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DRUGS ACTING ON CNS PRAVINKUMAR AWATE B.PHARM FINAL YEAR (COLLEGE OF PHARMACY, SOLAPUR )
Classification of CNS disease according to WHO:
Anesthetic agents Definition : drugs used to produce surgical anaesthesia Examples : halothane , propofol
Anxiolytics and sedatives Synonyms : hypnotics, sedatives, minor tranquillisers Definition : drugs that cause sleep and reduce anxiety Examples : barbiturates, benzodiazepines
Antipsychotic drugs Synonyms : neuroleptic drugs, antischizophrenic drugs, major tranquillisers Definition : drugs that are effective in relieving the symptoms of schizophrenic illness Examples : clozapine , chlorpromazine, haloperidol
4. Antidepressant drugs Definition : drugs that alleviate the symptoms of depressive illness Examples : monoamine oxidase inhibitors, tricyclic antidepressants, selective serotonin reuptake inhibitors
5. Analgesic drugs Definition : drugs used clinically for controlling pain Examples : opiates, carbamazepine
Psychomotor stimulants Synonym : psychostimulants Definition : drugs that cause wakefulness and euphoria Examples : amphetamine, cocaine and caffeine
Psychotomimetic drugs Synonyms : hallucinogens, psychodysleptics Definition : drugs that cause disturbance of perception (particularly visual hallucinations) and of behaviour in ways that cannot be simply characterised as sedative or stimulant effects Examples : lysergic acid diethylamide, mescaline and phencyclidine
8. Cognition enhancers Synonyms : nootropic drugs Definition : drugs that improve memory and cognitive performance Examples : acetylcholinesterase inhibitors (e.g. donepezil , galantamine , rivastigmine , NMDA receptor antagonists (e.g. memantine , piracetam (improves cognitive function in animal tests, but not proven in humans).
9. manic depressive psychosis
Examples: lithium, carbamazepam
10. neurodegenerative disorder
Alzheimer’s disease (dementia)
ischemic brain damage (stroke)
Neurodegenerative disease: Necrosis of neuron in the brain results in death of cells.
Mechanism of neuronal death:
protein deposition (amyloidosis)
excitotoxicity (glutamate conc. Increase)
Types of Neurodegenerative disorder:
Alzheimer’s disease (dementia)
ischemic brain damage (stroke)
5) Creutzfeldt-jacob disease
Parkinsonism is a progressive neurologic disorder of muscle movement, characterized by tremors, muscular rigidity, bradykinesia (slowness in initiating and carrying out voluntary movements), and postural and gait abnormalities.
Different between Alzheimer disease and Parkinson’s disease Alzheimer disease Parkinson’s disease Loss of cholinergic neuron in the nucleus basalis of maynert (cerebral cortex) Loss of dopamenergic neuron in substantial nigra and corpus striatum, it visualize by using positron-emission tomography and fluorodopa.
Classification of Parkinson’s drugs:
1) Drug affecting brain dopamenergic system:
Dopamine precursor: e.g. Levodopa ( L-dopa)
Peripheral decarboxylase inhibitor: e.g. Carbidopa, Benserazide .
Dopamenergic agonist: e.g. Bromocriptine, Ropinirol, Pramipexole, Pergolide.
MAO-B inhibitor: e.g. Selegiline (Deprenyl), Rosagiline (new drug).
COMT inhibitor : Entacapone, Tolcapone
Dopamine facilitator : Amantadine
2) Drug affecting brain cholinergic system: a) Central anticholinergics: e.g. Trihexyphenidyl (Benhexol), Procyclidine, Biperidine. b ) Antihistamines: Orphenadrine, Promethazine
A. Levodopa (L-dopa) and carbidopa Levodopa is a metabolic precursor of dopamine. It restores dopamine levels in the extrapyramidal centers (substantia nigra) that atrophy in Parkinsonism. Relief provided by levodopa is only symptomatic and lasts only while the drug is present in the body. 95% of oral dose is decarboxylated in the pheripheral tissue (gut and liver) thus DA formed acts on heart, blood vessel, and CTZ center. The effect of Levodopa on endocrine system is it inhibit the prolactin release. ADR of Levodopa : vomiting and BUN effect (increase blood urea nitrogen). b. Carbidopa: The effects of levodopa on the CNS can be greatly enhanced by coadministering carbidopa a DOPA decarboxylase inhibitor that does not cross the blood- brain barrier and act extracerebrally only. The addition of carbidopa lowers the dose of levodopa needed by 4- to 5-fold and, consequently, decreases the severity of the side effects of peripherally formed dopamine .
