Drugs Used in Neurodegenerative Disorders

(Anti-parkinsonian & Anit-alzheimer Drugs) 1

Parkinson's disease (PD)

PD: an extrapyramidal motor disorder characterized by :
– Muscular rigidity.
– Resting tremor: pill-rolling movements.
– Hypokinesia (bradykinesia)
– Disturbances of gait, mask like face, sialorrhea and dementia.

AntiPD drugs
1. Drugs affecting brain dopaminergic system
I. Drugs that replace dopa (dopamine precursor)- e.g., levodopa (L-dopa)
II. Peripheral decarboxylase inhibitors- carbidopa.
III. Drugs which prevent breakdown of dopamine:
o MAO-B inhibitors: selegiline, rasagiline
o COMT inhibitors: entacapone, tolcapone.
IV. Drugs that mimic the action of dopamine (dopaminergic agonists):
Bromocriptine, pergolide, lisuride, ropirinole, pramipoxole, apomorphine.
V. Drugs that facilitate dopaminergic transmission: amantadine

2. Drugs affecting brain cholinergic system

I. Central anticholinergics- benztropine.
II. Antihistaminics- diphenhydramine, promethazine.

1. Drugs affecting brain dopaminergic system

I. Ldopa (prodrug)
• Usually given with a dopa decarboxylase inhibitor (DDCI- carbidopa).
DDC
• L-Dopa à dopamine (acts on D2 rec. mainly, D1 also)
• > 95% of L-dopa is decarboxylated in liver and other tissues to dopamine.
• Only 1-2% L-dopa crosses brain by active process, reaches presynaptic nerve
terminals of dopaminergic neurons in striatum is converted to active compound
dopamine.
CNS
• Normal person- no effect is seen.
• In patient with PD- improvement occurs in hypokinesia, rigidity & tremors .
• Then secondary symptoms (posture, gait, handwriting, speech, facial expression,
mood, self care and interest in life)- gradually improve.
• Behavior: a general alerting response - may progress to excitement -frank
psychosis, inappropriate increase in sexual activity.

CVS
• Tachycardia, positive inotropic action.
• Postural hypotension due to D or NE decreasing sympathetic outflow- tolerance
develops.
• With large doses- rise in BP due to stimulation of α adrenergic receptors (NE).
• Renal vasodilatation.

CTZ
Stimulation - nausea, and vomiting. Tolerance develops.

Endocrine
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Inhibits prolactin release.

ADME
• Absorbed by active transport in small intestine.
Bioavailability affected by: amino acids present in food, gastric emptying, pH.
• Undergoes high first pass metabolism in GI mucosa and liver.
• 95% of L dopa converted to dopamine in peripheral tissues by dopa decarboxylase
and less than 1% enters the brain.
• When L-dopa is administered with carbidopa, 10% reaches brain.
Metabolism:
Decarboxylase MAO COMT
L-dopa à Dopamine à DOPAC à HVA

• T ½ 1-3 hours.
• Metabolites exc.in urine after conjugation.
• Urine may be red colored and turn brown.

Adverse effects of L dopa

Most are dose related.
A. Acute effects (at beginning of therapy)- minimized by starting with a small dose.
i. GI toxicity- nausea and vomiting, anorexia- tolerance develops.
Domperidone & carbidopa prevent this.
ii. CV toxicity: postural hypotension, palpitation, tachycardia, inc. AV
conduction & arrhythmias, and exacerbation of angina.
iii. CNS toxicity: psychological effects: schizophrenia- use atypical
antipsychotics (clozapine or olanzapine) for psychosis- does not worsen
PD. Behavioral effects: mild anxiety, confusion, disorientation, insomnia,
nightmares, euphoria.
iv. Miscellaneous
– Alteration in taste and smell sensation.
– Mydriasis and acute attack of glaucoma
– Blood dyscrasias, +ve coomb's test, aggravation of gout,
hemolysis, hot flushes, brownish discoloration of saliva, urine and
vaginal secretion, increase in SGOP and PT, increase in BUN,
priapism.
B. On chronic use (after prolonged therapy- 2-5 years)
i. Abnormal movements (dyskinesia): dose limiting side effect, no tolerance
develops. Seen more with use of carbidopa. Treatment- reduction in dose
and drug free holidays
ii. On /off phenomenon or fluctuation in response
On - dyskinesia due to excess of dopamine.
Off - rigidity and akinesia (end of dose).
This is due to degeneration of neurons- loss of buffering capacity. D is
synthesized on a moment to moment basis.
Treatment :
– Dose fractionation and more frequent adm.
– Use of slow release L-dopa
– Addition of dopamine agonist.
Cautions/contraindications
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IHD, peripheral vascular disease, recent MI, cerebrovascular accident, psychosis, hepatic,
and renal disease; peptic ulcer; glaucoma, malignant melanoma (dopamine is precursor of
melanin).

How to enhance central effects of L-dopa and minimize peripheral effects.

