Dr. Carl B. Goodman Professor of Pharmacology College of Pharmacy & Pharmaceutical Sciences Florida A&M University 308 FSH-SRC

Sedative: Depress the CNS-Calm down, treat agitation Hypnotic: Induce sleep go to sleep fast, feel refreshed tomorrow !!! Anxiolytic: Reduce anxiety physical, emotional, cognitive

BENZODIAZEPINES (BZDs) Dose-dependent depression of the CNS Selective anxiolytic effect Relieve anxiety without sedative effects BARBITURATES (BARBS) Were once extensively used for antianxiety and sedation, but have been largely replaced by the benzodiazepines

Sedative-Hypnotic: treat insomnia Anxiolytic (antianxiety): Anxiety (panic, obsessive compulsive disorders, phobias) Muscle Relaxant: spasticity, dystonias Anticonvulsant: absence, status epilepticus, and generalized seizures (rapid tolerance develops) Other Uses: Pre-operative medication & endoscopic procedures Withdrawal from chronic use of ethanol and other CNS depressants.

Increasing doses produce sedation, hypnosis and stupor, but BZ’s are NOT general anesthetics. While analgesia has been reported in humans after IV use, this is related to the anterograde amnesia produced - BZ’s are NOT analgesics. Diazepam (Valium) given iv has shown to have analgesic actions

BZs bind to GABA A receptors in the limbic system (amygdala, septum, hippocampus).These brain regions are involved in emotional processes or mental function Sleep involves the ascending reticular formation Muscle relaxation involves the medulla Ataxia involves the cerebellum

Pentameric structure composed of alpha, beta, delta, and gamma subunits GABA A Receptor has several binding sites: GABA site Increase G Cl- Hyperpolarization Inhibition Barbiturate site Increase GABA effect Benzodiazepine site Increase GABA effect Picrotoxin site Block Cl- channel

Agonists: GABA GABA binds to GABA A receptors which increases Cl- conductance and hyperpolarizes neurons Neuronal activity is inhibited by GABA Antagonists: Bicuculline Competitive block of GABA binding Reduces inhibition and produces convulsions Antagonists: Picrotoxin Non-competitive block of GABA actions Blocks the chloride channel Reduces inhibition and produces convulsions

BZs bind to a site on GABA A receptor (ionotropic Cl- channel). Enhance inhibitory effect of GABA by increasing Cl- influx (hyperpolarization). BZ’s increase FREQUENCY of Cl- channel opening in the presence of GABA. BZ’s alone (without GABA) don’t affect Cl-channel function.

AGONISTS: Zolpidem (non-BZ) Act at BZ receptor to produce pharmacological actions. INVERSE AGONISTS: Beta-carbolines Produce the opposite effects at the BZ binding site Decrease chloride conductance Anxiety, irritability, agitation, delirium, convulsions No therapeutic uses

Flumazenil BZD receptor antagonist Blocks both agonist & inverse agonist; Have no biological effect ; Can precipitate withdrawal in dependent persons High Ist pass metabolism Only i.v. Used to reverse BZD anesthesia BZD over dose 0.2mg/mt→If does not respond suspect other drugs along with BZD like alcohol

Chlordiazepoxide (Librax or Librium) Has a medium to long half life, but its active metabolite has a very long half life. Has amnestic, anxiolytic, hypnotic and skeletal muscle relaxant properties. Used for short term treatment of anxiety for 2-4 weeks & management of acute alcohol withdrawal syndrome Similar to Phenobarbital in its anticonvulsant properties. However, it lacks the hypnotic effects of Barbiturates

Hypnotics Diazepam, Nitrazepam (Mogadon), Alprazolam, Temazepam (Restoril), Triazolam Ant-anxiety: Diazepam, Chlordiazepoxide, Oxazepam, Lorazepam, Alprazolam Anti-convulsants: Diazepam, lorazepam, Clonazepam, Clobazam Non[Novel]-Benzodizapine hypnotics: Zopiclone, Zolpidem, Zaleplon

