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Central Nervous System Depressants These drugs cause depression of neuronal activity

Central Nervous System Depressants These drugs cause depression of neuronal activity in the CNS, that is, the brain and spinal cord. Classification of CNS depressants: They are classified into: 1- General anesthetics 2- Sedative-hypnotics

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Central Nervous System Depressants These drugs cause depression of neuronal activity

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  1. Central Nervous System Depressants These drugs cause depression of neuronal activity in the CNS, that is, the brain and spinal cord. Classification of CNS depressants: They are classified into: 1- General anesthetics 2- Sedative-hypnotics 3- Anxiolytics 4-Antiepileptics 5-Antipsychotics • General anesthetic agents: They produce very strong depression. They are used to produce loss of consciousness or sensation to painful surgical process. • Hypnotics: They compels the user to sleep, a stronger form of depression.

  2. Sedatives: They produce mild depression, calms anxiety and excitations without causing drowsiness or impaired performance. • Anxiolytic drugs: These are used in the treatment of the anxiety disorders. Examples of these disorders are generalized anxiety disorder, panic attacks and social phobia. • Antiepileptics drugs (AEDS): They are used to prevent or lessen the sudden excessive electrical activity in brain that is characteristic of epilepsy. • Antipsychotic drugs: They are used in the thought disorders (psychoses), most notably the schizophrenias.

  3. Sedatives and Hypnotics These induce a nonselectivereversible depression of CNS. Sedatives: calm anxiety and excitations without causing impaired performance (relaxation and rest but no sleep). Hypnotics: They are used to induce sleep. • Drugs that exert a general depressing effect on the CNS can elicit any degree of depression depending on the dose and route administration. • Large dose produces hypnotic activity while small dose of the same drug causes sedation. • There are few exceptional cases whereas KBr has good sedative and no hypnotic activity while thiopental sodium is powerful hypnotic and has no sedative effect.

  4. Ideal hypnotic • cause a transient decrease in the level of consciousness for the purpose of sleep. • not affects respiration. • no addiction, tolerance or dependence. Classification of sedatives-hypnotics They are classified into: A) Barbiturates : Cyclic ureides B) Nonbarbiturates:acyclic ureides, alcohols, amides, and imides.

  5. A) Barbiturates Chemistry: Barbiturates are cyclic ureides formed via condensation reaction of malonic acid or Its ester or malonyl chlorides with urea or thiourea. • These cyclic uerides are acidic owing to enolization X = O, S Z =OH, Cl, OC2H5 Malonylureaor barbituric acid or 2,4,6(1H, 3H, 5H) pyrimidinetrione Barbituric acid Barbituric acid Keto-form enol-form

  6. Structure activity relationship (SAR) 1. Barbituric acid not possesses any hypnotic activity due the presence of the hydrogen atoms at C5. If one hydrogen is present, tautomerization to a highly acidic trihydroxy pyrimidine (pka ~4) can occurs, so the compound is largely in the anionic form with little nonionic lipid-soluble part, can not cross the blood-brain barrier. 2. To possess good hypnotic activity, barbituric acid must be: a) weak acid b) lipid/water partition coefficient within certain limits

  7. 3. On the basis of the first criterion, barbituric acid derivatives are divided into two classes: • 1,3,5,5-Tetrasubstitut ed barbituric acid are not acidic (inactive) but in vivo through metabolism,they are converted to the active 1,5,5-trisubstituted one. 4. Many active compounds cause convulsions which prevents their clinical use. Whether a certain compound within the active classdisplays hypnotic activity on not is determined by the second criterion (partition coefficient).

  8. 5.The following features are required for hypnotic activity: A) Modifications at the fifth carbon: • Both hydrogen atoms must be replaced by alkyl groups. • The duration of action depends mainly on the substituents at 5- position which confer lipophilicity to the molecule. Optimal activity was obtained if the sum of the carbon atoms of both substituents at C5 between 6-10. Beyond 10 leads to inactive compounds. • Within the same series, branching, unsaturation, replacement of alicyclic or aromatic substituents instead of alkyl and introduction of halogen into the alkyl substituents  all increases the lipid solubility of the barbiturates.

