sedative and hypnotics
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The document discusses various classes of sedative and hypnotic drugs including barbiturates, benzodiazepines, and newer non-benzodiazepine drugs. It describes the mechanism of action of these drugs as potentiating the effects of the inhibitory neurotransmitter GABA in the brain through binding to GABAA receptors or barbiturate sites. This results in increased chloride conductance, membrane hyperpolarization, and central nervous system depression. The document also provides structure-activity relationships and examples of specific drugs from each class like diazepam, zolpidem, and pentobarbital along with their medical uses, side effects, and synthesis when relevant.
sedative and hypnotics
- 1. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 1 | P a g e • The drugs that act on the central nervous system (CNS) influence the lives of everyone at all times. These drugs can selectively relieve pain, reduce fever, suppress disordered movement, induce sleep or arousal, and reduce the desire to eat or ally the tendency to vomit. Selectively, acting drugs can be used to treat anxiety, mania, depression, or schizophrenia and do so without altering consciousness. • The electrophysiological signs of action in the CNS falls into two categories (i) excitatory (produce depolarization) and (ii) inhibitory (produces hyperpolarization) in the neurons. Sedative ❖ Sedatives are central nervous system (CNS) depressant drugs that reduce excitement, tension, and produce relaxation. ❖ A drug that subdues excitement and calms the subject without inducing sleep, though drowsiness may be produced. Sedation refers to decreased responsiveness to any level of stimulation; is associated with some decrease in motor activity and ideation. Hypnotic ❖ Hypnotics are drugs that depress the CNS and produce sleep like that of natural sleep. Difference b/w Sedatives and hypnotics ✓ Sedatives are drugs that decreases activity and have a calming, relaxing effect. Peoples use these drugs mainly to reduce anxiety. At higher doses, sedatives usually cause sleep. Drugs used mainly to cause sleep are called Hypnotics. ✓ The difference between sedative and hypnotic is usually the amount of the dose- At lower dose have a calming effect and higher doses cause sleep. ✓ At lower dose, the drug may act as sedative, while at a higher dose the same drug may act as hypnotic Sedatives and hypnotics are also used as the following: ✓ Antianxiety Agents ✓ Anticonvulsants ✓ Muscle Relaxants ✓ General Anaesthetics ✓ Preanaesthetic Medication ✓ Antipsychiatrics ✓ To Potentiate Analgesic Drugs ✓ Adjuvant to Anaesthesia
- 2. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 2 | P a g e ✓ A co-drug in the Treatment of Hypertension Different effect of HYPNOTICS of different doses Lower dose high dose very higher dose Sedative general anaesthetic respiratory depression Coma Death CLASSIFICATION OF SEDATIVES AND HYPNOTICS Barbiturates Benzodiazepines newer non-BZD’S Miscellaneous Long-acting barbiturates ✓ Barbital ✓ Phenobarbital ✓ Mephobarbital ✓ Metharbital Short-acting barbiturates ✓ Butobarbital ✓ Pentobarbital ✓ Secobarbital ✓ Amobarbital ✓ Cyclobarbital ✓ Heptabarbital Ultra short-acting barbiturates (15 min) ✓ Thiopentone ✓ methohexitone Hypnotics ✓ Diazepam ✓ Flurazepam ✓ Nitrazepam ✓ Alprazolam ✓ Triazolam Anti-anxiety ✓ Diazepam ✓ Chlordiazepoxide ✓ Oxazepam ✓ Lorazepam ✓ Alprazolam Anti-convulsant ✓ Diazepam ✓ Lorazepam ✓ Clonazepam ✓ clobazam Also known as Z-Drugs ✓ Zopiclone ✓ Zolpidem ✓ Zaleplon Amide & imides ✓ Glutethmide Alcohol & their carbamate derivatives ✓ Meprobomate ✓ Ethchlorvynol Aldehyde & their derivatives ✓ Triclofos sodium ✓ Paraldehyde
- 3. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 3 | P a g e Benzodiazepines (BZD) Chemistry of BZD ✓ All the BZD’s have a benzene ring (Blue color) attached to a diazepine ring (red color). ✓ BZD have a cyclic structure that includes one benzene ring with a heterocycle ring where 2 atoms are “Nitrogen” (Diazepine), Normally in 1 & 4th position, but which can also be in 1,5th and 2, 3rd position. ✓ Normally BZD used in clinically that are 1,4-dinitrogenated system. SAR of Benzodiazepines OR Possibilities of Modification at Ring A, Ring B and Ring C 1. RING-A
- 4. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 4 | P a g e • 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 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 methylene or imine nitrogen is sterically unstable. • 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 position with Halogen, increases the activity. • Substitution at 4’ position is unfavourable for activity. Mechanism of action BZD Bind to modulatory site on GABAA Potentiate the inhibitory effect of GABA Increases the frequency of Cl- channel opening Increases in chloride conductance Membrane hyperpolarization CNS depression
- 5. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 5 | P a g e OR Benzodiazepine receptors are present in the brain and they form a part of GABAA receptor’s chloride ion channel macromolecular complex. Binding of benzodiazepines to these receptors produces activation of GABAA receptor and increases chloride conductance by increasing the frequency of opening chloride ion channel. These in turn inhibit neuronal activity by hyper-polarization and de-polarization block. Action Clinical Use Anxiolytic Anxiety and panic/phobias, alcohol withdrawal symptoms Hypnotic Insomnia Muscle relaxant Muscle spasms, spasticity caused by CNS pathologies Anticonvulsive Attacks caused by drug intoxications, some forms of epilepsy Amnesic Perioperative or pre-surgery medication Side effects of BZD’s: - Common side effects drowsiness, confusion, blurred vision With other chronic use cause symptoms like tremors, insomnia, restlessness Occasionally: dizziness, headache, depression, confusion, dysphasia. Diazepam Uses: skeletal muscle relaxant, anticonvulsant and antianxiety agent. Side effect: drowsiness, sedation, muscle weakness.
