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Sedative is a substance that produces a calming effect by reducing irritability or excitement without inducing sleep (though drowsiness may be produced). Hypnotic (“sleeping pills”) is a substance that induces or maintains sleep and is used in the treatment of insomnia (sleeplessness), or surgical anesthesia. Hypnotic at lower dose may act as sedative. Because these two functions frequently overlap, they are often referred to collectively as sedative-hypnotic drugs. Anxiolytic (“antipanic” or minor tranquilizer) is a medication that inhibits anxiety. Anxiolytic medications are used for the treatment of anxiety/ anxiety disorders and its related psychological and physical symptoms. Types of sedatives Herbal sedatives: Chamomile Mentha (also known as ”mint”) Catnip / catmint Kava (Piper methysticum) Valerian Leonurus (motherwort) Cannabis Passiflora (passionflower or wild apricot) Validol (menthyl ester of isovaleric acid) Barbiturates Benzodiazepines Nonbenzodiazepine "Z-drugs" sedatives Antihistamines (1 generation) Therapeutic use To dull the patient's anxiety related to painful or anxiety-provoking procedures. They are commonly given to patients before highly uncomfortable and invasive procedures like cardiac catheterization, colonoscopy or MRI. They increase tractability and compliance of children or troublesome or demanding patients. ADR: Drowsiness Sedative dependence Misuse Dangers of combining sedatives and alcohol Worsening of Psychiatric Symptoms Hypnotics CLASSIFICATION I class -Barbiturates: Long acting Phenobarbital Short acting Pentobarbital, amobarbital II class - Benzodiazepines: Diazepam, Flurazepam, Lorazepam,Nitrazepam, Oxazepam, Clonazepam, Alprazolam, Triazolam III class - Non-benzodiazepines ("Z-drugs” hypnotics): Zopiclone, Zolpidem Antihistaminics (promethazine, diphenhydramine) Neuroleptic/antidepressants (chlorpromazine, amitriptyline) BARBITURATES Barbiturates have been popular hypnotics and sedatives of the last century upto 1960s, but are not used now to promote sleep or to calm patients. They are the prototype of CNS depressants. They are effective as: anxiolytics, hypnotics, anticonvulsants. They are still used: in general anesthesia, for epilepsy, For (where legal) assisted suicide and euthanasia PHARMACOLOGICAL ACTIONS CNS Depress all areas of the CNS. Barbiturates produce dose-dependent effects: sedation → sleep → anaesthesia → coma. Shortening the time taken to fall asleep and increases sleep duration. REM-stage sleep are decreased → REM-NREM sleep cycle is disrupted → Hangover (dizziness, distortions of mood, irritability and lethargy) occur in the morning after → after a few nights of use → a rebound increase in REM sleep → nightmares At daytime can produce drowsiness, reduction in anxiety and excitability, impair learning, short-term memory and judgement. Mechanism of action Barbiturates bind to receptor on the macromolecular complex → exert the GABA (gamma-Aminobutyric acid) facilitatory action → inhibitory action on the brain GABA-benzodiazepine-barbiturate receptor The BZD- receptor and barbiturate receptor modulate GABAreceptor → channel opening → facilitates GABA PHARMACOLOGICAL ACTIONS Respiration is depressed by relatively higher doses. CVS a slight decrease in BP and heart rate. Smooth muscles -Tone and motility of bowel is decreased slightly Barbiturates induce several hepatic microsomal enzymes and increase the rate of their own metabolism as well as that of many other drugs. ADVERSE EFFECTS Hangover Mental confusion, impaired performance and traffic accidents may occur. Idiosyncrasy Hypersensitivity (Rashes, swelling of eyelids, lips, etc.) Tolerance and dependence Psychological as well as physical dependence occurs and barbiturates have considerable abuse liability. This is one of the major disadvantages. Withdrawal symptoms are— excitement, hallucinations, delirium, convulsions; deaths have occurred. Acute barbiturate poisoning Mostly suicidal, sometimes accidental. Manifestations are due to excessive CNS depression— patient is flabby and comatose with shallow and failing respiration, fall in BP and cardiovascular collapse, renal shut down, pulmonary complications, bullous eruptions. Treatment 1. Activated charcoal in the stomach to prevent absorption 2. Supportive measures: such as, patent airway, assisted respiration, oxygen, maintenance of blood volume by fluid infusion and use of vasopressors—dopamine may be preferred for its renal vasodilating action. 3. Diuretics 4. Haemodialysis and haemoperfusion (through a column of activated charcoal or other adsorbants) are highly effective There is no specific antidote for barbiturates. The emphasis now is on keeping the patient alive till the poison has been eliminated. BENZODIAZEPINES (BZDs) This class has replaced barbiturates as hypnotic and sedative as well 1) BZDs produce a lower degree of neuronal depression than barbiturates. They have a high therapeutic index. 