B. Bromocriptine Bromocriptine an ergotamine (an alkaloid with vasoconstrictor action) derivative, is a dopamine receptor agonist. The drug produces little response in patients who do not react to levodopa, but it is often used with levodopa in patients responding to drug therapy. Side effects severely limit the utility of the dopamine agonists (Figure) The actions of bromocriptine are similar to those of levodopa, except that hallucinations, confusion, delirium, nausea, and orthostatic hypotension are more common, whereas dyskinesia is less prominent.
C. Amantadine It was accidentally discovered that the antiviral drug, amantadine effective in the treatment of influenza, has antiparkinsonism action. It appears to enhance the synthesis, release, or re-uptake of dopamine from the surviving neurons. [Note: If dopamine release is already at a maximum, amantadine has no effect.] The drug may cause restlessness, agitation, confusion, and hallucinations, and at high doses it may induce acute toxic psychosis. Amantadine is less efficacious than levodopa and tolerance develops more readily, but it has fewer side effects. The drug has little effect on tremor but is more effective than the anticholinergics against rigidity and bradykinesia.
D. Deprenyl: Deprenyl, also called selegiline selectively inhibits monoamine oxidase B (which metabolizes dopamine), but does not inhibit monoamine oxidase A (which metabolizes norepinephrine and serotonin). By thus decreasing the metabolism of dopamine, deprenyl has been found to increase dopamine levels in the brain (Figure). Therefore, it enhances the actions of 1evodopa, and when these drugs are administered together, deprenyl substantially reduces the required dose of Levodopa .
E. Antimuscannic agents: The antimuscarinic agents are much less efficacious than levodopa and play only an adjuvant role in antiparkinsonism therapy. All these drugs can induce mood changes and produce xerostomia (dryness of the mouth) and visual problems, as do all muscarinic blockers. They interfere with gastrointestinal peristalsis and cannot be used in patients with glaucoma, prostatic hypertrophy, or pyloric stenosis. Adverse effects are similar to those caused by high doses of atropine, for example, pupillary dilation, confusion, hallucination, urinary retention, and dry mouth.
Meaning: Psychopharmacological agents are those having primary effect on psyche (mental processes)
Classification of Psychopharmacological disease:
Classification is based on clinical use and it classified into 3 types
Psychoses : these are severe psychiatric illness with distortion of thought, behavior, and capacity to recognize reality.
a) Acute and chronic organic brain syndrome (cognitive disorders) : such as delirium (disturbed state of mind) and dementia, features are confusion, disorientation, defective memory and disorganized behavior.
b) Functional disorders: no cause defined, memory and orientation are retained but emotion, thought and behavior are seriously alter.
Schizophrenia (splitting of mind)-
Paranoid states- False beliefs
2) Affective disorders: - Primary symptoms is change in mood state
a) Mania - Elation, Hyperactivity, uncontrollable thought and speech.
b) Depression: - Sadness Physical and mental slowing and self destructive
Bipolar : - Alternating mania and depressive phase.
Unipolar :-Mania or depression .
3) Neuroses: - These are less serious, ability to comprehend reality is not lost.
Types of Neuroses:-
Anxiety :- unpleasant emotional state associated with uneasiness
Phobic states : - fair of unknown or some specific object.
Obsessive, compulsive :- limited abnormality of thought and behaviors
Reactive depression: - Due to physical illness.
Hysterical : - Serious physical illness but situational.
Psychotropic drugs are classified into following types
Antipsychotic (Neuroleptic, Ataractic, Major tranquillizer): - useful in all types of functional psychosis, especially schizophrenia.
Antianxiety (Anxiolytic-sedative, minor tranquillizer): -Useful for anxiety and phobic states.
Antidepressants: -Useful for minor as well as major depressive illness, phobic states, obsessive compulsive behavior and certain anxiety disorders.
Antimanic (mood stabilizers):- Useful to control mania.
Psychotomimetics (Psychedelic, Psychodisleptic, and hallucinogen): -Drugs produce psychosis like states. Note: -Antidepressants and Antimanic drugs are collectively known as drugs for affective disorders. Tranquillizers :-Drugs which reduce mental tension and produce calmness without inducing sleep but this term not used now a days.
