Sedative hypnotic drugs arf


Published on

Published in: Health & Medicine
No Downloads
Total views
On SlideShare
From Embeds
Number of Embeds
Embeds 0
No embeds

No notes for slide
  • Sleep is subdivided into : rapid eye movement (REM) sleep, which is characterized by high-frequency electroencephalogram (EEG) recordings and muscle atonia non-REM (slow-wave) sleep, characterized by low frequency EEG recordings and body rest
  • During sleep, the brain generates a patterned rhythmic activity that can be monitored bymeans of the electroencephalogram (EEG). Internal sleep cycles recur 4–5 times per night, each cycle being interrupted by a rapid eye movement (REM) sleep phase (A). The REMstage is characterized by EEG activity similar to that seen in the waking state, rapid eye movements, vivid dreams, and occasional twitches of individual muscle groups against a background of generalized atonia of skeletal musculature. Normally, the REM stage is entered only after a preceding non-REM cycle.
  • GABA neuron ending release GABA , agitate GABAA receptors on postsynaptic membrane . GABAA receptor is constructed by two αsubunits and two βsubunits . GABA binds to GABAA receptorβsubunit and open Cl channel , resulting in Cl - inflow , postsynaptic neurons potential decline and membrane hyperpolarization . The cell is hard to be excited . When GABA exhausted , the role of the drugs disappear , indicating that the role depends on GABA but not the receptor
  • Graded dose-dependent depression of central nervous system function is a characteristic of most sedative-hypnotics. However, individual drugs differ in the relationship between the dose and the degree of central nervous system depression. The linear slope for drug A (most non benzodiazepine drugs) is typical of many of the older sedative-hypnotics, including the barbiturates and alcohols. With such drugs, an increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. At still higher doses, these sedative-hypnotics may depress respiratory and vasomotor centers in the medulla, leading to coma and death. Deviations from a linear dose-response relationship, as shown for drug B, require proportionately greater dosage increments to achieve central nervous system depression more profound than hypnosis. This appears to be the case for benzodiazepines and for certain newer hypnotics that have a similar mechanism of action.
  • Depending on their blood levels, both benzodiazepines and barbiturates produce calming and sedative effects. At higher dosage, both groups promote the onset of sleep or induce it (C). At low doses, benzodiazepines have a predominantly anxiolytic effect. Unlike barbiturates, benzodiazepine derivatives administered orally lack a general anesthetic action; cerebral activity is not globally inhibited (the virtual impossibility of respiratory paralysis negates suicidal misuse) and autonomic functions, such as blood pressure, heart rate, or body temperature,are unimpaired. Thus, benzodiazepines possess a therapeutic margin considerably wider than that of barbiturates. Zolpidem (an imidazopyridine), zaleplone (a pyrazolopyrimidine) and zopiclone (a cyclopyrrolone) are hypnotics that, despite their different chemical structure, can bind to the benzodiazepine site on the GABAA receptor (p. 222). However, their effects do not appear to be identical to those of benzodiazepines. Thus, compared with benzodiazepines, zolpidem exerts a weaker effect on sleep phases, supposedly carries alower risk of dependence, and appears to have less anxiolytic activity. Heterogeneity of GABAA receptors may explain these differences in activity. GABAA receptors consist of five subunits that exist in several subtypes
  • Shortening of REM sleep (normally~ 25% of total sleep duration) results in increased irritability and restlessness during the daytime. With undisturbed night rest, REM deficits are compensated by increased REM sleep on subsequent nights Hypnotic drugs can shorten REM sleep phases With repeated ingestion of a hypnotic on several successive days, the proportion of time spent in REM vs. non-REM sleep returns to normal despite continued drug intake. Withdrawal of the hypnotic drug results in REM rebound, which tapers off only over many days Since REM stages are associated with vivid dreaming, sleep with excessively long REM episodes is experienced as unrefreshing. Thus, the attempt todiscontinue use of hypnotics may result in the impression that refreshing sleep calls for a hypnotic, probably promoting hypnotic drug dependence.
