‘On-off ‘ effect is minimized since levels of DA sustained.

13. 13 Bromocriptine Ropinirole Pramipexole Ergot derivative Non-ergot derivatives Non-ergot derivatives It has agonistic action at D2 and partial agonist at D1 receptors. D2 agonistic action More selective for D3 Dopamine receptor agonists Pharmacokinetics A – Orally D – in major organ brain and its capillaries M – liver , t½= 6-10hrs. E – in Urine Adverse effects: Vomiting, confusion, hallucinations, postural hypotension CI : Mental illness, peptic ulcers, MI and peripheral vascular diseases.

14. 14 COMT Inhibitors Tolcapone and Entacopone Reversible COMT ( catechol -o- methyltransferase ) Inhibitors. Tolcapone has both peripheral and central actions where as entacopone shows its action only at periphery. Combined preparation : Levodopa + Carbidopa + Entacopone CI : Tolcapone avoided in patients with liver diseases. Pharmacokinetics: A- Orally D- By binding with plasma albumin M- in the liver by cytochrome P450 E- in Faeces and Urine Adverse effects Dyskinesia , diarrhoea, hallucinations

15. 15 MAO-B Inhibitors Selegiline and Rasagiline Selectively and irreversibily inhibits MAO-B enzyme. Rasagiline is more potent and longer acting than selegiline . CI: Seligiline avoided with TCAs and SSRIs Adverse effects Dyskinesia , diarrhoea, hallucinations

16. 16 NMDA receptor antagonist Amantidine Amantadine may also reduce the fluctuations in motor symptoms experienced by many people with PD. MAO Amantidine may increase dopamine release and block dopamine reuptake in the brain. Advesre effects Headache, Heart failure, Hallucinations, dry mouth, Livedo reticularis ( discolured patches on skin)

17. 17 Central anticholinergics Benzhexol and Benztropine These act by reducing the increased cholinergic activity in the straitum . Mainly involved in relieving tremor and rigidity of parkinsonism. Adverse effects Dry mouth, Constipation, drowsiness, blurring of vision Antihistamines Promethazine and Diphenhydramine These are effective in decreasing cholinergic overactivity in basal ganglia

18. 18 Alzhimers disease Alzheimer's disease is a progressive neurologic disorder that causes the brain to shrink (atrophy) and brain cells to die. A continuous decline in thinking, behavioral and social skills that affects a person's ability to function independently. Symptoms Memory loss Difficulty recognizing people & objects Impaired writing & speech abilities Depression, aggression, moodiness Impaired motor skills

19. 19 Pathophysiology

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24. 24 Pharmacological therapy Cholinesterase Inhibitors NMDA Antagonists Tacrine ( Cognex ) Memantine ( Namenda ) Donepezil (Aricept) Rivastigmine (Exelon) Galantamine ( Razadyne )

25. 25 Tacrine MOA – Centrally active reversible inhibitor of acetylcholinesterase Kinetics Food decreases drug concentrations Metabolism – CYP1A2, has an active metabolite Half-life – 2-4 hours Excretion – urine Adverse effects Nausea, vomiting, diarrhea, weight loss, dizziness, headache Severe: hepatotoxicity

26. 26 DONEPEZIL MOA – Reversible and noncompetitive inhibitor of central acetylcholinesterase Kinetics Absorption – well absorbed Distribution – large Vd , lipophilic Metabolism – extensive via CYP2D6 & 3A4, metabolites (inactive & active) Half-life – 70 hours (15 days to steady state) Excretion – urine 57% (17% unchanged drug), feces 15% Adverse effects Insomnia, nausea, vomiting, diarrhea, infection, accidental injury, headache, dizziness, weight loss, fatigue, arrhythmia, rhabdomyolysis

27. 27 RIVASTIGMINE MOA – Reversible inhibition of the hydrolysis of acetycholine by cholinesterase. Kinetics Absorption – oral, rapid & complete, transdermal 30-60 minutes Metabolism – hydrolysis by cholinesterase in the brain, demethylation & conjugation in the liver Half-life – oral 1.5 hours, patch ~ 3 hours upon removal Excretion – urine (97% metabolites) Adverse effects Headache, agitation,weight loss, nausea, vomiting , diarrhea, abdominal pain, tremor, fatigue, insomnia, confusion and Redness at application site Interactions Avoid use with beta blockers Food delays absorption but increases bioavailability

28. 28 Galantamine MOA – Competitive & reversible central cholinesterase inhibitor, may also increase glutamate & serotonin levels. Kinetics Distribution – large Protein binding – low Metabolism – CYP2D6 & 3A4 Half-life – 7 hours Excreted – urine (20%) Adverse effects Nausea, vomiting, headache, diarrhea, weight loss

29. 29 Memantine MOA – noncompetitive antagonist of the N-methyl-D- aspartate (NMDA) receptor for glutamate, decreases glutamate activity under conditions of excessive excitation (does not effect normal neurotransmission). Kinetics Absorption – well absorbed Metabolism – Liver Half-life – 60-80 hours Excretion – urine (unchanged) Adverse effects Hypertension & hypotension , dizziness, confusion, headache, anxiety, diarrhea, constipation

30. 30 Memantine

31. 31 Newer Drugs Parkinson disease Pimavanserin Opicapone Istradefylline Alzhimers Disease Aducanumab BACE-1(beta- amyloid precursor protein cleaving enzyme) inhibitors

32. 32 Goodman and Gillman‘s. Pharmacological Basis of Therapeutics. Katzung , B.G. Basic and Clinical Pharmacology. Tripathi , KD. Essentials of Medical Pharmacology. Craig Charles R. & Stitzel Robert E., Lippincott Publishers . Modern Pharmacology with Clinical Applications . References

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