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- 1.
- 2. It isunpleasant state of tension, apprehension or uneasiness a fear seem to arising from unknown source. Symptoms are tachycardia, sweating trembling and palpitation. Since many anti anxiolytic drugs cause sedation so same drug is clinically used as both anxiolytic and hypnotic (sleep inducing ) drug. Anxiety
- 3. Anxiolytic-hypnotic drugshave both properties of Sedation hypnosis Anxiolytic-hypnotic drugs
- 4. An effectivesedative (anxiolytic) agent should reduce anxiety and exert a calming effect. The degree of central nervous system depression caused by a sedative should be the minimum consistent with therapeutic efficacy. Sedative-Hypnotics
- 5. A hypnoticdrug should produce drowsiness and encourage the onset and maintenance of a state of sleep. Hypnotic effects involve more pronounced depression of the central nervous system than sedation, and this can be achieved with most drugs in this class simply by increasing the dose. Sedative-Hypnotics
- 6. NORMAL ANXIETY _________ _________________ SEDATION HYPNOSIS Confusion,Delirium, Ataxia Surgical Anesthesia COMA DEATH
- 7. I. ANTIAXIETY DRUGS/SEDATIVES Variousantianxiety have been used throughout the ages to alleviate feelings of stress, anxiety, discomfort, etc Currently, benzodiazepines are among the most widely prescribed antianxiety drugs because of their safety and efficacy than older agents . Figure 22-1. Dose-response curves for two hypothetical sedative-hypnotics 7
- 8. 1. Benzodiazepines 2. Barbiturates 3.Antihistamines 4. Other anxiolytic- hypnotics Classification of anxiolytic-Hypnotics drugs
- 9. chlordiazepoxide diazepam(Valium® ) clonazepam clorazepate lorazepam oxazepam alprazolam (Xanax® ) Triazolam 9 1.Benzodiazepines-Anxiolytics
- 10. GABA isthe major inhibitory neurotransmitter in the CNS. The target of BZD is GABA receptor. These receptors are composed of ἀ,ᵝ and ᵞ subunit families. BZD binds to the “benzodiazepine receptors” on GABA neuron located at the interface of alpha and gemma 2 subunit. Benzodiazepines relieve anxiety through enhancement of the inhibitory activity of GABA No antipsychotic, No analgesic, Not affect ANS 10 Benzodiazepines Mechanism of Action
- 11. GABAA receptor-chloride ionchannel macromolecular complex pentameric structure assembled from five subunits
- 12.
- 14. Binding ofBZD results in the increase frequency of the chloride channel opening produced by GABA. The influx of chloride ions cause a hyperpolarization resulting in inhibition of the formation of the action potential. MOA
- 16. 1.Reduction of anxiety ἀ²-GABAreceptors 2.Sedative and hypnotic action ἀ¹-GABA receptors 3.Anterograde amnesia ἀ¹-GABA receptors 4.Anticonvulsant ἀ¹-GABA receptors 5.Muscle relaxant ἀ²-GABA receptors Pharmacological effects
- 17. Generalized AnxietyDisorder Panic Disorder (alprazolam) Insomnia Schizophrenia Muscular spasms (diazepam) Seizure Disorders, epilepsy (clonazepam , diazepam) Delirium Alcohol Withdrawal(clorazepate) 17 Benzodiazepines-Indications
- 18. Pharmacokinetics Absorption andDistribution The rates of oral absorption of benzodiazepines differ depending on a number of factors, including lipophilicity. Oral absorption of triazolam is extremely rapid, and that of diazepam. Benzodiazepines
- 19. Lipid solubilityplays a major role in determining the rate at which a particular sedative-hypnotic enters the central nervous system. For example, diazepam and triazolam are more lipid-soluble than chlordiazepoxide and lorazepam; thus, the central nervous system actions of the former drugs are more rapid in onset. Benzodiazepines
- 20. Biotransformation Metabolic transformationto more water- soluble metabolites is necessary for clearance of sedative-hypnotics from the body. The microsomal drug-metabolizing enzyme systems of the liver are most important Benzodiazepines
- 21. Excretion The water-solublemetabolites of benzodiazepines and other sedative-hypnotics are excreted mainly via the kidney. The Benzodiazepines & Barbiturates
- 23. Drowsiness andconfusion: These effects are the two most common side effects of the benzodiazepines. Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an automobile. Cognitive impairment (decreased long-term recall and retention of new knowledge) can occur with use of benzodiazepines. Adverse effects of benzodiazepines
- 24. Triazolam, oneof the most potent oral benzodiazepines with the most rapid elimination, often shows a rapid development of tolerance, early morning insomnia, and daytime anxiety, along with amnesia and confusion. Adverse effects of benzodiazepines
- 25. Alcohol andother CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines. Benzodiazepines are, however, considerably less dangerous than the older anxiolytic and hypnotic drugs. As a result, a drug overdose is seldom lethal unless other central depressants, such as alcohol, are taken concurrently. Precautions
- 26. a selectivecompetitive antagonist of BZD receptors (Bz1). Blocks action of benzodiazepines and reverse the its effects Rapid but short acting Half life 1hr IV available FLUMAZENIL
- 27. Long acting(1-2days) Phenobarbital Shortacting (3-8hrs) Pentobarbital Secobarbital Amobarbital Ultra short acting(20min) thiopental 2. Barbiturates
- 28. Barbiturates are secondchoice as sedative – hypnotic. Mechanism of Action: Facilitation of GABA action on the brain. increase the duration of the GABA gated channel opening but in large dose, they can directly activating chloride channels. (not through BZD receptors).
