Benxidizipam.docx

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Classification of anxiolytic and hypnotic drugs • • • • • • • • •

Zolpidem Act like benzodiazepine Used as hypnotic , minimal anxiolytic action Zaleplion Act like benzodiazepine Half-life of one hour Zopiclone Act like benzodiazepine Half-life of one hour

 Anxiolytic Or Antianxiety drugs:  Anxiolytics drugs are medicines that calm and relax people with excessive anxiety, GAD, nervousness, or tension, or forshortterm control of social phobia disorder or specific phobia disorder.  are a type of prescription medication used to treat symptoms of acute anxiety.  Anxiolytics are also known as minor tranquilizers  These medications tend to work quickly. However, they can be habit-forming and are usually prescribed for short-term use. 

Anxiolytics are not recommended for people with a history of substance abuse.

 What are Benzodiazepines? • Benzodiazepines are a group of drugs that act on the central nervous system. Used to treat anxiety, stress, sleeping problems and other disorders. Brand name Valium Xanax Ativan Librium        

Generic name Diazepam Alprazolam Lorazepam Chlordiazepoxide

Street name Vallies, Roche Xanies Downers

History: 1903 Barbiturates 1957 Chlordiazepoxide synthesized 1960 Marketed as Librium 1959 Diazepam synthesized 1963 Valium launched 1978 Valium – most widely prescribed drug in the world 1980 Risk of dependence realised

Current average time from synthesis to commercial availability is 14 years

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 Mechanism of Action: Benzodiazepines work by increasing the efficiency of a natural brain chemical, GABA which decreases the excitability of neurons. This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.

 Benzodiazepines:  Related Neurotransmitters 

GABA:- Benzodiazepines facilitate GABA binding

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Agonistic action on GABA may account for the sedative-hypnotic and anesthetic properties.

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Properties:  Allosteric action -

 Benzodiazepines increase the affinity of the receptor for GABA, and thus increase Cl conductance and hyperpolarizing current  Therefore, benzodiazepines are indirect agonists of the GABA receptor GABA receptor Site and Structure of Action:      

Site of action is the GABA receptor Structure of GABA receptor Comprised of 5 subunits 2 α subunits (to which GABA binds) 2 β subunits (to which barbiturates bind) 1 γ subunit (to which benzodiazepines bind)

Most commonly prescribed Benzodiazepines: • • • • • • • • • • •

All Benzodiazepines are classified as Controlled Drugs in some countries. Most are CD Schedule 4 Diazepam (Valium,Anxicalm) Alprazolam (Xanax) Bromazepam (Lexotanil) Clobazam (Frisium) Lormetazepam (Noctamid) Nitrazepam (Mogadon) Two are CD Schedule 3 Flurazepam Temazepam

(Rohypnol) (Nortem)

Pharmacokinetics:  Absorption Mostly oral, some are available parenterally  Distribution Peak plasma concentrations are achieved in about one hour  Metabolism Metabolized in liver

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    

Elimination Through urine Rapidly absorbed in the GI tract following oral administration (75% reaches plasma) Only approx. 20% is metabolized in first-pass metabolism Metabolized in the liver and excreted by the kidney’s Peak plasma levels reached in approx. 1 hour

Pharmacodynamics:

Effect on the CNS:a. Sedation They relieve anxiety and make the patient calm and quite. Benzodiazepine also reduce excitement. b. Sleep They cause drowsiness and sleep when used in larger doses. c. Amnesia At high doses anterograde amnesia is most likely with benzodiazepine then with other hypnotics. At High dose loss of consciousness may also occur but do not cause general anesthesia. d. Antiepileptic Some benzodiazepines have anticonvulsant effect i.e diazepam and lorazepam can be used for various type of epileptic attacks. e. Skeletal muscle relaxation Diazepam and meprobamate are effective in causing relaxation of skeletal muscles by acting on neuron of spinal-cord. 2. Effect on Respiration: Benzodiazepine has no effect on the normal respiratory system but they may cause severe respiratory depression in patient suffering from asthma and other serious respiratory diseases. 3.Effect on the CVS: In therapeutic doses , they have no effect on the cardiovascular system but in patient suffering from low blood volume, and serious cardiac diseases may cause significant depression of the cardiovascular system. 4. Effect on the CVS In therapeutic doses, they have no effect on the cardiovascular system but in patient suffering from low blood volume, and serious cardiac diseases may cause significant depression of the cardiovascular system.  Clinical use: Reduction of anxiety mainly generalized anxiety disorder or acute anxiety states. i.e Diazepam and lorazepam.

