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Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU 1.

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Presentation on theme: "Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU 1."— Presentation transcript:

1 Dr. M G Azam Asstt. Professor Dept. of Pharmacy, NSU 1

2 The antipsychotic drugs (also called neuroleptic drugs, or major tranquilizers) are used primarily to treat Schizophrenia. Antipsychotic drugs that alleviate symptoms of Schizophrenia decrease dopaminergic and/or serotonergic neurotransmission. “Neuroleptic” originally indicated drug with antipsychotic efficacy but with neurologic (extrapyramidal motor) side effects – Typical neuroleptic: older agents fitting this description. PHENOTHIAZINES (Chlorpromazine, Thioridazine), THIOXANTHENE (Thiothixene), Haloperidol – Atypical neuroleptic: newer agents: antipsychotic efficacy with reduced or no neurologic side effects. Risperidone, Clozapine.

3 Positive Symptoms Hallucinations Delusions (bizarre, persecutory) Disorganized Thought Perception disturbances Inappropriate emotions Negative Symptoms Blunted emotions Anhedonia Lack of feeling Cognition New Learning Memory Mood Symptoms Loss of motivation Social withdrawal Insight Demoralization Suicide Schizophrenia - symptoms FUNCTION Negative/passive symptoms also include social withdrawal, loss of drive, diminished affect, lack of speech. impaired personal hygiene

4 The traditional or typical neuroleptic drugs (also called conventional or first-generation antipsychotics) are competitive inhibitors at a variety of receptors, but their antipsychotic effects reflect competitive blocking of dopamine receptors. E.g., Chlorpromazine is a low-potency drug, and fluphenazine is a high- potency agent In contrast, the newer antipsychotic drugs are referred to as atypical (or second-generation antipsychotics), because they have fewer extrapyramidal adverse effects than the older, traditional agents. These drugs appear to owe their unique activity to blockade of both serotonin and dopamine (and, perhaps, other) receptors. Typical neuroleptics do not produce a general depression of the CNS, e.g. respiratory depression Abuse, addiction, physical dependence do not develop to typical neuroleptics. Typical neuroleptics are generally more effective against positive (active) symptoms of schizophrenia than the negative (passive) symptoms. Typical neuroleptic vs. atypical neuroleptic

5 Typical neuroleptics block the dopamine-2 receptor

6 DOPAMINE RECEPTOR- BLOCKING ACTIVITY All of the older and most of the newer neuroleptic drugs block dopamine receptors in the brain and the periphery The clinical efficacy of the typical neuroleptic drugs correlates closely with their relative ability to block D2 receptors in the mesolimbic system of the brain. On the other hand, the atypical drug (clozapine) has higher affinity for the D4 receptor and lower affinity for the D2 receptor, which may partially explain its minimal ability to cause extrapyramidal side effects (EPS).

7 SEROTONIN RECEPTOR BLOCKING ACTIVITY IN THE BRAIN: Abnormalities in serotonergic functioning through release and uptake at the presynaptic auto receptors (5- HT 1A/1D ), the serotonin reuptake transporter site (SERT), or effect of 5-HT at the postsynaptic receptors (e.g., 5-HT 1A, 5-HT 2A, and 5-HT 2C ) may play a role in anxiety disorders. Most of the newer atypical agents appear to exert part of their unique action through inhibition of serotonin receptors (5-HT), particularly 5-HT2A receptors Thus, clozapine has high affinity for D1, D4, 5-HT2, muscarinic, and adrenergic receptors, but it is also a dopamine D2-receptor antagonist

8 1 1 2 2 3 3 5 5 4 4 CHOLINERGIC (MUSCARINIC RECEPTOR α- adrenergic receptor Dopamine receptor Serotonin receptor H1- Histamine receptor 1.Thioridazine, chlorpromazine 2.Chlorpromazine 3.All, haloperidol, fluphenezine, thiothixene 4.Clozapine 5.chlorpromazine - --- - Neuroleptic drugs block at Dopaminergic& Serotonergic receptor as well as Adrenergic,Cholinergic and Histamine binding receptor


10 Older antipsychotic drugs: phenothiazines, thioxanthenes, butyrophenones Some newer antipsychotic drugs

11 TREATMENT OF SCHIZOPHRENIA OTHERS USES PREVENTION OF SEVERE NAUSEA & VOMITING alcoholic hallucinosis, neuropsychiatric diseases such as autism and others marked by movement disorders

12 Adverse effects of the neuroleptic drugs can occur in practically all patients and are significant in about 80 percent. Although antipsychotic drugs have an array of adverse effects, their TI is high. TREMORS POSTURAL HYPOTENSION CONSTIPATIO N URINARY RETENTION CONFUSION SEXUAL DYSFUNCTION



