Sedative Med Chem Lecture

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Lecture Notes for Med Chem/ CNS drugs/ B pharmacy of Purbanchal University, Nepal

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  • Nystagmus /nɪˈstæɡməs/ is a condition of involuntary eye movement, Ataxia is neurological sign consisting of lack of voluntary coordination of muscle movements
  • Only lorazepam and midazolam show this effect
  • The main symptoms of delirium tremens are nightmares, agitation, global confusion, disorientation, visual and auditory hallucinations, fever, hypertension, diaphoresis, and other signs of autonomic hyperactivity (tachycardia and hypertension)
  • Sedative Med Chem Lecture

    1. 1. Defination • A sedative drug decreases activity and excitement of the patient and clams anxiety by producing mild depression of CNS without causing drowsiness or sleep • A hypnotic drug produces drowsiness, forcing the patient to sleep by depressing the CNS, particularly the reticular activity which influences wakefulness
    2. 2. Dose dependent activity • All sedative, hypnotic and GA depress the CNS • The observed effect depends on the dose given to patient • Small dose cause sedation (calmness) • Medium dose cause hypnosis (sleepy) • Largerdose causes surgical anesthesia
    3. 3. Utility Sedatives counter various types of anxiety such as • Obsessive-compulsive disorder (OCD) • Post-traumatic stress disorder (PTSD) • Social anxiety disorder • Specific phobias Hypnotics is for insomnia. Insomnia is a condition where person is not able to fall sleep
    4. 4. Ideal properties of hypnotics 1. Cause a temporary decrease in the level of consciousness for the purpose of falling asleep without any alteration to sleep cycle 2. Must not decrease or arrest respiration, even at high doses 3. Cause no addiction, tolerance or dependence
    5. 5. • sleep cycle : Sleep proceeds in cycles of light sleep and deep sleep • Light sleep – NREM sleep, lasts for about 90 mins • Easy to wake in this period • Deep sleep – REM sleep, last 5 to 10 mins • Difficult to wake in this time
    6. 6. Drug classification 1. Barbiturates :Phenobarbitone* 2. Benzodiazepines: Alprazolam, Diazepam, Nitrazepam, Lorazepa m 3. Non-Benzodiazepines: zolpidem, Zalephon 4. Others: paraldehyde, Glutethimide, Chloral Hydrate 5. Herbal sedatives: Ashwagandha, Valerian and passiflora
    7. 7. Barbiturates • All derivatives of Barbituric acid • They are CNS depressants. They are effective as anxiolytics, hypnotics, anticonvulsants and analgesics. • They have addiction potential, both physical and psychological. • Thus Benzodiazipines have largely replaced them in term of sedative-hypnotic
    8. 8. Types Barbituric Acid Amobarbital Pentobarbital Short actingIntermediate acting Long-Acting Thiopental sodium Ultra shortacting Phenobarbital
    9. 9. Factors effecting Duration of action as by the SAR Phenobarbital Thiopental Sodium Branched R group Short ethyl chain Total carbon = 2 (not counting aromatic) Long chain of R group Total C = 7 Additional improvements to Thiopental Sodium tofurther decrease duration of action •N methylation (potency also inc) •Unsaturated R group
    10. 10. • Mode of action of barbiturates 1. They have positive allosteric effect at GABA receptor. They bind at a different site than GABA or Benzodiazepines and stimulate the pharmacologic action of GABA which is the principal inhibitory neurotransmitter in the CNS 2. They inhibit AMPA receptor, which binds glutamate which is principal excitatory neurotransmitter in the CNS 3. At higher does they inhibit Ca2+ dependent release of neurotransmitters
    11. 11. • Allosteric drugs bind the receptor at different site. They can both stimulate or inhibit the receptor function. • Agonist can only stimulate the receptor function • Antagonist can only inhibit the receptor function
    12. 12. Structure-Activity Relationship• Barbituric acid itself does not possess any hypnotic properties. •Activity requires a balance of acidic and lipophilic properties. To make the drug sufficiently acidic, both or at least one of the two nitrogen must be unsubstituted To make drug sufficiently lipophilic, the two hydrogen atoms at position 5 : 5 must have the appropriate substituent (e.g., alkyl or aryl groups) The type of substituent's control 2 aspects of the drug Potency Duration of Action.