  9. Replacement of one hydrogen by a phenyl group imparts anticonvulsant properties leading to compounds used in epilepsy. • Introduction of a polar groups (OH, NH2,COOH, SO3H) into the 5-alkyl substituent destroys potency. • A limit is reached, however, the lipophilic character , the hydrophilic character . Although lipophilic character determines the ability of compound to cross the blood-brain barrier, hydrophilic character determines solubility in biologic fluids and ensures that the compound reaches the blood-barrier.

  10. B) Modifications at the nitrogen: • Methylation of one of the imide hydrogen leads to compounds with rapid onest and short duration of action (due to increase in lipophilicity) due to very fast uptake into CNS, then rapid redistribution to the fatty tissues. • Attachment of alkyl substituents to both nitrogen renders the drugs nonacidic making them inactive. C) Modifications at the oxygen: • Replacement of carbonyl oxygen at 2-position by sulfur leading to thiobarbiturate which has quick onset and short duration of action as for example:

  11. Thiamylal(ultrashort-acting) > Secobarbital (short-acting) Thiopental (ultrashort-acting) > Pentobarbital(short-acting).

  12. Classification of barbiturates They are classified according To their onset and duration of action into: (a) Long-acting barbiturates • Onset time : one hour • Duration of action : 6-10 hours. (b) Intermediate-acting barbiturates • Onset time : 30 minutes • Duration of action : 2-6 h Uses:(1) Insomnia (2) as preoperative sedative (3) I.V. as anticonvulsant.

  13. (c) Short-acting barbiturates Onset time: 15 min Duration of action: 1-2 hours Uses: • Insomnia • As pre-operative medication. (d) Ultra Short-acting • Onset time: within seconds • Duration of action: about 30 minutes

  14. Thiobarbiturates 1- Thiamylal sodium 2- Thiopental sodium, (Surital Sodium)(Pentosal, Intraval, Nesdonal) Sodium,5-ethyl-5-(1-methyl butyl)-2-thiobarbiturate Sodium,5-allyl-5-(1-methyl butyl)-2-thiobarbiturate

  15. Assay of barbiturates (1) Nonaqueous titration(for all barbiturates) Dissolve in DMF and titrate with 0.1N sodium ethoxide using thymol blue as indicator. (2) Gravimetric titration (for barbiturate Salts) Solution (barbiturate Salts in water) + HCl  liberate free barbiturate, then extract with ether, evaporate to dryness and weigh. (3) Bromometric titration(unsaturated barbiturates) Allow to react with known excess of 0.1N Br2 (KBr + BrO3), add KI and titrates the liberated I2 with Na2S2O3 using starch or CHCl3 as indicator.

  16. Mode of action of barbiturates: • In general, sedative-hypnotics act by interfering with functions of the reticular activating system either by stimulating the sleep center or by inhibiting the function of the arousal center. Disadvantages • Tolerance and dependence • Hypersensitivity • Drug interactions a) Ethanol, isoniazide and antihistaminics depression b)Absorption of dicumarol and griseofulvin is . 4. Toxicity: greater CNS depression, death may occur due to respiratory and circulatory paralysis. Antidotes: Pentetrazole, bemigride and picrotoxin N.B.: Currently, the barbiturates get minimal use as sedatives and hypnotics but used as anesthetics and antiseizure drugs.

  17. General procedure for preparation of barbiturates:

  18. (B) Nonbarbiturates 1- Acyclic Ureides These are derivatives of urea and monocarboxylic acids. R- CONHCONH2 Carbromal (Adalin) 2-Bromo-2-ethylbutyrylurea Uses: Weak hypnotic drug. It is used as daytime sedative for anxiety. 2- Cyclic imides and amides (Piperidinediones) They are structurally related to barbiturates. Glutethimide (Doriden) 3-ethyl-3-phenyl-2,6-piperidinedione Uses: It is used safely for inducing sleep in all types of insomnia without causing depression of respiration or hypotension. Its hypnotic action is parallel to intermediate-acting barbiturates.