Short- Acting alprazolam= Xanax *greater efficacy for panic and phobic disorders oxazepam= Serax midazolam= Versed triazolam = Halcion *widely used for primary insomnia and other sleep disorders temazepam= Restor Intermediate Acting lorazepam= Ativan estazolam= ProSom *widely used for primary insomnia and other sleep disorders temazepam= Restor Long- Acting chlordiazepoxide= Librium *used for management of withdrawal states in physiologically dependent on ethanol and other sedative-hypnotics clonazepam= Klonopin *greater efficacy for panic and phobic disorders clorazepate=Tranxene diazepam= Valium flurazepam= Dalmane *widely used for primary insomnia and other sleep disorders temazepam= Restor

Lipid-soluble: fast cross blood-brain-barrier: rapid onset of action. Persist longer in high fat-to-lean body mass obese, elderly Abuse liability (Valium) Biotransformation & Half-Life: Hepatic oxidation: long-t1/2, active metabolites Glucuronidation: short-t1/2, no active metabolite

Metabolic rates vary among Sedative-Hypnotics-BZDs Many are converted initially to active metabolites with long half-lives (Diazepam & Fluazepam) which can lead to excessive sedation with several days of therapy. Lorazepam and Oxazepam undergoes extrahepatic conjugation and does not form active metabolites.

DrugHalf-lifeUses DiazepamLong (> 24 hrs)Anxiety, Withdrawal, Muscle Relaxant TemazepamIntermediate (6-24 hrs)Insomnia, Anxiety TriazolamShort (2-6 hrs)Insomnia MidazolamUltra-short (< 2 hrs)Pre-anesthetic Medication

BZ’s have a high therapeutic index (TI) TI = LD50/ED50= 100’s Overdose usually not life threatening TREATMENT: Support respiration & blood pressure Gastric lavage, activated charcoal, cathartic (Sorbitol) Give antagonist: Flumazenil (Romazicon) Short acting (~2 hr) Injected IV, quickly reverses BZ-induced respiratory depression.

Benzodiazepines have largely replaced Barbiturates because they are much safer Death Coma Anesthesia Ataxia Sedation Anticonvulsion Antianxiety LowHi Dose

PHARMACODYNAMIC Due to “down-regulation” of CNS response CROSS-TOLERANCE With other BZ and CNS depressants (e.g., EtOH, BARBS) ACQUISITION OF TOLERANCE Anticonvulsant > Sedation >> Muscle Relaxant > Antianxiety

Abuse Potential is low, however... Physical and/or psychological dependence may develop Physical dependence is present when withdrawal symptoms occur: Mild: anxiety, insomnia, irritability, bad dreams, tremors, anorexia Severe: agitation, depression, panic, paranoia, muscle twitches, convulsions

Minimal induction of liver drug metabolizing enzymes, therefore few drug interactions are produced. Additive CNS effects Severe CNS depression and coma can result from BZs taken with other CNS depressants such as ethanol Death from BZ overdose is usually associated with ingestion of a CNS depressant

Somnolence (difficulty staying awake) Mental confusion Hypotension Hypoventilation Impaired motor functions Impaired reflexes Impaired coordination Impaired balance Dizziness Muscle weakness Coma

Were once extensively used for antianxiety and sedation, but have largely been replaced by the benzodiazepines. Clinical uses are similar to those for the benzodiazepines Advantages: Barbiturates are effective and relatively inexpensive Barbiturates have been extensively studied and there is a vast amount of information available related to side effects and toxicity

IV anesthesia: Thiopental (Pentothal) and Methohexital (Brevital) Convulsions: emergency treatment (eclampsia, tetanus, status epilepticus), but benzodiazepines are preferable. Epilepsy Rarely used as a sedative due to the availability of safer benzodiazepine agents.

