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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NEURO DEGENERATIVE DISEASES
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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
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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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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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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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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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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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