Sedative, Hypnotics & Anxiolytic Drugs

1. Benzodiazepines: (anti-anxiety = Minor tranquillizers)

Classification:
-Long acting (t > 24 hours: diazepam, nordazepam, clonazepam, flurazepam and clorazepate. -Intermediate acting (t 6-24 hours): temazepam, oxazepam, lorazepam, halazepam, alprazolam and chlordiazepoxide. -Short acting (t < 6 hours); triazolam and midazolam. Pharmacokinetics: -Absorbed orally (slow for oxazepam), rapid for diazepam, triazolam. Clorazepate is a prodrug (decarboxylated in gut into nordazepam). -They are bound to plasma proteins 85-95%. When given I.V. and rapidly absorbed orally, are taken first in the brain, then redistributed to less perfused tissues. -They are metabolized by liver microsomal enzymes into active metabolites while oxazepam, lorazepam and temazepam are converted into inactive metabolite. Excreted conjugated with glucuronic acid. Mechanism of action: -Benzodiazepines act on specific receptors so enhance the effect of GABA on GABAA receptors without directly activating GABA receptors increase Cl influx hyperpolarization neuronal inhibition. -Benzodiazepine receptors are referred as omega receptors and are of two types (BZ1 = 1 and BZ2 = 2) BZ1 for anxiolytic, sedative and hypnotic effects BZ2 for muscle relaxant and anticonvulsant effects. -Zolpidem and Zaleplon act on BZ1 receptors and they have minimal muscle relaxant effect. -Action of benzodiazepines could be blocked by flumazenil (specific benzodiazepine receptor antagonist). Actions: Dose dependent CNS depression -Anti-anxiety and relieve neurosis. -Sedative and hypnotic effect by flurazepam, temazepam, and triazolam. -Central muscle relaxant action especially diazepam. -Anticonvulsant and antiepileptic action especially diazepam, lorazepam and clorazepate.

-Anesthesia: They produce drowsiness, amnesia, and finally unconsciousness especially diazepam and midazolam I.V. -Slight effect on C.V.S and respiration except in intoxication. Therapeutic uses: 1.Treatment of anxiety. 2.Sedative and hypnotic in insomnia. They are preferred than barbiturates due to: -High therapeutic index. -Minimal effect on sleep rhythm. -Mild physical dependence. -Little respiratory depression and little cardiovascular effects. -Little or no hangover. -Not significantly enzyme inducers (so little interactions). -Slow development of tolerance. 3. Muscle spasm and rigidity. 4. Status epilepticus (by diazepam or lorazepam) and petit mal epilepsy (by clonazepam). 5. Preanaesthetic medication, induction and maintenance of anaesthesia for procedures that do not require analgesia as endoscopy, cardioversion, catheterization and radiodiagnostic procedures. 6. Treatment of alcohol withdrawal. 7. Alprazolam is used in anxiety with depression. Side effects: -Confusion, anterograde amnesia, dysarthria, weakness and headache, hypotension and syncope particularly in elderly. -Light headedness, lassitude, ataxia, increased reaction time, night mares, hallucination, euphoria, depression, impair mental, psychomotor, and sexual function. -Nausea, vomiting, epigastric distress, diarrhea, dry mouth, bitter taste. -Allergy and bone marrow depression. -Thrombophlebitis after I.V. administration. -Chronic use of high doses produces tolerance and dependence. Withdrawal after long use may not appear for a week or more after abrupt discontinuation. Abstinence syndrome include insomnia, anxiety, dysphoria, irritability, anorexia, sweating, tremors, unpleasant dreams, agitation, depression, myalgia, muscle twitches and even convulsions.

