PHARMACOLOGY Sedative-Hypnotic-Anxiolytic Drugs Lecturer: Deo L.

Panganiban, MD, FPSECP

I. Sedative-Hypnotic II. The Drugs III. Benzodiazepines a. Diazepam IV. Newer Sedative Hypnotics a. Zolpidem b. Buspirone V. Barbiturates

Transcriber: Cj Editor: MGB Number of pages: 9

a. Phenobarbital VI. Ethanol VII. Pharmacotherapy of Alcoholism a. Disulfiram

Sedative Decreases activity Moderates excitement Calming or tranquilizing effect Used as pre-medication for surgical procedures Hypnotic Produces drowsiness Facilitates the onset and maintenance of sleep that resembles natural sleep and from which the person can be aroused easily I. SEDATIVE-HYPNOTIC DRUGS CNS depressants depress the CNS in a dose dependent manner, progressively producing sedation, sleep, unconsciousness, surgical anesthesia, coma and ultimately fatal depression of respiratory and cardiovascular function

5. Chloral dervatives** (older sedative-hypnotic) Chloral hydrate 6. Carbamates** (older sedative-hypnotic) Meprobamate 7. Piperidinediones Glutethimide Thalidomide: (kakasawa na to haha; initially prescribed as a sedative for pregnant women, until they eventually realized that it was a teratogenic; now it can be used as an immunosuppressant/anti-cancer drug) 8. Antihistamines: the older antihistamines; because the newer ones were developed para hindi antukin (Finals review! 1st generation Antihistamines make you drowsy, eg. Diphenhydramine; while 2nd and 3rd generation Antihistamines do not, eg. Loratadine (2nd), Cetirizine(2nd), Desloratadine (3rd)) Diphenhydramine Hydroxyzine

III. BENZODIAZEPINES
Potentiate GABA effects Increase FREQEUNCY of Cl- Channel opening Have no GABA mimetic properties Act through Benzodiazepine receptors These receptors are part of GABAA complex Bz1 mediates sedation Bz2 mediates anti-anxiety and cognitive functions **Shows that the effects of sedative-hypnotics are dosedependent; the greater the dose, the wilder the effect II. THE DRUGS 1. Benzodiazepines Diazepam Midazolam: more water soluble than Diazepam; less painful when injected IV 2. Non-Benzodiazepines Zolpidem Buspirone 3. Barbiturates Phenobarbital Amobarbital Thiopental 4. Alcohol Ethanol Benzodiazepines were first introduced in 1960s with the synthesis of the 1st benzodiazepine, Chlordiazepoxide As a class, they all have similar CNS effects and adverse effects; while they only differ in their onset and duration of action. Composition: a benzene ring fused to a 7membered diazepine ring structure. A halogen or nitrogen substituent in the 7 position sedativehypnotic effect

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Relatively wide margin of safety Prolonged, daily use may produce dependence Have little effect on respiratory or cardiovascular function compared to the Barbiturates Fatality from overdose is rare except when taken with alcohol or other CNS depressants Exert qualitatively similar clinical effects Low capacity to produce fatal CNS depression Coma may occur at very large doses Has displaced other agents as first line Sedative hypnotics.

GABAA receptor: An Oligomeric glycoprotein (, , , , ,, etc) Major player in inhibitory synapses A Cl- channel Binding of GABA causes the channel to open and Cl- to flow into the cell with the resultant membrane hyperpolarization Various receptors are actually part of the GABAA receptor, with each receptor accommodating a specific ligand