• Use or carbidopa/ benserazide to inhibit DDC in periphery.
• Use of selegiline/ rasagiline- a MAO-B inhibitor- inhibits metabolism of
dopamine in CNS.
• Use of entacapone/tolcapone - a COMT inhibitors- inhibits dopamine degradation
in CNS.
• Use of domperidone – a peripheral dopamine receptor blocker.

II. Peripheral decarboxylase inhibitors

Carbidopa and benserazide are extracerebral dopa-decarboxylase inhibitors.
Benefits obtained with DDCI :
• T ½ of L dopa is prolonged and its dose is reduced to 1/4th to 1/8th .
• Dec. in nausea and vomiting.
• Dec. cardiac complications.
• Less On-Off effect- cerebral D levels more sustained.
• Higher degree of improvement.
Currently L-dopa is practically always used with a decarboxylase inhibitor, except in
patients who develop marked involuntary movements with the combination.

Preparations:
Standard release: senemet: contains carbidopa and L-dopa in a ratio of 1:10 or 1:4; taken
30-60 minutes before food.
Sustained release preparation.

III. Selective MAO-B inhibitors: selegiline, rasagiline

a. Selegiline
Actions:
i. Prevention of breakdown of dopamine: given with L-dopa or L-dopa +
carbidopa- prevents breakdown of dopamine, inc. conc. & storage of dopamine in
striatum. No cheese reaction in usual dose but doses >10 mg/d may inhibit MAO-
A - avoid this dose.
ii. Mechanism of neuroprotective action: MAOB inhibitors prevent the neuronal
damage by following mechanism:
MAOB
• Exogenous neurotoxin MPTP à MPP + (methyl phenyl pyridinium
ion)àtoxic to neurons.
• Free radicals like 6-OHD superoxide, hydroxyl radicals formed by
oxidation of dopamine by MAO-B in nigrostriatal tract are not removed
and these produce neuronal damage. Desmethylselegiline exerts
antiapoptotic effect.

Adverse effects:
• Postural hypotension
• Nausea, confusion, accentuation of L-dopa induced involuntary movements and
psychosis.
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• Selegiline is metabolized to amphetamine, which may cause anxiety, insomnia

should not be given late in the evening.
• Should not be given to patient receiving meperidine, SSRI.
• Recently it has been seen that mortality is higher on triple therapy (L-dopa +
carbidopa + selegiline) than with L-dopa alone. So don’t use triple therapy in new
cases.

Rasagiline: More potent than selegiline.

Uses:
• Alone in early cases; retards progression of disease- exerts neuroprotective effect,
its metabolite desmethylselegiline is involved in antiapoptotic mechanism.
• More commonly used with L-dopa, reduces its dose.

b. COMT inhibitors
• Inhibition of DDC is associated with increased metabolism by other pathways-
COMT- leading to increased plasma levels of 3-O-methyldopa (3OMD) which
competes with L-dopa for active transport in the brain.
• COMT inhibitors prolong L dopa action by inhibiting its peripheral metabolism,
increases availability of L dopa, which provides more prolonged on time.
• Decrease the dose of Ldopa.
• Smoothen out L-dopa effect.

Tolcapone and Entacapone: Entacapone, though less potent and has only peripheral
effects, is preferred because it is not hepatotoxic.
Adverse effects:
With both (L-dopa excess):
• Dyskinesisa, nausea and confusion.
• Diarrhoea, abdominal pain, orthostatic hypotension, sleep disturbances, an orange
discoloration of urine.
With tolcapone, acute hepatic failure may occur- monitor LFT.

IV. Drugs that mimic the action of dopamine (dopamine agonists): advantages
over L-dopa:
• More effective than L-dopa in late PD; have longer duration of action.
• Act on striatal D receptors, good for patients who have lost the capacity to
synthesize, store and release D from levodopa.
• Don’t require enzymatic conversion to active metabolite.
• Don’t form potential toxic metabolite.
• No competition with other substances for active transport.
• There is lower incidence of response fluctuation.
• Preferred as first line drug for PD in younger patients with mild disease and
no cognitive deficit. However, in most patients L-dopa has to be started in 1-5
years.
• One may respond to one compound and other to other.

a. Bromocriptine (BC)
• Potent agonist of D2 receptors.
• Is an ergot derivative.
• Inhibits prolactin release from anterior pituitary.
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• If used alone, doses are high and produce side effects like vomiting,
hallucinations, hypotension, nasal stuffiness, conjunctival congestion.
• Duration of action 6-10 hours.
Uses
• PD:
– As a first line drug in the treatment of PD.
– As a supplement to Ldopa in late cases, having peak dose dyskinesias or
on-off phenomenon
– In patients refractory to L-dopa
• In hyperprolactinemic conditions like galactorrhea- to suppress lactation.
• Gynecomastia in males and infertility in females.
• Acromegaly.

b. Pergolide:
D1 and D2 agonist, more effective than BC, decreases the dose of L-dopa.

c. Ropinirole (D2) and Pramipexol (D3): Newer dopamine agonists.