15 ANIMAL SCREENING TESTS  Inhibition of conditioned avoidance behavior in response to an aversive stimulus, such as a foot-shock, following a warning stimulus. Escape or avoidance responses in such circumstances are selectively inhibited by most antipsychotics, whereas unconditioned escape or avoidance responses are not.  Another is the inhibition of amphetamine- or apomorphine-induced stereotyped behavior (motor activity). Nearly all antipsychotics, including newer agents, diminish spontaneous motor activity and reverse increases in motor activity induced by apomorphine, amphetamine, or phencyclidine (PCP). Antipsychotics also block apomorphine-induced climbing in mice, which is believed to reflect D 2 -like receptor activation.  This inhibition is undoubtedly related to the D 2 receptor-blocking action of the drugs, countering these dopamine agonists.

16 Animal behavioral models  Other tests that may predict antipsychotic action are reduction of exploratory behavior without undue sedation, induction of a cataleptic state, inhibition of intracranial self-stimulation of reward areas, and prevention of apomorphine-induced vomiting.  Most of those tests are difficult to relate to any model of clinical psychosis.  The psychosis produced by phencyclidine (PCP) has been used as a model for schizophrenia. Because this drug is an antagonist of the NMDA (N-methyl-D-aspartate) glutamate receptor, attempts have been made to develop antipsychotics that work as NMDA agonists. Sigma opioid and cholecystokinin type b (CCK b ) antagonism have also been suggested as potential targets. Thus far, NMDA receptor- based models have pointed to agents that modulate glutamate release as potential antipsychotics. Glutamic acid

17 KEY CONCEPTS All neuroleptics are equally effective in treating psychoses, including schizophrenia, but differ in their tolerability. All neuroleptics block one or more types of DOPAMINE receptor, but differ in their other neurochemical effects. All neuroleptics show a significant delay before they become effective. All neuroleptics produce significant adverse effects. Atypical antipsychotics have serotonin blocking effects as well as dopamine blockade DOPAMINE-2 RECEPTOR BLOCKADE IN THE BASAL GANGLIA RESULTS IN EXTRAPYRAMIDAL MOTOR SIDE EFFECTS (EPS).


19 Sedatives are the drugs that reduce anxiety, excitement and exert a calming effect with little or no effect on motor or mental functions (sleep). Sedatives exert mild depression and the degree of depression should be consistent with therapeutic efficacy. Hypnotics are the drugs that induce sleep ( drowsiness), used in the treatment of severe insomnia, including barbiturates, benzodiazepines, zolpidem. A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state. Anxiolytics, Sedatives and Hypnotics: CNS depressant drugs Anxiolytics: Drugs used for the treatment of symptoms of anxiety, including benzodiazepines.

20  Sedatives at higher doses induces hypnosis, i. e hypnotic effects involve more pronounced CNS depression. more pronounced depression of the central nervous system than sedation, and this can be achieved with most sedative drugs simply by increasing the dose.  Graded dose dependent CNS depression should be the characteristics of sedatives and hypnotics agents; however individual drugs differ in their dose and degree of CNS depression.  However, individual drugs differ in the relationship between the dose and the degree of central nervous system depression CNS depression by Sedatives/Hypnotics

21 Progressive grade of CNS depression Dose-response curves for two hypothetical sedative-hypnotics

22 GABA is an inhibitory neurotransmitter found in high concentrations throughout the brain. GABAa and GABAb αβγδεπρ Patho-physiological condition of anxiety At least following possible neurotransmitter involve in anxiety GABA Serotonine Adrenaline Corticotropin-releasing hormone Cholecystekinin GABA

23 Treatment approaches Long acting BZDs: Chlordiazepoxide Flurazepam Desmethyle diazepam Oxazepam Lorazipam Nitrazepam Short/ultra short acting BZDs: Tiazolam Midazolam Aprazolam Ethizolam Barbiturate derivatives Barbutale Phenobarbitale Mephpobarbitale Secobarbitale Meprobamate Chlorhydrate Secobarbital Non-bezodiazipam sedatives Buspiron Zolpidem Zaleplon SSRI Sertaline Chlorimipramine Antagonist : Flumazenil β- adrenoreceptor antagonist GABAa receptor agonist:

