Sedative-Hypnotics, Anxiolytic Drugs. A sedative is an agent that lowers excitement and

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1 Sedative-Hypnotics, Anxiolytic Drugs A sedative is an agent that lowers excitement and activity. A hypnotic is an inducer of sleep. The major use of sedative-hypnotic drugs is the treatment of sleep disorders known as insomnias, restless leg syndrome, jet lag, sleepwalking... Sleeping pills which cause drowsiness, facilitates the initiation and maintenance of sleep. Anxiety is a feeling of apprehension, uncertainty and fear without apparent stimulus. It is associated with physical changes such as 1 tachycardia, sweating, tremor An ideal hypnotic should cause: 1. temporary decrease in consciousness levels without remaining effects. 2. similar to natural sleep. 3. even at high doses, it must not affect respiration. 4. non-addictive. Hypnotic drugs with clinical use include: 1. Benzodiazepines. 2. Barbiturates. 3. miscellaneous groups. 2 1

2 Classification of hypnotics I- GABA A receptor agonists A- Benzodiazepines B- Imidazopyridine and cyclopyrrolone C- Pyrazolopyrimidine D- Barbiturates II- Chloral III- Melatonin receptor agonists IV-Antihistamines V- Antidepressants VI- Herbal preparations 3 GABA A Major composed of α, β, γ in ratio of 1:2:1 α 1 β 2 γ 2 composed 60% of GABAA receptors α 2 β 3 γ 2 composed 15-20% of GABAA receptors α 1 subunit binding drugs is related to sedation and seizure protection α 2 subunit binding drugs is related to anxiolytic and myorelaxant activity Benzodiazepines that bind to α 2 are nonsedating 4 2

3 GABA A Receptor Neurotansmitter-gated ion channel that when activated, allow the entry of chloride ion into cell, thereby hyperpolarizing the neuron and making cell firing less likely to occur (Upon activation, Cl- influx is increased and the membrane becomes hyperpolarized, resulting in neuronal inhibition.) Benzodiazepines bind to secondary binding site other than GABA receptor in the presence of GABA lead to activation of the receptor

4 Benzodiazepines Used as anxiolytic, sleep inducer, anesthetics, anticonvulsants and muscle relaxants Act on the GABAA receptors Formulation (capsule or tablet) is important for activity-kinetic and dynamic importance Flurazepam is absorbed most rapidly Benzodiazepines which are slowly eliminated or metabolized to slowly eliminated active metabolites can be used as hypnotics They have the, Hangover effect (the effect of hypnotic during daytime) Does not interact with other drugs (no induction or inhibition of CYP450) 7 Behavior of benzodiazepine as Hypnotic depends on: 1- Is acute tolerance is developed 2- Redistribution rate from brain to other tissues is rapid 3- Rate of drug biotransformation and the activity of the metabolite 8 4

5 Structure activity relationships Small modifications in the chemical structure of a ligand can shift the intrinsic activity from agonist to antagonist to inverse agonist. Ring A The minimum requirements for binding of 5-phenyl-1,4- benzodiazepin-2- one derivatives to the BZR includes an aromatic or heteroaromatic ring (ring A), which is believed to participate in π-π stacking with aromatic amino acid residues of the receptor. 10 5

6 11 Ring A An electronegative group (e.g., halogen or nitro) substituted at the 7- position mark increases functional anxiolytic activity, albeit effects on binding affinity in vitro are not as dramatic. Substituents at positions 6, 8, or 9 generally decrease anxiolytic activity. Other 1,4-diazepine derivatives in which ring A is replaced by a heterocycle generally show weak binding affinity in vitro and even less pharmacological activity in vivo when compared to phenyl-substituted analogues 12 6

7 Ring B A proton-accepting group is a structural requirement of benzodiazepine ligand binding to the GABA A receptor which h interacts t with a histidine residue that t serves as a proton source in the GABA A α 1 subunit For the benzodiazepines, optimal affinity occurs when the proton-accepting group in the 2-position of ring B (i.e., the carbonyl moiety) is in a coplanar spatial orientation with the aromatic ring A. Substitution of sulfur for oxygen at the 2-position (as in quazepam) may affect selectivity for binding to GABA BZR subpopulations, but anxiolytic activity is maintained. Substitution of the methylene 3-position or the imine has no effect on agonist (i.e., anxiolytic) activity (e.g., clobazam) 13 Derivatives substituted with a 3-hydroxy moiety have comparable potency to non-hydroxylated analogues and are excreted faster. Esterification of a 3-hydroxy moiety also is possible without loss of potency. Neither the 1-position amide nitrogen nor its substituent is required for in vitro binding to the BZR, and many clinically used analogues are not N-alkylated. Although relatively long N-alkyl side chains do not dramatically decrease BZR affinity, sterically bulky substituents (as tert-butyl) drastically reduce receptor affinity and in vivo activity. Annulating the 1,2-bond of ring B with an additional electron-rich (i.e., proton acceptor) ring, such as triazole or imidazole, results in pharmacologically active 14 benzodiazepine derivatives with high affinity for the BZR. 7