• Ropinirole: metabolised in liver.
• Pramipexole: also exerts a neuroprotective effect by scavenging H2O2. Excreted
through kidney.

Uses of dopamine agonists:

• Monotherapy in mild cases of PD. Advantages over L dopa: long acting, less
chances of on/off effects and dyskinesias, no oxidative stress and damage to
neurons, are also better tolerated and therapeutic dose can be achieved soon.
• With L-dopa to smoothen its effects in severe cases.

d. Apomorphine:
• Short acting dopamine agonist, given SC.
• Acts rapidly in 5-10 minutes.
• Used as a rescue medication in akinetic emergencies. Always use domperidone
(antiemetic) with it.

Adverse effects of dopamine agonists

Adverse effects:
• GIT- anorexia, nausea, vomiting (give with meals), constipation, dyspepsia,
reflux esophagitis, bleeding from peptic ulcer.
• CVS- postural hypotension at the beginning, painful digital spasm (Bc, pergolide),
cardiac arrhythmias. Peripheral edema.
• CNS
– Seizures, psychosis, confusion, hallucinations, delusions and other
psychiatric illnesses.
– Dyskinesias- reduce dose

Miscellaneous:
i. With BC, pergolide, lisuride (ergot derivatives) :
 Headache, nasal congestion, conjunctival congestion.
 Erythromelalgia (red, tender, painful, swollen feet and occasionally
hands, arthralgia) and digital vasospasm (painless).
 Pleural, peritoneal fibosis.
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ii. With pramipexole, ropinirole: sudden attacks of sleep during daytime

activities.

Contraindications
Psychosis, recent MI, peripheral vascular disease (BC, pergolide), peptic
ulceration.

V. Drugs that facilitate dopaminergic transmission:

Amantadine
• An antiviral drug for influenza A2, accidentally found to have antiparkinsonian
activity.
• Causes release of dopamine, acts on dopamine receptors, and prevents its reuptake
into neuron.
• Has antiglutamate action - NMDA antagonist
• Also causes release of catecholamines from peripheral stores

Adverse effects:
• Similar to L-dopa but are less severe.
• A characteristic side effect - due to release of catecholamines results in
vasoconstriction, livedo reticularis and edema of ankles- responds to diuretics.
Uses
• It may be used in milder cases or in short courses to supplement submaximal
doses of L-dopa. It is less potent than Ldopa and its benefits are short lived.
• As adjunct to L-dopa in patients with on/off phenomenon.

Contraindications:
H/O seizures or heart failure.

2. Centrally acting anticholinergics

.i. Atropine like drugs- have a higher central: peripheral anticholinergic ratio than
atropine.
ii. Some H1 antihistaminics, like diphenhydramine - significant central
anticholinergic property
• These reduce tremors more than rigidity or hypokinesia.
• Decrease salivation by their peripheral action.
• Overall efficacy is much lower than L-dopa.

Adverse effects:
• Similar to atropine – peripheral side effects :dry mouth, acute suppurative
parotitis, constipation, impaired vision, urinary retention, palpitation, etc - may be
trouble some.
• Impairment of memory, sedation and confusional states in elderly.

Uses:
• Drug induced parkinsonism (phenothiazines, butyrophenones, reserpine,
metoclopramide, cholinergic drugs, etc.).
• In patients where dopaminergic drugs are contraindicated e.g., schizophrenia and
cardiac arrhythmia.
• May be used alone in mild cases or may be used with L-dopa to reduce its dose.
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• The antihistaminics are less effective but better tolerated by older patients, their
sedative effect also helps.

Alzheimer’s disease (AD)

Neurochemistry
• Selective loss of cholinergic neurons, reduced activities of choline acetyl
transferase and cholinesterase - seen in the basal forebrain cortex and
hippocampus.
• Reduction in nicotinic receptors but not muscarinic receptors in cortex
• Other neurotransmitters involved: glutamate, 5-HT and neuropeptides.

Therapy
A. To augment cholinergic function of the brain: Centrally acting AniChEs:
i. Tacrine
Rapidly absorbed; has extensive first pass metabolism in the liver -2-3 %
bioavailable; T ½ - 2-3 H.
Side effects:
– Cholinergic side effects (abdominal cramps, nausea, vomiting,
and diarrhea)
– Hepatotoxicity- regular biweekly monitoring of LFT is a must- it
has become drug of 2nd choice.

ii. Donepezil- first line drug; highly selective centrally active antiChE, with
minimal peripheral effects. 100% bioavailable. T ½ long (70h) hence-
given once a day
Adverse reactions: nausea, vomiting, diarrhea and insomnia.
Not hepatotoxic
Drug of choice at present.

iii. Other antiChE: galantamine (also stimulates nicotinic receptors),

rivastigmine- like donepezil- no hepatotoxicity.

B. NMDA receptor antagonist: memantine- for severe cases added to AChEIs,

delays deterioration.
Adverse reactions:
Dizziness, headache, confusion, constipation, skin rashes