Review of Pharmacology - 9E (2015)

Review of Pharmacology
(and thus decreased abnormal movements). At normal doses these inhibit only MAO-B and
thus have no interaction with cheese or tricyclic antidepressants. However, at high doses,
they also inhibit MAO-A and can lead to hypertensive crisis (cheese reaction) with tyramine
containing foods and serotonin syndrome with TCAs. Rasagiline is more potent than
selegiline. These drugs are thought to reduce the disease progression.
Central Nervous System
Ergot alkaloids are short acting
and can cause digital vasosopasm
(leading to gan-grene)
and pleural, peritoneal and cardiac
fibrosis.
Pramipexole and ropinirole
are long acting and do not cause
gangrene. These are now the
first choice drugs for Parkinsonism.
Pramipexole and Ropinirole
are used for treatment of restless
leg syndrome
Subcutaneous apomorphine
(D 4
agonist) has been approved
as a rescue therapy of ‘off’
episodes when oral dopamine
agonists or COMT inhibitors fail
to control these episodes.
Rotigotine is a dopamine agonist
that can be adminis-tered
through a transdermal patch
but was discontinued due to
crystal formation on the patches.
C. Dopamine Agonists
These drugs directly activate D 2
receptors and can be used as monotherapy in Parkinsonism.
Ergot derived dopamine agonists include bromocriptine and pergolide. These drugs are
short acting and can cause digital vasosopasm (leading to gangrene) and erythromelalgia.
These drugs can also result in pleural, peritoneal and cardiac fibrosis. Ergot alkaloids require
slow upward titration of dose. Long term use of pergolide is associated with cardiac valvular
defects. Newer non-ergot dopamine agonists; pramipexole and ropinirole do not have these
limitations (these are long acting and do not cause gangrene). All four drugs can cause
confusion and hallucinations. In developed countries, these are now the first choice drugs
for Parkinsonism (preferred over levo-dopa). Ropinirole has also been approved for restless
leg syndrome. Pramipexole is excreted mainly by kidney whereas ropinirole is metabolized
by liver. Rare but important adverse effect of these drugs is excessive day time sleepiness.
Recently, dopamine agonists have been associated with impulse-control disorders including
pathological gambling, hypersexuality, etc.
Rotigotine is a dopamine agonist that can be administered through a transdermal patch
but was discontinued due to crystal formation on the patches. Apomorphine can be given
subcutaneously for temporary relief of off-periods. However, it cause troublesome nausea.
D. Drugs Increasing Dopamine Level at Synapse
Amantadine is an antiviral drug that is also useful in Parkinsonism. It increases synaptic
dopamine level by increasing presynaptic release and decreasing its reuptake. It also
possesses anticholinergic and antiglutaminergic (NMDA blocking) activity. Adverse effects
of this drug include nausea, insomnia, ankle edema and livedo reticularis. It ameliorates
dyskinesia associated with chronic levo-dopa therapy.
Drugs Inhibiting Brain Cholinergic Transmission
Central anticholinergic drugs like trihexiphenidyl (benzhexol), procyclidine, benztropine,
orphenadrine and biperiden are the drugs of choice for drug induced Parkinsonism. Drugs
that act by blocking D 2
receptors in the brain (like antipsychotics, metoclopramide etc.) can
cause Parkinsonism. In this condition, increasing dopamine level is not effective because
the receptors on which it has to act (D 2
) are already occupied, therefore anticholinergics are
preferred.
First generation antihistaminics with high antimuscarinic activity like promethazine
and diphenhydramine can also be used for this indication.
Adverse effects of antimuscarinic drugs include urinary retention, blurred vision, dry
mouth and constipation.
Other Neurodegenerative Diseases
318
Central anticholinergic drugs
like trihexiphenidyl (benzhexol),
procyclidine, benztropine,
orphenadrine and biperiden are
the drugs of choice for drug
induced Parkinsonism.
Alzheimer’s Disease (AD)
• It is a form of senile dementia that is due to the deposition of amyloid plaques in
the hippocampus (Presence of neurofibrillary tangles). There is loss of cholinergic
neurons in the brain. Anticholinesterases that can cross the blood brain barrier are
the mainstay of treatment of this disease.
• Tacrine was used previously but its use has declined due to its hepatotoxic potential
and the need of frequent (four times a day) dosing.
• Donepezil, rivastigmine and galantamine are newer cholinesterase inhibitors
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