- 30. Mechanisms of Action 1)Enhance GABAergic Transmission frequency of openings of GABAergic channels. Benzodiazepines opening time of GABAergic channels. Barbiturates receptor affinity for GABA. BDZs and BARBS
- 31. Barbiturates -Actions Barbituratesare less selective in their actions than benzodiazepines 1. Cns depression: since they also depress the actions of excitatory neurotransmitters (eg, glutamic acid) in parallel with their effects on GABA neurotransmission. 2. This multiplicity of sites of action of barbiturates may be the basis for their ability to induce full surgical anesthesia and for their more pronounced central depressant effects (which result in their low margin of safety) compared to benzodiazepines. 3. Respiratory depression 4. Its also induce the CYP p450microsomal enzyme of the liver.
- 32. Anesthesia Anticonvulsant Anti anxiety Therapeutic use
- 34. Advantages of BZDover barbiturates 1. Selective: minimal respiratory and cardiovascular depression. 2. High therapeutic index. 3. Less dependence with minimal withdrawal symptoms 4. Has specific antagonist
- 35. Some antihistamine have sedative properties Diphenhydramine Hydoxyline Doxylamine Effective in treating mild form of insomia But not for all types Further more they have numerous undesired effects(anticholinergic) 3.Antihistamine
- 36. 4.Other sedative-hypnotics 1. Zolpidem-hypnotic 2. Zaleplon- hypnotic 3. Chloral hydrate- hypnotic 4. Buspirone-sadative 5. ethanol-sadative
- 37.
- 38. Zolpidem imidazopyridine derivative. acts on benzodiazepine receptors & facilitate GABA mediated neuronal inhibition. Induce hypnotic effect for 5 hrs rapidly absorbed from GIT and metabolized to inactive metabolites via liver CYT P450. Short duration of action ( 2- 4 h).
- 39. Zolpidem has nomuscle relaxant effect. has no anticonvulsant effect. Minimal tolerance & dependence. Minimal rebound insomnia. Its efficacy is similar to benzodiazepines.
- 40. Zolpidem Minor effecton sleep pattern Respiratory depression occur at high doses in combination with other CNS depressant as ethanol. Uses a hypnotic drug for short term treatment of insomnia
- 41. Nightmares Headache GI upset Dizziness Daytime drowsiness. ADRS
- 42.
- 43. Zaleplon Binds toBZs receptors and facilitate GABA action, cause hypnosis. Rapid absorption Short onset of action (30min) Short duration of action (3 hr) Metabolized by liver microsomal enzymes metabolism is inhibited by cimetidine
- 44. Zaleplon Little effecton sleep pattern Potentiates action of other CNS depressants (alcohol). Used as hypnotic drug The ultrashort half-life gives zaleplon a unique advantage over other hypnotics because of its lack of next-day residual effects on driving and other performance-related skills
- 45. Anxiolytic Usedin GAD Moa action different from BDZ Bind to the serotonin and dopamine receptors. Lack anticonvulsant property . Lack muscle relaxant property Dependence is unlikey ADRS Low frequency of ADR Increase prolactin and growth hormone. Cause hypopthermia Nervousness Light headedness Buspirone-sedative
- 46. Cns depressant Ethanol potentiates GABA-receptor actions via a mechanism independent of benzodiazepine- receptor Sedation ultimately hypnosis Readily absorbed Large vol. of distribution Metabolised in liver Excreted by kidney Ethanol – sedative
- 48. Disulfaram Itblocks the oxidation of acetaldehyde to acetic acid by inhibiting aldehyde dehydrogenase Treatment for alcohol dependence
- 49. This resultsin the accumulation of the acetaldehyde resulting in Tachycardia Flushing Hyperventilation Nausea These response induce patient to avoid alco.hol
- 50.
Editor's Notes
- #6 Delirium :A state of uncontrolled excitement or emotion: Ataxia: Loss of the ability to coordinate muscular movement Ataxia is a lack of muscle coordination which may affect speech, eye movements, the ability to swallow, walking, picking up objects and other voluntary movements. A person with persistent ataxia may have damage in the part of the brain that controls muscle coordination - the cerebellum. Dyskinesia refers to a category of movement disorders that are characterized by involuntary muscle movements, including movements similar to tics or chorea and diminished voluntary movements. Tardive dyskinesia: A neurological syndrome characterized by repetitive, involuntary, purposeless movements caused by the long-term use of certain drugs ... akinesiaabsence or loss of the power of voluntary movement. 2. the temporary paralysis of a muscle by the injection of procaine. akinesia al´gera a condition characterized by generalized pain associated with movement of any kind Dystonia:a state of abnormal muscle tone resulting in muscular spasm and abnormal posture, typically due to neurological disease or a side effect of drug therapy.
