Sedatives and Hypnotics Lecture Notes PDF

Anxiolytics, Sedatives and Hypnotic Drugs  Intended learning outcomes At the end of this lecture, student will be able to: Define and differentiate between Sedatives and hypnotics Categorize the sedative-hypnotic agents Describe the SAR of Benzodiazepine’s. Identif...

Anxiolytics, Sedatives and Hypnotic Drugs  Intended learning outcomes At the end of this lecture, student will be able to: Define and differentiate between Sedatives and hypnotics Categorize the sedative-hypnotic agents Describe the SAR of Benzodiazepine’s. Identify other types of sedatives and hypnotics. Sedatives (before development of barbiturates) ❖ Since e antiquity, alcohol beverages and potions containing laudanum and various herbals have been used to induce sleep. ❖ Morphine was used for quick management of aggressive patients In 1800: most widely used sedative in asylums ❖ In 1857: Bromide was the first agent to be introduced specifically as a sedative and soon thereafter as a hypnotic History Definitions Anxiolytics are a class of medications used to prevent or treat anxiety symptoms or disorders. Sedatives are agents that can produce mild depression and calms anxiety & excitation without causing drowsiness or induction of sleep Decreases excitability, restlessness, emotional tension and relieve anxiety without affecting alertness Hypnotics are agents that can induce sleep when natural sleep is impossible they are useful in the treatment of insomnia The ideal hypnotic drug should induce sleep that is similar to natural sleep.  Classification ❑ They are not characterized by common structural features. ❑ According to Mode of action are classified into: ✓GABAA receptor modulators: ✓ Antipsychotics and anticonvulsants ❖ Benzodiazepines ✓ Piperidinediones (Amide and imides) ❖ Nonbenzodiazepine hypnotics (Z-drugs): ❖ Barbiturates ✓ Sedative H1-antihistamines ✓ Melatonin-1 receptor (MT1) agonists ✓ Atypical azaspirodecanediones ✓ Antidepressants (SSRIs) ✓ Chloral Hydrate ✓ β-Adrenoceptor antagonists Factors affecting the pharmacokinetic profile of sedatives and hypnotics Most of them are in the nonionized form at physiological pH, their high lipophilicity is an important factor for following properties: ❖ Most of them are absorbed well from the gastrointestinal (GI) tract, with good distribution to the brain. This property is responsible for the rapid onset of CNS effects of triazolam, thiopental, and newer hypnotics. ❖ Many sedative–hypnotics cross the placental barrier during pregnancy. ❖ They are also detectable in breast milk. ❖ Some drugs with highest lipophilicity have short duration of action because of their redistribution. ❖ Most drugs in this class are highly protein bond. ❖ Metabolism to more water-soluble metabolites is necessary for their clearance from the body. Their duration of action depends mainly on the rate of metabolism and if their metabolites are active. GABAA receptor modulators:  GABAA receptor is the target for many anxiolytics and sedative–hypnotic agents including benzodiazepines, barbiturates, non-benzodiazepines, many other drugs that bind to different binding sites of the GABAA receptors in neuronal membranes in the CNS. Benzodiazepines Leo Sternbach  [i] Benzodiazepines ❑Benzodiazepine refers to a structure composed of a benzene ring fused to a seven- membered diazepine ring. ❑Among the different types of benzodiazepine derivatives, the currently used benzodiazepine drugs are related to 5-aryl-3H-1,4-benzodiazepine structure. Classification of Benzodiazepines A) 1, 4-Benzodiazepine-4-oxides ❖ It was the first BZPs marketed for clinical use. ❖ The half-life is 6 to 30 hours. ❖ This drug is long acting because of the long half-life of parent drug and its active metabolites 1960 ☼ Metabolism: B) 1,4-Benzodiazepine-2-ones ☼ SAR: Possibilities of Modification at RING -A The minimum requirement for 5-phenyl-1,4-benzodiaipin-2-one derivatives to BZD include an aromatic or hetero aromatic ring. An electronegative group (halo or nitro) substituted at R1(7 position) markedly increase activity and binding affinity Substitution on 6,8 and 9 decrease the activity. Replacement of ring A with heterocyclic ring have weak activity and affinity as compared to phenyl derivatives. RING-B Alkyl substitution at R2 position will increases the activity. A proton accepting group C=O (carbonyl oxygen) at 2nd position of ring B is necessary to interact with receptor binding site. Substitution at 3rd position with hydroxy moiety have comparable potency to CH analogue but are excreted faster. Phenyl substitution at 5th position increases the activity. RING-C Replacement of Ring C with aromatic heterocyclic ring increases the anxietolytic activity. Substitution at R3 (2’ position) with Halogen, increases the activity. Substitution at 4’ position is unfavorable for activity. 