24 1)Barbiturates (BARBs). 2)Benzodiazepines (BZDs). 3)5-HT 1A receptor agonists. 4)5-HT 2A, 5-HT 2C & 5-HT 3 receptor antagonists. Anxiolytics If ANS symptoms are prominent: ß-Adrenoreceptor antagonists.  2 -AR agonists (clonidine). 1)Benzodiazepines (BZDs): Alprazolam, diazepam, oxacepam, triazolam 2)Barbiturates: Pentobarbital, phenobarbital 3)Alcohols: Ethanol, chloral hydrate, paraldehyde, trichloroethanol, 4)Imidazopyridine Derivatives: Zolpidem 5)Pyrazolopyrimidine: Zaleplon Hypnotics

25 1,4-benzodiazepines

26 Types Barbituric Acid Amobarbital Pentobarbital 15-50 hr 10-40 hr Short acting Intermediate acting Long-Acting Thiopental sodium 3-10hr Ultra shortacting Phenobarbital 80-120 hr All derivatives of Barbituric acid Depressants of the central nervous system (CNS) that impair or reduce the activity of the brain by acting as a Gamma Amino Butyric Acid (GABA) potentiators Barbiturates 2,4,6-trioxohexahydropyrimidine

27 Preclinical Evaluation Methods of Sedative drugs Invivo Test 1.Sleeping test 2. Hole board test 3. Open field test 5. Elevated maze test Invitro test 1. Radioligand binding Assay 2. Enzymatic fluromatric assessment of cAMP/ Adenyle cyclase activity

28 DIAZEPAM SLEEPING MODEL PRINCIPLE : This test is used to evaluate the effect of different drugs on the sleeping induced by the diazepam. PROCEDURE  Swiss albino mice (18-22 g) are divided in groups of 5 mice : one for control and other for test drugs  The animals of group I served as the control (normal saline, 0.9% w/v, 5 ml/kg)  The other groups should be given the test drug by i.p route  After 30 min all the mice were treated with diazepam at a dose of 2 mg/kg.  The onset and duration of sleep was recorded for each mouse.  The loss of righting reflex is regarded as the onset of sleep while the time difference between the disappearing and the recovery of the righting reflex is taken as the duration of sleep. Invivo Methods

29  Data tabulation. Drug TreatmentDose mg/kg Mean onset of sleep (mins) (M±SEM) Mean Duration of sleep (mins.) (M±SEM) Normal saline Test 1 Test 2 CRITICAL ASSESSMENT OF THE METHOD  Diazepam binds to GABA A receptor and potentiates its activation.  This enhancement of neuronal inhibition by GABA produces sedation (reduction of motor activity) which is mediated via α 1 GABA A receptors (Tobler et al., 2001)

30 The experimental animal groups are administered (i.p.) with the test sample. An interval of 30 minutes is given to assure proper absorption. Then sodium phenobarbitone (50 mg/kg body weight) is administered intraperitonially to all the groups and the time for onset of sleep and total sleeping time is recorded for both control as well as experimental groups. Phentobarbital induced hypnotic test CNS depressant activity of ethanol extract of Derris trifoliata, Saifullah Al Mamoon, Farhad Hossen, Md. Golam Azam, Int. J. of Pharm. Sci. Res. 2012, 3: 1388-1392.

31 Hole board test A board (40X40 cm) has 16 holes (3 cm diam) arranged square in a plane. Each animal ( 30 min after administration of the test compound) is placed carefully in the center of the board and the number of holes passed and head dipping are recorded Making the lighting dull enable the mice to take a look into the hole and dark light make the mice comfortable and in a leisurely manner. Nose poking of animals into the holes is thought to indicate curiosity.

32 Open field test (OFT) The number of squares traveled by the animal is recorded for 15 min (2/3 min interval) in OFT.  Interruption of light beams is used to measure movements of rats/mice in a cage(“Open field”). The open-field test is used to assess locomotor activity and anxiety-related behaviors.  The open field is a table that may have surrounding walls to prevent escape. Commonly the field is marked in a grid and square crossings, rearing, and time spent moving are used to assess the activity of the rodent.  In the modern open field apparatus, infrared beams can be used to automate the assessment process.  The OFT is also often used to assess anxiety by including additional measures of defecation, time spent in the center of the field, and the first five minutes of activity

33 PRINCIPLE Rodents have aversion for high and open space and prefer enclosed arm and therefore spend greater amount of time in enclosed arm when the animals enter in to open arm they show fear like movement, freeze and become immobile Advantages of this test are simple fast and less time consuming No prior training is required ELEVATED PLUS MAZE TEST (EPM): Widely used behavioral assay for rodent and validated to assess the anti-anxiety effects of pharmacological agents.

34 REQUIREMENTS for (EPM): :  Animal : mice(20-25 g)  Diazepam (1 mg/ kg ; i.p.)  Elevated plus-maze apparatus consist of 2 open arms (16 x 5 cm for mice & 50 x 10 cm for rats), 2 closed arms (16 x 5 x 12 cm for mice and 50 x 10 x 40 cm for rats), an open roof with entire maze elevated (25 cm for mice and 50 cm for rats) from the floor.