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Better response: For somatic and psychological symptoms, symptoms with clear stressors and of shorter duration. Poor response: For depressive , phobic and hypochondria –cal symptoms. Among the preferred SSRIs for generalized anxietydisorder are paroxetine (Paxil), escitalopram (Lexapro), and venlafaxine (Effexor), which alsohas norepinephrine. OtherSSRIs are fluoxetine (Prozac) and sertraline (Zoloft). Venlaf axine and Paroxetine have been shown particularly effectivein relieving symptoms of social anxiety.. Use for shortest possible d smallest effective dose: Not for more than 4 weeks duration: Hypnotics:   

Benzodiazepines especially short-acting one are effective in insomnia its better to avoid drug for insomnia, causes of insomnia should be explored and treated accordingly. Prolong use of it can lead to addiction and tolerance. Following are mostly used Flurazepam , zolpidem , loprazolam etc.

Sedation and sleep: Decrease time taken to get to sleep and increase total sleep Effect decline if taken for more then 2 weeks Best used for acute not chronic stress Alcohol withdrawal:  Reduce withdrawal symptoms  Prevent seizures  Long half-life better i.e cholordiazpoxide  Reducing dose over 5-10 days. Other therapeutic use: In psychosis:  High doses in acute psychotic state can reduce severe agitation  Tolerance can develop therefore limit to a few days. Antidepressant effect:  Alprazolam is found to be effective in endogenous depression  Drowsiness, dizziness, and nausea at therapeutic doses  Severe nausea and vomiting greatly limit overdoses Adverse Effects: 

Drowsiness, dizziness, and nausea at therapeutic doses, severe nausea and vomiting greatly limit overdoses.

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Tolerance:  

The need for larger dose to achieve the same effect with repeated administration. Thus to maintain the pharmacological action of a drug in the body dose of benzodiazepines may have to be increased with the passage of time

Relatively quickly (days – weeks):  

Sedative , hypnotic , anticonvulsant and muscle relaxant effect Rarely (months):

Dependence:  

Dependence occur when large dose of benzodiazepines are used for a long period of time. In such case withdrawal symptoms occur when the drug are suddenly stopped. The preferred SSRIs for generalized anxiety disorders.

Withdrawal:  Occur in approximately 45% of patients using benzodiazepines for more then 6 months.  Symptoms in the first week, last 7-10 days  Short acting benzodiazepines cause more acute withdrawal effect (rapid drop in plasma concentration).  Alprazolam lead to immediate and severe withdrawal symptoms. Withdrawal symptoms:Anxiety symptoms  Anxiety  Dysphoria  Tremor  Muscle pain  Sleep disturbance

Perceptual disturbances 1-Hypersensitivity to stimuli 2-Abnormal bodily sensation and sense of moment 3-Depersonalization 4-Visual disturbances 4-In Severe cases Paranoid, psychosis, hallucination etc.

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Headache Nausea Loss of appetite fatigue

Widrawal: Rebound anxiety  Rebound insomnia, restlessness, agitation, irritability, and unpleasant dreams  Rarely, hallucinations, psychosis, and seizures have been reported

seizures

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Managing withdrawal: • • •

Short half-life drug change to long half-life drug Slow and gradual taper-off or gradual reduction Anxiety management, relaxation exercise etc.