2) Hypnotic doses do not affect respiration or cardiovascular functions. 3) BZDs have no action on other body systems. 4) BZDs cause less distortion of sleep architecture; rebound phenomena on discontinuation of regular use are less marked. 5) They have lower abuse liability: tolerance is mild, psychological and physical dependence, drug seeking and withdrawal syndrome are less marked. 6) A specific BZD antagonist flumazenil is available which can be used in case of poisoning. BZDs Antianxiety: all Sleep-problems: all Muscle relaxant: Clonazepam and diazepam Anticonvulsant: Clonazepam, diazepam, nitrazepam, lorazepam and flurazepam Analgesia: only diazepam i.v. (but not others) NON-BENZODIAZEPINE HYPNOTICS This lately developed group of hypnotics are chemically different from BZDs, but act as agonists on a specific subset of BZD receptors The non-BZD produce only hypnotic-amnesic action (not antianxiety, muscle relaxant and anticonvulsant effects). They have lower abuse potential than BZDs. They are being preferred over BZDs for the treatment of insomnia. Z-drugs Zopiclone and Zolpidem Not to disturb sleep architecture → not next morning impairment. Are indicated for short term (< 2 weeks) treatment of insomnia. Low abuse potential Side effects are metallic or bitter after-taste, impaired judgement and alertness, psychological disturbances, dry mouth. ANTIANXIETY DRUGS Anxiety It is an emotional state, unpleasant in nature, associated with uneasiness, discomfort and concern or fear about some defined or undefined future threat. Treatment is needed when it is disproportionate to the situation and excessive. Cardiac neurosis (unfounded fear of heart disease— palpitation, functional precordial pain); social anxiety (fear of being observed and evaluated by others); obsessive-compulsive disorder (OCD), post-traumatic stress disorder and various forms of phobias are some specific types of anxiety disorders. Antianxiety drugs These are mild CNS depressants, which are aimed to control the symptoms of anxiety, produce a restful state of mind without interfering with normal mental or physical functions. The anxiolytics are close to sedative- hypnotics. They: Have anticonvulsant property. Produce physical dependence and carry abuse liability. CLASSIFICATION 1. Benzodiazepines Diazepam Chlordiazepoxide Oxazepam Lorazepam, Alprazolam 2. Azapirones Buspirone, Gepirone, Ispapirone 3. Sedative antihistaminic Hydroxyzine 4. β blocker Propranolol 5. Antidepressants are effective in OCD, phobias, panic and many types of severe generalized anxiety disorders. BENZODIAZEPINES BZDs have a strong action on anxiety relief at low doses without producing significant CNS depression. They are selective for the limbic system and have proven clinically both quality and quantity of improvement in anxiety and stress-related symptoms. Because anxiety is a common complaint and is a part of most physical and mental illness, and because the BZDs— have little effect on other body systems have lower dependence producing liability than barbiturates and other sedatives; withdrawal syndrome is milder and delayed due to their long half lives are relatively safe even in gross overdosage, they are presently one of the widely used class of drugs. Azapirones ! ! ! ! ! Buspirone, Gepirone, Ispapirone Do not produce sedation Have no muscle relaxant or anticonvulsant activity. Do not interact with BZD receptor or modify GABA-ergic transmission. Do not produce tolerance or physical dependence. Do not suppress BZD or barbiturate withdrawal syndrome. Relieve only mild-to-moderate anxiety, but are ineffective in severe cases (panic reaction and OCD) Side effects are minor: dizziness, nausea, headache, light- headedness, rarely excitement. They are a non-sedating alternative to BZDs for chronic treatment of mild forms of generalized anxiety (BZDs are not suitable for long-term therapy). Hydroxyzine An H1 antihistaminic with: sedative, antiemetic, antimuscarinic and spasmolytic properties. It is claimed to have selective anxiolytic action, but the accompanying sedation is quite marked. Hydroxyzine may be used in reactive anxiety or that associated with marked autonomic symptoms. Due to antihistaminic and sedative property, it is useful in pruritus and urticaria(hives, rash). β Blockers Many symptoms of anxiety (palpitation, rise in BP, shaking, tremor, gastrointestinal hurrying, etc.) are due to sympathetic over-activity, and these symptoms reinforce anxiety. Propranolol and other nonselective β blockers help anxious patients troubled by these symptoms, by cutting the vicious cycle and provide symptomatic relief. They do not affect the psychological symptoms such as worry, tension and fear, but are valuable in acutely stressful situations (examination fear, unaccustomed public appearance, etc.). They may be used for