Classification according to duration of action: 1. Short-acting (T <6 hours): makes good preanesthetic drugs due to short action Triazolam Midazolam Zolpidem (2hrs) and zopiclone (5-6 hrs) non benzodiazepines but are active at the benzodiazepine receptor 2. Intermediate acting (T 6-24 hours) Lorazepam: The date-rape drug :> **24 hours of anterograde amnesia :> Chlordiazepoxide Alprazolam Estazolam Flunitrazepam Temazepam 3. Long acting (>24 hours): usually used for longer sedation periods Flurazepam Quazepam Diazepam** (prototype) Benzodiazepine Receptors 1. Bz1 or Omega 1 mediate sedative, hypnotic action 2. Bz2 or Omega 2 mediate cognition, memory, motor control 3. Bz3 outside CNS; abundant in the kidneys Characteristics of Benzodiazepine Receptors: Benzodiazepine receptor is a part of the GABAA receptor Upon binding, this will cause an allosteric change in the GABAA receptor GABAA receptors are responsible for most inhibitory neurotransmission in the CNS Benzodiazepine binding enhances coupling of GABA to its receptor High affinity Saturable and stereospecific; a certain dose will occupy all the receptors

A. DIAZEPAM Mechanism of Action: Interaction of Benzodiazepine with Benzodiazepine receptor in the Chloride ionophore (ionophore: substance that is able to transport particular ions across a lipid membrane in a cell.) This leads to an allosteric change in the GABAA receptor, causing enhanced binding of GABA This enhanced binding of GABA leads to an increase in Cl- conductance Hyperpolarization of neuronal membrane (increases the FREQUENCY of channel opening) Pharmacologic actions and effects: 1. CNS Sedation calming effect Hypnosis facilitate onset and maintenance of sleep Anticonvulsant Muscle relaxation; not as marked as when neuromuscular blockers are used Anterograde amnesia 2. Respiratory system hypnotic dose has no effect in normal individuals caution in children, elderly and patients with impaired hepatic function (I.e. alcoholics)

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hypnotic doses worsen sleep-related breathing disorders by decreasing muscle tone in the upper airway muscles or by decreasing the ventilator response to CO2 Eg. Obstructive sleep apnea (OSA)

**OSA - a contraindication to the use of alcohol or any sedative-hypnotic agent, including a benzodiazepine; **Partial airway obstruction of those who snore regularly may be converted to OSA under the influence of these drugs.

exaggerated effects in patients with pulmonary disease Eg. COPD

Biphasic plasma concentration time curve: o An initial rapid and extensive distribution phase (half-life 3 hrs.) o Prolonged elimination phase (half-life 2048 hrs.) Elimination half-life may be prolonged in the newborn, elderly, patients with hepatic or renal disease High protein binding (99%) readily crosses the blood brain barrier CNS concentration approximates plasma concentration crosses the placenta and secreted in breast milk

**As dose is increased, effects are also increased in progression. Benzodiazepines however, dont reach the peak of this curve. They cannot produce respiratory depression, but can still induce coma. They are safer compared to barbiturates, pero not really that safe, kasi nakakapagcause din ng coma. Lesser evil lang. **Ethanol can cause respiratory depression. A friendly post-evals encouragement/reminder :D

**Diazepam IV reaches therapeutic concentration at a faster time + less dose compared to PO, since PO route goes through hepatic first-pass effect

3. CVS negative inotropic effect Coronary vasodilatation on IV administration decrease BP and increase heart rate 4. GIT Decrease nocturnal gastric secretion Relieves anxiety-related GI disorders Pharmacokinetics: completely absorbed from the GIT o All the benzodiazepines are absorbed completely, except clorazepate very high lipid solubility high rate of entry into CNS rapid onset, short duration o ~99% lipid solubility: concn in the CSF is approx equal to the concn of free drug in plasma Peak plasma concentration in 30-90 minutes after oral intake onset after IM administration is variable, but faster than oral

Benzodiazepines are metabolized by CYP3A4 and CYP2C19 to active metabolites, Nordazepam and Temazepam; then both metabolites are further metabolized to Oxazepam (see the following diagram) Temazepam and Oxazepam subsequently undergoes glucuronidation do not induce activity of hepatic microsomal enzymes Drug and its metabolites are excreted in urine.