Antipsychotic drugs:- It is also known as antischizophrenic drugs. Schizophrenia (Bleuler) is a defect in selective attention. Crow classified schizophrenias into two types based on symptoms: 1) Positive symptoms:- a) Delusion (mistaken belief) b) Hallucination (see same think which not actually present) c) Thought disorder. d) Abnormal behaviors (aggressive and serotypes) 2) Negative symptoms:- a) Withdrawal from social contact b) Flattening of emotional responses
Schizophrenia - symptoms Positive Symptoms Hallucinations Delusions (bizarre, persecutory) Disorganized Thought Perception disturbances Inappropriate emotions Abnormal behaviors (aggressive and serotypes ) Negative Symptoms Blunted emotions Anhedonia Lack of feeling Cognition New Learning Memory Mood Symptoms Loss of motivation Social withdrawal Insight Demoralization Suicide FUNCTION €
Positive/active symptoms include thought disturbances, delusions, hallucinations
Negative/passive symptoms include social withdrawal, loss of drive, diminished affect, paucity of speech. impaired personal hygiene
Classifications of Antipsychotic drugs:- 1) Phenothiazines a) Aliphatic side chain Chlorpromazines, Promazines, Triflupromazine. b) Piperidine side chain Thioridazine, Mezoridazine, Piperacetazine c) Piperazine Side chain Trifluoperazine, Fluphenazine, Perphenazine. 2) Butyrophenones Haloperidol, Droperidol, Penfluridol, Trifluoperidol. 3) Thioxanthenes Thiothixene, Flupenthixol. 4) Other heterocyclics (RPL) Pimozide, Loxapine, Reserpine. 5) Atypical Neuroleptics (CROSSQ) Clozapine, Risperidone, Olanzapine, Sulpiride, Sertindole, Quetiapine.
Mechanism of action: Dopamine receptor-blocking activity : All of the neuroleptic drugs block dopamine receptors in the brain and in the periphery. Five types of dopamine receptors: D1 and D5 receptors activate adenylyl cyclase, and D2, D3 and D4 receptors inhibit adenylylcyclase. Typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain.on other hand, the atypical drug clozapine has a high affinity for D4 receptor result in minimal ability to cause extrapyramidal side effects. The actions of the neuroleptic drugs are antagonized by agents that raise dopamine concentration, for example, L-dopa and amphetamines.
Serotonin receptor-blocking activity in brain: The newer "atypical" agents appear to exert part of their unique action through inhibition of serotonin (5-HT) receptors. Thus, clozapine has high affinity for D1 and D4, 5-HT2, muscarinic and alfa-adrenergic receptors, but it is also a dopamine D2-receptor antagonist. Another new agent, risperidone blocks 5-HT2 receptors to a greater extent than it does D2 receptors. Both of these drugs exhibit a low incidence of extra pyramidal side effects.
Actions :- The antipsychotic actions of neuroleptic drugs reflect blockade at dopamine and/or serotonin receptors. However, many of these agents also block cholinergic, adrenergic, and histamine receptors, causing a variety of side effects. Antipsychotic actions: The neuroleptic drugs reduce the hallucinations and agitation associated with schizophrenia by blocking dopamine receptors in the mesolimbic system of the brain. In contrast to the central nervous system (CNS) depressants, such as barbiturates, the neuroleptics do not depress intellectual function of the patient, and motor incoordination is minimal.
Extrapyramidal effects: Parkinsonian symptoms, akathisia (motor restlessness), and tardive dyskinesia (inappropriate postures of the neck, trunk, and limbs) occur with chronic treatment. Blocking of dopamine receptors in the nigrostriatal pathway probably causes these unwanted parkinsonian symptoms. Clozapine and risperidone exhibit a low incidence of these symptoms .
Antiemetic effect: With the exception of thioridazine , most of the neuroleptic drugs have antiemetic effects that are mediated by blocking D2 dopaminergic receptors of the chemoreceptor trigger zone of the medulla.
Antimuscarinic effects : All of the neuroleptics, particularly thioridazine and chlorpromazine, cause anticholinergic effects, including blurred vision, dry mouth, sedation, confusion, and inhibition of gastrointestinal and urinary smooth muscle, leading to constipation and urinary retention.
Other effects : Blockade of Alfa-adrenergic receptors causes orthostatic hypotension. In the pituitary, neuroleptics block D2 receptors, leading to an increase in prolactin release.
Antipsychotic Drugs – New Generation s „atypical“
About 40-60% do not respond to phenothiazines.
Questions remain about the efficacy of phenothiazines and haloperidole for negative symptoms
Drugs needed that are low in extrapyramidal side effects and at least equal in efficacy for positive symptoms, perhaps better for negative.
Parkinsonian effects: The inhibitory effects of dopaminergic neurons are normally balanced by the excitatory actions of cholinergic neurons. Blocking dopamine receptors alters this balance, causing a relative excess of cholinergic influence and resulting in extrapyramidal motor effects.