    13. 13. N NH O O O HN NH O O O HN NH O O O HN NH O O O Inactive inactive coz not lipophilic enough R R R R R R N N O O O RR R R Inactive coz not acidic enough activeactiveinactive coz not lipophilic enough Barbituric acid
    14. 14.  the total number of carbon atoms present in the two groups at carbon 5 must not be less than 4 and more than 10 and influences onset of action and duration Total carbon Duration of action 7-9 Rapid onset n shorter duration 5-7 Intermediate duration of action 4 Slowest onset and longest duration of action
    15. 15. Only one of the substituent groups at position 5 may be a cyclic group. C N C C CHN C2H5 O O O CH3 Methylepentobarbital
    16. 16. The branched chain isomer exhibits greater activity but shorter duration. The greater the branching, the more potent is the drug (e.g., pentobarbital > amobarbital). This Branched, cyclic or unsaturated alkyl groups reduce duration of action due to increased ease of metabolic inactivation Pentobarbital Amobarbital
    17. 17. (iv) Double bonds in the alkyl substituent groups produce compounds more readily vulnerable to tissue oxidation ; hence, they are short-acting. Pentobarbital Sodium
    18. 18.  Aromatic and alicyclic moieties exert greater potency than the corresponding aliphatic moiety having the same number of carbon atoms. C HN C C CHN C2H5 O O O C N H C C C HN C2H5 O O O 1 2 3 4 5 6 1 2 3 4 5 6 more potent than
    19. 19. Short chains at carbon 5 resist oxidation and hence are long-acting. Long chains are readily oxidized and thus produce short-acting barbiturates. Pentobarbital SodiumBarbital
    20. 20. Inclusion of a halogen atom in the 5-alkyl moiety enhances activity. Inclusion of polar groups (e.g., OH, CO, COOH, NH2, RNH, and SO3H) in the 5-alkyl moiety reduces potency considerably. Methylation of one of the imide hydrogens enhances onset and reduces duration of action Methylepentobarbital
    21. 21. The replacement of O-atom with an S-atom, at C- 2 position of the barbiturates significantly enhances the lipid solubility. The resulting modified versions of the barbiturates thus obtained exert a rapid onset of activity by virtue of the fact that they attain maximal thiobarbiturate-brain levels. Therefore, such drugs as ‘thiopental sodium’ find their profuse and abundant application as ‘intravenous anaesthetics’. Thiopental sodium HC HN C C CHN SNa O O C2H5 CH (CH2)2CH3 CH3
    22. 22. Inclusion of more sulphur atoms (at C-2 and C-6) decreases activity. Likewise replacement of Oxygen with Nitrogen abolishes activity N N NH O O RR R R Inactive
    23. 23. Phenobarbital • Phenobarbital or phenobarbitone is a barbiturate which is most widely used anticonvulsant worldwide and the oldest still commonly used. Phenobarbital C C N H C NH C O O O C2H5
    24. 24. • It also has sedative and hypnotic properties but, as with other barbiturates, has been outdated by the benzodiazepines for these indications. • first-line for partial and generalized tonic- clonic seizures • first line choice for the treatment of neonatal seizures
    25. 25. • Sedation and hypnosis are the principal side effects of phenobarbital. Also dizziness, nystagmus and ataxia are common. • In elderly patients, it may cause excitement and confusion while in children, it may result in paradoxical hyperactivity. • Overdose may also lead to pulmonary edema and acute renal failure
    26. 26. • It is one of the longest-acting barbiturates available – it remains in the body for a very long time (half-life of 2 to 7 days) and has very low protein binding • Phenobarbital is metabolized by the liver, mainly through hydroxylation and glucuronidation • It is excreted primarily by the kidneys
    27. 27. Synthesis of Phenobarbi tone Benzyl cyanide i)Acid hydrolysid ii) EtOH C C O CH2 CH2 C O OC2H5 Ethyl phenyl acetate EtOH and Na (-OC2H5) Diethyl oxalate CH C OC2H5 O C C OC2H5 O O Distilled at 180O C (-CO) H C C OC2H5 O C OC2H5 O CN Phenyl malonic ester Diethyl phenyl-oxyalo- acetate C2H5-Br(ethyl bromide) C2H5-ONa (sodium ethoxide) C C OC2H5 O C OC2H5 OC2H5 H2N C O NH2 urea -2 EtOH Ethylphenyl malonic ester Phenobarbital OC2H5 O C2H5O C C N H C NH C O O O C2H5 -HBr