**Diagram of the text

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Therapeutic uses of Diazepam: 1. Anxiety 2. Insomnia 3. Seizure disorders Status epilepticus and spasms due to tetanus Lorazepam as alternative 4. Anesthesia Pre-anesthetic medication (Lorazepam as alternative) Induction agent Midazolam 5. Muscle spasticity Reflex muscle spasm due to trauma to muscles, bones and joints Spasticity due to upper motor neuron lesions 6. Control signs and symptoms of withdrawal from alcohol acute agitation tremors impending or acute delirium tremens hallucinosis Adverse Effects: Sedation and impairment of performance o motor incoordination o impairment of mental and motor function o increased reaction time o residual daytime sedation Memory impairment o anterograde amnesia may be associated with inappropriate behaviour o dose-related o tolerance may develop Increase risk of respiratory depression in patients with chronic respiratory insufficiency Increase arterial carbon dioxide tension and decrease oxygen tension in patients with chronic obstructive pulmonary disease Increase frequency of seizures in patients with epilepsy Disinhibition (paradoxical) reactions (dose realted): o restlessness, agitation, irritability o Aggressive, inappropriate behavior o delusions, hallucinations o hostility, acute rage Pregnancy and Lactation o Teratogenic o Fetal respiratory depression o Floppy infant syndrome hypothermia hypotonia, poor sucking respiratory depression

Abuse and Dependence: Abuse potential decreased when properly prescribed and supervised BUT CAN STILL HAPPEN dependence may occur at therapeutic doses taken on regular basis for prolonged periods Shorter acting Benzodiazepines produce the greatest dependence; since theyre short acting, they have a shorter effect, and after the short effect you want more, so you take multiple short effect drugs. Withdrawal syndrome: similar in character with those of barbiturates and alcohol occurs after abrupt discontinuation of drug withdrawal symptoms may include temporary intensification of the problems that originally prompted their use (e.g. insomnia, anxiety) other symptoms include dysphoria, palpitations, panic attacks, hypersensitivity to light, sound and touch major syndrome includes convulsions, confusional state, hyperthermia; death can occur can be prevented by gradually tapering the dose before stopping treatment abuse by the pregnant mother can result in withdrawal syndrome in the newborn

IV. THE NEWER SEDATIVE HYPNOTICS A. ZOLPIDEM an imidazopyridine structurally unrelated to Benzodiazepines but binds to the Bz1 receptor shortens sleep latency and prolongs total sleep time currently approved for short term treatment of insomnia (7-10 days) rarely produce residual daytime sedation or amnesia do not produce respiratory depression even at large doses

Mechanism of Action: binds selectively to Bz1 receptors Facilitates GABA-mediated neuronal inhibition Actions can be antagonized by Flumazenil Pharmacokinetics: readily absorbed from the GIT first pass hepatic metabolism results in an oral bioavailability of about 70%. (lower when the drug is ingested with food)

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Peak plasma concentration in 2-3 hrs (may be increased n those with cirrhosis and in older patients; adjustment of dose is necessary) plasma half-life is approx. 2 hours rapidly metabolized by liver enzymes into inactive metabolites dosage should be reduced in the elderly, in patients with hepatic dysfunction, patients taking Cimetidine and other drugs that inhibit drug metabolizing enzymes

Available only for IV administration with short t of (0.7 1.3 hours) because benzodiazepines have a longer duration of action, there is a need to repeat administration of flumanezil Adverse effects: agitation, confusion, dizziness, and nausea. Seizure and cardiac arrhythmias on px with tricyclic antidepressant

