Sedative-Hypnotic and Anxiolytic Drugs PDF

Sedative–Hypnotic and Anxiolytic Drugs ► Sedatives and anxiolytic drugs are CNS depressants drugs that calm the patient without fells drowsy, ►Hypnotics are CNS depressants drugs that induce a state like sleep in case of insomnia. ► ►The ideal anxiolytic drug should calm the patient without causing...

Sedative–Hypnotic and Anxiolytic Drugs ► Sedatives and anxiolytic drugs are CNS depressants drugs that calm the patient without fells drowsy, ►Hypnotics are CNS depressants drugs that induce a state like sleep in case of insomnia. ► ►The ideal anxiolytic drug should calm the patient without causing too much daytime sedation and drowsiness and without producing physical or psychological dependence. ►Similarly, the ideal hypnotic drug should allow the patient to fall asleep quickly and should maintain sleep of sufficient quality and duration so that the patient awakes refreshed without a drug hangover. ► ► insomnia includes a wide variety of sleep disturbances, such as difficulty in falling asleep, early or frequent awakenings, and remaining unrefreshed after sleep. ►Causes of insomnia: 1- psychic diseases 2- CNS stimulants e.g. caffeine 3- chronic alcoholism 4- addiction to certain drugs 5- endocrine abnormalities e.g. menopause 1 Prof. Dr. Gehan Hussein Heeba Neurochemical changes during insomnia : 1- Increase in dopamine, NE in RAS leading to failure to induce sleep 2- Decrease in 5-HT in brain stem leading to failure of maintenance of sleep. Gaminobutyricacid (GABA) GABAA receptor activation leads to increased Cl- ion influx; GABAB receptor activation causes increased efflux of K+ Both mechanisms result in membrane hyperpolarization. ► Most sedatives-hypnotics drugs facilitate the actions of GABA, a major inhibitory transmitter in the CNS. GABAA receptor-chloride channel complex: ► The pentameric structure of the GABAA receptor has binding sites for benzodiazepines (BZ receptors) and for other drugs, including barbiturates and ethanol. 2 Prof. Dr. Gehan Hussein Heeba Pharmacological treatment of insomnia and anxiety: I- Benzodiazepines II- Barbiturates III- Other Sedative-Hypnotic Drugs 1- Non-Benzodiazepines : Zolpidem and Zaleplon 2- Melatonin 3-Antihistamines (first generation) 4- Older hypnotic (Chloral Hydrate) IV- Non-sedating anxiolytic drugs 1- Buspirone 2-Propranolol 3 Prof. Dr. Gehan Hussein Heeba 1- Benzodiazepines ♦ The most commonly used group of anxiolytics and sedative–hypnotics. They have a great margin of safety over previously available sedative–hypnotic agents ♦ The first member of this group, chlordiazepoxide, was introduced, many congeners have been marketed. Pharmacokinetics ► The benzodiazepines are lipophilic, completely absorbed after oral administration (oral absorption is good and rapid) , rapidly distribute and penetrate into the CNS. ► Duration of action: They divided into short-, intermediate-, and long-acting groups. -The longer-acting agents form active metabolites with long half-lives giving them long duration of action (e.g.diazepam). –Short acting drugs are metabolized by conjugation into inactive metabolites followed by renal clearance. ► Dependence: Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given for a prolonged period. All benzodiazepines are controlled substances. Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms Prof. Dr. Gehan Hussein Heeba 4 Classification Short acting (t½ < 8h): midazolam – triazolam Intermediate acting (t½ 10-20 h): alprazolam – lorazepam – clonazepam- Temazepam- Estazolam Long acting (t½ > 24 h): diazepam – clorazepate – flurazepam All BZ are sedatives 5 Prof. Dr. Gehan Hussein Heeba Mechanism of Action ► BZ have special receptors in the CNS and peripheral tissue and binds with high affinity to specific receptors in the CNS. These benzodiazepine-binding sites (receptors) are closely associated with the receptors for GABA, which is the major inhibitory neurotransmitter in the CNS. ► BZ potentiates GABA neurotransmission in essentially all areas of the CNS. This enhancement