PCL 412: Sedative-Hypnotics PDF

PCL 412: SEDATIVE-HYPNOTICS M.A.AKANMU B.Pharm., M.Sc (Ife); PhD (Tokyo) M. Phil. (Stellenbosch) MPSN, FNAPharm., FWASP DEPARTMENT OF PHARMACOLOGY FACULTY OF PHARMACY 6/23/2024...

PCL 412: SEDATIVE-HYPNOTICS M.A.AKANMU B.Pharm., M.Sc (Ife); PhD (Tokyo) M. Phil. (Stellenbosch) MPSN, FNAPharm., FWASP DEPARTMENT OF PHARMACOLOGY FACULTY OF PHARMACY 6/23/2024 1 OUTLINE…. A. Definitions B. Types of anxiolytics/hypnotics C. Barbiturates D. Benzodiazepines E. “Z” compounds & Buspirone  Neurobiology of Anxiety Disorders -CNS equilibrium is determined by a balance between excitatory and inhibitory neurotransmission Excitation - Glutamate Inhibition - GABA -Inhibition via GABA is primarily mediated by the ionotropic GABA-A receptor. GABA binding to GABA-A results in an increase in neuronal Cl- conductance and subsequent neuronal hyperpolarization. DEFINITIONS…  Anxiolytic – a drug which reduces anxiety and causes calm and quietness in the patient  Sedative – a drug that decreases activity and calms the recipient  Hypnotic – a drug that produces drowsiness and facilitates the onset and maintenance of a state of sleep that resembles natural sleep DEFINITIONS…  Anxiety→ Drowsiness→ Sleep→ Anaesthesia→ Coma→ Death  The difference between sedatives and hypnotic is usually the dose: – Lower dose – calming effect – Higher dose – cause sleep  Some newer medicines have separated the effects e.g. Buspirone- an anxiolytic without sedation  ANXIETY  Anxiety is a normal adaptive response  anxiety is a disorder if: – chronic – disproportionate to the situation – occurs without an identifiable stimulus – interferes with a person’s concentration and ability to do routine tasks ANXIOLYTICS/SEDATIVES/HYPNOTICS 1. Barbiturates e.g. Phenobarbital 2. Benzodiazepines 3. “Z”componds e.g. Zolpidem 4. Chloral Hydrate 5. Buspirone 6. Melatonin Congeners e.g. Ramelteon  Barbiturates Long-acting: Phenobarbital (phenobarbitone) has the least lipid-solubility, slow GI absorption, slow onset and long duration of action (6-8 hours). Intermediate-acting: Amobarbital has moderate lipid- solubility, moderate GI absorption, moderate onset and moderate duration of action (4-6 hours). Short-acting: Pentobarbital have high lipid-solubility, rapid GI absorption, rapid onset and short duration of action (2-4 h) Ultrashort-acting: Thiopental has very high lipid- solubility, very rapid onset (within 30 seconds) and very short duration of action (20-30 minutes). Mechanism of action Barbiturates act on the reticular activating system (RAS) and the cortex. Barbiturates share with benzodiazepines the ability to enhance the action of GABA, but they bind a different site on the GABA-receptor/chloride channel, and their action seems to prolong the duration of the opening of GABA-activated chloride channels. At high concentrations, barbiturates can directly produce GABA effect on Cl- channels (GABA- mimetic action) leading to marked CNS depression. Pharmacokinetics They are well absorbed from GIT and distributed, mainly concentrated in the brain. Ultrashort-acting barbiturates (thiopental) are highly lipophilic and penetrate rapidly BBB and have rapid onset of action, while long- acting barbiturates (phenobarbital) are less lipophilic and have slower penetration through BBB and slow onset of action Barbiturates are redistributed from the brain to the peripheral tissues as skeletal muscles and adipose tissue. They are metabolized by hepatic microsomal enzymes. They are hepatic microsomal enzyme inducers and increase rate of their own metabolism and metabolism of other drugs. Metabolites are excreted in urine. Barbiturates are acidic and rate of excretion is increased in alkaline urine. Therapeutic uses: Ultra short-acting barbiturates (thiopental) are used for