L3 Anxiolytic and Hypnotic Drugs PDF

28/03/1446 L3 3hrs Anxiolytic, sedative and hypnotic drugs Anxiolytic drugs: used to treat the symptoms of anxiety. Sedative drugs: used to calm the patients without promot...

28/03/1446 L3 3hrs Anxiolytic, sedative and hypnotic drugs Anxiolytic drugs: used to treat the symptoms of anxiety. Sedative drugs: used to calm the patients without promoting sleep. Hypnotic drugs: used to promote sleep. Sedative-anxiolytic Hypnotic Unconsciousness Death Note: the sedative-anxiolytic-hypnotic drugs may be employed as antiepleptic, anticonvulsant and muscle- relaxant. 1 28/03/1446 The symptoms of anxiety are in the form of: Tachycardia, sweating, palpitation, tremor, trembling, gastrointestinal disorder, sleep disturbance …etc. Those symptoms are not only caused by anxiety but they may add feeling of anxiety. *Hypnotic and anxiolytic sedative drugs: *1. Benzodiazepines: Over 2000 of Benzodiazepines (BZDs) have been synthesized, and more than 100 have used as (hypnotics, sedatives, relieve of anxiety). The most common used agents: alpraolam, chlorodiazepoxide, clonazepam, diazepam, Estazolam, flurazepam, Lorazepam, Midazolam, Oxazepam, Temazepam and Triazolam. 2 28/03/1446 Types of (BZDs): to determine what specific types of this group, we must test the following parameters: 1. t ½ of the drug. 2. The presence of active metabolites of the drug and the t ½ of them. 3. Remarks: speed of absorption, solubility and passage of the drug into CNS. BZDs with long t ½ drug/ metabolites are appropriate for anxiety. Short t ½ drugs/metabolites are appropriate for hypnotics. The following figure shows the data on some of BZDs. Figure 9.10 Therapeutic disadvantages and advantages of some anxiolytic and hypnotic agents. CNS = central nervous system. 3 28/03/1446 *Mechanism of actions: *Three types of receptors for BZDs (BZD1, BZD2 and BZD3). These receptors are distributed in different region of the brain. The BZD receptors appear to be located in closed to GABA receptor (GABA: is a major inhibitory neurotransmitter in the mammalian C.N.S) and chloride ion channel to form a complex (BZD- GABA-chloride ion channel receptor complex. The interaction of BZD compounds with their specific receptor enhances the inhibitory of GABA and opening the chloride channels producing sedation…. etc. 4 28/03/1446 *Pharmacological actions: The BZDs have no analgesic action and do not affect the autonomic nervous system. The BZDs exhibit the following actions: 1. Reduction of anxiety: At low doses, the BZDs are anxiolytic. Reduce of anxiety by selectively inhibiting neuronal circuits in the limbic system of the brain. 2. Sedative and hypnotic actions: All of the BZDs used to treat anxiety have some sedative properties. At higher doses certain BZDs produce hypnosis. 3. Anticonvulsant: Several of the BZDs have anticonvulsant activity and are used to treat epilepsy. 4.Muscle relaxant: The BZDs relax the spasticity of skeletal muscle, probably by increasing presynaptic inhibition in the spinal cord. 5. Amnesia: The shorter-acting agents are often employed as premedication for anxiety-provokin unpleasant procedures such as endoscopic, bronchoscopic and certain dental procedures. Therapeutic uses: BZDs are used to treat: anxiety (without or with Psychotic states), panic attack, Insomnia, alcohol withdrawal, somnambulism(children), Muscle spasm due to variety of causes including epilepsy, anaesthesia and sedation for endoscopies. 5 28/03/1446 BZDs are relatively safe, since the lethal dose is over 1000 times greater than typical therapeutic dose. Ratio of lethal dose to effective dose for morphine and the anxiolytic, hypnotic drugs, phenobarbital and diazepam. *Sleep disorders: Not all of the BZDs are useful as hypnotic agents, although all have sedative or calming effects. The three most commonly prescribed BZDs for sleep disorders are long acting flurazepam, Intermediate-acting temazepam and short-acting triazolam. The longer acting agents form active metabolites with long half-life. *Pharmacokinetics: *1.Absorption and distribution. BZDs are rapidly and completely absorbed after oral doses and are distributed throughout the body. All BZDs cross the placenta so they will cause depression of the neonatal after delivery, and also they are excreted in milk cause CNS depression of neonate. 6 28/03/1446 2.Duration of actions. The half-life of the BZDs are very important clinically, since the duration of action may determine the therapeutic usefulness. The longer acting agents form active metabolites with long half-life. Tolerance occurs with chronic use and there is cross-tolerance within the group. Tolerance induced by diazepam may also affected by nitrazepam doses. Dependence occurs earlier with the short t1/2 members shown by the occurrence of withdrawal symptoms. The dependence may develop when the drug is used for few weeks. Withdrawal symptoms begin after 2-4 days with alprazolam and lorazepam but may be delayed for 2-3 weeks with diazepam Alprazolam (t1/2 16h) Metabolites are inactive We need 5t1/2 to Lorazepam to be eliminated withdrawal appears after 2-4 days Diazepam (t1/2 30h) metabolites to active Substance desmethyldiazepam (t1/2 80h i.e 4days) withdrawal appears after 2-3 weeks. 