  • Sedative-hypnotic drugs. In: Basic and clinical pharmacology, 8 th  edition. Katzung BG. USA: The McGraw Hill Companies, Inc, 2001:364–381. Benzodiazepines (BDZs) bind to the gamma sub-unit of the GABA-A receptor. Their binding causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity. BDZs do not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential A model of the GABA A receptor-chloride ion channel macromolecular complex. The complex consists of five or more membrane-spanning subunits. GABA appears to interact with alpha or beta subunits triggering chloride channel opening with resultant membrane hyperpolarization . Binding of BZs to gamma subunits facilitates the process of channel opening
  • The speed of Absorption and the extent of plasma binding are in equilibrium with liposolubility . More than 90 % bind -> absorbed quickly, such as diazapam , etc. Liver metabolism : metabolised to a range of active substances by liver drug enzyme , t1 / 2 longer than the mother nuclide . Demethyldiazapam is metabolised to a wide range of active metabolins, t1/2 20-100 hr.
  • Fig. 3 : demonstrates the short-acting drugs are those that are metabolised directly by conjugation with glucuronide. gradual bild-up and slow disappearance of nordazepam from the plasma gives long-acting drugs. Remember AGE: advancing age affects the rate of oxidative reactions more than that of conjugation. the effect of long-acting BZs tends to increase with age (drowsiness and confusion)
  • reduction of anxiety and agression : Note: BZ may paradoxically produce an increase in irritability and aggression in some individuals (particularly if short- acting drugs are given (triazolam) Advantages : high selectivity , wide safety margin , slow elimination , lasting effects ,low dependence and light withdrawal symptoms. Clinical applications : anxiety with obsessive-compulsive disorder , gastrointestinal neurosis ,heart neurosis . Strychnine and other drugs cause seizures. sedation and induction of sleep BZs decrease the time taken to get to sleep increase the total duration of sleep (only in subjects who normally sleep for less than about 6 hours each night) REM sleep ( rapid eye movement) is less affected if compared with the same effect of other hypnotics. Is that important? Yes , artificial interruption of REM sleep causes irritability and anxiety even if the total amount of sleep is not reduced). Clinical applications : Narcotic administration —— calm Treat insomnia —— difficult to fall asleep , wake up easily and early reduction of muscle tone and coordination may be clinically useful: increased muscle tone is a common feature of anxiety states and may contribute to pains (headache). Influence of manual skills (!) anticonvulsant effects (GABA A receptors) clonazepam to treat epilepsy diazepam (i.v.) status epilepticus to control life-threatening seizures anterograde amnesia BZs obliterate memory of events experienced while under their influence Lapsus memoriae : damage in recent memory (reversible)
  • At low doses symptoms can include sedation, drowsiness, ataxia, lethargy, mental confusion, motor and cognitive impairments, disorientation, slurred speech, amnesia, dementia, etc. At high doses mental and psychomotor dysfunction can progress to hypnosis (i.e., pass out) o        Respiration is not seriously depressed, unless benzo is taken concurrently with another CNS depressant (i.e., alcohol) o        Short-acting agents taken at bedtime can result in both early-morning wakening and rebound insomnia the following night o        Long-acting agents taken at bedtime can result in daytime sedation the following day Cognitive impacts are considerable: o        Inhibition of learning behaviors, academic performance, and psychomotor functioning common These symptoms can persist long after treatment is discontinued Ethanol strengthen toxicity Through the placenta : teratogenicity role
  • Reputation for causing only a low incidence of abuse and dependence, however, when taken for prolonged periods of time, dependence can develop and result in withdrawal    Withdrawal symptoms include:      Return (and possible intensification) of anxiety state, increases in rebound insomnia, restlessness, agitation, irritability, etc. 
  • Clinical Pharmacology
  • The centrol role is related to the activation of GABAA receptors . Barbiturates can function as GABA in the absence of GABA , which can increase the permeability of Cl - channel , leading to the cell membrane hyperpolarization . Different from BZ drugs which increase Cl - channel opening frequence , barbiturates mainly extend the Cl - channel opening time . In addition , barbiturates can weaken or block the excited reaction resulted from depolarization caused by the glumatic acids and inhibit the CNS .
  • Oral and intramuscular injection absorption->distribution all over the body , body fluid ->brain High liposolubility ( metabolised by liver drug enzyme )-> eliminated in urine ( short maintenance time ) Low liposolubility-> eliminated in original form ( long maintenance time )
  • Barbiturates generally inhibit the CNS . It has sedative , hypnotic , anticonvulsant , antiepileptic and anaesthetic effect at different doses from low to large , respectively . Inhibit cardiovascular system at large dose . 10 times of hypnosis dose can cause respiratory paralysis and death . Poor safety , easy to cause dependence . The application has been declining and is mainly used for anticonvulsant , antiepilepsia and anaesthesia .