  19. Assay: A weighed quantity is refluxed with known excess of alcoholic KOH (0.5N) and excess KOH is back titrated with HCl (0.5N) using ph.ph. as indicator. 3- Aldehydes and their derivatives a) Chloral hydrate (Noctec) Assay: A weighed quantity is dissolved in H2O, known excess standard NaOH is added and residual alkali is back titrated with standard H2SO4.

  20. b) Triclofos sodium, (Triclos) 2,2,2-Trichloroethyl dihydrogen phosphate monosodium salt. • Triclofos is a latent form of chloral hydrate. It is prepared to avoid the side effects of chloral hydrate. It is a non-irritant, water soluble sodium salt of the phosphate ester of trichloroethanol.

  21. 4) Alcohols Several alcohols exert sedative and hypnotic actions. Structure-activity relationship: 1- Hypnotic activity  with  chain length until n-octanol 2-Unsaturation  both activity and toxicity 3- The order of activity for alcohols with the same number of carbon atoms are 3ry > 2ry >1ry. This is due to 3ry and 2ry alcohols are not metabolized by oxidation to the corresponding carboxylic acid. Branching  depression 4- Introduction of halogenincreases potency. 5- Introduction of another OH group (glycols) tends to  toxicity and activity.

  22. Ethchlorvynol (Placidyl) : Ethchlorvynol is a mild sedative-hypnotic used in single insomnia with a rapid onset and short duration of action. Disadvantage: physical dependence Assay: Dissolve in excess AgNO3 and back titrate excess AgNO3 with NH4SCN 1-chloro-3-ethyl-1-penten-4-yn-3-ol

  23. General Anesthetics • These are drugs that produce reversible depression of the CNS leading to loss of sensation and consciousness. • The first hospital operation under ether anesthesia was performed in Boston in 1846. Ideal anesthetic 1- Rapid induction and recovery. 2- Sufficient relaxation and analgesia 3- Potent 4-Wide safety margin. 5-Non-reactive and non-toxic. 6-Nonflammable and non-explosive,

  24. Pharmacokinetic principles of volatile anesthetics • The production and maintenance of the anesthesia depends on pH, pka, rate and concentration or partition coefficients of the anesthetic agent in the brain. • The blood must be saturated with the anesthetic before enter brain. Therefore, anesthetics that are highly soluble in the blood (high blood: gas partition coefficients) will require a longer time to achieve saturation of the blood. In such cases theinduction peroid is long (methoxyflurane, c = 11.12).. • On the other hand, an anesthetic that is poorly soluble in blood (low blood: gas partition coefficients) will quickly saturate the blood and then rapidly enter the tissues to produce a short induction period (isoflurane, c = 1.4).

  25. The induction and recovery times of volatile anesthetics are dependent on their blood/gas partition coefficients (i.e. solubility). • Recovery from anesthesia requires a reduction in the concentration of the anesthetic in the brain by stopping its delivery through the lungs. • As the patient continues to breath the anesthetic is continually removed which favors diffusion from the brain to the blood, to the lungs and finally to the expired air. The rate at which this occurs parallels that of induction.

  26. Partition Coefficients and Metabolism of Volatile Anesthetics • Classification of anesthetics They are classified according to their route of administra tion into two groups: I-Inhalation anesthetics II- Intravenous anesthetics

  27. I. Inhalation Anesthetics A. Historical Aspects 1. Ether: C2H5-O-C2H5 Synthesis: (A) C2H5OH + H2SO4 C2H5HSO4 + H2O C2H5HSO4+ C2H5OH  C2H5-O-C2H5 + H2SO4 (B) H2C=CH2 + H2SO4 C2H5HSO4 C2H5HSO4 + C2H5OH  C2H5-O-C2H5 + H2SO4 Advantages: • Potent • It produces analgesia and neuromuscular relaxation.