performance/situational anxiety or as adjuvant to BZDs. Antidepressants The SSRIs and SNRIs are now extensively used in most forms of chronic anxiety disorders, but are not good for acute anxiety→ can be combined with BZDs. The SSRIs are now drugs of choice for social anxiety, OCD, eating disorders and PTSD in which BZDs, though effective, carry abuse potential on long-term use. Epilepsy Brief episodes (seizures) of loss or disturbance of consciousness, with or without characteristic body movements (convulsions), sensory or psychiatric phenomena. These episodes are unpredictable and their frequency is highly variable. Epilepsy has a focal origin in the brain Types of epilepsy I. Generalised seizures 1. Generalised tonic-clonic seizures (major epilepsy, grand mal): commonest, lasts 1–2 min. The usual sequence is aura—cry—unconsciousness—tonic spasm of all body muscles—clonic jerking followed by prolonged sleep and depression of all CNS functions. 2. Absence seizures (minor epilepsy, petit mal): lasts about 1/2 min. Momentary loss of consciousness, patient apparently freezes and stares in one direction, no muscular component or little bilateral jerking. 3. Atonic seizures (Akinetic epilepsy): Unconsciousness with relaxation of all muscles due to excessive inhibitory discharges. Patient may fall. 4. Myoclonic seizures: Shock-like momentary contraction of muscles of a limb or the whole body. II. Partial seizures Focal epilepsy: lasts 1/2–1 min. Often secondary. Convulsions are confined to a group of muscles or localized sensory disturbance depending on the area of cortex involved in the seizure, without loss of consciousness III. Status epilepticus In status epilepticus, two or more seizures occur without recovery of full consciousness in between episodes. Status epilepticus is life threatening and requires emergency treatment CLASSIFICATION Na-channel blockers : — phenytoin; — carbamazepine; GABA-ergic system stimulants: — barbiturates: (phenobarbital) — benzodiazepines:(diazepam; clonazepam; lorazepam) — vigabatrin; — valproic acid; — topiramate. Excitatory amino acids inhibitors: —lamotrigine Ca2+ channel blockers: — ethosuximide. Major mechanisms of anticonvulsant action Effect on membrane potential → synaptic transmission blocked → stabilizing influence on neuronal membrane → prevents repetitive detonation of normal brain cells during ‘depolarization shift’ that occurs in epileptic patients Choice of antiseizure drugs Carbamazepine Uses Grand mal: it is the most effective drug for CPS and also the most commonly used drug for generalised tonic-clonic seizures Trigeminal and related neuralgias: Carbamazepine is the drug of choice. Carbamazepine is not an analgesic, but has a specific action (almost diagnostic) in these neuralgias. Manic depressive illness and acute mania: as an alternative to lithium ANTIEPILEPTIC DRUGS Valproic acid (Sodium valproate) is the drug of choice for absence seizures It is an alternative/adjuvant drug for GTCS. Myoclonic and atonic seizures—control is often incomplete, but valproate is the drug of choice Ethosuximide Clinically it is effective only in absence seizures (drug of 2nd choice). Phenytoin is a first line antiepileptic drug, but less commonly used now because side effects are frequent and marginal overdose causes steep rise in plasma concentration, producing neurotoxicity. Indications are: Generalized tonic-clonic, simple and complex partial seizures. It is ineffective in absence seizures. Adverse effects Hypersensitivity reactions Haematotoxicity (agranulocytosis,aplastic anaemia) Neurotoxicity (Ataxia, vertigo, diplopia, nystagmus ,drowsiness, behavioral alterations, mental confusion, hallucinations, disorientation and rigidity) Teratogenicity (spina bifida and other neural tube defects in the offspring) Status epilepticus When seizure activity occurs for > 5 min (previous definitions used a 30-minute time limit), or two or more seizures occur without recovery of consciousness, the condition is called status epilepticus. Recurrent tonic-clonic convulsions without recovery of consciousness in between is an emergency; Fits (attacks) have to be controlled as quickly as possible to prevent death and permanent brain damage. An ambulance should be called for seizures lasting longer than 5 minutes. Status epilepticus treatments 1) BZDs (IV or IM) Benzodiazepines are the preferred initial treatment after which typically phenytoin is given. IV- lorazepam, clonazepam, diazepam IM- midazolam appears to be a reasonable option especially in those who are not in hospital. 2) Barbiturates (Thiopental or pentobarbital) IV These are used to induce a “barbituric coma” if the seizures have to be stopped immediately 3) Phenytoin (IV) is another first-line therapy. Because it takes 15–30 minutes to work, a BZDs or barbiturate is often coadministered with phenytoin. 4) General anaesthesia(fail to respond to drugs above)