  • Clinical Pharmacology
  • After effect :dizziness , drowsiness , fine uncoordinate movement Allergic response : nettle rash , angioneuroedema , erythema mlutiforme Tolerance Dependence Acute intoxication :significant inhibit respiration center
  • The drug is a inducer of liver drug-metabolizing enzymes and promote metabolism of other drugs . The main cause of death of barbiturates is deep respiratory inhibition . In pregnant and lactant period , the thyroid function is low . Patients who have fever , anaemia , hypotension , hemorrhagic shock , heart , liver , kidney dysfunction and old people with mental disease should take the drug with caution . Patients with respiratory inhibition caused by bronchial asthma and head injury , severe liver dysfunction , uncontrolled diabetes and who is allergic are forbidden to take
  • Clinical Pharmacology
  • binds selectively to the BZ 1 subtype of BZ receptors and facilitates GABA-mediated neuronal inhibition like the BZs, the actions of zolpidem are antagonised by f l u m a z e n i l minimal muscle relaxing and anticonvulsant effects the risk of development of tolerance and dependence with extended use is less than with the use of hypnotic BZs
  • Short half-life hypnotics , e.g., triazolam, zolpidem, and zaleplon, are essentially gone from the blood within 8 hours. Thus, they cause little hangover, but may not help patients with early awakening. Indeed, triazolam (and zolpidem cause early awakening for some patients, particularly with prolonged usage. These drugs may also produce daytime agitation or anxiety. Hypnotics with half lives of 8-12 hours, e.g., temazepam, help promote sleep at the end of the night, but they may still have significant blood concentrations in the morning. Accordingly, they cause considerable hangover. Eszopiclone, with a half-life of 6-9 hours, is somewhere between the short and intermediate half-life drugs, as is Ambien CR. None of these drugs will accumulate, since they are largely gone by the following bedtime. Drugs such as flurazepam with long-lasting active metabolites (and active metabolites of diazepam) have a half-life of several days. Thus, they will accumulate night after night. In the elderly, the half-lives of these drugs may extend to a week or more. Accordingly, patients who take these drugs (especially elders) may experience insidious obtundation, confusion, or impaired behavior. Because of the long half-life, it may take a week or two for patients to recover from these drugs. On the other hand, stopping these drugs causes no immediate withdrawal symptoms.
  • Simulated absorption and metabolism of hypnotics is shown, when a sleeping pill is taken at bedtime. Low concentrations 5-8 hours after bedtime may lead to withdrawal and early awakening. After getting out of bed, residual concentrations of the sleeping pill will produce possible hangover. The curve for eszopiclone shows metabolism estimated for a person about 60-70 years old. For a younger adult, the eszopiclone curve would be closer to the Ambien CR curve.
  • Katzung
  • Katzung
  • Katzung
  • Sedative hypnotic drugs arf

    1. 1. SEDATIVE HYPNOTIC DRUGS Aditia Retno Fitri
    2. 2. OUTLINES <ul><li>Sleep </li></ul><ul><li>Hypnotic vs Sedative </li></ul><ul><li>Hypnotic Sedative Drugs </li></ul><ul><li>Benzodiazepine </li></ul><ul><li>Barbiturates </li></ul><ul><li>Miscellaneous Agents </li></ul><ul><li>Summary </li></ul>
    3. 3. SLEEP
    4. 4. Normal sleep cyclic and repetitive , consists of distinct stages,based on three physiologic measures: the electroencephalogram, the electromyogram, and the electronystagmogram. <ul><li>Non-rapid eye movement(NREM) sleep : 70%-75% </li></ul><ul><li>Stage 1,2 </li></ul><ul><li>Stage 3,4:slow wave sleep, SWS </li></ul><ul><li>Rapid eye movement(REM) sleep </li></ul>Normal sleep
    5. 7. <ul><li>SEDATIVE - HYPNOTIC </li></ul>
    6. 8. SEDATIVE <ul><li>Drugs that have an inhibitory effect on the CNS to the degree that they reduce: </li></ul><ul><ul><li>Nervousness </li></ul></ul><ul><ul><li>Excitability </li></ul></ul><ul><ul><li>Irritability without causing sleep </li></ul></ul><ul><ul><li>(McKenry et al., 2003) </li></ul></ul><ul><li>An effective sedative (anxiolytic) agent should reduce anxiety and exert a calming effect with little or no effect on motor or mental functions. </li></ul><ul><li>(Katzung et al., ed 11) </li></ul>
    7. 9. HYPNOTICS <ul><li>Calm or soothe the CNS to the point that they cause sleep </li></ul><ul><li>A hypnotic drug should produce drowsiness and encourage the onset and maintenance of a state of sleep that as far as possible resembles the natural sleep state. </li></ul><ul><li>A sedative can become a hypnotic if it is given in large enough doses  dose dependent </li></ul><ul><li>(Katzung; Goodman & Gilman) </li></ul>
    8. 10. CNS Depression <ul><li>Sedation </li></ul><ul><li>Hypnosis </li></ul><ul><li>General Anesthesia </li></ul><ul><li>Poisoning </li></ul><ul><li>Death </li></ul>
    9. 11. Anxiolytics: reduce anxiety Sedatives: decrease activity, calming effect Hypnotics: induce sleep Some drugs have anxiolytic and sedative/hypnotic effects.