N.B.: Flumazenil is a benzodiazepine antagonist, given orally or better I.V., metabolized in liver. It is used to reverse the effects of benzodiazepines. 2. Zolpidem and Zaleplon are non-benzodiazepine sedative and hypnotic used for short-term treatment of insomnia. They binds to benzodiazepine receptor type I (BZ1=omega1 subtype so facilitate effect of GABA) 3. Buspirone is anxiolytic drug, which acts as a partial agonist on 5HT1A presynaptic receptors in brain. It has no hypnotic or anticonvalsant or muscle relaxant action. There is no rebound anxiety or withdrawal signs if stopped suddenly. * It is rapidly absorbed orally, metabolized into active metabolite and its major metabolite blocks 2 receptors. * Side effects : Tachycardia, palpitation, nervousness, parasthesia, gut upset, miosis and hypertension with MAOIs. Psychomotor impairment is less than benzodiazepines.

Local anesthesia
Classifications 1. Esters of benzoic acid: cocaine (natural). 2. Esters of PABA: Procaine, tetracaine, benzocaine. 3. Amides: Lidocaine, dibucaine, prilocaine, mepivacaine and ropivacaine. -Procaine, lidocaine, tetracaine and dibucaine are soluble and are given by injection or used locally except procaine (not for surface anaesthesia). -Cocaine and phenacaine are used topically on eye and are soluble. Fate: Esters are hydrolyzed by pseudocholinesterase so they have short duration, while amides are degraded by liver microsomal enzymes. Mechanism of action : -Interfere with ionic changes (inhibit permeability to Na+ so block voltage gated Na+ channel = stabilize membrane) and act from inner side. -In alkaline medium local anesthetics will be non ionized, so can penetrate tissue. If medium is acidic, they dissociate and can not penetrate through nerves so injection of local anesthetic in inflamed area is ineffective. -Sensory fibers (pain, then cold, touch, pressure) and lastly motor fibers are affected in this order. Unmyelinated fibers are affected before myelinated.

Properties of ideal locat anesthetic:

It should be water soluble, stable in solution, non irritant, low toxicity, rapid onset, long duration, potent, low cost, not addictive, non allergic and does not produce permanent damage to nerves or tissues Factors affecting action of local anesthetics: 1. pH : Increased pH will increase the action due to increased the non ionized form, while decreased pH will decrease their action. 2. Elevated extracellular Ca++ antagonizes their action, while elevated K+ enhances their effect. 3. Increased tissue level of CO2 increased intracellular acidosis and accumulate charged (ionized) form increase the action. 4. Vasoconstrictors as adrenaline prolong the duration. Actions: -Vasodilatation of blood vessels (except cocaine which is V.C. due to block off uptake-1 of noradrenaline). So vasoconstrictors are added with them to prolong their duration. -Depression of heart except cocaine. 4

-C.N.S. stimulation anxiety, tremors, convulsions followed by R.C. depression. So give diazepam before. -Spasmolytic action on smooth muscles. Toxicity of local anaesthesia: A-systemic : -C.N.S. stimulation then depression. -Shock, vasovagal attack and quinidine like action on heart. -Allergic reactions (more with PABA esters). -Methaemoglobinemia (with prilocaine). B-Local : -Persistent parasethesia or anaesthesia, oedema, hematoma, pain at site of injection and facial nerve paralysis. Methods of administration: 1-Surface anesthesia: direct application on mucus membrane 2-Infiltration anesthesia: injection directly into the tissue to reach fine nerve branches. 3-Nerve block anesthesia: injection close to nerve trunk 4-Caudal anesthesia: injection in sacral canal. 5-Spinal anesthesia: injection in lumbar region. 6-epidural anesthesia: injection outside the dura between dura and bony spinal canal. It is less liable to produce hypotension. Complications of spinal anesthesia: 1. Hypotension due to arteriolar and venous dilatation. 2. Headache. 3.Respiratory paralysis. 4.Septic meningitis due to bacterial contamination. Hypotension is prevented by ephedrine and is treated by elevation of legs, intravenous fluids and noradrenaline drip. Contraindications: 1-Advanced liver disease 2-Hypertension, heart disease and hyperthyroidism (dont give adrenaline with local anesthetic).