IV anesthesia. They are used alone in minor surgical procedures and used for rapid induction of general anesthesia. Barbiturates are not used now as sedative-hypnotics and are replaced by benzodiazepines. Disadvantages of barbiturates Narrow safety margin (overdoses lead to marked depression of respiratory and vasomotor centers). High liability for drug abuse (more addictive) with marked withdrawal symptoms. Powerful microsomal enzyme inducers leading to many drug interactions  They alter normal sleeping pattern (depression of REM sleep and increase duration of NREM sleep). After discontinuation, there is rebound increase in REM sleep and nightmares. Hangover effect occurs. No specific antagonist in available Adverse effects After effect: hangover---dizzy, drowsiness, amnesia, impaired judgment, disorientation. Tolerance: decreased responsiveness to a drug following repeated exposure because of down- regulation of receptors and induction of hepatic drug- metabolising enzymes. Dependence: including psychologic and physiologic dependence. Withdrawal symptoms: excitation, insomnia, tremor, anxiety, hallucinations and sometimes convulsions. Depressant effect on respiration: can cross the placental barrier during pregnancy and secrete in breast milk. -Others: Skin eruptions and porphyria Treatment of acute overdosage An overdose can result in coma, diminished reflexes, severe respiratory depression, hypotension leading to cardiovascular collapse, and renal failure. Treatment: supporting respiration and circulation. alkalinizing the urine and promoting diuresis. Hemodialysis or peritoneal dialysis.  BENZODIAZEPINES  The term benzodiazepine refers to the portion of the structure composed of a benzene ring (A) fused to a seven-membered diazepine ring (B).  Approved for use ~ 50 years ago – Chlodiazepoxide - 1960 – Diazepam - 1961  MODE OF ACTION   – Aminobutyric acid (GABA) – the predominant inhibitory neurotransmitter in CNS.  GABAA receptor is a ligand-gated ion channel GABA binds to GABAA receptor  Influx of Cl- ions Hyperpolarization of the neuronal cell membrane  Excitability  MODE OF ACTION Benzodiazepines binds to GABAA receptor Facilitate GABA- GABAA receptor activity allosterically  Frequency of the channel opening &  affinity of GABA for the receptor  Chloride ion conductance  Hyperpolarization of the neuronal cell membrane PHARMACOLOGICAL EFFECTS 1. Reduction of anxiety and aggression 2. Induction of sleep 3. Anterograde amnesia 4. Anticonvulsant effect 5. Reduction of muscle tone and coordination 6. Effects on respiration 7. Effects on CVS  Reduction of anxiety and aggression  All benzodiazepines show anxiolytic effects  Can cause paradoxical hyperexcitability - range from talkativeness and excitement, to aggressive and antisocial acts  Induction of Sleep  Reduce sleep latency, increase sleep time, reduce the number of awakenings after sleep onset, and improve overall sleep quality  Alter sleep architecture – Reduce rapid eye movement (REM)sleep (increase REM sleep after withdrawal)  Anterograde Amnesia  Minor surgical or invasive procedures can be performed without leaving unpleasant memories Anticonvulsant Effect  All the benzodiazepines have shown anticonvulsant activity in animal tests  Clonazepam used as an antiepileptic and diazepam in acute seizures  Effect on Muscle Tone  Benzodiazepines reduce muscle tone by a central action on GABAA receptors primarily in the spinal cord Effect on CVS  In preanesthetic doses, all benzodiazepines decrease blood pressure and increase heart rate  Midazolam – via reduced peripheral resistance  Diazepam – via negative inotropic effect  Effect on Respiration  Can decrease hypoxic respiratory drive and cause respiratory acidosis  Can only affect respiration in children and individuals with