1. Diazepam: (Valium) 1960 It is prototypical and was the first member of the benzodiazepine-2-one group to be introduced. It is very lipophilic and is thus rapidly and completely absorbed after oral administration. With a half-life of about 46 hours Like chlordiazepoxide repeated administration of diazepam leads to accumulation of an active nordazepam. ☼ Metabolism: 2. Clorazepate Dipotassium: ❖ It can be considered a prodrug. ❖ Inactive itself, it undergoes rapid decarboxylation by the acidity of the stomach to nordazepam, which has a long half-life and undergoes hepatic conversion to active oxazepam. ❖ Despite the polar character of the drug as administered, because it is quickly converted in the GI tract to an active nonpolar compound, it has a quick onset, overall long half-life. L.O.T. drugs ❖ Many clinicians favor the so-called “L.O.T. drugs” in this population (lorazepam, oxazepam, and temazepam) as they do not require oxidative metabolism in the liver and have no active metabolites. ❖ Agitation, associated with dementia is a common reason for medical intervention in the elderly and benzodiazepines may be useful, especially in situations where anxiety is prominent. ❖ Short-term use is the recommendation with special care needed to use only the lowest effective dose. BZD toxicity in the elderly can cause cognitive impairment even with short- term therapeutic doses. C) 1,2-Annealated 1,4-Benzodiazepines (Triazolobenzodiazepines) 1. Alprazolam: (Xanax) It is rapidly absorbed from the GI tract. Protein binding is lower (~70%) than with most benzodiazepines because of its lower lipophilicity. α-Hydroxylation of the methyl group to the methyl alcohol followed by conjugation is rapid; consequently, the duration of action is short. The drug is a highly potent anxiolytic on a milligram basis. 1. Triazolam: (Halcion) An ultra–short-acting hypnotic because it is rapidly α-hydroxylated to the 1-methyl alcohol, which is then rapidly conjugated and excreted. Consequently, it has gained popularity as sleep inducers, especially in elderly patients, because it causes less daytime sedation. 1. Midazolam: This drug is used intravenously as a short-acting sedative–hypnotic and as an induction anesthetic because of its short half-life (t1/2 ~ 2 h) for the same reason. Triazolam Triazolo-benzodiazepine derivatives Short half-life (4 hr) No active metabolite Estazolam Triazolo-benzodiazepine derivatives Duration of action (8-28 hr) No active metabolite ❖Triazolam and estazolam, with high receptor binding affinity and more rapid elimination ❖Daytime sedation are eliminated ❖The duration of action for triazolam, which has an ultrashort half-life of less than 4 hrs [ii] Non-Benzodiazepines [with  affinity to BDZ receptor → GABA agonists] Cyclopyrrolone derivatives Imidazopyridine derivatives Zopiclone Zolpidem Advantages: 1. No withdrawal symptoms. 1. Rapid onset & short duration. 2. No accumulation after repeated doses. 2. No rebound effects upon withdrawal of the 3. Rapidly induce sleep. drug. Metabolism: Metabolism: Hydroxylation of the methyl gps →followed 1. Major: N-Oxide zopiclone (less active). by further oxidation →→ the carboxylic acid, 2.Minor: N-desmethyl zopiclone (inactive). which then conjugated for excretion. Benzodiazepine Toxicity treatment ❖ Fortunately, overdose with benzodiazepines and Z-drugs responds to an antagonist, flumazenil. ❖ This benzodiazepine antagonist, flumazenil, is available for the treatment of acute benzodiazepine intoxication and has been shown to reverse also the sedative effects of all three Z-drugs ❖ It is a BZD with high affinity, which is able to displace other BZDs and has very short half-life, of approximately 1 hour. It is used for: BZDs or Z-drugs intoxications To reverse the effects of anesthesia caused by a BZD Diagnosis of states of coma, which have an unknown origin  [iii] Melatonin Receptor Agonist ❑Melatonin is poor drug because of its poor absorption, low oral bioavailability (less than 10%, rapid first pass metabolism. ❑The melatonin molecule was reengineered by ❑Substituting the nitrogen of the indole ring with carbon to give an indane ring bio-isostere of melatonin ❑Constructing the conformational flexibility of the 5-methoxy group into a furan ring to form either an angular indeno[5,4-b]furan ❑The selectivity of the resulting ramelteon for MT1 receptor is eight times more than that of MT2 receptor. ❑Ramelteon has no addiction liability. As a result, it has recently been approved for the treatment of insomnia.