is thought to occur indirectly at the postsynaptic GABAA receptor complex. ► Drug–receptor complex regulates the entrance of chloride into the postsynaptic cells. This facilitation of GABA-induced chloride conductance results in greater hyperpolarization of these cells and therefore leads to reduced synaptic transmission. ► Benzodiazepines increase the frequency of channel openings produced by GABA. The clinical effects of the various benzodiazepines correlate well with the binding affinity of each drug for the GABA receptor–chloride ion channel complex. ► In addition to their effects on GABA, BZ also inhibits the neuronal reuptake of adenosine. This action increases the inhibitory effect of adenosine on neurons that release acetylcholine which is thought to be an important mediator of excitement and awakeness. ► 6 Prof. Dr. Gehan Hussein Heeba Schematic diagram of benzodiazepine–GABA–chloride ion channel complex. GABA = γ-aminobutyric acid. 7 Prof. Dr. Gehan Hussein Heeba Pharmacologic Effects: 1 ► Reduction of anxiety: At low doses, the benzodiazepines are anxiolytic. 2 ► Sedative/hypnotic: All benzodiazepines have sedative and calming properties, and some can produce hypnosis (sleep) at higher doses. The hypnotic effects are mediated by the α1-GABAA receptors. 3 ► Amnesia: Temporary impairment of memory with use of the benzodiazepines (in large doses). 4 ► Anticonvulsant: This effect is partially, although not completely, mediated by α1-GABAA receptors. 5 ► Central Skeletal Muscle relaxation: benzodiazepines relax the spasticity of skeletal muscle, by increasing presynaptic inhibition in the spinal cord, where the α2-GABAA receptors are largely located. Therapeutic uses: ►Anxiety disorders and sleep disorders (insomnia). ► Muscle spasm (as muscle relaxants). ► Short surgical procedures: Short acting benzodiazepines (e.g., midzolam) are preferred before surgery or endoscopy. ► Preanesthetic medications ► Seizure disorders ► Alcohol withdrawal Syndrome Prof. Dr. Gehan Hussein Heeba 8 ►Alprazolam (Xanax): Anxiety, panic, phobias (the most commonly used anxiolytic) ►Diazepam (Valium): Anxiety, muscle relaxation, status epilepticus and withdrawal states. ►Lorazepam (Ativan): Anxiety ►Triazolam : Insomnia (very rapid Tolerance in few days) ►Chlordiazepoxide : Anxiety, alcohol withdrawal ►Chlorazepate (Tranxene): Anxiety ►Flurazepam : Anxiety and Insomnia ►Oxazepam (Serax): Anxiety ►Temazepam : Insomnia ► Clonazepam (Rivotril): Seizure disorders ►Flumazenil (Anexate): (BZ antagonist) Reverse BZ-induced sedation ► Benzodiazepine antagonist ► Flumazenil is a receptor antagonist that selectively blocks the effects of other BZ at their binding sites; it has clinical application in the treatment of benzodiazepine overdose and in the reversal of benzodiazepine-induced sedation and respiratory depression resulting from IV administration of these drugs. Flumazenil is given IV, has a rapid onset of action, and has a short duration of action. 9 Prof. Dr. Gehan Hussein Heeba Adverse Effects 1- Sedation, drowsiness, dizziness and motor incoordination. 2-They may affect concentration, judgment, and planning, and interfere with driving and other psychomotor skills. 3- Apnea after rapid i.v. injection (flumazenil is the antidote) 4-Long-term use of the benzodiazepines may produce tolerance and physical dependence, the severity is proportional to the dosage and duration of adminisiration (1-2 weeks). (Triazolam very rapid Tolerance in few days) After several months of continued use, most patients develop some degree of physical dependence. If their medication is abruptly discontinued, they will experience a withdrawal syndrome, characterized by rebound anxiety, insomnia, headache, irritability, and muscle twitches. So, the dosage of benzodiazepines should be gradually tapered over a period of several weeks. ► Nevertheless, the benzodiazepine hypnotics are contraindicated during pregnancy by the FDA. ► ► Unlike barbiturates, however, the benzodiazepines do not induce their own metabolism or cause pharmacokinetic tolerance. ► In contrast to the barbiturates, the orally administered BZ do not produce respiratory depression, coma, or death unless they are administered with another CNS depressant, such as alcohol. 