    28. 28. Thiopental sodium •Ultra short acting barbiturate (5-10 mins) •Rapid action (10 -15 sec) and rapid recovery •Used mainly as inducing anesthetic • has no analgesic properties • anesthetic state maintained by inhalation anesthetic eg N20 •it is a poor muscle relaxant HC HN C C CHN NaS O O C2H5 CH (CH2)2CH3 CH3
    29. 29. • it possesses potent anticonvulsant activity it may be given to treat epileptic seizures that do not respond to other therapy. • It is stored as a solid white salt and needs to be prepared in sterile water to inject the patient • Rapid recovery not due to rapid metabolism • It is due to lowered concentration caused by redistribution of drug from brain to blood. This is made possible becoz of the salt form of drug
    30. 30. • Dose: 3 to 7 mg/kg. • It does not have any direct toxic effects on the liver or kidney • Although it crosses the placenta it is a safe agent for induction in pregnancy
    31. 31. Synthesis of Thiopental sodium i) Preparation of Diethyl ester of ethyl-(1-methyl butyl) malonic acid C2H5 O C C O O OC2H5 Na C2H5 O C C O O OC2H5 C2H5-Br Ethyl Bromide - NaBr C2H5 O C C O O OC2H5 C2H5 C-CH2-CH2-CH3 2-Bromopentane - HBr CH3 C2H5 O C C O O OC2H5 C2H5 H Sodium Metal Diethyl malonate Diethyl ester of ethyl malonic acid C-CH2-CH2-CH3 CH3 Br Diethyl ester of ethyl- (1-methyl butyl) malonic acid H H Na H -H
    32. 32. ii) Preparation of Thiopental sodium C2H5 O C C C O O OC2H5 C2H5 C-CH2-CH2-CH3 CH3Diethyl ester of ethyl- (1-methyl butyl) malonic acid C NH2 NH2 S HN C HN C C C S O O C2H5 - 2 EtOH NaOH N C HN C C C HS O O C2H5 C-CH2-CH2-CH3 CH3 C-CH2-CH2-CH3 CH3 Thiourea Keto formEnol form HN CH HN C C C NaS O O C2H5 C-CH2-CH2-CH3 CH3 Thiopental sodium
    33. 33. Thiamylal • Ultra short acting barbiturate • Rapid action but not rapid recovery due to high lipophilicity and subsequent drug accumulation in the fatty tissues • Used mainly as inducing anesthetic in lab animals • anesthetic state maintained by inhalation anesthetic eg N20 • Use limited to Veterinary field. Only its sodium salt is used in humans
    34. 34. Benzodiazepines • Chemically they are a fusion of a benzene ring and a diazepine ring • Benzodiazepines enhance the effect of the GABA at the GABAA receptor, resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety) anticonvulsant, and muscle relaxant properties •useful in treating anxiety, insomnia, seizures, muscle spasms, alcohol withdrawal and preanesthetic • are safer than barbiturate and not additive
    35. 35. MOA of benzodiazepines 1. They have positive allosteric effect at GABA receptor. They bind at a different site than GABA or Benzodiazepines and stimulate the pharmacologic action of GABA which is the principal inhibitory neurotransmitter in the CNS 2. They block reuptake of Adenosine which is sedating neurotransmitter, thus promoting its sedative action. Attach to and directly block the Acetylcholine (ACh) receptors in the hippocampus thus causing amnesia. (Hippocampus is where memory is stored and processed. This is how date rape drug Flunitrazepam works)
    36. 36. SAR of benzodiazepinez
    37. 37. R2= carbonyl group ( C=O)
    38. 38. Mostly Cl or NO2 is used at position 7
    39. 39. But para substitution (position 4’) decreases activity
    40. 40. (Note--> inclusion of OH,NH3,SO4,PO4, COOH groups increase polarity)
    41. 41. Types of benzodiazepines Half life example Long acting > 24 hrs Diazepam,Nitrazepam chlordiazepoxide, flurazepam Intermediate acting 12-24 hrs alprazolam, lorazepam clonazepam, flunitrazepam, Short acting < 1-12 hrs midazolam and triazolam. Based on drug elimination (metabolism + kidney filtration), 3 category of benzodiazepines exist longer-acting benzodiazepines are recommended for the treatment of anxiety Short- and intermediate-acting are preferred for the treatment of insomnia;
    42. 42. Midazolam • Midazolam has a rapid onset of action, high effectiveness and low toxicity level and fast recovery time • Properties: It has potent anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties • Uses: Used for treatment of acute seizures, moderate to severe insomnia and for inducing sedation and amnesia before medical procedures • used mostly as a premedication for sedation and less commonly for induction or maintenance of anesthesia. • MOA- alloteric GABAA enhancer