    10. 12.
    12. 14. SEDATIVE-HYPNOTIC DRUGS <ul><li> SEDATIVE-HYPNOTICS </li></ul><ul><li>Benzodiazepines Barbiturates Miscellaneous agents </li></ul><ul><li>Short Ultra </li></ul><ul><li>action action </li></ul><ul><li> Intermediate Short Buspirone </li></ul><ul><li> action action Chloral hydrate </li></ul><ul><li> Long Long Zaleplon </li></ul><ul><li> action action Zolpidem </li></ul><ul><li>Ramelteon </li></ul>
    13. 15. GABA System <ul><li>is the major inhibitory neurotransmitter in the brain. </li></ul><ul><ul><li>It has specific receptors in chloride channels present on the membrane of post synaptic neurons. </li></ul></ul><ul><ul><ul><li> regulates the entrance of chloride into the postsynaptic cells. </li></ul></ul></ul><ul><li>Binding of GABA to its receptor (GABA A receptor) </li></ul><ul><ul><li>results in opening of the chloride channel and increased conductance of cl¯ ions to inside the post-synaptic neuron.  hyperpolarization of the postsynaptic neuron and decreased synaptic neurotransmission. </li></ul></ul>
    14. 16. Site and Structure of Action <ul><li>Site of action is the GABA A receptor </li></ul><ul><li>Structure of GABA A receptor </li></ul><ul><ul><li>Comprised of 5 subunits </li></ul></ul><ul><ul><ul><li>2 α subunits (to which GABA binds) </li></ul></ul></ul><ul><ul><ul><li>2 β subunits (to which barbiturates bind) </li></ul></ul></ul><ul><ul><ul><li>1 γ subunit (to which benzodiazepines bind) </li></ul></ul></ul>
    15. 17.
    16. 18.
    17. 19. Characteristics of an “Ideal” Hypnotic <ul><li>Rapid absorption </li></ul><ul><li>No active metabolites </li></ul><ul><li>Optimal half-life </li></ul>Adapted from Bartholini G. In: Sauvanet JP, Langer SZ, Morselli PL, eds. Imidazopyridines in Sleep Disorders . 1988:1-9. <ul><li>Rapid sleep induction </li></ul><ul><li>Physiological sleep pattern </li></ul><ul><li>Mechanism other than general CNS depression </li></ul><ul><li>Sleep maintenance </li></ul><ul><li>Improved Daytime Function </li></ul><ul><li>No residual sedation </li></ul><ul><li>No respiratory depression </li></ul><ul><li>No ethanol interaction </li></ul><ul><li>No tolerance </li></ul><ul><li>No physical dependence </li></ul><ul><li>No rebound insomnia </li></ul><ul><li>No effect on memory </li></ul>Ideal Hypnotic Pharmacokinetic Properties Pharmacokinetic Effect Side Effect
    18. 20. Sedative/hypnotics death surgical anesthesia coma unconsciousness sleep sedation Drug dose Most non-benzodiazepine sedative/hypnotics Benzodiazepines, Zolpidem, Zaleplon
    19. 21.
    20. 22.