10 Prof. Dr. Gehan Hussein Heeba 2- Barbiturates Chemistry. The barbiturates are synthesized from urea and malonic acid. ►They are replaced by BZ because: (BZ are more selective, higher therapeutic index, with less side effects , less respiratory depressant effect, no enzyme inducing action with less interaction with other concurrent drugs, and available antidote) The action of barbiturates is not selective, i.e. increasing their doses produce generalized CNS and medullary depression Pharmacokinetics. The onset and duration of action of barbiturates are determined by their lipid solubility and rate of metabolic inactivation. ► Barbiturates are classified according to their duration of action into: 1- Long acting: barbital, phenobarbital 2- Intermediate acting: amobarbital, butabarbital 3- Short acting: pentobarbital, secobarbital 4- Ultrashort acting: thiopental, thiamylal ►Highly lipid-soluble drugs, such as pentobarbital, and thiopental, are rapidly absorbed from the gut, are rapidly redistributed from the brain to peripheral tissues ►Phenobarbital, a more polar drug, is more slowly absorbed from the gut and more slowly redistributed from the brain, and this contributes to its longer duration of action. 11 Prof. Dr. Gehan Hussein Heeba Mechanisms and Effects ►Barbiturates bind to a site on the GABAA-chloride ionophore that is distinct from the site to which benzodiazepines bind. ►Barbiturates increase the affinity of the receptor for GABA and the duration of time that the chloride channel remains open. ►In contrast to the benzodiazepines, the barbiturates also act to directly increase chloride influx in the absence of GABA. For this reason, barbiturates do not exhibit a ceiling effect. ►They have a linear dose-response curve. The higher doses progressively depress the CNS, causing respiratory depression, coma, and death (Na thiopental-Lethal injection). Side effects of Barbiturates ►Barbiturates may cause hangover and daytime sedation. ►Barbiturates may also cause tolerance and physical dependence during continuous use, and a withdrawal syndrome occurs if the drugs are abruptly discontinued. ►Short-acting barbiturates, such as pentobarbital, have been extensively abused. ► Hypotension and CVS depression at higher doses due to depression of vasomotor center (VMC) ► Liver microsomal enzyme inducers 12 Prof. Dr. Gehan Hussein Heeba Prof. Dr. Gehan Hussein Heeba 13 Interactions ►Barbiturates induce cytochrome P450 enzymes in the liver and thereby accelerate their own metabolism (pharmacokinetic tolerance), as well as that of other drugs metabolized by these enzymes. ► Tolerance, psychological and physical dependence Indications ►Barbiturates were extensively used for the treatment of anxiety disorders and insomnia prior to the development of benzodiazepines, but they are seldom used for these purposes today. Unlike the benzodiazepines, the barbiturates do not produce significant muscle relaxation and are not used in treating muscle spasm or spasticity disorders. ► Amobarbital and pentobarbital have been primarily used as hypnotics for the treatment of insomnia. ► Phenobarbital is used occasionally for the treatment of seizure disorders (neonatal), and thiopental is administered IV to induce anesthesia. 