    43. 43. Diazepam • Long acting benzodiazepine (>20 hrs) • due to high blood protein binding of 98.5% which reduces rate of elimination and it’s metabolic product is also active • Properties: It has anxiolytic, anticonvulsant, hypnotic - sedative, skeletal muscle relaxant, and amnestic properties • Uses :anxiety, panic attacks, insomnia, seizures , muscle spasms (such as in tetanus cases), restless legs syndrome, alcohol withdrawal, opiate withdrawal syndrome • Not used for long term epilepsy due to development of tolerance • Avoid during pregnancy • MOA – Allosteric GABAA enhancer
    44. 44. Lorazepam • high-potency, intermediate acting duration benzodiazepine drug Properties: anxiolysis, short term amnesia, sedation/hypnosis, anticonvulsion, muscle relaxation Uses: • short-term treatment of anxiety, insomnia, acute seizures, sedation of aggressive patients • to decrease the likelihood of agitation and seizures in patients who have overdosed on stimulant drugs • lorazepam has advantage over diazepam, as in – Better at ending seizures and – more prolonged anticonvulsant effect
    45. 45. Lorazepam • lorazepam is removed from the blood more rapidly than many other benzodiazepines, there is less chance that lorazepam concentrations in blood will reach high levels and become toxic • MOA- alloteric GABAA enhancer
    46. 46. Alprazolam • It belongs to intermediate acting benzodiazepine • Properties: It has potent anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant, and sedative properties • Main uses: Alprazolam is used for the treatment of anxiety disorders and panic attacks • can cause fetal abnormalities and should not be used in pregnancy • It is excreted in breast milk and should not be used by women who are nursing • MOA- alloteric GABAA enhancer
    47. 47. Nitrazepam • A long acting benzodiazepine • Properties: It has anxiolytic, anticonvulsant, hypnotic - sedative, skeletal muscle relaxant, and amnestic properties • Uses: Nitrazepam is used to treat short-term sleeping problems (insomnia) and short term management of epilepsies • Nitrazepam is not suitable for use in the elderly, children, pregnant women, or those with chronic obstructive pulmonary disease • MOA- alloteric GABAA enhancer
    48. 48. Barbiturates vs Benzodiazepines Barbiturates Benzodiazepines They cause high physiological and psychological dependence They cause very less physiological and psychological dependence Long term use avoided due to toxicity Long term use is relatively safe Sleep induced by it causes hangover effect after waking up Sleep induced by it is just like natural sleep and is refreshing to wake up Increase duration of GABA Cl channel opening Increase frequency of GABA Cl channel opening High Respiratory depression Manageable Respiratory depression
    49. 49. Different alpha units of GABAA have different effects GABA A receptors containing alpha 1 subunits are involved in sleep. GABA A receptors containing alpha 2 or alpha 3 subunits are involved in anxiety.
    50. 50. GABAA Alpha 1 Selective Hypnotics – MOA of Zaleplon and Zolpidem • The GABAA receptor contain 6 different alpha subunits • Benzodiazepines bind to four of GABAA alpha subunits: alpha 1, alpha 2, alpha 3 and alpha 5. • Each of these subunits is associated with different effects, and thus benzodiazepines not only cause sedation but are also anxiolytic, cause muscle relaxation, and have alcohol potentiating actions. • The hypnotics zaleplon and zolpidem bind selectively to GABA-A receptors that contain the alpha 1 subunit (sleep).
    51. 51. Advantages over benzodiazepines • A relatively short half life so one does not wake up with a "hangover" the following day • Having little effect on sleep staging, allowing the individual to obtain approximately the same amount of time in each stage of sleep as one would without the medications • Less likely to cause addiction, withdrawal, or tolerance relative to older sleeping medications.
