SEDATIVES AND HYPNOTICS

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SEDATIVES AND HYPNOTICS:

SEDATIVES AND HYPNOTICS JISHA SHAMSUDEEN MPHARM PART 1

SEDATIVE:

SEDATIVE A drug that decrease the activity and excitement of the patient and calms the anxiety by producing mild depression of the CNS without causing drowsiness and sleep

HYPNOTICS:

HYPNOTICS A Hypnotic drug produces drowsiness compelling the patient to sleep by depressing the CNS particularly the reticular activity which characterises wakefulness.

SEDATIVES AND HYPNOTICS:

SEDATIVES AND HYPNOTICS Drugs with quicker onset of action ,steeper dose response curves are hypnotics Drugs acting slower with flatter dose response curves are sedatives .

Classification:

Classification Barbiturates Benzodiazepines Antihistamines Halogenated Compounds Heterocyclic compounds Acyclic hypnotics containing Nitrogen Other sedatives-hypnotics

Barbiturates:

Barbiturates Substituted derivatives of barbituric acid Barbituric acid as such is not a hypnotic, alkyl and aryl substituents on C5 makes it a hypnotic.

Barbiturates:

Barbiturates On the basis of acidity, barbiturates are of two classes Hypnotics Inactive compound Hypnotic class : 5,5, disubstituted barbituric acid, 5,5 disubstituted thio barbituric acid 1,5,5 trisubstituted barbituric acid

Acidity of barbiturates:

Acidity of barbiturates Acidity is attributed to the lactam-lactim and keto-enol tautomerism. In un substituted barbituric acid , all the four hydrogen may be involved in tautomerism

Lipophilicity:

Lipophilicity Barbiturates should satisfy the criteria of lipid/water partition coefficient for its hypnotic property

Mechanism of action:

Mechanism of action They primarily act on GABA benzodiazepine receptor chloride channel complex Potentiate inhibitory action by increasing the life time of chloride channel opening induced by GABA.

Structure Activity Relationship:

Structure Activity Relationship Total number of carbon atom of both substituents at C5 should be between 6 and 10 Branching of substituents at C5 increases the activity and has shorter duration of action

C5 substitution:

C5 substitution Introduction of polar groups like -OH-,COOH- into the aromatic group at C5 decreases lipid solubility and potency Introduction halogen in the same series increases activity

Substitution on nitrogen:

Substitution on nitrogen Substitution of one imide hydrogen by alkyl groups increase lipid solubility As the size of alkyl group increases, lipid solubility increases Substitution at N1 and N3 makes them non acidic and inactive.

Modification on oxygen:

Modification on oxygen Replacement of C2 by sulphur increases lipid solubility

Classification of barbiturates :

Classification of barbiturates Long duration of action (<6hours)-Mephobarbital, Phenobarbital Intermediate duration of action (3-6hours)-Amobarbital, Butabarbital. Short duration of action(>3hours)-Pentobarbital, Secobarbital.

Synthesis of phenobarbital:

Synthesis of phenobarbital

Benzodiazepines:

Benzodiazepines They are psychoactive drugs formed by the fusion of benzene ring with diazepine ring.

Structure Activity Relationship:

Structure Activity Relationship An electronegative atom at position 7 is required for activity Position 6,8,9 should not be substituted Substitution at N1by alkyl, haloalkyl,alkynyl, amino alkyl increases activity

Structure Activity Relationship:

Structure Activity Relationship The 2 carbonyl function is optimal for activity Alkyl substitution at position 3 decreases activity Saturation of 4,5 double bond or shift of the double bond to 3,4 position decreases activity.

Structure Activity Relationship:

Structure Activity Relationship Polar groups at position 3 is essential pharmaco kinetically because such compounds have short life because of rapid conjugation with glucuronic acid. A phenyl ring at position 5 increases activity.

