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Neurodegenerative Drugs Pharma.pptx
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- 2. Contents 2 • Neurodegenerative diseases •Parkinson Disease a. Pathophysiology b. Pharmacological Therapy c. Adverse Effects d. Contraindications • Alzhimer’s Disease a. Pathophysiology b. Pharmacological Therapy c. Adverse Effects d. Contraindications • Newer Drugs
- 3. Neurodegenerative Diseases 3 • Neurodegenrationrefers 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. PARKINSON DISEASE It isa 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 4
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- 8. • Dopamine ReplacementTherapy • COMT Inhibitors • MAO-B Inhibitors • Peripheral decarboxylase Inhibitors • Dopaminergic agonists • NMDAreceptor antagonist Levodopa(L-DOPA) Entacapone Tolcapone Rasagaline Selegeline Carbidopa Bromocriptine Ropinirole Amantadine Pharmacological Therapy Drugs affecting brain dopaminergic neurons 8
- 9. Drugs affecting braincholinergic neurons 9 • Centrally acting anticholinergic drugs o Benztropine o Benzhexol o Procyclidine o Biperiden • Antihistaminics(with anticholinergic activity) o Promethazine o Diphenhydramine o Orphenadrine
- 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- DOPAis decarboxylated in the periphery. 10
- 11. Pharmacokinetics 11 • On oraladministration, 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. Peripheral decarboxylase inhibitors Carbidopaand Benserazide 12 Levodopa is always given in combination with carbidopa/benserazide. Levodopa + Carbidopa(4:1or 10:1 ratio) Levodopa + Benserazide(4:1) Advantages o Cardiac complications are minimized o Pyridoxine reversal of Levodopa effect does not occur o The ‘On-off ‘ effect is minimized since levels of DA sustained.
- 13. Bromocriptine Ropinirole Pramipexole Ergotderivative 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 13 Dopamine receptor agonists CI : Mental illness, peptic ulcers, MI and peripheral vascular diseases. 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
- 14. COMT Inhibitors Tolcapone andEntacopone 14 • 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. MAO-B Inhibitors Selegiline andRasagiline 15 • 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. NMDA (N-methyl-D-aspartate) receptor antagonistAmantadine 16 Amantadine may also reduce the fluctuations in motor symptoms experienced by many people with PD. MAO Amantadine 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. Central anticholinergics Benzhexol andBenztropine 17 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. Alzhimers disease Alzheimer's diseaseis 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 18
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- 24. Pharmacological therapy 24 Cholinesterase Inhibitors Tacrine (Cognex) Donepezil (Aricept) Rivastigmine(Exelon) Galantamine (Razadyne) NMDAAntagonists Memantine (Namenda)
- 25. Tacrine 25 MOA – Centrallyactive 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. DONEPEZIL 26 MOA– Reversible andnoncompetitive 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. RIVASTIGMINE MOA – Reversibleinhibition of the hydrolysis of acetycholine by cholinesterase. 27 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. Galantamine 28 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. Memantine 29 MOA – noncompetitiveantagonist 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
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- 31. Newer Drugs 31 Parkinson disease Pimavanserin Opicapone Istradefylline Alzhimers Disease Aducanumab BACE-1(beta-amyloid precursor protein cleaving enzyme) inhibitors