    22. 24. BENZODIAZEPINES : Pharmacodynamic <ul><li>act selectively on gamma-aminobutyric acid A (GABA A ) receptors , which mediate fast inhibitory synaptic transmission through the CNS. </li></ul><ul><ul><li>bind to the gamma sub-unit of the GABA-A receptor. </li></ul></ul><ul><ul><ul><li> causes an allosteric (structural) modification of the receptor that results in an increase in GABA A receptor activity. </li></ul></ul></ul><ul><ul><li>not substitute for GABA, which bind at the alpha sub-unit, but increase the frequency of channel opening events which leads to an increase in chloride ion conductance and inhibition of the action potential </li></ul></ul><ul><li>The antagonist – f l u m a z e n i l </li></ul>
    23. 25. BENZODIAZEPINES : Pharmacodynamic
    24. 26. BENZODIAZEPINES: Pharmacokinetics <ul><li>A bsorption: </li></ul><ul><ul><li>well absorbed if given orally , Cma x reached in about 1 h </li></ul></ul><ul><li>B inding: </li></ul><ul><ul><li>strongly bound to plasma proteins </li></ul></ul><ul><li>D istribution: </li></ul><ul><ul><li>large Vd: accumulation in body fat (high lipid solubility) </li></ul></ul><ul><li>M etabolism : </li></ul><ul><ul><li>Hydroxylation </li></ul></ul><ul><ul><li>conjugation with glucuronic acid </li></ul></ul><ul><ul><li>short-, medium- and long-acting BZ </li></ul></ul><ul><ul><li>the role of N-desmethyldiazepam </li></ul></ul>
    25. 27. BENZODIAZEPINES : Biotransformation
    26. 28.
    27. 29.
    28. 30. BENZODIAZEPINES: Short Acting and the Elderly <ul><li>Short-lasting benzo’s are not converted to active intermediates; they are metabolized directly into inactive products </li></ul><ul><li>The elderly have a reduced ability to metabolize long-acting benzo’s (and their active metabolites) </li></ul><ul><li>Pharmacokinetics are not drastically altered with the short-acting benzo’s </li></ul>
    29. 31. <ul><li>Benzodiazepine Binding Site Ligands </li></ul><ul><li>Three types of ligand-benzodiazepine receptor interactions have been reported: </li></ul><ul><li>Agonists </li></ul><ul><li>facilitate GABA actions  occurs at multiple BZ binding sites </li></ul><ul><li>nonbenzodiazepines zolpidem, zaleplon, and eszopiclone are selective agonists at the BZ sites that contain an  1 subunit. </li></ul><ul><li>(2) Antagonists </li></ul><ul><li>are typified by the synthetic benzodiazepine derivative flumazenil, which blocks the actions of benzodiazepines, eszopiclone, zaleplon, and zolpidem </li></ul><ul><li>(3) Inverse agonists </li></ul><ul><li>act as negative allosteric modulators of GABA-receptor function. </li></ul><ul><li>Their interaction with BZ sites on the GABAA receptor can produce anxiety and seizures, an action that has been demonstrated for several compounds, especially the  -carbolines, eg, n-butyl-  -carboline-3-carboxylate (  -CCB ). In addition to their direct actions, these molecules can block the effects of benzodiazepines. </li></ul>
    30. 32. Pharmacological effects <ul><li>Those compounds that bind and enhance the inhibitory actions of GABA are complete agonists </li></ul><ul><ul><li>(Ex) Lorazepam, midazolam, etc. </li></ul></ul><ul><li>Those compounds that bind with “less than complete agonist action” are termed partial agonists </li></ul><ul><ul><li>(Ex) Ambien (zolpidem) </li></ul></ul><ul><ul><li>Those compounds that bind and decrease the inhibitory actions of GABA are inverse agonists </li></ul></ul>
    31. 33. Receptor Ligands
    32. 34. Benzodiazepines: Main Effects <ul><li>The main effects of benzodiazepines are: </li></ul><ul><ul><li>reduction of anxiety and aggression </li></ul></ul><ul><ul><li>sedation and induction of sleep </li></ul></ul><ul><ul><li>reduction of muscle tone and coordination </li></ul></ul><ul><ul><li>anticonvulsant effect </li></ul></ul><ul><ul><li>anterograde amnesia. </li></ul></ul>
    33. 35. Benzodiazepines: Unwanted Effects <ul><li>Unwanted effects </li></ul><ul><li>acute overdosage </li></ul><ul><li>effects occuring during normal therapeutic use </li></ul><ul><li>tolerance and dependence </li></ul><ul><li>acute overdosage (BZs are relatively safe in overdose) </li></ul><ul><ul><li>BZs produce prolonged sleep, without serious depression of respiration or cardiovascular function </li></ul></ul><ul><ul><li>Severe even life-threatening respiratory depression may appear in BZ combination with other CNS depressants, particularly alcohol . </li></ul></ul><ul><ul><li>Acute overdosage can be counteracted with flumazenil </li></ul></ul>
    34. 36. Benzodiazepines: Unwanted Effects <ul><li>unwanted effects occuring during therapeutic use </li></ul><ul><ul><li>Influence of manual skills (such as driving performance) due to drowsiness, confusion, amnesia and impaired coordination </li></ul></ul><ul><ul><li>enhance of depressant action of other drugs (in a more than additive way ) </li></ul></ul><ul><li>tolerance , dependence </li></ul><ul><ul><li>Tolerance (gradual escalation of dose needed to produce the required effect) occurs with all BZs. T.appears to represent a change at the receptor level. </li></ul></ul><ul><ul><li>Dependence – In human subjects and patients, stopping BZ treatment after weeks and months causes an increase in symptoms of anxiety, together with tremor and dizziness. </li></ul></ul><ul><ul><li>The withdrawal syndrome : short acting BZs cause more abrupt withdrawal effects </li></ul></ul><ul><ul><li>Addiction (-craving -severe psychological dependence) is not a major problem. </li></ul></ul>
    35. 37. Benzodiazepine Therapy
    36. 38.