Structure Activity Relationship:

Structure Activity Relationship The ortho or diortho substituent by electron attracting group increases activity Any substitution at 4* position decreases the activity

Mechanism of action:

Mechanism of action BZD receptors are found in the brain and they form a part of GABA receptor’s chloride ion channel macromolecu;ar complex.

Mechanism of action:

Mechanism of action Binding of benzodiazepines to this receptor produce activation of GABA A receptor and increases chloride ion conductance by increasing the frequency of opening ion channel This in turn inhibit neuronal activity by hyper polarisation and depolarisation block.

Synthesis of Diazepam:

Synthesis of Diazepam

Synthesis of Diazepam:

Synthesis of Diazepam

Heterocyclic compounds:

Heterocyclic compounds Encouraged by the success of barbiturates, compound containing heterocyclic rings containing lactam functional group were prepared and tested for hypnotic activity Methpyrolon, Glutethimide (Piperidinediones) Methaquolone, Ethinazone (Quinazolines)

Heterocyclic compounds :

Heterocyclic compounds Their mechanism of action is similar to that of benzodiazepines and they supress REM sleep at hypnotic doses. They cause minimal respiratory depression compared to barbiturates They cause problems of habituation, tolerance, physical dependence and addiction

Glutethimide:

Glutethimide 3 ethyl -3 phenyl piperidine2,6-dione Structurally similar to phenobarbital 500 mg is the safer dose conserned.

Methpyrolone:

Methpyrolone It significantly reduces REM sleep 300 mg is compared to be the hypnotic dose It is extensively metabolised to oxidised metabolites and further conjugated with glucuronic acid.

Synthesis of Methpyrolon:

Synthesis of Methpyrolon

Acyclic Hypnotics containing Nitrogen:

Acyclic Hypnotics containing Nitrogen Amides The agents of this class are used as good tranquilisers and muscle relaxants having good sedative properties Eg: Oxanamide, valnoctamide, Diethylallyl acetamide

Acyclic Hypnotics containing Nitrogen:

Acyclic Hypnotics containing Nitrogen Barbiturates are formed by condensation of malonic acid with urea, here monocarboxylic acids are used to acylate urea to yield ureides Usual dose -250-500 mg two or three times a day for sedation This class of drugs are rarely used due to low therapeutic index Carbromal

Halogenated compounds:

Halogenated compounds Chloral hydrate Ethchlorvynol

Chloral hydrate:

Chloral hydrate It significantly suppress REM sleep and can exert barbiturate like effects on GABA A receptors Used in hypnotic doses of 500 mg It has no analgesic or tranquilising effect and is devoid of adverse respiratory effects at therapeutic doses.

Synthesis of chloral hydrate.:

Synthesis of chloral hydrate.

Antihistamines:

Antihistamines They display the properties of sedative-hypnotics. Belong to the class of class H1 receptor antagonists They competitively antagonise at histamine receptor sites and histamines are responsible for vasodilation, increased capillary permeability, itch reaction in skin. Antihistamines can cross BBB and are responsible for sedative properties. Eg: Diphenhydramine, Hydroxyzine

Recent advances:

Recent advances The medications currently approved for the treatment of insomnia include 9 benzodiazepine receptor agonist (BZRA) hypnotics and the selective melatonin receptor agonist ramelteon. The BZRA hypnotics include the newer nonbenzodiazepine agents as well as benzodiazepines; the nonbenzodiazepine hypnotics tend to have shorter half-lives and are better at targeting sedation exclusively during the nighttime .

Recent advances:

Recent advances The development of modified-release formulations of BZRA hypnotics, such as zolpidem extended-release, has been a key innovation. These formulations allow both rapid and sustained release of the medication and may reduce the risk of next-day effects. Ramelteon has been shown to improve sleep during the early portion of the sleep period. Investigational agents include alternate-delivery formulations of BZRA compounds, which may help treat nighttime awakenings. (Drug Benefit Trends. 2009;21:266-271)

Thankyou:

Thankyou