    52. 52. • These drugs are very lipophillic which increases absorption into brain • They are metabolized by liver into water soluble metabolites which is rapidly cleared out in urine and thus avoid accumulation Zolpidem Zalephon
    53. 53. • Zalephon : hypnotic dose 6-10 mg Used as hypnotic drug Good at inducing sleep but not good at maintaining it since it has short elimination half life • Zolpidem : hypnotic dose 5-10 mg Used as hypnotic drug Slower acting but maintains effect overnight period due to long elimination half life
    54. 54. Paraldehyde • Paraldehyde is the cyclic trimer of acetaldehyde molecules. It is a colorless liquid and sparingly soluble in water and highly soluble in alcohol. • Properties: It has an effective anticonvulsant, hypnotic and sedative • MOA: Paraldehyde increases the effects of GABA, a inhibitory neurotransmitter that depresses CNS, at the GABAa receptor and decreases levels of glutamate, which is stimulatory neurotransmitter that excites CNS
    55. 55. Uses: •to induce sleep, and is also used to calm psychiatric patients •it is used to prevent hallucinations and tremors caused due to alcohol withdrawal •used to control seizures in infantsm not responding to phenobarbitone and phenytoin, • Unlike diazepam and other benzodiazepines, it does not suppress breathing at therapeutic doses and so is safer when the patient's breathing is already compromised. •It is very addictive and Paraldehyde also can stress the gastrointestinal tract so that a patient can develop ulcers •Synthesis • H3C CH3 O O O O CH3H3C CH3 H2SO4 ACETALDEHYDE PARALDEHYDE
    56. 56. Glutethimide • Properties: sedative, hypnotic • Use: was used for insomnia but rarely prescribed today just as likely to cause addiction and caused severe withdrawal symptoms as barbiturates. • When taken with codeine, it stimulates metabolic conversion of codeine into morphine, which is used for its hallucinogenic effect • MOA: It binds at the GABAa receptor which increases the effects of GABA which is a inhibitory neurotransmitter that depresses CNS
    57. 57. Chloral Hydrate • Synthesis 4 Cl2 + C2H5OH + H2O → Cl3CCH(OH)2 + 5 HCl Chloral hydrate is metabolized to trichloroethanol, which is responsible for its physiological and psychological effects. Higher doses can depress respiration and blood pressure. Properties: seadtive, hypnotic Use: It has a very narrow therapeutic window making this drug difficult to use. Instead benzodiazepines are preferred. • short time (no more than 2 weeks) treatment of insomnia • Used in organic synthesis as a reagent MOA: It binds at the GABAa receptor which increases the effects of GABA which is a inhibitory neurotransmitter that depresses CNS Cl C Cl Cl CH OH OH metabolized Cl C Cl Cl CH2 OH Trichloroethanol (Active compound) Chloral Hydrate
    58. 58. Herbal sedatives • Ashwagandha • Valerian • Passiflora
    59. 59. Ashwagandha • Withania somnifera, also known as Ashwagandha, is a plant in Solanaceae or nightshade family. Uses: • Ashwagandha is effective for insomnia but does not act as a good sedative
    60. 60. Main compounds • Steroids :withaferin A • Alkaloids :anaferine • MOA • increases the effects of GABA which is a inhibitory neurotransmitter that depresses CNS by binding at the GABAa receptor N H NH O anaferine withaferin A
    61. 61. Valerian Valerian (Valeriana officinalis), a member of the Valerianaceae family. chemical compounds responsible for sedative effect is Valerenic acid MOA:Enhances GABA effect on GABAa receptor Uses: Alternate medicine for Insomnia,anxiety OHO H
    62. 62. Passiflora incarnata • Use: Its herbal medicine is used to treat anxiety and insomnia. • Active component in the extract is GABA itself • the anxiolytic effects were comparable to a 2 mg/kg of diazepam • MOA • Binds and GABAa receptor and depresses CNS
    63. 63. THANK YOU
    64. 64. Selectivity for GAB-A Receptor Subunits GABA A receptors containing alpha 1 subunits are involved in sleep. GABA A receptors containing alpha 2 or alpha 3 subunits are involved in anxiety.
    65. 65. Alpha 1 Selective Hypnotics - Zaleplon and Zolpidem • The hypnotics zaleplon and zolpidem bind selectively to GABA-A receptors that contain the alpha 1 subunit (sleep). This subunit is important for sedation and possibly for anticonvulsant and amnesic actions.
    66. 66. Existing Benzodiazepines are Non-selective • Benzodiazepines bind to GABA-A alpha subunits: alpha 1, alpha 2, alpha 3 and alpha 5. • Each of these subunits is associated with different effects, and thus benzodiazepines not only cause sedation but are also anxiolytic, cause muscle relaxation, and have alcohol potentiating actions.
    67. 67. The future of sedative-hypnotics Selectivity for Phasic GABA Inhibition - Avoiding Addiction Benzodiazepine sensitive GABA A receptors contain gamma and alpha (1 through 3) and alpha 5 subunits are intra-synaptic and mediate phasic inhibition triggered by peak concentrations of synaptically released GABA. GABA A receptors containing alpha 4, alpha 6 , gamma 1 or delta subunits are located extrasynaptically and regulate tonic inhibition (tonic inhibition is not addictive).
    68. 68. Location of RAS in brain (no. 7) RAS is brain centre for arousal and sleep cycle

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