    37. 39. Effects on Pregnancy <ul><li>Benzodiazepines (and their metabolites) can freely cross the placental barrier and accumulate in fetal circulation </li></ul><ul><ul><li>Administration during the first trimester can result in fetal abnormalities </li></ul></ul><ul><ul><li>Administration in third trimester (close to the time of birth) can result in fetal dependence, or “floppy-infant syndrome” </li></ul></ul><ul><li>Benzodiazepines are also excreted in the breast milk </li></ul><ul><li>  </li></ul>
    38. 40.
    39. 41. BARBITURATES
    40. 42. Barbiturates: Pharmacodynamic <ul><li>BA: the sleep-inducing properties were discovered early </li></ul><ul><li>in the 20th century . Until the 1960s, they formed the largest </li></ul><ul><li>group of hypnotics and sedatives in clinical use. </li></ul><ul><li>Pharmacodynamics: </li></ul><ul><li>increase the duration of the GABA-gated chloride channel openings. </li></ul><ul><li>At high concentrations, the barbiturates may also be GABA-mimetic, directly activating chloride channels. </li></ul><ul><li>β subunits binding site in GABA receptor </li></ul><ul><li>more pronounced central depressant effects </li></ul>
    41. 43. <ul><li>Absorption </li></ul><ul><ul><li>small intestine </li></ul></ul><ul><li>Distribution </li></ul><ul><ul><li>lipid solubility </li></ul></ul><ul><ul><li>rapidly cross placenta </li></ul></ul><ul><li>Elimination </li></ul><ul><ul><li>liver microsomal enzymes </li></ul></ul><ul><ul><li>renal tubular reabsorption </li></ul></ul>Barbiturates : Pharmacokinetics
    42. 44. <ul><li>CNS depression </li></ul><ul><li>Respiratory depression </li></ul><ul><li>CV depression </li></ul><ul><ul><li>decreased myocardial contractility, vasodilation, hypotension </li></ul></ul><ul><li>GI motility inhibition </li></ul><ul><li>Poor safety , easy to cause dependence </li></ul><ul><li>The application has been declining and is mainly used for anticonvulsant , antiepilepsia and anaesthesia . </li></ul>Barbiturates : Clinical Effect
    43. 45. Table 12-3 Barbiturates: Onset and Duration
    44. 46.
    45. 47. Barbiturates: Disadvantage of use <ul><li>if given in a large dose </li></ul><ul><ul><li>death from respiratory and cardiovascular depression (flumazenil not effective) </li></ul></ul><ul><li>a high degree of tolerance: </li></ul><ul><ul><li>BA strongly induce the synthesis and activity of hepatic CYP450 and conjugating enzymes thus increasing the rate of metabolic degradation of many other drugs </li></ul></ul><ul><li>drug-drug interactions </li></ul><ul><li>dependence </li></ul><ul><li>BA are now little used </li></ul><ul><li>as anxiolytic and hypnotic drugs </li></ul>
    46. 48. <ul><li>CNS system </li></ul><ul><ul><li>consciousness change </li></ul></ul><ul><ul><li>respiratory depression </li></ul></ul><ul><ul><li>areflexia </li></ul></ul><ul><li>CV system </li></ul><ul><ul><li>low cardiac output </li></ul></ul><ul><li>GI system </li></ul><ul><ul><li>ileus </li></ul></ul>Barbiturate Poisoning
    47. 49.