Respiration: depression with increasing doses Cardiovascular: decreased BP and HR at sedative- hypnotic doses Liver: bind cytochrome P450 Induce drug metabolizing and other enzymes Increases metabolism of steroids, vitamins K/D, cholesterol and bile salts.

General Mechanisms Potently depress the activity of neurons in the reticular formation (pons, medulla) and cortex.

Specific Mechanisms Bind to a site on GABA A receptors while inhibiting excitatory AMPA receptors. AMPA receptors are the subtype of glutamate receptors sensitive to kainate or quisqualate. Increase the open time of Cl- channels in the presence of GABA. Increases Cl- influx Enhances the inhibitory effects of GABA At high concentrations directly increase Cl- conductance in the absence of GABA (act as GABAmimetics).

Mostly all BARBs are lipid soluble and are well absorbed from the GI tract, with good distribution to the brain. Thiopental has the highest lipid solubility and enters the CNS rapidly and is used as an inducting agent in anesthesia. Termination of Thiopental occurs by rapid redistribution of the drug from the brain to other tissues.

Liver microsomal drug metabolizing enzymes many complex reactions With the exception of Phenobarbital, which is excreted partly unchanged in the urine, the BARBs are extensively metabolized via oxidation at the C5 position. Most barbiturates are dealkylated Conjugation by glucuronidation Renal excretion

DrugHalf-lifeUses PhenobarbitalLong ( hrs)Anticonvulsant PentobarbitalIntermediate (15-50 hrs)Preoperative Sedation AmobarbitalShort (10 hrs)Preoperative Sedation ThiopentalUltra-short (3-10 hrs)Anesthesia Induction

SIDE EFFECTS: Common Effects: Sedation & confusion CONTRAINDICATIONS: Pain: can increase sensitivity to painful situation resulting in restlessness, excitement and delirium. Pulmonary insufficiency: respiratory depression.

Enhance CNS depressive effects of: Antipsychotics, antihistamines, ethanol, and tricyclic antidepressants. Accelerate metabolism of: Beta-blockers, Ca2+-channel blockers, corticosteroids, estrogens, phenothiazines, valproic acid and theophylline.

Barbiturate poisoning: Major problem. Serious toxicity at only 10X hypnotic dose. Respiratory depression, circulatory collapse, renal failure and pulmonary complications can be life threatening. Symptoms: Severe respiratory depression, coma, severe hypotension, hypothermia. Treatment: Support respiration and blood pressure Gastric lavage if recent ingestion. Activated charcoal and a cathartic (Sorbitol).

METABOLIC: Induction of hepatic metabolic enzymes Occurs within a few days PHARMACODYNAMIC: Decreased CNS response with chronic exposure Occurs over several weeks Mechanism unknown CROSS-TOLERANCE: Tolerance to other general CNS depressants

Physical dependence: Develops with continued use dependence is manifested by withdrawal symptoms Withdrawal Symptoms: Mild symptoms: anxiety, insomnia, dizziness, and nausea. Severe symptoms: vomiting, hyperthermia, tremors, delirium, convulsions, and death.

If non-pharmacological treatment of insomnia (such as moderate exercise). In addition to use of pharmacological agents, management of insomnia should include (a) a search for an underlying cause, elimination of "performance anxiety" related to falling asleep. Adjusting the patient's biological clock such that sleepiness corresponds to the time of attempted sleep Suppression of the use of alcohol or over-the-counter sleep aids

Ethanol Ethanol should not be used to manage insomnia because of numerous adverse effects. For insomnia, despite reducing sleep latency, it may cause sleep fragmentation. Barbiturates However, these drugs should be avoided: Liabilities associated with barbiturate use include abuse potential, physical potentially life-threatening withdrawal reactions, dependence, and life-threatening toxicity with overdosage. Meprobamate (Equanil) Pharmacological properties like Benzodiazepines & Barbiturates Mechanism of action unknown