- #16 Anterograde amnesia is a loss of the ability to create new memories after the event that caused the amnesia, leading to a partial or complete inability to recall the recent past, while long-term memories from before the event remain intact.
- #23 Ataxia:Loss of the ability to coordinate muscular movement. Precludes: prevent
- #44 sleep pattern:
- #46 Alcohol is a multiple-action depressor of the Central Nervous System, and the depression caused by it is dose-dependent. Although alcohol is mainly used because of its stimulating action, this action is only apparent and happens only with moderate doses. It results from the depression of inhibitory controlling mechanisms. Under the effect of alcohol the cortex is freed from its integrative role, thus resulting confuse and disorganized thinking, as well as disruption of adequate motor control. Ethanol diffuses through lipids, modifying proteins fluidity and functions. High concentrations of ethanol can decrease the eletron-transporting functions of the Na+K+/ATPase pump, thus impairing electrical conduction in the nerve cells. Neuropharmacology of Alcohol Only recently was it possible to understand the neurobiological mechanisms responsible for many clinical manifestations of alcoholism. Ethanol affects different cerebral neurotransmitters. One of them is the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). The interaction between ethanol and the GABA receptor is evident in studies showing decrease in the symptoms of alcoholic-withdrawal syndrome by the use of substances that increase GABA activity, like GABA-reuptake blockers and benzodiazepines, thus demonstrating the possible influence of the GABAergic system on the physiopathology of human alcoholism. Ethanol potentiates GABA-receptor actions via a mechanism independent of benzodiazepine-receptor. See the animation GABAergic pathways play an important inhibitory action on the other neuronal pathways. GABA-receptor is associated with the chloride channel and the benzodiazepine receptor, making up a functional complex. When GABA binds to its receptor, it promotes an increase in the opening frequency of chloride channels, thus allowing a greater flow of this ion to the intracellular medium, making it more negative, and thus promoting neuronal hyperpolarization. Low alcohol concentrations could promote facilitation of GABAergic inhibition on the cerebral cortex and spinal cord. Some phenomena observed in alcoholism, such as tolerance and dependence, could be explained by the effects consequent to chronic ethanol exposure. The quick tolerance to the increased chloride influx mediated by GABA begins already in the first hours and becomes established during chronic alcohol use. Alcohol selectively modifies the cerebral synaptic action of glutamate. The glutamatergic system, whose neurons use glutamate as neurotransmitter, and is one of the main excitatory pathways in the central nervous system, also seems to play a relevant role in the nervous alterations induced by ethanol. Glutamate is the major neuroexcitatory neurotransmitter in the brain, accounting for 40% of all synapses. Post-synaptic actions of glutamate in the central nervous system are mediated through two types of receptor: One of them is the inotropic receptor, related to ionic channels causing neuronal depolarization. The second type of receptor is the metabotropic (since its answers need cellular signalization metabolic steps); its intracellular actions are mediated by G-protein. One of the inotropic glutamate receptors has two families diferentially identified by their pharmacological, biophysical, and molecular characteristics. In the first family we find the NMDA (n-metil-D-aspartate receptor), voltage-dependent, that sustains the currents, and is associated with ion channels permeable to calcium, sodium and potassium. In the second family of glutamate receptors we find the AMPA/Ka, whose preferental agonist is a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid. Glutamate participates in synaptic plasticity and in long term potentiation (LTP), and it seems to play a critical role in memory and cognition. The prevailing eletrophysiological effect of ethanol is the reduction of excitatory glutamatergic neurotransmission. It has been observed that low concentrations of ethanol can inhibit the stimulating actions mediated by NMDA upon hippocampal cells in culture. In concentrations associated to "in vivo" intoxication, ethanol inhibits NMDA receptor current. These findings could also explaim part of the genesis of physical dependence to alcohol, through a process that is the opposite to that of GABA. That means that when ethanol is interrupted, glutamatergic pathways induce overexcitement of the central nervous system, causing convulsions, anxiety, and delirium. Calcium influx into the cells has an important function in the release of neurotransmitters in the synaptic cleft, as well as in the activity of cellular second messengers. Ethanol, in concentrations of 25mM, seems to inhibit calcium flow through ionic channels, thus decreasing neurotransmitters release. This could also be one of the mechanisms responsible for dependence and tolerance, because when alcohol-intake is stopped these ionic channels would increase calcium influx and, consequently, neurotransmission, giving rise to signs and symptoms of withdrawal syndrome.