    49. 51. Ramelteon : Melatonin receptors <ul><li>Pharmacodynamic: </li></ul><ul><ul><li>Melatonin receptors  circadian rhythms </li></ul></ul><ul><ul><li>an agonist at MT 1 and MT 2 melatonin receptors located in the suprachiasmatic nuclei of the brain. </li></ul></ul><ul><ul><li>no direct effects on GABAergic neurotransmission </li></ul></ul><ul><li>Indication </li></ul><ul><ul><li>reduced the latency of persistent sleep with no effects on sleep architecture and no rebound insomnia or significant withdrawal symptoms. </li></ul></ul>
    50. 52. Ramelteon: Melatonin Receptors ....cont’d <ul><li>Pharmacokinetic </li></ul><ul><ul><li>rapidly absorbed per oral administration </li></ul></ul><ul><ul><li>first-pass metabolism !!!! </li></ul></ul><ul><ul><ul><li>f orming an active metabolite with longer half-life (2–5 hours) </li></ul></ul></ul><ul><ul><ul><li>The CYP1A2 isoform and CYP2C9of cytochrome P450 are involved. </li></ul></ul></ul><ul><li>Drug Interaction </li></ul><ul><ul><li>should not be used in combination with : </li></ul></ul><ul><ul><ul><li>inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9 (eg, fluconazole) </li></ul></ul></ul><ul><ul><ul><li>The CYP inducer rifampin markedly reduces the plasma levels of both ramelteon and its active metabolite. </li></ul></ul></ul><ul><ul><li>caution in patients with liver dysfunction. </li></ul></ul><ul><li>Adverse effects </li></ul><ul><ul><li>dizziness, somnolence, fatigue, and endocrine changes as well as decreases in testosterone and increases in prolactin. </li></ul></ul>
    51. 53. Buspirone : 5 -HT1A -receptor agonists <ul><li>Pharmacodynamic: </li></ul><ul><ul><li>selective anxiolytic effects  relieves anxiety without causing marked sedative, hypnotic, no anticonvulsant or muscle relaxant properties. </li></ul></ul><ul><ul><li>does not interact directly with GABAergic systems. </li></ul></ul><ul><ul><li>a partial agonist at brain 5-HT 1A receptors , but it also has affinity for brain dopamine D 2 receptors. </li></ul></ul><ul><ul><li>no rebound anxiety or withdrawal signs on abrupt discontinuance. </li></ul></ul><ul><ul><li>not effective in blocking the acute withdrawal syndrome from abrupt cessation of use of benzodiazepines </li></ul></ul><ul><ul><li>minimal abuse liability . </li></ul></ul><ul><ul><li>anxiolytic effects of buspirone may take >1 week to become established  less effective in panic disorders </li></ul></ul>
    52. 54. Buspirone : 5 -HT1A -receptor agonists <ul><li>Pharmacokinetic: </li></ul><ul><ul><li>rapidly absorbed orally  extensive first-pass metabolism </li></ul></ul><ul><ul><li>The elimination half-life of buspirone is 2–4 hours, and liver dysfunction may slow its clearance. </li></ul></ul><ul><ul><li>Rifampin, an inducer of cytochrome P450, decreases the half-life of buspirone; inhibitors of CYP3A4 (eg, erythromycin, ketoconazole, grapefruit juice, nefazodone) can markedly increase its plasma levels. </li></ul></ul><ul><li>A dverse effect: </li></ul><ul><ul><li>causes less psychomotor impairment than benzodiazepines </li></ul></ul><ul><ul><li>does not potentiate effects of conventional sedative-hypnotic drugs, and elderly patients do not appear to be more sensitive to its actions. </li></ul></ul><ul><ul><li>Nonspecific chest pain, tachycardia, palpitations, dizziness, nervousness, tinnitus, gastrointestinal distress, and paresthesias and a dose-dependent pupillary constriction </li></ul></ul><ul><ul><li>FDA category B drug in terms of its use in pregnancy. </li></ul></ul>