B. BUSPIRONE Mechanism of Action: Acts as partial agonists at the serotonin (5-HT1-A) receptor, thereby reducing release of 5-HT & other mediators ***(More serotonin mas happy; Buspirone acts as a substitute for serotonin, so by negative feedback, decreased yung release ng serotonin, kasi yung Buspirone, acts like serotonin aka partial agonist) Clinically, partial agonists (in this case, Buspirone) can activate receptors to give a desired submaximal response when inadequate amounts of the endogenous ligand (Serotonin) are present Has affinity for brain Dopamine (DA2) receptors: o Ipsapirone, Gepirone - related anxiolytics o Anxiolytic effects of buspirone takes more than a week to become established o Not anticonvulsant or muscle relaxant Used to treat generalized anxiety disorders (GAD) Relieves anxiety without causing marked sedative, hypnotic or euphoric effects Minimal sedation Cognitive and psychomotor dysfunction is low Ineffective in control of panic attacks Adverse effects : o headaches, nervousness, dizziness but not sedation or loss of consciousness C. FLUMENAZIL: Benzodiazepine antagonist Structure similar with benzodiazepines but with replacement of keto function at position 5 and a methyl substituent at position 4 Management of suspected Benzodiazepine overdose o Cumulative dose of 5 mg should produce response Reversal of sedative effects of Benzodiazepine during either general anesthesia, or diagnostic or therapeutic procedures Antagonism of benzodiazepine-induced respiratory depression is less predictable

V. BARBITURATES
Prolong GABA activity Increase DURATION of Cl- channel opening Have GABA mimetic property at high doses Do not act through Benzodiazepine receptors Have their own binding sites on the GABA complex Also inhibit complex 1 of electron transport chain most commonly used drug for sedation and hypnosis before the advent of Benzodiazepines toxic and highly addictive abrupt withdrawal can cause death poisoning accounted for a great number of deaths from sedative hypnotics low degree of selectivity (whether you give it for anxiety, it may still produce sedation or coma) Low therapeutic index (finals review. Haha therapeutic index is a measure of how safe a drug is. TI = . LD = lethal dose, ED = effective dose.

The lower the therapeutic index, the more dangerous the drug is.) less selective than Benzodiazepines produce strong physiological dependence on long term use depresses the medullary respiratory center also produce loss of brainstem vasomotor control and myocardial depression

Classification according to duration of action: 1. Long acting Phenobarbital** (prototype) 2. Intermediate acting Amobarbital 3. Short acting Pentobarbital Secobarbital 4. Ultrashort acting Thiopental: used for induction of anesthesia

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A. PHENOBARBITAL Mechanism of Action: Binds to Barbiturate receptor in the GABAA receptors Enhance binding of GABA to GABAA Receptor Increase Chloride conductance Hyperpolarization of neuronal membrane (increases the DURATION of channel opening) Pharmacologic actions and effects: 1. Central nervous system Mild sedation to deep coma Hypnotic doses decrease sleep latency and increase total sleep time Over dosage can produce death due to respiratory depression mood alteration anticonvulsant at low doses Sub-anesthetic doses may increase reaction to painful stimuli aka paradoxical excitement 2. Peripheral Nervous structures selectively depress transmission in autonomic ganglia and reduce nicotinic excitation by choline esters 3. Respiratory system Depress both the respiratory drive and the mechanisms responsible for the rhythmic character of respiration. hypnotic doses produced same degree of respiratory depression during physiologic sleep Degree of respiratory depression is dose dependent Hypostatic pneumonia Coughing, sneezing, hiccoughing and laryngospasm esp. for very acute use of Thiopental 4. Gastrointestinal tract decrease tone and amplitude of intestinal contraction constipation Hypnotic doses does not significantly delay gastric emptying time The relief of various GI symptoms by sedative doses is probably largely due to the centraldepressant action. 5. Liver does not impair normal hepatic function Induction of liver enzymes at high doses (CYP450, delta aminolevulinic acid synthetase, aldehyde dehydrogenase, etc.) Acutely, it may inhibit the biotransformation of some drugs and endogenous substrates, such as steroids