7 28/03/1446 *Withdrawal symptoms are the action we used the drug against: anxiety, irritability, confusion, delirium, psychotic attacks, insomnia, tremor, muscle rigidity, convulsion, sweating and diarrhea. *Withdrawal of BZDs should be gradual after 3 weeks use, but for long-term users, it should be very slow. This is done by decreasing 1/8 of the original dose every 2 weeks aiming to complete it in 6-12 weeks. To wards the end of *withdrawal of a short t1/2 drug it may useful to substitute with a long t1/2 drug (diazepam) to minimize rapid fluctuations in plasma concent. *Interactions of BZDs: *1.There are additive effects with CNS depressants including alcohol, which also speeds benzodiazepine absorption. *2.Cimetidine may increase plasma concentration of diazepam and chlorodiazepoxide by as much as 50% (delayed metabolism and clearance), this does not happen with oxazepam and lorazepam. *3.High caffeine intake reduces the anxiolytic effect (due to its stimulatory effect). 8 28/03/1446 *Overdose: BZDs are very safe group of drugs, because even if administration 10 times the therapy it will only induce sleep, which the subject can be waken up. *Adverse effects of BZDs include: Sleepiness, impaired psychomotor function and * amnesia (causing hazard with car driving or operating any machine), dependence, additive effects with alcohol, paradoxical behavioral effect (on some subject i.e instead of inducing sleep, they induce anxiety. *BZDs antagonist: *-Flumazenil. Is a competitive antagonist at BZD receptors which has some agonist action i.e it is a partial agonist. Heavily sedated patients become alert within 5 minutes after I.V dose of flumazenil. *Clinical uses: *-Reverse the effect of BZD after short operation. *-In diagnosis the patient poisoning with BZD. *Adverse effects: Vomiting, brief anxiety, seizures in epileptic patients treated with a BZDs 9 28/03/1446 *-Buspirone. Other e.g of BZD antagonist -blocks both dopamine and serotonin receptors. -It has no hypnotic, muscle relaxant or antiepleptic effect and it does not benefit BZD withdrawal symptoms. -Buspirone is metabolized in the liver, it has an active metabolite that may accumulate over weeks.-Anxiolytic efficacy is similar to or rather less than BZDs. 2.Barbiturates: barbiturates are used to sedate the patients or to induce and maintain sleep. Today, they have been largely replaced by the benzodiazepine because they are unsuitable as hypnotics due to: a.Low therapeutic indexes (10 times the therapeutic dose will danger to the life by unconsciousness and respiratory depression. b.Induce tolerance. c.Physical dependence occurs, with sever withdrawal syndrome. d.Potent enzyme inducers with interaction with other drugs. 10 28/03/1446 The therapeutic useful barbiturates have been classified according to their duration of action: 1.Ultra-short acting as thiopental (pentothal) and thiamylal. 2.Short-acting barbiturates as secobarbital and pentobarbital. 3.Intermediate-acting barbiturates as amobarbital and butabarbital. 4.Long-acting barbiturates as phenobarbital (luminal) and barbital. Pharmacological action of barbiturates: -C.N.S. Barbiturates provide depression of the C.N.S ranging from mild sedation to surgical anaesthesia. Their mechanism of action is similar to BZDs (barbiturates potentiate GABA action on chloride entery into the neuron by prolonging the duration of the chloride-channel openings. In addition, barbiturates can block excitatory glutamate receptors and the inhibitory effect of glycine. Barbiturates antagonize analgesics (this should be remembering in-patient takes analgesic). Their actions are not antagonize by flumazenil. 11 28/03/1446 -Anticonvulsant. Barbiturates are potent antidotes of the convulsant drugs and they can also abolish convulsion that arises in disease states as: Tetanus, Eclampsia (convulsion or coma happen in the pregnant women after born of the child, against the lethal doses of local anesthesia such as procaine and cocaine. -Respiration. Increasing the doses of ultra-short acting barbiturates induce death due to the respiratory failure as a consequence the depression of respiratory center. -C.V.S. Barbiturates lower blood pressure at hypnotic and anesthetic doses by reducing cardiac output. Toxic doses of barbiturates can produce heart failure that means marked fall in B.P. -Tolerance. Tolerance may develop within 14days using of the drug. This tolerance may be due to enzyme induction. -Psychological and