    53. 55. <ul><li>Differences between buspirone and benzodiazepines: </li></ul><ul><li>1- The full anxiolytic effect of buspirone takes several weeks to develop , whereas the anxiolytic effect of the benzodiazepines is maximal after a few days of therapy. </li></ul><ul><li>2- In therapeutic doses, buspirone has little or no sedative effect and lacks the muscle relaxant and anticonvulsant properties of the benzodiazepines. </li></ul><ul><li>3- Buspirone does not potentiate the central nervous system depression caused by sedative–hypnotic drug or by alcohol </li></ul><ul><li>4- Buspirone does not prevent the symptoms associated with benzodiazepine withdrawal. </li></ul>
    54. 56. Zolpidem <ul><li>Effect: </li></ul><ul><ul><li>binds selectively to the BZ 1 subtype of BZ receptors and facilitates GABA-mediated neuronal inhibition </li></ul></ul><ul><ul><li>Useful for the short-term treatment of insomnia </li></ul></ul><ul><ul><li>Primarily a sedative (rather than an anxiolytic) </li></ul></ul><ul><ul><li>are antagonised by f l u m a z e n i l </li></ul></ul><ul><ul><li>risk of tolerance and dependence < BZ </li></ul></ul><ul><li>Pharmacokinetics : </li></ul><ul><ul><li>Rapidly absorbed in the GI tract following oral administration (75% reaches plasma) </li></ul></ul><ul><ul><li>Metabolized in the liver and excreted by the kidney’s </li></ul></ul><ul><ul><li>Dosage reduction in hepatic dysfuction, elderly </li></ul></ul>
    55. 57. Zaleplon & Zopiclone <ul><li>Short half-life resembles zolpidem, t 1/2 = 1h </li></ul><ul><li>Rapid onset and short duration of action are favorable properties for those patients who have difficulty falling asleep. </li></ul><ul><li>Only approx. 30% of an orally administered dose reaches the plasma, and most of that undergoes first-pass elimination </li></ul><ul><li>Half as potent as zolpidem </li></ul><ul><li>Improves sleep quality w/o rebound insomnia, and little chance of developing dependency </li></ul>
    56. 58. Sedative-Hypnotic: Misuse and Abuse <ul><li>Motivational Factors </li></ul><ul><ul><li>The search for sleep </li></ul></ul><ul><ul><li>Coping with stress </li></ul></ul><ul><ul><li>Appetitive drug use-motivated by desire for pleasurable responses and sensations </li></ul></ul><ul><ul><li>Escape-avoidance drug use-motivated by desire for relief from an unpleasant sensation, tension, fear, or anxiety </li></ul></ul><ul><ul><li>Potentiating (synergistic)- exaggerated depressant effect </li></ul></ul><ul><ul><li>Offset effects of stimulant drugs </li></ul></ul>
    57. 59. Sedative-Hypnotic : Withdrawal Syndrome <ul><li>First 12-15 hours, patient appears to improve </li></ul><ul><li>16+ hours </li></ul><ul><ul><li>Restless, anxious, tremulous, weak, abdominal cramping </li></ul></ul><ul><ul><li>Vomiting, orthostatic hypotension, tremors, increased deep tendon flexion, convulsions </li></ul></ul><ul><li>Days 2-3 </li></ul><ul><ul><li>Delirium, hallucinations (persecutory) disorientation to time & place </li></ul></ul><ul><ul><li>Once delirium starts can’t be reduced by administration of other sedative hypnotics-has to run its course </li></ul></ul><ul><ul><li>Includes hyperthermia (increased body temp), exhaustion, cardiovascular collapse & sometimes death </li></ul></ul><ul><li>Depending upon type of drug, withdrawal symptoms reach peak severity at days 2-3 & last upwards of a week ( & in some cases, some of the symptoms may last several weeks) </li></ul>
    58. 60. Sedative-Hypnotics : Clinical Uses <ul><li>For relief of anxiety </li></ul><ul><li>For insomnia </li></ul><ul><li>For sedation and amnesia before and during medical and surgical procedures </li></ul><ul><li>For treatment of epilepsy and seizure states </li></ul><ul><li>As a component of balanced anesthesia (intravenous administration) </li></ul><ul><li>For control of ethanol or other sedative-hypnotic withdrawal states </li></ul><ul><li>For muscle relaxation in specific neuromuscular disorders </li></ul><ul><li>As diagnostic aids or for treatment in psychiatry </li></ul>
    59. 61.
    60. 62.
    62. 64. SUMMARY
    63. 65.
    64. 66. Summary
    65. 67. Summary
    66. 68. Summary
    67. 69. THANK YOU