6. Cardiovascular system hypnotic dose produce slight decrease in BP and heart rate Myocardial depression at toxic doses 7. Uterus Decrease tone and frequency of contractions 8. Abuse and dependence potential the barbiturates may have euphoriant effects Pharmacokinetics: weak acid rapid absorption following oral administration Sodium salts are more rapidly absorbed from GIT available in tablet, liquid, parenteral and rectal formulations onset of action: 10 mins to 60 mins presence of food decreases rate of absorption distributed rapidly to all tissues and body fluids low lipid solubility low plasma protein binding Long duration of action; plasma half-life is 53-118 hrs. metabolized primarily in the liver by glucuronide conjugation metabolic products are excreted in the urine 25% of Phenobarbital is excreted unchanged in the kidneys Phenobarbital excretion can be increased by alkalinization of the urine. In the elderly and in those with limited hepatic function, dosages should be reduced. Phenobarbital causes auto metabolism by induction of liver enzymes Adverse Effects: 1. Hypersensitivity reaction Stevens Johnson syndrome 2. Central nervous system drowsiness, residual CNS depression paradoxical excitement paradoxical dysphoria hyperreactivity 3. Respiratory system Hypoventilation, manifested as apnea Hypostatic pneumonia Cough, hiccough/hiccup Laryngospasm 4. Cardiovascular system bradycardia Hypotension, syncope 5. Gastrointestinal Nausea, vomiting Constipation

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6. Enhance porphyrin synthesis may be fatal in patients with acute intermittent porphyria (disorders of certain enzymes in the heme bio-synthetic pathway) 7. Toxicity acute unsteady gait, slurred speech, sustained nystagmus chronic confusion, poor judgment, irritability, insomnia, somatic complaints 8. Drug Interaction Additive CNS depression with ethanol

2. Anesthesia Pre-anesthetic medication 3. Kernicterus and Hyperbilirubinemia: because barbiturates induce protein (albumin) synthesis, thereby increasing hepatic glucuronyl transferase activity Contraindications: Pregnancy and lactation Acute intermittent porphyria or porphyria variegata Pulmonary disease

Dependence: Similar to chronic alcoholism Arises from repeated administration on a continuous basis in amounts exceeding usual therapeutic doses Withdrawal syndrome: Minor withdrawal symptoms appear 8-12 hrs. after the last dose o Symptoms appear in the following order: anxiety, muscle twitching, tremors in hands and fingers, progressive weakness, distortion in visual perception, nausea, vomiting, insomnia, orthostatic hypotension Major withdrawal symptoms such as convulsions and delirium occur within 16 hrs. and last up to 5 days after abrupt cessation of drug use. Symptoms of withdrawal can be very severe and cause death Alcoholics, opiate, sedative-hypnotic and amphetamine abusers are susceptible to Phenobarbital abuse and dependence Intensity of withdrawal symptoms gradually declines over a period of approximately 15 days Tolerance: develops with prolonged use Amount needed to maintain the same level of intoxication increases Mechanisms: o Pharmacodynamics o Pharmacokinetics Tolerance to the effects on mood, sedation, and hypnosis occurs more readily and is greater than that to the anticonvulsant and lethal effects; thus, as tolerance increases, the therapeutic index decreases. Therapeutic uses of Barbiturates: 1. Seizure disorders Grand mal seizures aka Tonic-Clonic seizures Benign febrile convulsion

VI. ETHANOL widely used for its social value tolerance develops after chronic use Blood Alcohol Levels in human beings can be estimated readily by the measurement of alcohol levels in expired air Legally allowed Blood Alcohol Level is set at below 80 mg % (80 mg ethanol per 100 ml blood; 0.08% w/v), Each of the following contains approximately 14 g Ethanol which will produce a BAL of approximately 30mg% to 70-kg person: o 12 oz. bottle of Beer o 5 oz. glass of wine o 1.5 oz. shot of 40% liquor BAL is determined by a number of factors, including the rate of drinking, sex, body weight and water percentage, and the rates of metabolism and stomach emptying

Pharmacokinetics: Rapidly absorbed after oral administration Peak blood levels occur about 30 min after ingestion when stomach is empty (Correlation: Kumain kung gusto tumagal) Presence of food delays absorption undergoes first pass metabolism in the stomach and liver by alcohol dehydrogenase (ADH) Aspirin increases ethanol bioavailability by inhibiting gastric ADH. Ethanol is metabolized largely by sequential hepatic oxidation, first to acetaldehyde by ADH and then to acetic acid by aldehyde dehydrogenase (ALDH) Hepatic cytochrome P450 (CYP2E1) and catalase also contribute to ethanol metabolism Zero order kinetics 90-95% of ingested Ethanol undergoes hepatic metabolism to acetate small amounts are excreted in urine, sweat and breath