impaired hepatic function, such as alcoholics  Usually need respiratory support in toxicity if taken with another CNS depressant e.g. alcohol  TOLERANCE  Tolerance (i.e. a gradual escalation of dose needed to produce the required effect) occurs with all benzodiazepines  Tolerance occurs to hypnotic effect after 1-2 days of use  Also seen with muscle relaxant and anticonvulsant effects  PHARMACOKINETICS  Well absorbed after oral administration  Bind strongly to plasma proteins  Metabolized extensively by hepatic CYPs  Metabolised and eventually excreted as glucuronide conjugates in the urine, several converted to active metabolites  PHARMACOKINETICS  Vary greatly in duration of action  Short-acting compounds – better hypnotics with reduced hangover effect on wakening  Long-acting compounds -better anxiolytics and anticonvulsant drugs BIOTRANSFORMATION  SEDATIVE-HYPNOTIC D R U G S 1Benzodiazepins 2-Barbiturates 3-Miscellaneous agents Short acting Ultra action Zolpidem Zaleplon Chloralhydrate Buspirone Intermediate acting Short acting Long acting Intermediate acting Long acting  Drug Peak Blood Elimination Comments Level (Hours) Half-Life1 (Hours) Alprazolam 1-2 12-15 Rapid Oral Absorption Chlordiazepoxide 2-4 15-40 Active metabolites; erratic bioavailability from IM injection Diazepam 1-2 20-80 Active metabolites; erratic bioavailability from IM injection Lorazepam 1-6 10-20 No active metabolites Temazepam 2-3 10-40 Slow oral absorption; no active metabolites Triazolam 1 2-3 Rapid onset; short duration of action Oxazepam 2-4 10-20 No active metabolites 1 Includes half-lives of major metabolites  ADVERSE EFFECTS – Sedation Hangover effect – Ataxia(impaired coordination) - affect ability to drive or operate machinery – Anterograde amnesia – Confusion – Muscle weakness  DEPENDANCE  Psychological and physical  Psychological dependence refers to drug craving that can lead to drug-seeking behaviour  Physical dependence occurs when the drug is stopped and symptoms of withdrawal occur  WITHDRAWAL SYMPTOMS  Typically mimic symptoms of anxiety disorders – Anxiety – Insomnia, Anorexia – Muscle twitching, Tremor, perspiration – Unsteadiness – Hypersensitivity to light and noise – Convulsions – Delirium tremens  "Z “ COMPOUNDS e.g. zolpidem, zopiclone  Structurally unrelated to benzodiazepines  Act as agonists on the benzodiazepine site of the GABAA receptor  Little effect on the stages of sleep  Tolerance and physical dependence – rare  BUSPIRONE  An anxiolytic medicine  EFFICACY: similar to that of benzodiazepines in anxiolytic effect  MODE OF ACTION: Act as a partial agonist for serotonin 5-HT1A receptors in the brain  BUSPIRONE  ADVANTAGES: – No physical dependence/ withdrawal – No abuse potential – Less sedation and psychomotor impairment – Lack of interaction with alcohol  DISADVANTAGES: – Slow onset of action (1-2 weeks) – Short t1/2 (2.5h) b.d./ t.d.s. administration Chloral hydrate relatively safe hypnotic, inducing sleep in a half hour and lasting about 6h. used mainly in children and the elderly, and the patients when failed to other drug. A Melatonin Receptor Agonist -Ramelteon Mechanism of Action: binds selectively to MT1 and MT1 melatonin receptors to mimic and enhance the actions of the endogenous melatonin that has been associated with the maintenance of circadian sleep rhythms. It does not appear to have high abuse potential. Pharmacokinetics rapid absorbtion – high fat meals delays Tmax and increases AUC (» 30%) extensive first pass metabolism short half-life of 1-3 hrs moderate protein binding (82%) large Vd ( » 74 L) metabolism via CYP 1A2, 2C9, 3A4 However, caution should be used in patients with: liver disease; sleep apnea. depression or suicidal thoughts, individuals over 65; may still use but dose may need to be adjusted