8 SAR of Benzodiazepines 15 Ring B Neither the 4,5-double bond, nor the 4-position nitrogen (the 4,5- [methyleneimino] group) in ring B is required for in vivo anxiolytic activity, albeit in vitro BZR affinity is decreased if the C=N bond is reduced to C N. It is proposed that in vivo activity of such derivatives results from oxidation back to C=N The 4-oxide moiety of chiordiazepoxde can be removed without loss of anxiolytic activity. 16 8

9 Ring C The 5-phenyl ring C is not required for binding to the BZR in vitro. This accessory aromatic ring may contribute favorable hydrophobic or steric interactions to receptor binding and its relationship to ring A planarity may be important. Substitution at the 4 -(para)-position position of the 5-phenyl ring is unfavorable for agonist activity, but 2 -(ortho)- substituents are not detrimental to agonist activity, suggesting that limitations at the para position are steric, rather than electronic Feb

10 19 Drugs Used in the Treatment of Anxiety Benzodiazepines The major factors considered when selecting an agent include: - rate and extent of absorption, - presence or absence of active metabolites, and - degree of lipophilicity. These factors help to determine how a benzodiazepine is marketed and used; for example: an agent that is rapidly absorbed, highly lipid soluble, and without active metabolites would be useful as a hypnotic but less useful for treatment of chronic anxiety state

11 MOA Benzodiazepines bind at the GABA A chloride channel. receptors, The α 2 are required for anxiolytic effect and γ 2 subunit, binding is also required for positive allosteric effect. Hypnotics: Temazepam, Flurazepam (insomnia), Trizolam, Quazepam, Midazolam (sedative-hypnotic, also anxiolytic nature and anesthetic). Anxiolytics: Diazepam (Valium), Halazepam, Alprazolam (potent anxiolytic)

12 23 Metabolism 24 12

13 Metabolism Related compounds Non-benzodiazepine GABA A Agonists (hypnotics). Zolpidem (Ambien) is an imidazopyridine Binds to α 1 greater than α 2. physical dependence. onset of action 1.6 hrs. half-life 2.3hrs. No rebound effects. Zaleplon (Sonata) a pyrazolopyrimidine Bind with GABA A α 1 omega-1 (ω-1) receptors. Very similar to Zolipdam

14 Nonbenzodiazepine GABA A agonist Zolpidem, Zopiclone and Zaleplarie (the Z drugs) Short acting sedative hypnotics. Very lipophilic facilitate rapid absorption. No active metabolites in plasma and brain. Less than benzodiazepines in causing abuse and physical dependence. Depend on the liver for their metabolism before being regally excreted. Zolpidem and Zopiclone are better for maintaining complete nights sleep (has longer elimination half-life). Barbiturates Used as sedatives, hypnotics, anticonvulsants, or anesthetics. ti Less used compared to benzodiazepines due the higher toxicity, induction of liver drug. metabolizing enzymes, dependence and tolerance. The barbiturates that are slowly eliminated so it is capable of producing hangover effect. Should not be withdrawn suddenly but tapered slowly

15 Barbiturates Generally replaced by safer benzodiazepines, due to greater CNS depression and induction of liver drug metabolizing enzymes. Named by ygroup-barbital. 5,5-substituted barbituric acids are synthesized as follows: O H H O O O Diethylmalonate R 5 -X NaOEt O H O R' 5R5 R 5 R' 5 -X O O O O O NaOEt O Monoalkyl diethylmalonate Dialkyl diethylmalonate O H 2 N NH 2 NaOEt R 5 R' 5 O NH O N O - Na + Sodium 5,5'- dialkylbarbiturate H + R 5 O R' NH 5 N-methylation R 1 O N O H 29 5,5'-dialkylbarbituric acid Barbiturates (SAR) 1. A barbiturate must be a weak acid and must have a lipid/water coefficient between certain limits. 2. Only 5,5-disubstituted barbituric acids, the 5,5- disubstituted thiobarbituric acids, and the 1,5,5- trisubstituted barbituric acids possess acceptable hypnotic, anticonvulsant and anesthetic activity. 3. All other substitution patterns, as 5-monosubstituted barbituric acids,1,3-disubstituted barbituric acids, or 1,3,5,5-tetrasubstituted barbituric acid are inactive or produce convulsions