physical dependence: They occur with regular dosage 0.4gm/day or more of barbiturate. Withdrawal syndrome begins in 8-38hrs and passes off over 8-14 days. It comprises anxiety, twitching, intention, tremor, weakness, dizziness, distorted vision, nausea, delirium, convulsion and coma. 12 28/03/1446 Pharmacokinetics: Barbaiturate are absorbed orally and distributed widely throughout the body from the brain to skeletal muscle, and finally to adipose tissues. This movement is important in causing the short duration of action of thiopental and short-acting derivatives. They readily cross the placenta and can depress the fetus. Excretion. Little urinary excretion (mainly hepatic) except in case of phenobarbitone. Contraindication: Pulmonary insufficiency, hepatic failure, porphyria, elderly because of paradoxical effect can occur like excitement, paranoid effect and suicidal tendency. Acute adverse effect of barbiturates: -Are almost entirely those of overdose: -Coma and respiratory and circulatory failure, leading to renal failure, allergic reactions, particularly with phenobarbitone. 13 28/03/1446 3.Trichloroethanol derivatives: -Chloralhydrate. The chloralhydrate is converted in the body to the active intermediate tricloroehanol by the action of alcohol dehydrogenase, useful as hypnotic. When the drug is diluted in water it causes some gastric irritation, but when diluted in some flavored solution, it is less irritating. induces sleep in 30 minutes for 6-8hrs. the active intermediate trichloroethanol is conjugated with glucuronic acid to an inert form. Other chloral derivatives: Triclofose and Chloralbetaine. They are alternatives. Drug interaction: -interaction with ethanol. Trichloroethanol is a competitive inhibitor of the conversion of ethanol to acetaldehyde so that plasma concentration is higher. If chloral has been taken for several days, ingestion of alcohol may induce vasodilatation, hypotention and tachycardia. -Interaction with warfarin gives enhanced anticoagulant effect. 14 28/03/1446 4. antidepressants: Many antidepressants have proven efficacy in managing the long-term symptoms of chronic anxiety disorders and should be seriously considered as first-line agents, especially in patients with addiction or dependence to other substances. 5.Phenothiazine. Drugs belong to this group. -Promethazine. Is a useful long-lasting hypnotic especially in children. It is an antihistamine (H1 receptor -Trimeprazine: is used for short-term sedation and hypnotic in children. It is also an antihistamine. 6.Zolpidem. Is a new hypnotic drug. Is not a benzodiazepine in structure, but it acts on BZ1 receptor. It is as effective as flunitrazepam and it has a rapid onset of action and short half-life and provide a hypnotic effect for approximate 5 hours. Zolpidem undergoes hepatic oxidation by the CYP450 system to inactive product. Thus drugs such as rifampin, which induce this enzyme, shorten the half-life zolpidem. Other agents like zolpidem in its action zaleplon and eszopiclone. 7.Meprobamate and chlormezanone. They are centrally acting muscle relaxants produce sedative-hypnotic effects. 15 28/03/1446 8.Bromides. Are handled in the body like chloride. The ratio of chloride to bromide excreted in the urine is higher as bromide is more readily reabsorbed in tubules of the kidney. It is thought that depression of the neurons of the CNS results due to the replacement of chloride ion which causes by the action of bromide. Replace of Cl in CNS depression Sedation or Hypnosis 9.Antihistamines. Some of antihistamine drugs such as Diphenhydramine and Doxylamine are used in mild types of sleep disorder (insomnia) due to undesirable side effects of these antihistamine drugs, make them less useful than the benzodiazepines. 10. Ramelteon. It is a novel hypnotic drug that activates a Melatonin receptors in the brain. It has no direct effect on GABAergic neurotransmitter in the CNS. 16 28/03/1446 10.Ethanol. Has anti-anxiety and sedative effects but its toxic. The sedation and hypnosis produce with the increasing the dose of alcohol. Ethanol synergizes with many other sedation agents and can produce sever CNS depression as with antihistamine or barbiturates. 11. Melatonin receptor agonists Ramelteon and tasimelteon are selective agonists at the MT1 and MT2 subtypes of melatonin receptors. Melatonin is a hormone secreted by the pineal gland that helps to maintain the circadian rhythm underlying the normal sleep-wake cycle. Stimulation of MT1 and MT2 receptors by ramelteon and tasimelteon is thought to induce and promote sleep. They have minimal potential for abuse, and no evidence of dependence or withdrawal has been observed. Therefore, ramelteon and tasimelteon can be administered long-term. Ramelteon is indicated for the treatment of insomnia characterized by difficulty falling asleep (increased sleep latency). 17