35 PROCEDURE of (EPM): Prior to test, animals are housed in pairs (4-5 mice in one group) in the apparatus for 10 days, meanwhile mice are handled by investigator on alternate days to reduce stress. 30min. after i.p. administration of test/standard drug, mice is placed in centre of the maze, facing one of the enclosed arms. Behavioral response, like no. of entries into and time spent in the open and enclosed arm, total no. of arm entries, are taken for 5 minutes. Procedure is conducted in sound attenuated room

36 TABLE of observation (EPM): GROUPOPEN ARMCLOSED ARM No. of entries (M±SEM) Time spent (in sec.) (M±SEM) No. of entries (M±SEM) Time spent (in sec.) (M±SEM) CONTROL STANDARD EVALUATION : Motor activity and open arm exploratory time are registered. The values of treated groups are expressed as percentage of controls. Benzodiazepines decrease motor activity and increase open arm exploratory time. The method is a reliable measure of anxiolytic activity. Computerized automatic systems are available for elevated plus maze, radial maze, Y-maze, and T-maze.

37 [ 3 H]-GABA RECEPTOR BINDING PRINCIPLE:  Abnormalities in GABA system have been found in neurological and psychiatric diseases like anxiety, schizophrenia, epilepsy etc.  Radio labeled GABA is bound to synaptic membrane preparations of mammalian brain.  Labeling of the synaptic receptor with 3 H-GABA requires careful attention to possible interference from non synaptic binding since 3 H- GABA can also bind non-specifically to plasma membranes. The most prominent of which is Na dependent binding of GABA to brain membranes.  Sodium-independent binding of 3 H-GABA has characteristics consistent with the labeling of GABA receptors.  Therefore, the sodium-independent binding of 3 H-GABA provides a simple and sensitive method to evaluate compounds for GABA- mimetic properties. IN VITRO METHODS

38 Rats (100–150 g) are decapitated, brain removed homogenized in 15 vol. of ice-cold 0.32 M sucrose Centrifuged at 1000 g for 10 min discard pellet & recentrifuged supernatant, 20000 g, 20 min. discard supernatant & pellet is resuspended in 15 vol. dist. water using a Tekmar homogenizer. The suspension is centrifuged at 8000 g for 20 min collect Supernatant and resuspend the pellet’s soft, upper, buffy layer. centrifuged at 48000 g for 20 min. The final pellets are resuspended in 15 vol. of dist. H 2 0 and centrifuged at 48000 g for 20 min. TISSUE PREPARATION supernatant is discarded, and the centrifuge tubes containing pellet are capped with parafilm and stored frozen at –70 °C. IN VITRO METHODS

39 ASSAY PROCEDURE 1 ml of the 0.05 M Tris-maleate homogenate 20 μ l of 3 H-GABA 20 μl of test drug or 20 ml of 0.1 mM isoguvacine or muscimol  Incubate at 4 °C for 5 min, the reaction is terminated by centrifugation for 15 min at 5000 rpm.  Supernatant fluid is aspirated & pellet washed twice with 1ml of the Tris-maleate buffer.  2ml of liquiscint are added to each tube which is then vigorously vortexed.  The contents of tubes are transferred to scintillation vials, tubes rinsed with an additional 2ml of cocktail.  An additional 6 ml of liquiscint are added to each scintillation vial.  The radioactivity is measured by liquid scintillation photometry. IN VITRO METHODS

40 EVALUATION Specific 3 H-GABA binding is defined as the radioactivity which can be displaced by a high concentration of unlabeled GABA and is obtained by subtracting from the total bound radioactivity the amount of radioactivity bound in the presence of 0.1 mM isoguvacine. Results are converted to percent of specifically bound 3 H-GABA displaced by a given concentration of test drug. IC50 values with 95% confidence limits are then obtained by computer derived linear regression analysis. IN VITRO METHODS

41 2. SEROTONIN ( 5 -HT 1 B ) RECEPTORS IN BRAIN: BINDING OF [ 3 H]5-HYDROXYTRYPTAMINE ([ 3 H] 5 -HT) PURPOSE AND RATIONALE To determine the affinity of test compounds for the serotonin (5-HT 1B ) receptor in brain. The existence of two populations of 5-HT 1 receptors in rat brain was shown by differential sensitivity to spiroperidol (Pedigo et al. 1981). The spiroperidol-sensitive receptors were designated as the 5-HT 1A subtype and the insensitive receptors were referred to as the 5-HT 1B subtype (Middlemiss and Fozard 1983).


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