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

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Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 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. RIPER
AUTONOMOUS
NAAC &
NBA (UG)
SIRO- DSIR
Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 2
Contents
• 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
• References

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K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 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

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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

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Pathophysiology
NORMAL PARKINSON

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Dopamine Acetyl choline
Dopamine
Acetyl choline

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• 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

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

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10. RIPER
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K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 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.

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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

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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
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.

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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.

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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

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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

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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)

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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

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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

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Pathophysiology

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23. RIPER
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Raghavendra Institute of Pharmaceutical Education and Research - Autonomous
K.R.Palli Cross, Chiyyedu, Anantapuramu, A. P- 515721 23

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

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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

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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

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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

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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

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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

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Memantine

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

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

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