Normal  ANXIOLYTIC _________  _________________ Drowsiness/decrease reaction time  HYPNOSIS  Confusion, Delirium, Ataxia  Surgical Anesthesia  Coma  DEATH

ANXYOLITICS:

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Alprazolam Chlordiazepoxide Diazepam Lorazepam Oxazepam Triazolam Phenobarbital Halazepam Prazepam

HYPNOTICS:          

Chloral hydrate Estazolam Flurazepam Pentobarbital Lorazepam Quazepam Triazolam Secobarbital Temazepam Zolpidem Side Effects of Benzodiazepines:

 Drowsiness & Light-headedness the next day  Confusion & Ataxia (especially in the elderly)  Increase in fractures -> increase in hospitalisation  Amnesia  Dependence, Tolerance  Dysarthria (Slurred speech)  Respiratory depression (more so if taken with alcohol or other CNS depressants).  increase in aggression  Demotivation - Inhibition of learning behaviour, academic performance  Coma  Decreased libido.

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Interactions: Increased Effects with: Alcohol Analgesics (Fentanyl) Antibacterials (Clarithromycin, Isoniazid) Antifungals (ketokonazole, itraconazole) Antipsycotics Antivirals Muscle relaxants (baclofen) –

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• Decreased Effects with:  antibacterial (Rifampicin)  Probenecid  Theophylline  Neoquinolone   Effects on Pregnancy: • • • •

Benzodiazepines (and their metabolites) can freely cross the placental barrier and accumulate in fetal circulation Administration during the first trimester can result in fetal abnormalities Administration in third trimester (close to the time of birth) can result in fetal dependence. Benzodiazepines are also excreted in the breast milk

 Treatment of Withdrawal: • Stabilization: diazepam, chlordiazepoxide, phenobarbital (cross-dependence). • Drug tapered off slowly => prevention of onset of withdrawal (reversible only early in its course). • Propranolol or clonidine for tremors and twitching. • No use of antipsychotic. • No use of alcohol (toxicity).  Why Benzodiazepines should not be sold or passed on:  The National Drug-Related Death Index • Benzodiazepines were implicated in 31% of drug related deaths • Huge increase in number of cases seeking treatment for misuse • Age profile of under 18 yr olds seeking help had risen • Are highly addictive • Withdrawal effects are very unpleasant  Should only be taken by the patient they are prescribed for as drug choice and dose are specific to patient needed.  Should not be sold or passed on even if symptoms are similar.  You are not helping anybody by sharing this medication with them. Sedative Hypnotics:          • • • •

Club Drugs Alcohol Rohypnol GHB LSD MDMA (Ecstasy) Ketamine (Special-K) Amphetamines Methamphetamine. Diazepam , pharmacokinetics: Absorption following IM erratic Highly lipid soluble Diffuse into CNS rapidly Found in breast milk

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Crosses placenta

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Newborn infant metabolize it slowly, it accumulation can lead to respiratory depression.

 Diazepam-Adverse effect: A. common:  Drowsiness  Dizziness  Psychomotor impairment B. Rare:  Amnesia  Restlessness  Skin rash C-Occasional:  Dry mouth  Blurred vision  Gastrointestinal upset  Ataxia  Headache  Reduced BP

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Machnanism of action:  Barbiturates share with benzodiazepines the ability to enhance the action of GABA ,but theybind with different receptor site on the GABA receptor/choloride channel,and their actoion seems to prolon the duration of the opening of GAB activated choloride channels.  At high rate barbiturates can inhibit the release of Ca2 dependent neurotransmitter.

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Mechanism of action of buspirone : Act as a partial agonist at the 5-HT receptor presynaptic ally inhibiting serotonin release.

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Zaleplon is being marked as hypnotic Although a non benzodiazepine drug it acts on the benzodiazepine receptor located on the alpha sub-Unit of the GABA receptor(causing sedation) Side effects: • • • • • • •

Headache Drowsiness Dizziness Nausea Sedation lethargy Acute confusion related to the action of the medication on CNS. It Should not be used for more then one week at a time

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Abrupt withdrawal after long term use

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Effect of intoxication and overdose Zopiclone:-

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Zopiclone belongs to a new class of benzodiazepines drugs act on the GABA receptors, but at a site distinct from that of benzodiazepines Has a short duration of action as well as onset After oral administration , absorbed rapidly , with peak plasma concentration in about 60 mints. Usual dose is 3.75-7.5 mg at bedtime ( lower in elderly and patients with severe hepatic failure) Side effect include bitter taste , dry mouth , nausea , drowsiness , headache etc.