  28. Disadvantages: • explosive (explosive peroxides) • flammable when mixed with oxygen. • Long recovery period accompanied by vomiting (irritant). • excessive bronchial secretions complicating ventilation. Atropine is given as pre-medication to inhibit bronchial and salivary secretions. 2. Cyclopropane. It is also explosive and is no longer used. Synthesis:

  29. 3. Chloroform • Chloroform (carcinogen) not used now due to it causes hepatotoxic, nephrotoxic,arrhythmias and severe hypotension. 4. Ethyl chloride (C2H5Cl) • It is used now topically as spray on intact skin but not as general anesthesia dueto its liver toxicity. C2H5OH + NaCl + H2SO4C2H5Cl + NaHSO4+ H2O

  30. B. Clinically useful agents: fluorinated hydrocarbons • The addition of halogens (Cl, Br, F) to the hydrocarbon or ethers increases potency and decreases flammability. • Examples: halothane, methoxyflurane, enflurane and isoflurane. 1) Halothane (Fluthane) 2-Bromo-2-chloro-1, 1, 1-trifloroethane Synthesis:

  31. Advantages: • Nonflammable andhigh potency . • low blood/gas partition coefficient (c = 2.3). Accordingly, induction of and recovery from anesthesia are rapid. Disadvantages: 1) Narrow safety margin. 2) Respiratory depression, 3) Mechanical ventilation and oxygen supply are required. 3) Analgesics e.g. morphine are needed. Overall, halothane is not much used today.

  32. 2. Methoxyflurane (Penthrane) 2,2-dichloro-1,1-difluoroethyl methyl ether. Advantages: • Excellent analgesia • Good muscle relaxation. Disadvantages: 1) Slow induction of anesthesia (large blood/gas partition coefficient, c = 11.12). 2) Recovery is slow (very soluble in lipids) 3) Its metabolites (oxalic acid and fluoride ions) cause renal damage which, limit its clinical use.

  33. 3) Isoflurane (Forane) It is non inflammable ideal inhalation anesthetic. 1-chloro-2,2,2-trifluroethyl difluoromethyl ether Advantages: • Induction and recovery are rapid (very low blood/gas partition coefficient, c = 1.4). • The wide safety margin, muscle relaxation and analgesia. • Dilatation of the bronchial muscles (asthmatic patients). • Less toxic than enflurane because (its metabolites less than 0.2%, drug is excreted unchanged). • Non-inflammability and chemical stability. enflurane Isoflurane

  34. 4) Nitrous oxide (N2O), laughing gas • least toxic and safest but also the least potent • good analgesia. • It is drug of choice in dental surgery due to its rapid recovery and metabolism % is zero. • The terminology laughing gas is due to some patients get an attacks of hysteria. Synthesis :

  35. II. Intravenous anesthetics They are classified into: (A) Ultra-short acting barbiturate group This group will be discussed under sedative-hypnotic drugs. (B) Benzylamine group, e.g., ketamine HCl. (C) Benzodiazepine group This group will be discussed under anxiolytics drugs. • Ultra-short acting barbiturate group The sodium salts of ultra-short acting barbiturates (Methohexital, Thiamylal, Thiopental) are administered. Volatile anesthetics, such as enflurane is employed for maintenance of anesthesia to avoid the respiratory depression associated with barbiturates.

  36. Advantages: • quick with short duration. • smooth induction • Absence of salivary secretion. • Fair muscle relaxation and non explosive. Drawbacks: • Rapid administration causes fall in BP. • Tissue irritation. • Marked respiratory depression. (B)Benzylamine group Ketamine HCl, USP (Ketalar) ()2-(2-Chlorophenyl)-2-( methylamino) cyclohexanone.HCl

  37. Ketamine HCl (pka 7.5) is structurally related to the hallucinating agent phencyclidine. • It has a different mode of action from the other agents. It blocks glutamic acid N-methyl-D-aspartate (NMDA) receptors as phencyclidine. • It causes dissociative anesthesia, since the patient may appears to be awaken, but is dissociated from the events and does not respond to pain. Dissociative anesthesia is characterized by dreams or hallucinations which are common in adults than in children. Uses: • Used alone for minor surgical procedures in children.

  38. Advantages: • Rapid acting. • Anesthesia accompanied by deep analgesia. Synthesis:

  39. (C) Benzodiazepines. Benzodiazepines alone cannot produce surgical anesthesia but diazepam and midazolam are used i.v. to induce anesthesia. Diazepam: • It has a high lipid/water partition coefficient and so, it is long acting. So, it is not used for induction of short-term anesthesia. Midazolam: • It has lower lipid/water partition coefficient and so, it is used for induction of short-term anesthesia.

  40. Thank you

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