16 4. Substitution of one imide hydrogen by alkyl groups increases lipid solubility which result in a quicker onset and a shorter duration of activity. 5. As the size of the N-alkyl substituent increases (methylethyl-propyl), py the lipid solubility increases. 6. Disubstitution on the nitrogen renders the drug nonacidic making them inactive. 7. Attachment of large alkyl groups (starting with the ethyl group) to the nitrogen imparts convulsant activity of barbiturate. 8. Replacement of C2 oxygen by sulfur increases lipid solubility. Because maximal thiobarbiturate brain levels are quickly reached, onset of activity is rapid. As a result, these drugs (i.e., thiopental) are used as intravenous 31 anesthetics. pka of barbiturates SAR notes: 32 16

17 Metabolism Increasing lipid/water partion coefficient causes an increase in the rate of metabolism. Up to a limit when the drug is stored in lipid/fat tissue. Low ring opening reactions observed

18 35 Chloral 1. Chloral hydrate does demonstrate initial and short-term effectiveness for sleep induction and maintenance. 2. After 2 weeks of drug administration, i ti marked decrease in effectiveness is observed. 3. Chloral hydrate has no analgesic, tranquilizing effect or adverse respiratory effects at therapeutic doses. 4. The CCl 3 group is sufficiently electron withdrawing that chloral hydrate is a weak acid (pka =10.04). 5. A 10% solution of chloral lhydrate in water has a ph of This acidity makes it quite irritating to membranes, such as in the stomach (gastrointestinal upset). 6. Chloral hydrate is readily absorbed from the 36 gastrointestinal tract following oral or rectal doses. 18

19 Chloral It is quickly reduced to trichoroethanol, its active metabolite, by alcohol dehydrogenase in the liver and erythrocytes (half life of 8 to 11 hours). Oral administration of 500 mg to 1 g of chloral hydrate usually produces sleep within 30 min -1 hr; this sleep lasts for 4-8 hrs. The initial hypnotic effect of chloral hydrate is exerted by the drug, but the more prolonged effect is caused by trichloroethanol

20 Melatonin agonists Hormone of darkness. Melatonin itself is a poor sedative due to: Poor absorption and low oral bioavailability Rapid first pass metabolism. 39 Ramelteon Is structurally related to Melatonin (O instead of N). Selective for Melatonin M 1 receptors. Rapidly absorbed and undergo extensive first pass metabolism. It is important in initiating sleep but not maintaining it. It does not depress cognitive function, memory, concentration at normal doses. 40 No abuse liability. 20

21 It appears to be distinctly more efficacious than melatonin but less efficacious than benzodiazepines as a hypnotic. Unlike melatonin, it is more effective in initiating sleep (MT1 activity) rather than to readjust the circadian rhythm (MT2 activity). 41 Antihistamines and Anticholinergics Must cross the BBB to exert their sedative effect. Diphenhydramine and doxylamine (H 1 -antagonist). Have little effect when given to normal subjects at bedtime but cause drowsiness, tendency to sleep and impaired performance when given during the day

22 Herbal preparations Herbal preparations are used as sedatives for the treatment of sleep disorders, including valerian, German camomile, kava, lavender, hops, lemon balm, and passiflora. Kava is no longer recommended because of potential hepato-toxicity. 43 Valerian Valerian has been most extensively studied for its effectiveness in treating insomnia, but the evidence verifying its sedative effect is still inconclusive. The fraction associated with the sedating effects of valerian is the aqueous extract, which contains no valepotriates or volatile oils, and effects may not be seen until valerian has been used for a few weeks. When taken at night, valerian does not affect cognitive or motor performance the following day with no addiction to valerian has been reported. At high doses, disturbance of cardiac function and CNS depression may occur. It is unknown exactly what active component (s) is responsible for its proposed sedative effect, and the variability between species and types of extract makes the study of valerian very difficult

23 Anxiolytics in clinical use 45 Anxiolytics in clinical use 46 23

24 Anxiolytics in clinical use 47 24