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chronic alcohol consumption induces activity of hepatic enzymes acute alcohol consumption inhibits activity of hepatic enzymes

Malabsorption Acute and chronic pancreatitis Fatty infiltration of the liver, hepatitis and cirrhosis

7. Vitamin and Mineral Deficiencies Peripheral neuropathy Korsakoffs psychosis (a neurological disorder caused by the lack of thiamine (vitamin B1) in the brain. Its onset is linked to chronic alcohol abuse and/or severe malnutrition) Wernickes encephalopathy (syndrome characterized by ataxia, ophthalmoplegia, nystagmus, confusion, and impairment of short-term memory) Osteoporosis Hypomagnesemia 8. Sexual function Disinhibiting effects initially Excessive long term use can lead to deterioration of sexual function o Gonadal atrophy, decrease fertility o Impotence in men Decrease sexual arousal Increased ejaculatory latency Decreased orgasmic pleasure 9. Hematologic and Immunologic Anemia Thrombocytopenia leukopenia Immunosuppression

**Sequential hepatic metabolism of Ethanol (also see figure

on the last page)

Pharmacologic actions and effects: 1. Central nervous system Depressant Mild depression to general anesthesia Death can result due to respiratory depression Behavioral disinhibition Neurotoxic 2. Cardiovascular system French paradox (is the observation that French people suffer a relatively low incidence of coronary heart disease, despite having a diet relatively rich in saturated fats.) Light to moderate amounts may be cardioprotective o Increase HDL o Anti-clotting mechanism Cardiac arrhythmias Cardiomyopathy Hypertension, Hemorrhagic stroke 3. Skeletal muscle Decrease muscle strength Muscle atrophy 4. Body temperature Hypothermia 20 to cutaneous vasodilatation increased sweating 5. Kidneys Inhibition of ADH release 6. Gastrointestinal tract Esophageal dysfunction Peptic ulcer disease

Acute Ethanol Intoxication: Blood ethanol concentration of 20-30 mg/dL will produce o Increased reaction time o Impulsive behavior o Diminished fine motor control o Impaired judgment 50-80 mg/dL intoxicated 400 mg/dL can be fatal Tolerance and Dependence: reduced behavioral or physiological response to the same dose of Ethanol Withdrawal syndrome include sleep disruption, sympathetic activation, tremors and in severe cases, seizures (physical dependence) 2 or more days after withdrawal, delirium tremens may occur characterized by hallucinations, delirium, fever and tachycardia Delirium tremens can be fatal psychological dependence - craving and drugseeking behaviour

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Teratogenic Effect: Fetal Alcohol Syndrome Craniofacial abnormalities o Microcephaly, long and smooth philtrum o Shortened palpebral fissures, flat midface o Epicanthal folds CNS dysfunction o Hyperactivity, attention deficits o Mental retardation o Learning disabilities Pre and/or post natal stunting of growth

*** Disulfram - inhibits acetaldehyde dehydrogenase

VII. PHARMACOTHERAPY OF ALCOHOLISM Disulfiram** Naltrexone Acamprosate A. DISULFIRAM Inhibits acetaldehyde dehydrogenase, therefore acetaldehyde accumulates Given alone, relatively non-toxic Given to persons who ingest alcohol will produce signs and symptoms of Acetaldehyde poisoning o Hot and flushed face o Throbbing headache o Respiratory difficulty o Copious vomiting o Hypotension, chest pains

**Note: DIAZEPAM, ALPRAZOLAM, MIDAZOLAM, ZOLPIDEM, (Benzodiazepines) PENTOBARBITAL SODIUM, PHENOBARBITAL SODIUM (Barbiturates) NEED S2 NUMBER, NO REFILL PER Rx IN PRESCRIPTION WRITING.

-Nothing follows-

Hepatic metabolism of Ethanol

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