14 Prof. Dr. Gehan Hussein Heeba III- Other Sedative-Hypnotic Drugs 1- Z drugs or Non-BZ hypnotics Zolpidem , Zaleplon, Zopiclone Non-benzodiazepines are the newest class of hypnotics. Also known as the 'Z' drugs ►They are unique imidazopyridine compounds, structurally unrelated to the benzodiazepines, but both drugs share pharmacological properties with benzodiazepine. They bind to (GABAA α1 subunit) receptors and facilitate GABA-mediated inhibition (by action on α1 subunit) ► More selective as hypnotic, with No anti-convulsant and muscle relaxant effects. ► Less respiratory depressant effect ► They appears to produce relatively less tolerance and dependence, and theirs short duration of action usually prevent daytime sedation and hangover. For these reasons, they are become the most widely used prescription drug for treating insomnia. ►Zolpidem (Stilnox) is used as immediate and controlled release tablet in treating insomnia. Zaleplon (Siesta, Sleep-aid) in short term treatment of insomnia. ►Principal side effects are gastrointestinal and central nervous system symptoms, including drowsiness, dizziness, and diarrhea. Zolpidem may increase the depressant effects of other sedative drugs, such as the antipsychotics, tricyclic antidepressants, and antihistamines. 15 Prof. Dr. Gehan Hussein Heeba 2- Melatonin ► ►The hormone interacts with specific receptors (MT1 and MT2) in the CNS, and it is believed to be the principal mediator of the biologic clock that determines circadian, seasonal, and reproductive rhythms in animal species. ► Ramelteon (Rozerem) is the first drug that acts as agonist on MT1 and MT2 subtypes of melatonin receptors. ►In humans, melatonin is released prior to the onset of sleep and produces drowsiness that facilitates sleep. ►Melatonin is available without prescription and is effective in the treatment of jet lag in individuals who have rapidly traveled across several time zones and in the treatment of insomnia in shift-change workers. ►Melatonin may be effective in treating insomnia in elderly patients who do not secrete adequate melatonin ►Melatonin has relatively few adverse effects when taken as a drug, but it may cause fatigue and lethargy. For this reason and also because some tolerance to its hypnotic effect may develop, the lowest effective dose should be used. ► Prof. Dr. Gehan Hussein Heeba 16 3- Antihistamines ► Some of the histamine antagonists (antihistamines) cross the blood-brain barrier and produce varying degrees of sedation, and these drugs have been used in the treatment of mild insomnia and anxiety disorders. ► e.g. Doxylamine (Donormyl) and Diphenhydramine are the active ingredient in several nonprescription sleep preparations, and Hydroxyzine has been used in the treatment of mild anxiety and is sometimes used as a sedative before surgery. ►Some tolerance may occur during the long-term use of antihistamines, but these drugs are not associated with physical dependence or significant drug abuse. 4- Older hypnotic (Chloral Hydrate) ► Chloral hydrate is an older hypnotic and It is a prodrug that is converted to its active metabolite, trichloroethanol, by liver enzymes. Its effects are potentiated by alcohol. ► It produces hypnosis in 30 min and last for 6 hrs. ► It is used mainly as a hypnotic in children and elderly before short surgical or dental procedures but its use now is very limited. 17 Prof. Dr. Gehan Hussein Heeba IV- Non-sedating anxiolytic drugs Buspirone (Buspar) ►Buspirone is a partial agonist at serotonin 5-HT1A receptors in the midbrain ►Buspirone is used in the treatment of chronic anxiety and produces an anxiolytic effect without causing marked sedation, amnesia, tolerance, dependence, or muscle relaxation. ►This effect takes time to develop and would be consistent with the 3-4 week delay in the onset of the anxiolytic effect of buspirone. ► It is the choice anxiolytic drug for elderly patients ► No liability for drug dependence. ► side effects : it may cause headache, dizziness, nervousness and tachycardia , but these side effects are usually mild and temporary. ► Prof. Dr. Gehan Hussein Heeba 18 Propranolol ► Propranolol (Inderal) , a β-adrenergic receptor antagonist (β-blocker), is sometimes used to prevent the physiologic manifestations of stage fright, or acute situational or performance anxiety. ►When taken an hour before the anticipated anxiety- provoking event, propranolol prevents tachycardia and other signs and symptoms of acute anxiety caused by sympathetic stimulation. The drugs may act to block the effects of NE, but whether this action contributes to their anxiolytic effect is not certain. Prof. Dr. Gehan Hussein Heeba 19