Are preferable to barbiturates because of: greater therapeutic index, less disruption of sleep patterns, less danger of overdosage toxicity, less abuse liability. In the absence of daytime anxiety benzodiazepines with short half-lives (no active metabolites or only short-acting metabolites) are preferable. Triazolam (Halcion) is an example of a short-acting agent that has been used as a hypnotic. Short acting benzodiazepines may, however cause amnesia, early morning awakening, rebound daytime anxiety Some patients who have insomnia also have daytime anxiety. To manage those patients a longer-acting benzodiazepine may be appropriate. Use of these agents may result in: next-day cognitive impairment or delayed cognitive impairment as metabolites accumulate

Zolpidem (Ambien) Acts on Benzodiazepine type-1 receptor (sleep) Fast onset 30 min-2 hrs Elimination t1/2 3 hrs Increases quality of slow wave sleep, no effect on REM Minimal rebound insomnia, anxiety, or am sedation Probable less abuse potential, (caution) Zaleplon (Sonata) - Shortest duration of action - Undergoes even more rapid hepatic metabolism by aldehyde oxidase and cytochrome P450. Eszopiclone (Lunesta)

Used for the short-term treatment of Insomnia and as a sedative before minor medical or pediatric dentistry for diagnostic imaging procedures Today, it is commonly used as an ingredient in the veterinary anesthetic Equithesin (mixture of chloral hydrate, magnesium sulfate and pentobarbital sodium) Exerts its pharmacological properties via enhancing the GABA receptor complex. Effective within 60 minutes, it is metabolized (by oxidation) within 4 minutes into Trichloroethanol by erythrocytes and plasma esterases and many hours later into Trichloroacetic acid. Higher doses can depress respiration and blood pressure. But, the therapeutic index is similar to barbiturates

Duration of Actions From a few hours: Zaleplon < Zolpidem = Triazolam < Chloral Hydrate More than 30 hours: Chlordiazepoxide, Chorazepate, Diazepam and Phenobarbital

Benzodiazepines Factors that have promoted the popularity of these drugs include: Safety Pharmacology Patient demand. Benzodiazepines may be more efficacious and certainly safer in management of anxiety compared to barbiturates. Barbiturates and non-barbiturates such as Meprobamate have been used in the past to manage anxiety. However, these drugs are now rarely used. Barbiturates are also infrequently used for this indication because of: Excessive sedation/intoxication at anxiolytic dosages Tolerance Physical dependence

Benzodiazepines are commonly used for management of generalized anxiety disorder. Chlordiazepoxide (Librium) Diazepam (Valium) Oxazepam (Serax) Clorazepate (Tranxene) Lorazepam (Ativan) Alprazolam (Xanax) Halazepam (Paxipam)

Barbiturates are rarely prescribed Buspirone Has selective affinity of 5-HT 1A (mixed agonist antagonist activity), is a relatively new anxiolytic. Seems most effective in mild and generalized anxiety and is not effective compared to benzodiazepines and certain antidepressant agents in treatment of panic disorder. Does not exhibit cross-tolerance with benzodiazepines or other sedative-hypnotics. No physical dependence. No sedation or impaired cognition occurs with this drug. No anticonvulsant activity, will not protect from withdrawal symptoms Start 5 mg tid, max 60 mg/day. Onset of action is 1 to 3 weeks; limits it usefulness. No additive depression with ethanol

Tx of anxiety & insomnia, Non-addicting Some anticholinergic effects Diphenhydramine [Benadryl] mg hs sleep OR mgr prn anxiety Hydroxyzine [Atarax] mg hs sleep mg 1-4 times/day

Physiologic component of anxiety: tachycardia, palpitations, tremor, sweating No CNS depression non-addicting, no drowsiness Do not use in asthma, diabetes, CHF monitor BP and pulse Helpful for performance anxiety: Propranolol 10 mg prn

Sedatives Benzodiazepines Antipsychotics Hypnotics (Non-pharmacological 1st) Antihistamines Zolpidem Benzodiazepines (rapid onset, short t1/2) Anxiolytics Benzodiazepines (acute) Antidepressants (chronic)