- 6. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 6 | P a g e Synthesis of diazepam:
- 7. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 7 | P a g e Zolpidem: (all non-BZD’s drugs having same action as zolpidem) (“Z”-drugs) • Less hangover effect than BZD’s • Can given orally and well observed metabolized in liver & excreted by urine • Having short duration of action mostly used for short-term insomnia • Less tolerance and dependence MOA: Zolpidem Binds to selectively to BZD receptors GABA mediated neuronal inhibition CNS depression
- 8. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 8 | P a g e BARBITURATES • Barbiturates are derivatives of barbituric acid. Their hypnotic activity is conferred by the replacement of H-atom attached to the C-5 position by aryl or alkyl radicals. • The barbiturates were used extensively as sedative–hypnotic drugs. SAR of Barbiturates The acidity value within certain limits, gives proper ratio of ionized forms that leads to cross the Blood Brain Barrier (BBB). Based on acidity value, divided into 2 classes Active class Inactive class 1. 5,5’-disubstituted barbituric acid 2. 5,5’-disubstituted Thio barbituric acid 3. 1,5,5’-trisubstituted barbituric acid 1. 1-substituted barbituric acid 2. 5-substituted barbituric acid 3. 1,3-disubstituted barbituric acid 4. 1,5-disubstituted barbituric acid 5. 1,3,5,5’-tetrasubstituted barbituric acid Substitution at C-5 (R2, R3) position should be alkyl chain length is 6-10 carbon to attain optimal activity. Substitution at R2, R3 position with branched chain shows greater lipid solubility and hypnotic activity but has shorter duration of action. The greater branching shows more potent will be the drug. eg.: - pentobarbitone Alicyclic or aromatic substituted analogue are more potent than aliphatic substituted analogue with the same number of carbon atom. Substitution at C-5 position shows the higher potency. Replacement of Oxygen atom by Sulphur atom at C-4 and C-6 position, reduce the hypnotic activity. Replacement of Oxygen atom by Sulphur atom at C-2 position leads to rapid onset of action and shorter duration of action.
- 9. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 9 | P a g e Drug R1 R2 R3 Barbital H C2H5 C2H5 Phenobarbital H C2H5 Mephobarbital CH3 C2H5 Amobarbital H C2H5 Butabarbital H C2H5 Pentobarbital H C2H5 Secobarbital H CH2=CH-CH- Mechanism of action Barbiturates Bind to other modulatory site (barbiturate site) on GABAA Potentiate the inhibitory effect of GABA Increases the frequency of Cl- channel opening Increases in chloride conductance Membrane hyperpolarization CNS depression
- 10. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 10 | P a g e Barbiturates do not bind to benzodiazepine receptor promptly, but it binds to another site on the same macromolecular complex to exert the GABAergic facilitator actions. The barbiturate site appears to be located on α and β subunit. At high concentrations, barbiturates directly increase Cl– conductance and cause CNS depression. Barbital Synthesis Therapeutic uses Sedative and hypnotics Pre operative sedation Treatment of seizure Anticonvulsants Side effects
- 11. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 11 | P a g e Miscellaneous: 1. Glutethmide It is used as a hypnotic drug to induce sleep without depressing respiration. 2. Meprobomate It is used in the anxiety disorder and centrally action skeletal muscle relaxant. 3. Ethchlorvynol Used for short-term hypnotic therapy in the management of insomnia the exact mechanism of action is unknown, ethchlorvynol appears to depress the central nervous system in a manner similar to that of barbiturates 4. Triclofos sodium Used as hypnotics
- 12. Unit-IV_Sedatives and Hypnotics MEDICINAL CHEMISTRY-1 Prepared by- Subham Kumar Vishwakarma (Asst. Prof., Department of Pharmaceutical Chemistry, UIPS, Ujjain (MP) 12 | P a g e 5. Paraldehyde Paraldehyde was used historically as a sedative and hypnotic 1. It has been used in the treatment of seizures as an anticonvulsant Paraldehyde is believed to reduce the release of acetylcholine in response to neuronal depolarization 3. The exact mechanism of this effect is unknown.