Micaella Anne T.

Manuela

ANTIPSYCHOTICS AGENTS
 antipsychotic and neuroleptic
used interchangeably to denote a group of drugs that is used for treating schizophrenia and other psychoses
 used in western medicine for 50 years
 RESERPINE & CHLORPROMAZINE
First drugs found to treat schizophrenia
- Chlorpromazine is sometimes used to treat psychoses
 Psychosis
- Denotes to a variety of mental disorders
 Schizophrenia
- Particular kind of psychosis
- Characterized by clear sensorium marked by a thinking disturbance

Pharmacology of antipsychotic agents

 Structure-related activity of antipsychotics are classified into several groups
1. Phenothiazine derivatives
2. Chlorpromazine
3. Thioridazine
4. Trifluoperazine
5. Perphenazine
6. Fluphenazine
7. Thioxanthene derivatives
8. Thiothixene
9. Butyrophenone
10. Molindone
11. Loxapine Older drugs
12. Risperidone Newer drugs
13. Olanzapine
14. Aripiprazole
15. Pimozide
16. Clozapine
17. Quetiapine
18. Ziprasidone
19. Aripiprazole

THE DOPAMINE HYPOTHESIS

 For schizophrenia
 most fully developed hypotheses and is a basis for the rationale for drug therapy
 suggests that excessive dopaminergic activity plays a role in the disorder
 EVIDENCES:
- Strongly blocks post synaptic D2 receptors in CNS, especially in the mesolimbic-frontal system
- Drugs that increase dopaminergic activity either aggravate schizophrenia or produce psychosis de novo in
patients
- Dopamine receptor has been found, post mortem, to be increased in the brains of schizophrenics who have not
been treated with antipsychotics drugs
- Positron emission tomography (PET) has shown increased dopamine receptor density in both treated and
untreated schizophrenics compared with non-schizophrenics
- Successful treatment of schizophrenic patients has been reported to change the amount of homovanillic acid
(HVA), a metabolite of dopamine, in the cerebrospinal fluid, plasma, and urine
 Far from complete, however if an abnormality in dopamine physiology is responsible for the pathogenesis of
schizophrenia, antipsychotic drugs are used but are only partially effective and sometimes ineffective to patients
 Antagonists of NMDA receptor such as phencyclidine, when administered produce much more “schizophrenia-like”
symptoms than dopamine agonists
 Traditional antipsychotics
-bind D2 50 times more avidly than D1 or D3 receptors
 ANTIPARKINSONISM AGENTS
Parkinsonism
- characterized by a combination of rigidity, bradykinesia, tremor, and postural
instability.
pathophysiologic basis of the idiopathic disorder may relate to exposure to some unrecognized
neurotoxin or to the occurrence of oxidation reactions with the generation of free radicals.
- progressive, leading to increasing disability
- normally high concentration of dopamine in the basal ganglia of the brain is reduced
- restoration dopaminergic activity with levodopa and dopamine agonists have been successful in
alleviating many of the clinical features of the disorder
- alternative but complementary approach:
o restoration of the normal balance of cholinergic and dopaminergic influences on the basal
ganglia with antimuscarinic drugs
- pathophysiologic basis of these therapies:
o dopaminergic neurons in the substantia nigra that normally inhibit the output of GABAergic
cells in the corpus striatum are lost
- Drugs that induce parkinsonian
syndromes either are:
o dopamine receptor antagonists
o lead to the destruction of the dopaminergic nigrostriatal neurons

1. Levodopa is the levorotatory stereoisomer of dopa.

Dopamine does not cross the blood-brain barrier and if given into the peripheral circulation has no
therapeutic effect in parkinsonism. However, (–)-3-(3,4-dihydroxyphenyl)-L-alanine (levodopa), the
immediate metabolic precursor of dopamine, does penetrate the brain, where it is decarboxylated to
dopamine.

Dopamine receptors of the D1 type are located in the zona compacta of the substantia nigra and
presynaptically on striatal axons coming from cortical neurons and from dopaminergic cells in the substantia
nigra. The D2 receptors are located postsynaptically on striatal neurons and presynaptically on axons in the
substantia nigra belonging to neurons in the basal ganglia. The benefits of dopaminergic antiparkinsonism
drugs appear to depend mostly on stimulation of the D2 receptors, but D1-receptor stimulation may also be
required for maximal benefit. Dopamine agonist or partial agonist ergot derivatives such as lergotrile and
bromocriptine that are powerful stimulators of the D2 receptors have antiparkinsonism properties, whereas
certain dopamine blockers that are selective D2 antagonists can induce parkinsonism.

2. Bromocriptine is a D2 agonist; used to treat Parkinson's disease and has also been used to treat certain
endocrinologic disorders, especially hyperprolactinemia

3. Pergolide, another ergot derivative, directly stimulates both D1 and D2 receptors. It too has been
widely used for parkinsonism, and comparative studies suggest that it is more effective than bromocriptine in
relieving the symptoms and signs of parkinsonism, increasing "on-time" among response fluctuators, and
permitting the levodopa dose to be reduced.

4. Pramipexole, which is not an ergot derivative, has preferential affinity for the D3 family of
receptors. It is effective when used as monotherapy for mild parkinsonism. It is also helpful in
patients with advanced disease, permitting the dose of levodopa to be reduced and smoothing out
response fluctuations.

5. Ropinirole, another nonergoline derivative, is a relatively pure D2 receptor agonist that is effective
as monotherapy in patients with mild disease and as a means of smoothing the response to levodopa
in patients with more advanced disease and response fluctuations.

6. Amantadine, an antiviral agent, was by chance found to have antiparkinsonism properties. Its mode
of action in parkinsonism is unclear, but it may potentiate dopaminergic function by influencing the
synthesis, release, or reuptake of dopamine. Release of catecholamines from peripheral stores has
been documented.
Monoamine Oxidase Inhibitors
Two types of monoamine oxidase have been distinguished. Monoamine oxidase A metabolizes
norepinephrine and serotonin; monoamine oxidase B metabolizes dopamine. Selegiline (deprenyl), a selective
inhibitor of monoamine oxidase B, retards the breakdown of dopamine; in consequence, it enhances and
prolongs the antiparkinsonism effect of levodopa and may reduce mild on-off or wearing-off phenomena. It is
therefore used as adjunctive therapy for patients with a declining or fluctuating response to levodopa.

1. Rasagiline, another monoamine oxidase B inhibitor, is more potent than selegiline in preventing
MPTP-induced parkinsonism and is currently under study as a neuroprotective agent. The combined
administration of levodopa and an inhibitor of both forms of monoamine oxidase must be avoided, since
it may lead to hypertensive crises, probably because of the peripheral accumulation of norepinephrine.